This is one of the most common skin cancers, accounting for about 70% of all skin malignancies. For every case of a squamous cell carcinoma, there are 5 cases of basal cell carcinoma (BCC). They are almost always found on sun-exposed areas such as the head and neck and are common in fair-skinned individuals. There are also case reports of cases occurring in areas such as the penis, vulva, and below the nails. The classic appearance is a raised flesh to pink-red nodule with a pearly translucent edge and variable telangiectasia. Ulceration may be frequent and occasionally pigment may be observed. Although sun exposure is the best documented risk factor, other risk factors include irradiation, immunosuppression, nevus sebaceus of Jadassohn, xeroderma pigmentosum, basal cell nevus syndrome, and Bazex's syndrome.
Although this is a carcinoma, the actual risk of metastasis is exceedingly rare, occurring in 0.05% of all cases. Yet, these carcinomas are locally aggressive and from 5-9% may have multiple recurrences. If metastasis do occur, it is usually with large and ulcerated tumors (such as rodent ulcers) and may have metatypical or squamous features. Metastatic sites include the regional lymph nodes, bones, lungs, and livers.
Epidemiology Disease Associations Pathogenesis Laboratory/Radiologic/Other Diagnostic Testing Gross Appearance and Clinical Variants Histopathological Features and Variants Special Stains/
Differential Diagnosis Prognosis Treatment Commonly Used Terms Internet Links
EPIDEMIOLOGY CHARACTERIZATION SYNONYMS Basal cell epithelioma
N Engl J Med 1992;327:1649-1662
Very common-among Caucasians, it is the most common malignancy
70% of all skin malignancies
United States 300/100,000 Australia 1000/100,000 SEX (MALE:FEMALE) Both sexes are affected though in women, the lower limbs are more commonly affected AGE RANGE-MEDIAN Adults
JAMA. 2005 Aug 10;294(6):681-90. Abstract quote
CONTEXT: The incidence of nonmelanoma skin cancer is increasing rapidly among elderly persons, but little is known about its incidence in the population younger than 40 years.
OBJECTIVES: To estimate the sex- and age-specific incidences of basal cell carcinoma and squamous cell carcinoma in persons younger than 40 years in Olmsted County, Minnesota, and to evaluate change in incidence over time; to describe the clinical presentation, rate of recurrence and metastasis, and histologic characteristics of these tumors in this population-based sample.
DESIGN: Population-based retrospective incidence case review.
SETTING: Residents of Olmsted County, Minnesota, a population with comprehensive medical records captured through the Rochester Epidemiology Project.
PARTICIPANTS: Patients younger than 40 years with basal cell carcinoma or squamous cell carcinoma diagnosed between 1976 and 2003.
MAIN OUTCOME MEASURES: Incident basal cell carcinomas and squamous cell carcinomas and change in incidence of these tumors over time.
RESULTS: During the study period, 451 incident basal cell carcinomas were diagnosed in 417 patients and 70 incident squamous cell carcinomas were diagnosed in 68 patients. Of these tumors, 328 were histologically confirmed basal cell carcinomas and 51 were histologically confirmed squamous cell carcinomas. Overall, the age-adjusted incidence of basal cell carcinoma per 100,000 persons was 25.9 (95% confidence interval [CI], 22.6-29.2) for women and 20.9 (95% CI, 17.8-23.9) for men. The incidence of basal cell carcinoma increased significantly during the study period among women (P<.001) but not men (P = .19). Nodular basal cell carcinoma was the most common histologic subtype; 43.0% of tumors were solely nodular basal cell carcinoma and 11.0% had a mixed composition, including the nodular subtype. The incidence of squamous cell carcinoma was similar in men and women, with an average age- and sex-adjusted incidence per 100 000 persons of 3.9 (95% CI, 3.0-4.8); the incidence of squamous cell carcinoma increased significantly over the study period among both women (P = .01) and men (P = .04).
CONCLUSIONS: This population-based study demonstrated an increase in the incidence of nonmelanoma skin cancer among young women and men residing in Olmsted County, Minnesota. There was a disproportionate increase in basal cell carcinoma in young women. This increase may lead to an exponential increase in the overall occurrence of nonmelanoma skin cancers over time as this population ages, which emphasizes the need to focus on skin cancer prevention in young adults.
DISEASE ASSOCIATIONS CHARACTERIZATION Basal cell nevus syndrome (Gorlin Syndrome) Bazez's syndrome Immunosuppression LEUKEMIA, CLL
- High recurrence rates of Basal cell carcinoma after mohs surgery in patients with chronic lymphocytic leukemia.
Mehrany K, Weenig RH, Pittelkow MR, Roenigk RK, Otley CC.
Department of Dermatology, Mayo Clinic, Rochester, Minn.
Arch Dermatol. 2004 Aug;140(8):985-8. Abstract quote
To estimate and compare the recurrence rates of basal cell carcinoma (BCC) after Mohs surgery in patients with chronic lymphocytic leukemia (CLL) and controls and to evaluate differences among histologic subtypes of BCC.
DESIGN: Retrospective assessment of clinical histories, postoperative notes, and surgical photographs.
SETTING: Tertiary-care institution (Mayo Clinic, Rochester, Minn).Patients Twenty-four patients with CLL who underwent Mohs surgery for 33 BCCs and 66 controls matched for sex, age, and surgical year who underwent Mohs surgery for BCC of the head and neck from May 1988 through September 1998.
RESULTS: Among the 24 patients with CLL who underwent Mohs surgery for 33 BCCs, there were 4 recurrences. The cumulative incidence of recurrence on a per-tumor basis was 3% at 1 year, 12% at 3 years, and 22% at 5 years. Basal cell carcinoma was 14 times more likely to recur in patients with CLL than in controls (P =.02). Overall, there were no significant differences between patients with CLL and controls in preoperative tumor size (median, 1.6 cm vs 1.4 cm; P =.18) and proportion of aggressive histologic subtypes of BCC (58% vs 41%; P =.12).
CONCLUSIONS: Recurrence rates of BCC are significantly higher after Mohs surgery in patients with CLL. Overall, patients with CLL do not appear to have significantly larger BCCs or more aggressive histologic subtypes of BCC. In patients with CLL, close surveillance is warranted for recurrence of BCC and a decreased threshold is indicated for subsequent biopsies.
- A Collision Tumor Involving Basal Cell Carcinoma and Lentigo Maligna Melanoma.
Belisle A, Gautier MS, Ghozali F, Plantier F, Wechsler J.
From the *Department of Pathology, Henri Mondor University Hospital, University Paris-Val-de-Marne, Creteil, France; daggerDepartment of Dermatology, Henri Mondor University Hospital, University Paris-Val-de-Marne, Creteil, France; and double daggerDepartment of Pathology, Tarnier-Cochin University Hospital, Paris, France.
Am J Dermatopathol. 2005 Aug;27(4):319-321. Abstract quote
Basal cell carcinomas (BCC) are known to co-exist with other cutaneous lesions, but the collision of BCC with malignant melanoma is rare.
We report on the case of an 82-year-old woman with a translucent papule set on a beige-brown plaque on the right side of the nose. Histologic examination showed lesions of lentigo maligna melanoma (LMM) in situ and invasive melanoma involving nests of BCC that invaded the dermis. Immunohistochemical studies with S100 protein, HMB-45, and Melan-A antibodies showed the melanocytic component in the epidermis and dense clusters of "atypical" melanocytes in the dermal nests of BCC.
On examination of the biopsy specimen, melanoma was still in situ because it was limited to the nests of BCC and not detectable between dermal collagen bundles. However, the re-excision of the lesion showed residual BCC and invasive LMM, level II, measuring 0.2 mm in thickness. The diagnosis, pathogenesis, and prognosis of this collision tumor are discussed.
Nevus sebeceus of Jadassohn Smoking
Basal cell carcinoma in young women: An evaluation of the association of tanning bed use and smoking.
Boyd AS, Shyr Y, King LE Jr.
Departments of Medicine (Dermatology), Pathology, and Preventive Medicine, Vanderbilt University and Nashville Administration Medical Center.
J Am Acad Dermatol 2002 May;46(5 Pt 1):706-9 Abstract quote
Basal cell carcinomas (BCCs) typically occur in middle-aged to elderly patients but less commonly in younger ones. In our experience, most BCCs seen in patients younger than 40 years are found in women.
We evaluated 30 women with biopsy-proven BCC and 30 control patients matched for sex, age, and skin type to determine potential risk factors for this population. Tanning bed visits, pack-years of cigarette smoking, recreational sun exposure, number of blistering sunburns, and use of sunscreens were determined for both groups. Among patients with a BCC, the histologic type of tumor, site of involvement, method of treatment, follow-up period, incidence of recurrence, and presence of actinic keratoses were also evaluated. Patients with a BCC had a statistically greater number of pack years of smoking (P =.045), and a greater percentage of these women had experienced blistering sunburns (P =.028). Although women with a BCC had, on average, almost twice as many tanning salon visits (152.2 vs 83.1), this was not statistically significant. Sunscreen use and amount of recreational ultraviolet light exposure were essentially equal between the two groups.
Young women with a BCC are more likely to have a past or current history of cigarette smoking and blistering sunburns. Repeated exposure to tanning beds may also be a contributory factor.
Basal cell carcinomas developing in solid organ transplant recipients: clinicopathologic study of 176 cases.
Kanitakis J, Alhaj-Ibrahim L, Euvrard S, Claudy A.
Department of Dermatology, Edouard Herriot Hospital, Lyon, France.
Arch Dermatol. 2003 Sep;139(9):1133-7. Abstract quote
OBJECTIVE: To assess the clinicopathologic features of basal cell carcinomas developing in organ transplant recipients.
DESIGN: Case series.
SETTING: University department of dermatology.
PATIENTS: One hundred forty-six (7.2%) of 2029 transplant recipients followed up in our department who developed 176 histologically proven basal cell carcinomas. One hundred fifty-three random samples of basal cell carcinomas excised from nonimmunosuppressed patients served as controls.
MAIN OUTCOME MEASURES: Clinical data were gathered from the medical records. Histologic slides were retrospectively reexamined.
RESULTS: Basal cell carcinomas developed an average of 6.9 years after transplantation, sooner after heart than kidney transplantation, and showed a relative predilection for heart allograft recipients. The mean age of transplant recipients with basal cell carcinomas was significantly lower than that of controls (54.6 vs 69.8 years), especially for recipients of renal transplants, and a male preponderance was found (male-female ratio, 4.8:1 vs 1.3:1). In both groups, basal cell carcinomas were predominantly found on the head and neck, but extracephalic locations were significantly more frequent in transplant recipients (37.5%) than controls (24.5%). Histologically, superficial basal cell carcinomas were more frequent in transplant recipients than controls (33.6% vs 14.4%). The density of the peritumoral cell infiltrate was lower in tumors from transplant recipients compared with controls. The tumor thickness and the presence of epidermal ulceration did not differ significantly between the 2 groups.
CONCLUSIONS: Basal cell carcinomas in transplant recipients show some clinicopathologic differences from their "ordinary" counterparts, namely, a younger age at development, male preponderance, more frequent distribution in extracephalic sites, and higher frequency of superficial subtypes.
Basal cell carcinoma arising from surgical scars: a case and review of the literature.
Ozyazgan I, Kontacs O.
Department of Plastic and Reconstructive Surgery, Erciyes University, Faculty of Medicine, Kayseri, Turkey.
Dermatol Surg 1999 Dec;25(12):965-8 Abstract quote
BACKGROUND: Scar malignancies are generally known as Marjolin's ulcer and the majority of them are epidermoid carcinomas. In addition to epidermoid carcinomas, Basal cell carcinoma (BCC) also can grow in various scars. Basal cell carcinoma cases developing in surgical scars are extremely rare; only 5 cases have been encountered in available English literature.
METHOD: A 68-year-old woman who has a BCC originating from a surgical scar due to a previous inguinal hernia operation was presented.
CONCLUSION: Trauma has been suggested as one of the etiologic factors for BCC; but the role of trauma or resulting scar in BCC pathogenesis is not known. This unresolved issue can be explained with advanced studies revealing biochemical tissue changes occurring during wound healing and trauma.
Risk Factors for Basal Cell Carcinoma in a Mediterranean Population Role of Recreational Sun Exposure Early in Life
Rosamaria Corona, DSc, MD; Eugenia Dogliotti, DSc; Mariarosaria D'Errico, DSc; Francesco Sera, DStat; Ivano Iavarone, DSc; Giannandrea Baliva, MD; Luca M. Chinni, MD; Tommaso Gobello, MD; Cinzia Mazzanti, MD; Pietro Puddu, MD; Paolo Pasquini, MD, MPH
Arch Dermatol. 2001;137:1162-1168 Abstract quote
To investigate the role of pigmentary traits, different patterns of sun exposure, artificial sources of UV radiation, and lifestyle-related factors on the risk of basal cell carcinoma (BCC) in a Mediterranean population from central-southern Italy.
Hospital-based case-control study.
A referral dermatological hospital in Rome, Italy.
A convenience sample of 166 case patients with histologically confirmed BCC and 158 cancer-free control subjects with minor dermatological conditions observed between March 1995 and June 1997.
In the multivariate analysis, the mean number of weeks per year spent at the beach before the age of 20 years was significantly associated with BCC. A dose-response trend was found for subjects who had spent 3 to 4 (odds ratio, 1.8; 95% confidence interval, 0.8-4.4), 5 to 8 (odds ratio, 3.7; 95% confidence interval, 1.5-9.0), or more than 8 (odds ratio, 4.5; 95% confidence interval, 1.9-10.5) weeks per year at the beach (P = .01 for trend). There was a significant association with the presence of actinic keratoses or solar lentigines, whereas no effect was found for skin type, history of sunburns, exposure to nonsolar UV radiation, and lifestyle-related habits such as cigarette smoking, alcohol consumption, and coffee drinking. Subjects reporting a family history of skin cancer had an extremely increased risk of BCC.
The definite association with recreational sun exposure during childhood and adolescence and the strong relation with family history of skin cancer suggest that genetic predisposition and peculiar exposure patterns to UV radiation are key independent risk factors for the development of BCC in a southern European population.
High levels of patched gene mutations in basal-cell carcinomas from patients with xeroderma pigmentosum.
Bodak N, Queille S, Avril MF, Bouadjar B, Drougard C, Sarasin A, Daya-Grosjean L.
Laboratory of Molecular Genetics, Institut de Recherches Scientifiques sur le Cancer, Boite Postale 8, 94801 Villejuif, France.
Proc Natl Acad Sci U S A 1999 Apr 27;96(9):5117-22 Abstract quote
Recently, hptc, a human gene homologous to the Drosophila segment polarity gene patched (ptc), has been implicated in the nevoid basal-cell carcinoma (BCC) syndrome, and somatic mutations of hptc also have been found in sporadic BCCs, the most frequent cancers found in the white population.
We have analyzed the hptc gene, postulated to be a tumor suppressor gene, in 22 BCCs from patients with the hyperphotosensitive genodermatosis xeroderma pigmentosum (XP). Patients with XP are deficient in the repair of UV-induced DNA lesions and are characterized by their predisposition to cancers in sun-exposed skin. Analysis using PCR-single-strand conformation polymorphism of the hptc gene identified 19 alterations in 16 of 22 (73%) of the BCCs examined. Only two (11%) deletions of the hptc gene were found in XP BCCs compared with >30% rearrangement observed in non-XP sporadic BCCs, and 17 of 19 (89%) were base substitutions. Among the 17 base substitutions, 11 (65%) were CC --> TT tandem mutations, and 4 (23%) were C --> T substitutions, all targeted at bipyrimidine sites. Hence, a significantly higher number (15 of 19; 79%) of UV-specific alterations are seen in XP tumors, in contrast to non-XP sporadic BCCs. Interestingly, we have found that in 7 of 14 (50%) XP BCCs analyzed, both hptc and the tumor suppressor gene p53 are mutated.
Not only have our data indicated the key role played by hptc in the development of BCCs, they also have substantiated the link between unrepaired UV-induced DNA lesions and skin carcinogenesis, as exemplified by the UV-specific alterations of different genes in the same tumors.
PATHOGENESIS CHARACTERIZATION GENERAL
The tumor has several immunologic aberrations which help it to evade the immune system:
Absence of class II MHC (HLA-DR) and intercellular adhesion molecule 1 (CD54)
Production of IL-10 which suppresses expression of costimulatory molecules CD80 and CD86 by dendritic cells, inhibiting ability to activate T-cells
Overexpression of cell survival gene products such as bcl-2
Failure to express Fas antigen (CD95) avoiding killing by Fas ligand (CD95L) bearing cytotoxic T cells
Expression of Basigin in human fetal, infantile and adult skin and in basal cell carcinoma
Xiang Chen, etal.
J Cutan Pathol 2001;28 (4):184-190 Abstract quote
Background: Basigin is a glycosylated transmembrane protein belonging to the immunoglobulin superfamily and is thought to be associated with cell development and differentiation. We investigated the relation between Basigin expression and epidermal development in this study.
Methods: Basigin expression was immunohistochemically investigated during organogenesis of human skin and in human basal cell carcinoma (BCC).
Results: Human fetal skin showed negative staining at 10 weeks of gestation. At 20 weeks, the cytoplasm and membranes of adnexal germ and hair follicular cells were strongly positive, while epidermal basal cells showed weakly positive staining. After birth, basal cells, suprabasal cells, anagen hair follicular cells and eccrine glandular cells showed positive staining. Membranes of basal cells expressed more Basigin compared to other cell components. Basigin was not detectable in granular cells and telogen hair follicular cells. Sixteen of 30 BCCs were entirely negative for Basigin. However, cells at budding areas of tumor masses were positive in 14 of the 30 BCCs.
Conclusions: These findings suggest that 1) Basigin is associated with epidermal proliferation and differentiation, 2) most parts of BCCs might be derived from early fetal epidermal basal cells, and 3) that a part, only the budding area of BCCs, has the characteristics of epithelial germ cells.
Bax expression and growth behavior of basal cell carcinomas
Claudia M. L. J. Tilli, Angela J. W. Stavast-Kooy, Frans C. S. Ramaekers and H. A. Martino Neumann
J Cutan Pathol 2002;29:79-87 Abstract quote
Background:To understand the typical growth behavior of basal cell carcinoma (BCC) we searched for the correlation between proliferation and apoptosis and progression of BCC.
Methods:Expression of Bcl-2, Bax, and Ki-67 was immunohistochemically investigated in both normal skin and BCC cells, as well as in the epidermis overlying BCC.
Results:The results showed that in normal epidermis, Bcl-2 was homogeneously expressed in the basal cell compartment, whereas Ki-67 expression was largely restricted to the parabasal layer, the layer just above the basal cell layer, and exhibited a more scattered staining pattern. Bax was occasionally expressed in the basal layer and widely in the suprabasal compartment. Strikingly, the apparently normal epidermis overlying BCC showed an increased Bcl-2 staining. In BCC, cells stained homogeneously for Bcl-2, whereas Bax and Ki-67 showed scattered staining patterns. Simultaneous expression was seen for Bcl-2 and Bax in 80±7% of the tumor cells, and co-expression of Bcl-2 and Ki-67 in 20±7% of the tumor cells. The cells expressing Bcl-2 and Ki-67, but lacking expression of Bax, the progressive fraction, comprised on average 7±3% of the tumor cell population.
Conclusion:These results suggest that this small progressive fraction of tumor cells, in combination with the relatively high percentage of cells still prone to apoptosis, can explain the indolent growth behavior of BCC.
Differential expression of alpha1 (IV) and alpha5 (IV) collagen chains in basal-cell carcinoma.
Quatresooz P, Martalo O, Pierard GE.
Department of Dermatopathology, University Medical Center of Liege, Liege, Belgium.
J Cutan Pathol. 2003 Oct;30(9):548-52. Abstract quote
BACKGROUND: Basement membrane alterations are common in malignancies, and they may indicate tumoral aggressiveness. Distinct patterns of tumoral coverage by collagen IV were reported in nodular and aggressive basal-cell carcinomas (BCCs). Differential expressions of alpha (IV) collagen chains were also shown on frozen sections. The aim of our work was to document the immunohistochemical expression of alpha1, alpha3, and alpha5 (IV) collagen chains in BCC after routine fixation and processing.
METHODS: The patterns of distribution of alpha1 (IV), alpha3 (IV), and alpha5 (IV) collagen chains were studied in 20 formalin-fixed and paraffin-embedded BCCs showing different infiltrative patterns. One trichoblastoma was used as control.
RESULTS: In nodular BCCs, the expression of alpha5 (IV) collagen chain was downregulated and uneven. By contrast, alpha1 (IV) collagen chain expression was preserved around these tumors similar to the surrounding skin. However, the alpha1 (IV) collagen chain expression was discontinuous or absent in BCC areas showing an infiltrative pattern of extension. The alpha3 chain was absent both underneath all BCCs and non-neoplastic skin.
CONCLUSIONS: The basement membrane alterations around nodular BCCs involved more precisely the alpha5 (IV) collagen chains. Defects in alpha1 (IV) collagen chain expression seemed to be associated with a tumoral invasive and infiltrative pattern. The biological significance of these findings is unclear.
Loss of heterozygosity on chromosome 9q22.3 in microdissected basal cell carcinomas around the Semipalatinsk Nuclear Testing Site, Kazakhstan.
Iwata K, Takamura N, Nakashima M, Alipov G, Mine M, Matsumoto N, Yoshiura K, Prouglo Y, Sekine I, Katayama I, Yamashita S.
Atomic Bomb Disease Institute, Nagasaki University School of Medicine, Department of Dermatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Hum Pathol. 2004 Apr;35(4):460-4. Abstract quote
A high incidence of skin cancers has been noted around the Semipalatinsk Nuclear Testing Site (SNTS) in Kazakhstan. Recently, basal cell carcinoma (BCC) susceptibility genes, human homolog of the Drosophila pathed gene (PTCH), and the xeroderma pigmentosa group A-complementing gene (XPA), have been cloned and localized on chromosome 9q22.3.
To clarify the effect of low-dose irradiation on the occurrence of BCC, we used microdissection and polymerase chain reaction to identify loss of heterozygosity (LOH) at 9q22.3 using BCC samples obtained from this region. Ten Japanese samples were analyzed as controls. LOH with at least 1 marker was identified in 5 of 14 cases from around SNTS, whereas only 1 case with 1 marker was identified among the 10 Nagasaki cases. The total number of LOH alleles from SNTS (8 of 45) was significantly higher than the number from Nagasaki (1 of 26) (P = 0.03).
The higher incidence of LOH on 9q22.3 in BCC from around SNTS suggests involvement of chronic low-dose irradiation by fallout from the test site as a factor in the cancers.
Nonrandom karyotypic features in basal cell carcinomas of the skin.
Jin Y, Martins C, Salemark L, Persson B, Jin C, Miranda J, Fonseca I, Jonsson N.
Department of Clinical Genetics, University Hospital, S-221 85, Lund, Sweden.
Cancer Genet Cytogenet 2001 Dec;131(2):109-19 Abstract quote
Cytogenetic analysis of short-term cultured 44 basal cell carcinomas (BCC) revealed clonal karyotypic abnormalities in 38 tumors.
Relatively complex karyotypes (at least four structural and/or numerical changes per clone) with unbalanced structural as well as numerical aberrations were found in eight (approximately 21%) of the BCC, while the remaining BCC (79%) had simple karyotypes (1 to 3 aberrations per clone). Numerical changes only were found in 16 tumors, 15 BCC displayed both numerical and structural aberrations, and the remaining 7 BCC showed only structural aberrations. Extensive intratumoral heterogeneity, in the form of cytogenetically unrelated clones, was found in 21 tumors, whereas related subclones were present in 10 tumors. In order to obtain an overall karyotypic picture in BCC, the findings of our previously published 25 BCC have been reviewed.
Our combined data indicate that BCC are characterized by nonrandom karyotypic patterns. A large subset of BCC is characterized by nonrandom numerical changes, notably, +18, +X, +7, and +9. Structural rearrangements often affect chromosomes 1, 4, 2, 3, 9, 7, 16, and 17. A number of chromosomal bands are frequently involved, including 9q22, 1p32, 1p22, 1q11, 1q21, 2q11, 4q21, 4q31, 1p36, 2q37, 3q13, 7q11, 11p15, 16p13, 16q24, 17q21, and 20q13. When the genomic imbalance is assessed, it has been shown that several chromosome segments are repeatedly involved in losses, namely loss of the distal part of 6q, 13q, 4q, 1q, 8q, and 9p. A correlation analysis between the karyotypic patterns and the clinico-histopathologic parameters has been undertaken in the 44 BCC of the present series.
The cytogenetic patterns show a significant correlation with tumor status (P=.025), that is, that cytogenetically more complex tumors are also those clinically the most aggressive. Also, the frequency of cytogenetically unrelated clones is significantly higher in recurrent BCC than that in primary lesions (P=.05). No clear-cut association has been found between the karyotypic patterns and histologic subtypes or tumor sites.
Cytokine profiles in spontaneously regressing basal cell carcinomas.
Wong DA, Bishop GA, Lowes MA, Cooke B, Barnetson RS, Halliday GM.
Department of Medicine (Dermatology), The University of Sydney at Royal Prince Alfred Hospital, Gloucester House, Missenden Road, Camperdown, NSW 2050, Australia.
Br J Dermatol 2000 Jul;143(1):91-8 Abstract quote
BACKGROUND: Basal cell carcinomas (BCCs) can cause considerable morbidity due to their ability to enlarge progressively and to destroy underlying tissues. However, some BCCs may undergo spontaneous regression in the absence of therapy capable of inducing antineoplastic effects. Histological criteria for this process have been described, and previous studies have suggested that it may be mediated by infiltrating activated CD4-positive T cells.
OBJECTIVES: The purpose of this study was to compare the expression of cytokines in actively regressing and non-regressing BCCs, to ascertain if active regression is associated with a particular cytokine profile.
METHODS: Reverse transcriptase-polymerase chain reaction, a sensitive, quantitative technique allowing analysis of multiple cytokines from small tumour samples, was used.
RESULTS: Interferon (IFN)-gamma was significantly elevated in actively regressing BCCs compared with non-regressing BCCs. Furthermore, interleukin (IL)-2, tumour necrosis factor (TNF)-beta and CD3 delta tended to be elevated in actively regressing tumours, although not to statistically significant levels. IFN-gamma, IL-2, IL-10, TNF-beta, granulocyte-macrophage colony-stimulating factor and Fas ligand showed strong positive correlations with CD3 delta, indicating an association between infiltrating T cells and these cytokines.
CONCLUSIONS: These findings support a role for T-helper 1 type cytokines in mediating spontaneous regression of BCCs.
EMBRYONIC FUSION PLATES
- Correlation of embryonic fusion planes with the anatomical distribution of basal cell carcinoma.
Division of Dermatology, Albert Einstein College of Medicine, Bronx, New York, USA.
- Dermatol Surg. 2007 Aug;33(8):957-64; discussion 965. Abstract quote
BACKGROUND: The clinical relevance of the anatomic distribution of basal cell carcinoma is not completely understood. Embryonic fusion planes--the regions of mesenchymal migration and fusion of the five primordial facial processes during the 5th to 10th weeks of human development--have been implicated in the pathogenesis of basal cell carcinoma.
OBJECTIVE: This study sought to examine the predilection of midfacial basal cell carcinoma for cutaneous anatomical sites correlated to embryonic fusion planes.
METHODS AND MATERIALS: Using archived digital images and a detailed anatomic diagram, cases of basal cell carcinoma were coded according to their specific location and were aggregated into two anatomic domains according to their correlation to embryonic fusion planes. The relative tumor densities were calculated.
RESULTS: Of the 1,457 cases examined, 859 were located in the midface. Thirty-five percent of the midfacial lesions were located on the domain correlated to embryonic fusion planes, which represented 11.3% of the total surface area of the midface. The relative tumor density of lesions in the fusion plane domain was 3.06 compared to 0.74 for the remaining lesions (p< .001).
CONCLUSIONS: Although there is no consensus about the importance of anatomic location in the pathogenesis of basal cell carcinoma, these data indicate that, after adjusting for surface area, basal cell carcinoma was more than four times more likely to occur on an embryonic fusion plane than on other regions of the midface. These data support the possibility of an embryologic role for the pathogenesis of basal cell carcinoma.
Fas (CD95) J Clin Pathol 1995;48:242
Regression of basal cell carcinoma by intralesional interferon-alpha treatment is mediated by CD95 (Apo-1/Fas)-CD95 ligand-induced suicide.
Buechner SA, Wernli M, Harr T, Hahn S, Itin P, Erb P.
Department of Dermatology, University of Basel, Kantonsspital, Petersgraben 4, CH4031 Basel, Switzerland.
J Clin Invest 1997 Dec 1;100(11):2691-6 Abstract quote
Basal cell carcinoma (BCC) is the most common skin cancer in humans, and although metastasis rarely occurs, the tumor cells are nevertheless able to invade and destroy the surrounding tissue. Intralesional injection of IFN-alpha has been found to be highly effective in inducing BCC regression by an unknown mechanism.
We show that in untreated patients, BCC cells express CD95 ligand, but not the receptor, which may allow tumor expansion by averting the attack of activated CD95 receptor-positive lymphoid effector cells. The CD95 ligand of BCC cells is functional as CD95-positive cells incubated on BCC cryosections become apoptotic and are lysed. In IFN-alpha-treated patients BCC cells express not only CD95 ligand but also CD95 receptor, whereas the peritumoral infiltrate that mainly consists of CD4+ T cells predominantly contains CD95 receptor and only few CD95 ligand-positive cells.
Thus, in treated patients BCC most likely regresses by committing suicide through apoptosis induction via CD95 receptor-CD95 ligand interaction.
Prostaglandin E2 inhibits T cell activation-induced apoptosis and Fas-mediated cellular cytotoxicity by blockade of Fas-ligand induction.
Porter BO, Malek TR.
Department of Microbiology and Immunology, University of Miami School of Medicine, FL 33101, USA.
Eur J Immunol 1999 Jul;29(7):2360-5 Abstract quote
Prostanoids exhibit both pro-apoptotic and anti-apoptotic functions depending on the maturation stage and tissue localization of target cells.
Prostaglandin (PG) E2 has been shown to protect T lymphocytes from TCR-mediated activation-induced cell death, but the mechanism by which PGE2 inhibits apoptosis of T cells has not been established.
We show that this protection involves the down-regulation of Fas-ligand (Fas-L) mRNA levels in T cells. Modulation of cell surface Fas-L expression by physiological concentrations of PGE2 was shown to be both anti-apoptotic as well as capable of inhibiting Fas-L-mediated cytotoxicity of Fas-transfected P815 target cells.
Thus, this study provides direct evidence of the likely biological means by which PGE2 down-regulates T cell apoptosis.
Expression of CD95 (Fas) in sun-exposed human skin and cutaneous carcinomas.
Filipowicz E, Adegboyega P, Sanchez RL, Gatalica Z.
Division of Surgical Pathology, Department of Pathology, University of Texas Medical Branch, Galveston, Texas.
Cancer 2002 Feb 1;94(3):814-9 Abstract quote
BACKGROUND: Carcinomas of the skin are by far the most common human malignancies. Continuous exposure to ultraviolet (UV) light facilitates the development of precancerous lesions (actinic keratosis [AK]) that may progress to invasive squamous carcinomas. Apoptosis, triggered by the activation of CD95 (Fas), is one of the most important defense mechanisms against UV light-induced carcinogenesis in experimental models, but the dynamics of CD95 expression in patients with sun-induced lesions are largely unknown.
METHODS: The authors studied the expression of CD95 (Fas) in biopsy samples of normal skin (not exposed to sun) and compared it with chronically sun-exposed skin (as evidenced by solar elastosis), AK, squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), and keratoacanthomas (KA).
RESULTS: Normal skin keratinocytes expressed CD95 in cytoplasmic membranes and intercellular bridges in the basal layer. In chronically sun-exposed keratinocytes (solar elastosis, no evidence of dysplasia), CD95 expression was up-regulated and was observed throughout the entire thickness of the epidermis. However, in actinic keratosis there was a complete absence of Fas in approximately two-thirds of the cases (8 of 12). In invasive SCC, CD95 was expressed focally and weakly only at the sites of contact with stromal lymphocytes. Keratoacanthomas consistently expressed CD95 at the interface with the inflammatory cells. No staining was observed in BCC.
CONCLUSIONS: CD95 (Fas) up-regulation in chronically sun-exposed keratinocytes indicates an important role in the control of sun-induced damage. Further sun exposure results, however, in significant down-regulation of this defense mechanism, proportional to the degree of dysplasia.
- Molecular diagnosis of basal cell carcinoma and other basaloid cell neoplasms of the skin by the quantification of Gli1 transcript levels.
Hatta N, Hirano T, Kimura T, Hashimoto K, Mehregan DR, Ansai S, Takehara K, Takata M.
Department of Dermatology, Postgraduate School of Medicine, Kanazawa University, Kanazawa, Japan.
J Cutan Pathol. 2005 Feb;32(2):131-6. Abstract quote
Background: Distinguishing basal cell carcinoma (BCC) from other benign and malignant skin tumors is sometimes a difficult task for the pathologists. Because the activation of hedgehog signals and the up-regulation of its critical transcriptional factor Gli1 are well documented in BCC, a molecular technique measuring Gli1 transcripts may aide the diagnosis.
Methods: Gli1 transcript levels were measured by real-time quantitative reverse transcriptase polymerase chain reaction (RT-PCR) using RNA extracted from formalin-fixed, paraffin-embedded tissues of 68 cases of various skin tumors. Hematoxylin and eosin-stained pathology slides were independently reviewed by three expert dermatopathologists.
Results: The histological diagnoses were unambiguous in 53 tumors. The tumors included BCC (21), squamous cell carcinoma (13), seborrheic keratoses (8), trichoepithelioma (5), eccrine poroma/porocarcinoma (4), and sebaceous epithelioma/carcinoma (2). In these unambiguous cases, all BCC and trichoepithelioma tumors showed high expression of Gli1mRNA, while the expression was virtually absent in other tumors. The diagnosis was discordant among three pathologists in the remaining 15 tumors. Histological diagnoses included BCC, BCC with sebaceous differentiation, sebaceoma/sebaceous epithelioma, trichoblastoma, trichoepithelioma, basaloid follicular harmartoma, basosquamous carcinoma, etc. Six of them showed high Gli1 transcript levels.
Conclusions: Quantification of Gli1 transcripts by RT-PCR is helpful in discriminating BCC and trichoepithelioma from other skin tumors.
Giant basal cell carcinoma associated with human papillomaviruses infection.
Northington M, Tamburin L, Hamza S, Diwan H, Skelton H, Smith K.
Department of Dermatology and Pathology, University of Alabama, Birmingham, AL, USA.
J Cutan Pathol. 2004 Feb;31(2):174-8. Abstract quote
Different criteria have been used to define giant basal cell carcinoma (BCC). However, the majority of tumors of 10 cm or greater in diameter have a characteristic clinical and histopathologic presentation. As a group, these tumors often show metastatic spread as opposed to all other BCCs that rarely metastasize.
We present an additional patient with a giant BCC greater than 100 cm2. This tumor had a characteristic location and infiltrative growth pattern. Unusual features of this tumor included a lack of expression of BCL-2 with a greater proportion of cycling tumor cells expressing proliferation markers than conventional BCC, as well as expression of anogenital human papillomaviruses (HPV) subtypes with oncogenic potential.
The association of HPV with BCCs has rarely been studied and may not be identical to HPV-induced genital squamous cell carcinomas. However, the findings in this patient suggest that HPV may play a role in the development of some chronic giant BCCs.
Human papillomavirus infection and non-melanoma skin cancer in immunosuppressed and immunocompetent individuals.
Harwood CA, Surentheran T, McGregor JM, Spink PJ, Leigh IM, Breuer J, Proby CM.
Department of Academic Dermatology, Royal Hospitals NHS Trust, London, United Kingdom.
J Med Virol 2000 Jul;61(3):289-97 Abstract quote
The role of human papillomavirus (HPV) in anogenital carcinogenesis is established firmly, but a similar role in non-melanoma skin cancer remains speculative. Certain immunosuppressed individuals have an increased incidence of both viral warts and non-melanoma skin cancer, that has prompted the suggestion that HPV may play a pathogenic role. Differences in the techniques used to detect HPV DNA in skin, however, have led to discrepancies in the prevalence and spectrum of HPV types reported in these malignancies.
This study describes the use of a comprehensive degenerate PCR technique to compare the HPV status of 148 Non-melanoma skin cancers from immunosuppressed and immunocompetent individuals. HPV DNA was detected in 37/44 (84.1%) squamous cell carcinomas, 18/24 (75%) basal cell carcinomas and 15/17 (88.2%) premalignant skin lesions from the immunosuppressed group compared with 6/22 (27.2%) squamous cell carcinomas, 11/30 (36.7%) basal cell carcinomas and 6/11 (54. 4%) premalignancies in the immunocompetent group. Epidermodysplasia verruciformis HPV types prevailed in all lesion types from both groups of patients. In immunosuppressed individuals, cutaneous HPV types were also identified at high frequency, and co-detection of multiple HPV types within single tumours was commonly observed.
This study represents the largest and most comprehensive analysis of the HPV status of non-melanoma skin cancers yet undertaken; whereas there are clearly significant differences in non-melanoma skin cancers from immunosuppressed and immunocompetent populations, we provide evidence that the prevalence and spectrum of HPV types does not differ in squamous cell carcinomas, basal cell carcinomas or premalignancies within the two populations.
These data have important implications for future investigation of the role of HPV in cutaneous carcinogenesis at a functional level.
Overexpression of p53 protein in basal cell carcinomas of human skin.
Shea CR, McNutt NS, Volkenandt M, Lugo J, Prioleau PG, Albino AP.
Department of Pathology, New York Hospital-Cornell Medical Center, New York 10021.
Am J Pathol 1992 Jul;141(1):25-9 Abstract quote
Basal cell carcinoma (BCC) of the skin is the most common human cancer, but its molecular-genetic pathogenesis is unclear. In many other types of cancer, mutations of the tumor-suppressor gene p53 occur frequently and may lead to overexpression of a long-lived mutant form of p53 protein.
In this study, overexpression of p53 protein was detected immunohistochemically in 30 (83%) of 36 specimens of BCC of the head and neck. The same regions of tumor typically were reactive both with a monoclonal antibody (PAb240) specific for the mutant protein and with one (PAb1801) directed against an epitope common to both wild-type and mutant p53 protein. Keratinocytes of chronically sun-exposed epidermis adjacent to BCCs also focally overexpressed p53 protein in the majority of cases, whereas those of sun-protected buttock skin did not.
Mutation of p53 may form an important part of the pathogenetic sequence in a majority of cases of BCC.
p53 protein in aggressive and non-aggressive basal cell carcinoma.
De Rosa G, Staibano S, Barra E, Donofrio V, Salvatore G, Vessecchia G, Boscaino A.
Institute of Pathology, II Faculty of Medicine and Surgery, Naples, Italy.
J Cutan Pathol 1993 Oct;20(5):429-34 Abstract quote
Basal cell carcinoma (BCC) is the most frequent cutaneous neoplasm, with a generally favorable clinical behavior. Sometimes, indeed, it recurs after therapy and/or metastasizes. As point mutations in the coding sequence of the p53 tumor suppressor gene have been implicated in the progression of many human tumors, we studied the expression of p53 protein on this neoplasia.
We tested immunohistochemically the positivity for p53 protein (NCL-p53-CM1, YLEM) on 19 cases of morphologically "non aggressive" BCC (BCC1) and on 19 "aggressive" BCC (BCC2), all with one or more relapses and 3 with distant metastases also. Results were related to clinico-pathological and follow-up data. All but one BCC2 were found positive for p53 protein. Conversely, only 2 cases of BCC1 exhibited low immunoreactivity for p53 protein, with high statistical differences between the two groups. No correlation was found between the immunoreactivity, age of patients, and site of the lesions.
The availability of immunohistochemistry and the relatively easy interpretation of the results make screening for p53 protein a possibly useful tool in the prognostic evaluation of BCC.
p53 gene mutations in human skin cancers and precancerous lesions: comparison with immunohistochemical analysis.
Kubo Y, Urano Y, Yoshimoto K, Iwahana H, Fukuhara K, Arase S, Itakura M.
Department of Dermatology, School of Medicine, University of Tokushima, Japan.
J Invest Dermatol 1994 Apr;102(4):440-4 Abstract quote
Mutations of exons 3 through 9 of the p53 gene in skin lesions were screened in 23 cases of squamous cell carcinoma (SCC), 25 cases of basal cell carcinoma (BCC), two cases of Bowen's disease, 10 cases of solar keratosis, and five cases of keratoacanthoma by polymerase chain reaction--single strand conformation polymorphism analysis. Mutations of the p53 gene were detected in seven of 23 SCCs (30%), three of 25 BCCs (12%), and none in all cases of Bowen's disease, solar keratosis, or keratoacanthoma.
Of 23 cases of SCC, mutations were detected in four of 15 SCCs (27%) that originated in the sunlight-exposed skin region, in two of three SCCs (67%) that originated in the scar tissue, and in one of three SCCs (33%) that originated in radiation dermatitis. Mutations of C-->T transition predominated in SCC and BCC that originated in the sunlight-exposed skin region. Mutations of C-->A or CC-->AT observed in tumors that originated in the predisposed conditions, presumably unrelated to UV light, are different from those found in UV light-related SCC or BCC. Twelve cases of SCC were comparatively analyzed with the immunohistochemical staining with anti-p53 antibody. Two of four cases with positive staining had missense mutations, and three of eight cases with negative staining had nonsense mutations.
Based on these findings, immunohistochemical results do not necessarily mean the presence or absence of p53 gene mutations in skin tumors, and sequence analysis is essential for determining whether the gene is mutated.
Characterization of p53 gene mutations in basal-cell carcinomas: comparison between sun-exposed and less-exposed skin areas.
Matsumura Y, Nishigori C, Yagi T, Imamura S, Takebe H.
Department of Radiation Genetics, Faculty of Medicine, Kyoto University, Japan.
Int J Cancer 1996 Mar 15;65(6):778-80 Abstract quote
Mutations in the p53 gene in 32 basal-cell carcinomas (BCC) developed in Japanese patients were identified by the polymerase chain reaction and single-strand-conformation polymorphism analysis, followed by sequencing the DNA.
Among 16 BCC developed in continuously sun-exposed areas, 6 tumors showed 7 base substitutions, most of which were G:C to A:T transitions, mainly at the dipyrimidine sites. Seven out of 16 BCC developed in less-exposed areas showed 8 base substitutions, but the majority (75.0%) of them were transversions.
These results suggest that the mutation in the p53 gene plays a significant role in the tumorigenesis of BCC developed in less-exposed areas as well as those in sun-exposed areas in Japanese patients. There must be therefore causative factors other than UV irradiation for BCC in less-exposed areas.
Genomic analysis of single cells from human basal cell cancer using laser-assisted capture microscopy.
Ponten F, Williams C, Ling G, Ahmadian A, Nister M, Lundeberg J, Ponten J, Uhlen M.
Department of Pathology, University Hospital, Uppsala, Sweden.
Mutat Res 1997 Sep;382(1-2):45-55 Abstract quote
In this study, we show that direct mutational analysis of genomic DNA can be performed on single somatic cells extracted from a frozen, immunohistochemically stained tissue section using laser-assisted capture microscopy.
Eighty-nine single tumor cells were separately dissected from one case of human basal cell cancer (BCC) and p53 mutations were analyzed by direct semi-automated sequencing of PCR fragments. Amplification was obtained for at least one of the two analyzed exons from approximately 50% of the single tumor cells. Identical p53 mutations were found in widely spread areas of the tumor, suggesting a clonal proliferation originating from one cell. Interestingly, comparison between results of immunohistochemistry and genetic analysis of the single cells revealed the same p53 mutations irrespective of the p53 immunoreactivity.
We propose that this approach has a great potential to allow investigation of genotypic differences in single cells and more specifically to resolve important and fundamental questions determining cancer heterogeneity.
p53 mutations in basal cell carcinomas arising in routine users of sunscreens.
Rosenstein BS, Phelps RG, Weinstock MA, Bernstein JL, Gordon ML, Rudikoff D, Kantor I, Shelton R, Lebwohl MG.
Department of Radiation Oncology, Mount Sinai School of Medicine of NYU, New York 10029, USA.
Photochem Photobiol 1999 Nov;70(5):798-806 Abstract quote
Sun exposure histories were obtained from a series of patients age 35 or younger following diagnosis and removal of a basal cell carcinoma (BCC).
The DNA was extracted from tumor biopsy samples derived from BCC of 10 patients who reported that they did not use sunscreens during youth (age 18 or younger) and 10 patients who routinely employed sunscreens during this age period. Exons 5-9 of the p53 gene were then amplified in three fragments from these samples using a nested polymerase chain reaction (PCR) approach and screened for mutations using an RNA heteroduplex assay. All PCR products displaying evidence of a mutation were sequenced. It was found that 6 of the 10 patients who were not routine sunscreen users displayed mutations in these p53 exons. All of the mutations were located at dipyrimidine sites, five of the six were C-->T transitions and one mutation was a tandem double mutation, consistent with a role for solar UVB in BCC formation. In contrast, only one p53 mutation was detected in the group of 10 patients who routinely employed sunscreens during childhood and adolescence. Hence, a significantly (P = 0.029) lower level of p53 mutations was detected in the BCC obtained from sunscreen users compared with tumors derived from nonusers.
These findings suggest that the mechanisms involved in the etiology of skin carcinogenesis differ in sunscreen users compared with people who did not routinely employ sunscreens. These data are also indicative of a protective effect associated with sunscreen use against the formation of p53 mutations.
It is possible that the patients who were diagnosed with BCC despite their use of sunscreens possessed a genetic susceptibility for skin cancer formation and developed BCC through a p53-independent pathway. Alternatively, solar UVA wavelengths, that were generally not blocked by the suncare products employed by the sunscreen users, may have played a significant role in BCC development through induction of a mutation(s) in an oncogene and/or a tumor suppressor gene, other than p53, for these patients.
Analysis of p53 and BAX mutations, loss of heterozygosity, p53 and BCL2 expression and apoptosis in basal cell carcinoma in Korean patients.
Cho S, Hahm JH, Hong YS.
Department of Dermatology, Ewha Womans University, Tongdaemun Hospital, 70 Chongro-6-ka, Chongro-ku, Seoul, 110-126, Korea.
Br J Dermatol 2001 Apr;144(4):841-8 Abstract quote
BACKGROUND: Apart from some Japanese studies, there are few data on the gene mutations involved in the development of basal cell carcinomas (BCC) in Koreans or other Asians. Objective To gain insight into the molecular pathogenesis of BCC in Koreans.
METHODS: A collection of 33 cases of BCC were screened for mutations of p53 and BAX genes, p53 and BCL2 expression, loss of heterozygosity (LOH) and apoptosis.
RESULTS: Mutations of p53, found in 9% (three of 33) of the cases, were all mis-sense mutations (G-->C transversions) at codon 246 on exon 7. In 6% (two of 33), BAX gene showed frameshift mutations resulting from deletions in the poly(G) tract. LOH on chromosome 9q was seen in 58% (14 of 24), and p53 mutations developed only among the 9q LOH+ cases; LOH on chromosome 18q, where BCL2 gene is located, was found in 13% (four of 30). Immunohistochemical expression of p53 was seen in 27% (nine of 33), and its expression did not coincide with p53 mutations. BCL2 expression was seen in 39% (13 of 33). Apoptosis was revealed in 21%. In BCC, 9q LOH and p53 mutations seem to be closely related; the immunoreactivity of p53 and its mutations were not directly related; and p53 and BCL2 expression were negatively correlated. Frameshift mutations of the BAX gene in BCC are documented for the first time.
CONCLUSIONS: Various molecular mechanisms operate with redundant complexity in the pathogenesis of BCC. The LOH on chromosome 9q is the most frequent genetic alteration, as in other races; however, p53 mutations are much less frequent in Koreans than in Caucasians and suggest aetiologies other than ultraviolet radiation.
CUSP/p63 expression in basal cell carcinoma.
Dellavalle RP, Walsh P, Marchbank A, Grayson TE, Su LJ, Parker ER, DeGregori J, Penheiter K, Aszterbaum M, Epstein Jr EH, Lee LA.
Department of Dermatology, Department of Medicine, Department of Biochemistry and Molecular Genetics, and Department of Pediatrics, University of Colorado School of Medicine, Denver, Colorado, USA; Department of Dermatology, University of California, San Francisco, California, USA; Veterans' Affairs Medical Center, Denver, Colorado; Dermatology Service, Department of Medicine, Denver Health Medical Center, Denver, Colorado, USA.
Exp Dermatol 2002 Jun;11(3):203-208 Abstract quote
Chronic ulcerative stomatitis protein (CUSP), the most abundant cutaneous isoform of p63, is a p53-related gene essential for epithelial development. CUSP lacks the N-terminal transactivation domain found on other p53 family members and has been shown to inhibit p53 function in vitro.
In this study, biopsies of normal skin (21 of 21), benign neoplasms [seborrheic keratosis (3 of 3), acrochordon (2 of 3), and verruca plana (3 of 3)], and squamous cell carcinomas (SCC) (4 of 4) displayed strong nuclear CUSP immuno-reactivity in epidermal cells. In contrast few basal cell carcinomas (BCC) (7 of 27) and sebaceous nevi (1 of 2) displayed this pattern of CUSP immunoreactivity.
Thus, biopsies of cutaneous conditions characterized by sonic hedgehog (SHH) pathway dysregulation were more than 86 times as likely to lack CUSP/p63 immunofluorescence as were other cutaneous samples. Adjacent normal-appearing skin from patients with basal cell nevus syndrome (BCNS) (2 of 3) also lacked CUSP immuno-staining. Lastly, a BCC arising in a patched heterozygous mouse also lacked CUSP immuno-staining. Because CUSP mRNA and protein were detected via Northern and Western analysis in BCC samples lacking CUSP immuno-staining, we sequenced the coding region of CUSP from two non-staining BCCs but found no mutations.
Therefore, CUSP appears to be present, unmutated, and yet frequently undetectable by immunofluorescence in cutaneous lesions in both humans and mice that are associated with SHH pathway dysregulation (BCCs, BCNS, and nevus sebaceous).
p63 expression in normal skin and usual cutaneous carcinomas.
Reis-Filho JS, Torio B, Albergaria A, Schmitt FC.
IPATIMUP, Institute of Molecular Pathology and Immunology, University of Porto, Porto, School of Health Sciences, University of Minho, Braga, Department of Pathology, Hospital Fernando da Fonseca, Amadora-Sintra, Lisbon, and Porto Medical Faculty, University of Porto, Porto, Portugal
J Cutan Pathol 2002 Oct;29(9):517-523 Abstract quote
BACKGROUND: p63 is a p53 homologue that is mapped to chromosome 3q27. This gene encodes six different isoforms, which have either transactivating or dominant negative effects on p53-reporter genes. It has been described that in contrast to p53, p63 seems not to be associated with tumor predisposition, as neither p63 knockout mouse models nor germline p63 mutations are related to an increased risk of tumorigenesis. It has been demonstrated that p63 is a reliable keratinocyte stem cell marker and that it is involved in the maintenance of the stem cell population. Scant data on p63 expression in normal skin, basal cell carcinomas (BCCs), keratoacanthomas and squamous cell carcinomas (SCCs) have been reported. We herein evaluated p63 expression in 16 BCCs, one keratoacanthoma and 13 SCCs.
METHODS: Immunohistochemistry according to the streptavidin-biotin-peroxidase technique, using the antibody 4A4 raised against all p63 isoforms, was performed. p63 expression was evaluated in epidermal cells and skin appendages. Semi-quantitative evaluation (-, +, ++, +++) of p63 expression in BCCs, keratoacanthoma and SCCs was carried out. Only nuclear expression was considered as specific.
RESULTS: p63 was expressed in the nuclei of epidermal basal and suprabasal cells, in the cells of the germinative hair matrix and the external root sheath of hair follicles, in the basal cells of the sebaceous gland and in the myoepithelial/basal cells of the sweat glands. All terminally differentiated cells were negative for p63. All BCCs showed ++ to +++ immunoreactivity. At variance, keratoacanthomas and grade I and II SCCs showed variable p63 reactivity in a basal layer-like distribution, whereas undifferentiated cells of grade III SCCs showed ++ to +++ positivity. A grade IV spindle SCC showed + immunoreactivity. The SCCs in situ showed remarkable expression of p63 in all cell layers. Terminally differentiated squamous cells were either negative or showed only focal immunoreactivity in the carcinomas.
CONCLUSIONS: p63 is consistently expressed in the basal cells of epidermis and cutaneous appendages, including the basal/myoepithelial cells of sweat glands. Based on our findings, the balance of probabilities favors that p63 might play a role in the pattern of differentiation and in the oncogenesis of usual carcinomas of the skin.
PTCH GENE MUTATIONS
Nat Genet 1996;14:78-81.
Cancer Res 1997;57:2369-72.
Human homologue of the Drosophila patched gene, PTCH, is the second tumor suppressor gene (after p53) implicated in the development of BCC
PTCH gene has been mapped to chromosome 9q22.3 where a locus for NBCCS had been previously located
Sequence analysis of DNA from NBCCS individuals has shown a series of germline mutations in the PTCH gene
Subsequently, somatic mutations in the PTCH gene have also been identified in 20% to 30% of the sporadic BCCs studied
Mutations detected in the PTCH genes from sporadic BCC also contain UV-specific C to T and CC to TT nucleotide changes
Most of the PTCH mutations detected have been nonsense mutations, deletions, and insertions, which lead to altered PTCH proteins.
Loss of heterozygosity on chromosome 4q32-35 in sporadic basal cell carcinomas: evidence for the involvement of p33ING2/ING1L and SAP30 genes.
Sironi E, Cerri A, Tomasini D, Sirchia SM, Porta G, Rossella F, Grati FR, Simoni G.
Laboratory of Human Genetics, Dermatologic Clinic, Department of Medicine Surgery and Dental Sciences S. Paolo, University of Milan, Milan, Department of Dermatology, Hospital of Busto Arsizio, Busto Arsizio, and Department of Biomedical Sperimental Clinical Sciences, University of Insubria, Varese, Italy.
J Cutan Pathol. 2004 Apr;31(4):318-322. Abstract quote
BACKGROUND: Studies on basal cell carcinoma (BCC) have demonstrated that patched gene and p53 gene located at 9q22.3 and 17p13 are the main genes responsible for the onset of this tumor. In order to identify a possible involvement of other tumor suppressor genes, we screened 19 cases of BCCs for loss of heterozygosity (LOH).
METHODS: The analysis was performed on tumoral tissue and on corresponding normal tissue by using a panel of 37 polymorphic markers spanning 26 chromosomal regions.
RESULTS: We observed that only four chromosomal regions, 4q32 (30.00%), 4q35 (27.27%), 9q21-22 (28.57%), and 9q22-qter (35.71%), demonstrated a significative LOH (>20%), even if others show a borderline percentage (15-20%) of imbalance (1q32, 3p24, 10p22.1, and 17q21.3).
CONCLUSIONS: Our findings suggest that a new chromosomal region mapping in the long arm of chromosome 4 could be involved in sporadic BCC carcinogenesis. Further analyses indicate that the minimal deleted region in 4q32-35 includes p33ING2/ING1L and SAP30, whose deletion could impair the G1-phase checkpoint control and favor gene silencing, respectively.
Mutations in the human homologue of Drosophila patched (PTCH) in basal cell carcinomas and the Gorlin syndrome: different in vivo mechanisms of PTCH inactivation.
Unden AB, Holmberg E, Lundh-Rozell B, Stahle-Backdahl M, Zaphiropoulos PG, Toftgard R, Vorechovsky I.
Karolinska Institute, Department of Biosciences at Novum, Center for Nutrition and Toxicology, Huddinge, Sweden.
Cancer Res 1996 Oct 15;56(20):4562-5 Abstract quote
The nevoid basal cell carcinoma (Gorlin) syndrome (NBCCS) is an autosomal dominant disorder characterized by multiple developmental defects and cancer susceptibility, in particular to basal cell carcinoma. The human homologue of Drosophila patched (PTCH) was recently identified, mapped to the NBCCS locus on chromosome 9q22.3, and found mutated in patients with NBCCS and also in sporadic basal cell carcinomas.
Here we show germ-line PTCH mutations in three families with NBCCS. We demonstrate that a germ-line PTCH frameshift deletion in one patient with NBCCS was accompanied by loss of the normal copy of PTCH in a tumor developed in the same patient. Another basal cell carcinoma from this patient did not show the loss of the normal copy of PTCH, instead a missense mutation in a highly conserved residue was identified in the nondeleted allele, illustrating two different mechanisms of PTCH inactivation in different tumors derived from the same NBCCS patient. We also show somatic PTCH mutations in 4 basal cell carcinomas identified by analyzing 18 non-NBCCS patients with sporadic tumors.
These data provide further support for PTCH as an important tumor suppressor gene in the development of the most common human cancer.
Human patched (PTCH) mRNA is overexpressed consistently in tumor cells of both familial and sporadic basal cell carcinoma.
Unden AB, Zaphiropoulos PG, Bruce K, Toftgard R, Stahle-Backdahl M.
Department of Dermatology, Karolinska Hospital, Stockholm, Sweden.
Cancer Res 1997 Jun 15;57(12):2336-40 Abstract quote
Recently, a human homologue of the Drosophila patched gene, PTCH, was identified as a putative tumor suppressor mutated in both hereditary and sporadic basal cell carcinomas. Because PTCH controls its own transcription, inactivating mutations in PTCH may lead to overexpression of mutant PTCH mRNA due to loss of autoregulation.
The present study is aimed at evaluating whether deregulation of PTCH mRNA expression is a general feature of BCCs of varying histological growth pattern and malignant potential. Irrespective of histological subtype, PTCH mRNA was overexpressed consistently as determined by in situ hybridization in all of the sporadic (n = 16) and hereditary (n = 20) tumors examined. PTCH expression was found in all of the tumor cells but appeared stronger in the peripheral palisading cells. PTCH mRNA was not detected in adjacent nontumor epidermal cells or in other parts of the epidermis. In the majority of tumors (20 of 36), nuclear immunostaining for p53 was found in scattered cells, whereas seven tumors completely lacked p53 immunoreactivity.
Our finding of an up-regulation of PTCH mRNA levels in all of the BCCs analyzed indicates that deregulation of the PTCH signaling pathway constitutes an early rate-limiting event in BCC development.
Ultraviolet and ionizing radiation enhance the growth of BCCs and trichoblastomas in patched heterozygous knockout mice.
Aszterbaum M, Epstein J, Oro A, Douglas V, LeBoit PE, Scott MP, Epstein EH Jr.
Department of Dermatology, University of California San Francisco, Building 100, Room 269, 1001 Potrero Ave, San Francisco, California 94110, USA.
Nat Med 1999 Nov;5(11):1285-91 Abstract quote
Basal cell carcinomas, the commonest human skin cancers, consistently have abnormalities of the hedgehog signaling pathway and often have PTCH gene mutations.
We report here that Ptch+/- mice develop primordial follicular neoplasms resembling human trichoblastomas, and that exposure to ultraviolet radiation or ionizing radiation results in an increase in the number and size of these tumors and a shift in their histologic features so that they more closely resemble human basal cell carcinoma. The mouse basal cell carcinomas and trichoblastoma-like tumors resemble human basal cell carcinomas in their loss of normal hemidesmosomal components, presence of p53 mutations, frequent loss of the normal remaining Ptch allele, and activation of hedgehog target gene transcription.
The Ptch mutant mice provide the first mouse model, to our knowledge, of ultraviolet and ionizing radiation-induced basal cell carcinoma-like tumors, and also demonstrate that Ptch inactivation and hedgehog target gene activation are essential for basal cell carcinoma tumorigenesis.
The spectrum of patched mutations in a collection of Australian basal cell carcinomas.
Evans T, Boonchai W, Shanley S, Smyth I, Gillies S, Georgas K, Wainwright B, Chenevix-Trench G, Wicking C.
Institute for Molecular Bioscience, University of Queensland, Australia.
Hum Mutat 2000;16(1):43-8 Abstract quote
Inactivating mutations in the human patched (PTCH) gene have been identified in both familial and sporadic basal cell carcinomas (BCCs). In some tumors mutations have been detected in both alleles thereby supporting the role of PTCH as a tumor suppressor gene.
We have analyzed 22/23 coding exons of PTCH for mutations in 44 sporadic BCCs, and detected 10 novel mutations in nine tumors. In two of the mutant tumors the remaining allele was inactivated by loss of heterozygosity. Five novel PTCH polymorphisms were also identified. Most of the variations found were C>T substitutions at dipyrimidine sites, supporting previous studies which indicate a role for ultraviolet-B in the genesis of sporadic BCCs.
Role of PTCH and p53 genes in early-onset basal cell carcinoma.
Zhang H, Ping XL, Lee PK, Wu XL, Yao YJ, Zhang MJ, Silvers DN, Ratner D, Malhotra R, Peacocke M, Tsou HC.
Department of Dermatology, Columbia University, College of Physicians and Surgeons, New York, New York, USA.
Am J Pathol 2001 Feb;158(2):381-5 Abstract quote
Basal cell carcinoma (BCC) is the most common skin cancer in the Western world. Ultraviolet (UV) exposure, race, age, gender, and decreased DNA repair capacity are known risk factors for the development of BCC. Of these, UVB irradiation from sunlight is the most significant risk factor. The incidence of sporadic BCC increases in individuals older than age 55, with the greatest incidence reported in individuals who are older than 70, and is rare in individuals who are younger than 30.
In this study, we analyzed 24 BCC samples from individuals who had BCC diagnosed by the age of 30. Fifteen single-stranded conformation polymorphism variants in the PTCH gene were identified in 13 BCC samples. Sequence analysis of these single-stranded conformation polymorphism variants revealed 13 single nucleotide changes, one AT insertion, and one 15-bp deletion. Most of these nucleotide changes (nine of 15) were predicted to result in truncated PTCH proteins. Fifteen p53 mutations were also found in 11 of the 24 BCC samples. Thirty-three percent (five of 15) and 60% (nine of 15) of the nucleotide changes in the PTCH and p53 genes, respectively, were UV-specific C-->T and CC-->TT nucleotide changes.
Our data demonstrate that the p53 and PTCH genes are both implicated in the development of early-onset BCC. The identification of UV-specific nucleotide changes in both tumor suppressor genes suggests that UV exposure is an important risk factor in early onset of BCC.
UV-specific p53 and PTCH mutations in sporadic basal cell carcinoma of sun-exposed skin.
Ratner D, Peacocke M, Zhang H, Ping XL, Tsou HC.
Department of Dermatology, College of Physicians and Surgeons of Columbia University, New York, Ny, USA.
J Am Acad Dermatol 2001;44:293-7 Abstract quote
UVB irradiation is known to produce DNA damage at mutation hotspots in the p53 tumor suppressor gene, leading to the development of skin cancers. Mutations in the PTCH tumor suppressor gene, which is known to be responsible for the development of nevoid basal cell carcinoma syndrome, have also been identified in sporadic basal cell carcinomas (BCCs).
We describe the case of an 80-year-old welder in whom 3 novel p53 mutations, as well as UV-specific PTCH mutations, were detected in two BCC samples from sun-exposed skin.
The simultaneous presence of UV-specific p53 and PTCH mutations in the same BCC sample has not previously been reported.
PATCHED and p53 gene alterations in sporadic and hereditary basal cell cancer.
Ling G, Ahmadian A, Persson A, Unden AB, Afink G, Williams C, Uhlen M, Toftgard R, Lundeberg J, Ponten F.
Department of Genetics and Pathology, Rudbeck Laboratory, University Hospital, Uppsala University, S-751 85 Uppsala, Sweden.
Oncogene 2001 Nov 22;20(53):7770-8 Abstract quote
It is widely accepted that disruption of the hedgehog-patched pathway is a key event in development of basal cell cancer. In addition to patched gene alterations, p53 gene mutations are also frequent in basal cell cancer.
We determined loss of heterozygosity in the patched and p53 loci as well as sequencing the p53 gene in tumors both from sporadic and hereditary cases. A total of 70 microdissected samples from tumor and adjacent skin were subjected to PCR followed by fragment analysis and DNA sequencing. We found allelic loss in the patched locus in 6/8 sporadic basal cell cancer and 17/19 hereditary tumors. All sporadic and 7/20 hereditary tumors showed p53 gene mutations. Loss of heterozygosity in the p53 locus was rare in both groups. The p53 mutations detected in hereditary tumors included rare single nucleotide deletions and unusual double-base substitutions compared to the typical ultraviolet light induced missense mutations found in sporadic tumors.
Careful microdissection of individual tumors revealed genetically linked subclones with different p53 and/or patched genotype providing an insight on time sequence of genetic events. The high frequency and co-existence of genetic alterations in the patched and p53 genes suggest that both these genes are important in the development of basal cell cancer.
Anaplastic neoplasms arising from basal cellcarcinoma xenotransplants into SCID-beige mice.
Carlson JA, Combates NJ, Stenn KS, Prouty SM.
Divisions of Dermatopathology and Dermatology, Albany Medical College, Albany, New York, USA, Skin Biology TRC, Johnson and Johnson, Skillman, New Jersey, USA.
J Cutan Pathol 2002 May;29(5):268-78 Abstract quote
Background: An animal model for the study of basal cell carcinoma (BCC) is required to better understand its biology. Several attempts to grow BCC in immuno-incompetent animals have been only modestly successful.
Methods: To test the ability of BCC to grow in a mouse with complete and severe immuno-incompetence, 14 individual BCC were transplanted into the subcutaneous tissue of 18 SCID-beige mice (T, B and natural killer cell deficient). Light microscopy and immunophenotypic analyses were performed on primary BCC and first and seventh passage tumors.
Results: Transplantation of three BCC yielded rapidly growing anaplastic tumors for a tumor take of 18% (3/18). SCID-beige mice without tumor growth had mostly scars or epidermoid cysts at the transplant sites. The three patients whose BCC gave rise to the anaplastic tumors were significantly older than those without tumor growth (87 vs. 64, p = 0.001), but they did not differ with respect to BCC type or general health. These three anaplastic tumors were histologically and immunophenotypically similar, being composed of dyscohesive, pleomorphic cells that expressed vimentin and smooth muscle actin. In the first passage mice these tumors were locally invasive, tumor-forming nodules associated with an expansion of donor inflammatory cells (T and B lymphocytes and plasma cells), rare remnants of BCC epithelium and epidermoid cysts. By the seventh passage, the tumors were homogenous and metastasized widely throughout the mice. Changing transplantation location to the dermis to wound environment or supplementing the tumor with BCC-derived fibroblasts did not alter the phenotype or growth rate in SCID-beige mice. Anaplastic tumors also grew easily in SCID mice (T and B cell deficient). However, transplantation of the anaplastic tumors into normal mice (CB-17) or less severely immunodeficient mice (NCr and Balb/c: T and natural killer cell deficient) did not allow for growth. Furthermore, tumor growth could not be maintained in vitro.
Conclusion: Empirically, these data suggest that BCC has the potential to become an aggressive metastatic neoplasm, given the right immune and stromal environment. Moreover, a functional B lymphocyte system appears to prevent this growth. As human lymphocytes also engraft in SCID-beige mice, the original host immune response could be responsible for the lack of tumor growth in the majority of xenografts. Furthermore, the anaplastic and metastatic phenotype of these BCC derived neoplasms may be the experimental equivalent of metastatic BCC and BCC associated with carcinosarcoma.
- Am J Dermatopathol. 2006 Aug;28(4):293-307
Neoplastic progression is characterized in part by escape from immune surveillance and formation of growth-permissive stroma. Basal cell carcinoma (BCC) can be subclassified into low- and high-risk types for local recurrence.
To determine whether these types of BCC correlate with alterations in local host immune response and stroma and whether these changes follow stepwise histologic progression from low- to high-risk subtypes, we assessed the clinicopathologic features in 175 consecutive primary (nonrecurrent) BCC excision specimens. BCCs exhibited a significantly higher frequency of mixed rather than homogeneous growth patterns (76% vs. 24%, P=0.0001). Nodular (84%) was the most common pattern identified followed by superficial (77%), infiltrative (27%), morpheic (5%) and micronodular patterns (4%). Only superficial (12% of all BCC) and nodular (12%) patterns were identified in BCC with a homogeneous histologic phenotype. Micronodular and infiltrative-morpheic patterns were not identified together in mixed patterned BCCs, and these high-risk types were contiguous with nodular BCC. Superficial predominant BCC (major growth pattern) was significantly associated with trunk and extremity location (76%) and skin without solar elastosis (82%), whereas BCC harboring a nodular growth pattern component was significantly associated with a head and neck location (63%) and the presence of adjacent solar elastosis (all P< or =0.03).
Significant correlations were identified for BCC subtypes with inflammatory and stromal alterations: superficial BCC with old regression and moderate to dense peritumoral lymphocytic infiltrates; high-risk types correlated with active regression; infiltrative and morpheic BCC with fibrosing tumor stroma; and micronodular BCC with loss of both host inflammatory and stromal tumor responses. Evaluating the theoretical histologic stepwise model of BCC progression (superficial-to-nodular-to-micronodular, or superficial-to-nodular-to-infiltrative-to-morpheic BCC types) revealed significant linear correlations with host response and alterations of tumor stroma (r=0.54, P=0.0001).
BCC exhibit distinct epithelial-stromal-inflammatory patterns that correlate with BCC subtype and tumor progression. This ostensible pathway of diminishing host response and gain of permissive tissue environment highlights neoplastic evolution from low to high risk for local recurrence of BCC and implicates a histologic continuum reflecting dynamic host-BCC interactions.
Reduction of expression of tuberin, the tuberous-sclerosis-complex-gene-2 product in tuberous sclerosis complex associated connective tissue nevi and sporadic squamous and basal cell carcinomas.
Wienecke R, Klemm E, Karparti S, Swanson NA, Green AJ, DeClue JE.
Department of Dermatology and Allergology, Ludwig-Maximilians-University Munich, Munich, Germany, National Institutes of Health, National Cancer Institute, Laboratory of Cellular Oncology, Bethesda, Maryland, USA, Department of Dermatology, Semmelweis University, Budapest, Hungary, Oregon Health Sciences University, Department of Dermatology, Portland, Oregon, USA, Department of Medical Genetics and Conway Institute, University College Dublin, Ireland
J Cutan Pathol 2002 May;29(5):287-290 Abstract quote
Background: Patients affected with tuberous sclerosis complex (TSC) are prone to the development of multiple benign tumors of the skin and other organs. Tuberin, the protein product of the tuberous-sclerosis-complex-2 tumor suppressor gene (TSC2) has been shown to inhibit cell proliferation. In TSC associated kidney tumors and sporadic brain tumors the loss/reduction of tuberin has been shown.
Methods: Specimens of nine squamous cell carcinomas (SCC) and five basal cell carcinomas (BCC) from patients without TSC and six biopsies of connective tissue nevi (CTN) of patients with TSC were obtained. Specimens were analyzed by immunoblotting for the expression of tuberin. Results: Absent or reduced levels of tuberin were detected in the dermal parts of three of six shagreen patches, two of five BCC, and four of nine SCC.
Conclusions: In tumors/hamartomas of patients with TSC the complete loss of TSC2 and tuberin is a mechanism which could be shown for CTN, thereby excluding the possibility of haploinsufficiency of TSC2. In a substantial number of cutaneous BCC and SCC the loss or downregulation of tuberin seems to be epigenetic, as alterations of TSC2 are not known in these tumors. The absence or reduction of tuberin might contribute to their proliferation.
VASCULAR ENDOTHELIAL GROWTH FACTOR
Expression of vascular endothelial growth factor in basal cell carcinoma and cutaneous squamous cell carcinoma of the head and neck.
Bowden J, Brennan PA, Umar T, Cronin A.
Department of Oral and Maxillofacial Surgery, Poole General Hospital, Poole, UK, Department of Pathology, Bournemouth General Hospital, Bournemouth, Dorset, UK and Department of Oral and Maxillofacial Surgery, Queen Alexandra Hospital, Cosham, Portsmouth, UK.
J Cutan Pathol 2002 Nov;29(10):585-589 Abstract quote
BACKGROUND: Basal cell carcinomas (BCC) and squamous cell carcinomas (SCC) can both arise from any cutaneous epithelial surface. BCC are slow growing and rarely metastasise, whereas SCC are usually more aggressive. It is likely that the angiogenic process plays a key role in determining rate of growth and propensity for dissemination. Angiogenesis is a complex process requiring many factors and a pivotal group of proteins involved in this process is vascular endothelial growth factor (VEGF).
METHODS: Immunohistochemical expression of VEGF was assessed in 44 cases of BCC and 41 cases of cutaneous SCC from the head and neck region.
RESULTS: VEGF was expressed by blood vessel endothelial cells in both adjacent skin and tumour, and in the basal keratinocyte layer of epidermis. In BCC, VEGF was expressed by tumour epithelial cells, predominantly at the invasive tumour front, in 24/44 cases and its expression was significantly greater than in adjacent skin (p = 0.038). More widespread VEGF expression was found in 32/41 cases of SCC, and it was significantly associated with the degree of tumour differentiation (p < 0.001).
CONCLUSIONS: The patterns of VEGF expression in BCC and SCC may help to explain the different behaviour that is usually seen with these tumours.
Effects of biopsy-induced wound healing on residual basal cell and squamous cell carcinomas: rate of tumor regression in excisional specimens.
Swetter SM, Boldrick JC, Pierre P, Wong P, Egbert BM.
Dermatology Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, and Department of Dermatology, Stanford University Medical Center, Stanford, CA, USA.
J Cutan Pathol 2003 Feb;30(2):139-46 Abstract quote
BACKGROUND: Wound healing following a partial biopsy of basal cell (BCC) and squamous cell carcinomas (SCC) may induce tumor regression.
METHODS: Nonmelanoma skin cancer (NMSC) biopsy and re-excision specimens from 1994 to 2001 were reviewed for histologic evidence of scar vs. presence of residual tumor in excision specimens. Regressed and non-regressed tumors were analyzed to assess the influence of anatomic location, biopsy technique (punch vs. shave), histologic subtype of BCC or SCC, time interval between biopsy and excision, and patient age.
RESULTS: Nine hundred and ten excisions were performed for transected BCC or SCC, 217 (24%) of which showed scar with no residual tumor. Logistic regression analysis revealed significant differences in the regressed vs. non-regressed subsets. SCCs were more likely to regress than BCCs (40% vs. 20%, respectively, p < 0.00001). Independent of the NMSC type, tumors regressed more often following shave rather than punch biopsy (34% vs. 15%, respectively, p < 0.00001), as did tumors on the trunk and extremities compared with head and neck cases (31% vs. 21%, respectively, p < 0.01).
CONCLUSIONS: In our series, 24% of NMSCs transected on the initial biopsy showed no residual tumor in the excision specimens, implying that some event in the interval between biopsy and excision may lead to the eradication of residual tumor. The exact mechanism is unclear, but wound healing likely plays an important role.
CHARACTERIZATION RADIOLOGY POSITRON EMISSION TOMOGRAPHY
Positron emission tomography for basal cell carcinoma of the head and neck.
Fosko SW, Hu W, Cook TF, Lowe VJ.
Department of Dermatology, Saint Louis University Health Sciences Center, MO 63104, USA.
Arch Dermatol. 2003 Sep;139(9):1141-6. Abstract quote
OBJECTIVE: To determine the ability of fluorodeoxyglucose F 18 positron emission tomography (FDG-PET) to image basal cell carcinoma (BCC).
DESIGN: Case series study.
SETTING: Mohs surgery practice in a tertiary university hospital.
PATIENTS: Six patients with BCC larger than 1.0 cm of the head and neck region were identified.
RESULTS: Patients were imaged using FDG-PET before surgery. In 3 patients, PET imaging correlated well with the size and extent of the soft tissue invasion. Histologically, all 3 tumors were of the nodular subtype. The remaining 3 patients failed to demonstrate identifiable tumor activity on PET. Two of these 3 tumors were of the infiltrative histologic subtype, and 1 was of the nodular subtype. Perineural spread was detected by tissue biopsy in 1 infiltrative tumor, but not by FDG-PET imaging.
CONCLUSIONS: In our study, FDG-PET imaging was able to image and identify BCC in the head and neck region in 3 of 6 patients. In some cases, anatomic accuracy and the extent of soft tissue invasion were observed. The histologic subtype of the BCC appears to affect the ability of FDG-PET detection, with the nodular histologic subtype more likely to test positive on PET. This is a preliminary study, and future investigation is needed to evaluate the role of PET imaging in the management of patients with BCC.
DNA Ploidy and Cyclin D1 Expression in Basal Cell Carcinoma of the Head and Neck
Stefania Staibano, MD, PhD,1 Lorenzo Lo Muzio, MD, PhD,4 Giuseppe Pannone, DDS,1 Ernesto Mezza, BD,1 Giuseppe Argenziano, MD,2 Antonio Vetrani, MD,1 Antonio Lucariello, MD,3 Renato Franco, MD,1 Maria E. Errico MD,1 and Gaetano De Rosa, MD
Am J Clin Pathol 2001;115:805-813 Abstract
Basal cell carcinomas (BCCs) may be subdivided into primary with a favorable biologic course (BCC1) and recurrent and/or metastatic (BCC2). No clear association between primary tumor location, histologic subtype, or other clinicopathologic variables and predisposition for BCC2 has been found. Histopathologic criteria are limited for prognostication.
To identify prognostic factors useful for planning therapy, we studied cyclin D1 immunohistochemical expression, DNA ploidy, and epiluminescence light microscopic (ELM) patterns in 60 cases of BCC (30 BCC1 and 30 BCC2) in the head and neck region, half of which were hyperpigmented. Cyclin D1 was absent in 27 cases, expressed at low level in 4 cases, and overexpressed in 30 cases. Seven BCCs were euploid, 28 exhibited a mixed cellular population, and 25 were aneuploid. Among aneuploid tumors, hypodiploidy was found in 12. Among the 30 pigmented carcinomas, only 15 showed a typical ELM pattern. No association between pigmentation and more aggressive biologic behavior of BCC was found.
These results and follow-up data seem to indicate that an unfavorable outcome can be predicted by hyperexpression of cyclin D1, aneuploidy, and an atypical ELM pattern for pigmented cases. A definite hypodiploid peak was associated with worse prognosis.The analysis of cyclin D1 expression and DNA ploidy may help identify BCC with an aggressive phenotype and a poor clinical outcome.
CONFOCAL SCANNING LASER MICROSCOPY
Real-time, in vivo confocal reflectance microscopy of basal cell carcinoma.
Gonzalez S, Tannous Z.
Wellman Laboratories of Photomedicine, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School.
J Am Acad Dermatol 2002 Dec;47(6):869-74 Abstract quote
BACKGROUND: Real-time, near-infrared confocal laser scanning microscopy may provide a way to diagnose basal cell carcinoma in vivo and might potentially eliminate the need for invasive diagnostic biopsies in the future.
OBJECTIVE: The purpose of this study is to define the in vivo histologic features of basal cell carcinoma by using a high-resolution imaging technique.
METHODS: Five fair-skinned white patients with 8 basal cell carcinoma lesions were recruited for this study. Near-infrared reflectance confocal microscopy imaging was used to characterize the histologic features of these lesions in vivo. Subsequently, the confocal histologic features were correlated with the corresponding routine hematoxylin-and-eosin-stained sections obtained from invasive biopsies.
RESULTS: A uniform population of basal cell carcinoma cells with characteristic elongated nuclei oriented along the same axis was always present. Abundant blood vessels demonstrating prominent tortuosity were seen, as well as prominent, predominantly mononuclear inflammatory infiltrate admixed or in close apposition with basal cell carcinoma cells. Trafficking of leukocytes was visualized in real time.
CONCLUSION: Our results demonstrate that near-infrared confocal microscopy may facilitate diagnosis of basal cell carcinoma with the use of in vivo high-resolution confocal features. Accuracy studies to evaluate these in vivo histologic criteria are warranted.
CHARACTERIZATION VARIANTS BUCCAL MUCOSA
Basal Cell Carcinoma of the Buccal Mucosa
Raul N. Del Rosario, M.D.; Ronald J. Barr, M.D.; Jerald L. Jensen, D.D.S.; Kenneth A. Cantos, M.D.
Laboratory Service (Oral Pathology) Veterans Administration Medical Center Long Beach, CA (J.L.J.); Dermatopathology Laboratory, University of California Irvine Medical Center (R.D.R., R.J.B., K.A.C.).
Am J Dermatopathol 2001;23:203-205Abstract quote
True basal cell carcinoma (BCC) involving the oral mucous membranes is extraordinarily rare. Most of those described as occurring in the oral cavity usually involve the gingiva and are not true BCCs but peripheral ameloblastomas.
A true BCC, which arose on the buccal mucosa of a 69-year old man, is reported. It presented as a 1.3 cm ulcerated plaque without gingival connection. Histologically, the lesion exhibited classic features of BCC with palisading and retraction spaces, and focally communicated with the overlying squamous epithelium.
Although it is possible that this lesion also arose from a heterotopic odontogenic rest, the anatomical location, focal squamous (metatypical) features, and positive staining for Ber-EP4 support an origin from the basal cell layer of stratified squamous mucosa.
J Cutan Pathol. 2005 Aug;32(7):502-5. Abstract quote
Background: Basal cell carcinoma (BCC) is a common malignant skin neoplasm. The surface of the caruncle contains sebaceous glands, hair follicles, and lacrimal and sweat gland elements. Consequently, the caruncle may spawn any neoplasm that occurs in the conjunctiva, skin, or lacrimal gland. We report a patient with a primary BCC located on the lacrimal caruncle.
Methods: An 80-year-old man with a 5-month history of a gradually enlarging left caruncular neoplasm was seen. The lesion was nodular and irregularly brown-black colored, with no involvement of adjacent conjunctiva or skin. He had a history of sun exposure, but no personal or family history of other malignant neoplasms.
Results: The mass was excised completely. Histopathologic examination revealed a BCC originating in the basal layer of the conjunctival epithelium. No tumor recurrence has been noted after 7 years of follow-up. Primary BCC of the caruncle is unusual, and only four cases have been described in the PubMed. BCC should be considered in the differential diagnosis of caruncle and adjacent skin lesions.
Linear basal cell carcinoma: report of seventeen cases and review of the presentation and treatment.
Lim KK, Randle HW, Roenigk RK, Brodland DG, Bernstein SC, Marcil I.
Department of Dermatology, Mayo Clinic Scottsdale, Arizona, USA.
Dermatol Surg 1999 Jan;25(1):63-7 Abstract quote
BACKGROUND: Linear basal cell carcinoma was first described as a distinct clinical morphologic variant in 1985. Subsequently, twelve cases were reported.
OBJECTIVE: To review and identify cases of linear basal cell carcinoma in our institutions and determine optimal treatment based on review of our cases and those in the literature.
METHODS: Primary basal cell carcinomas treated at the three campuses of Mayo Clinic and the University of Montreal were reviewed retrospectively, as were the twelve cases in the literature.
RESULTS: Seventeen cases of linear basal cell carcinoma were identified. The age and sex ratios were similar to those of patients with standard basal cell carcinomas. Based on the review of the few reported cases of linear basal cell carcinoma (29), the percentage of aggressive histologic subtypes (38%) was increased compared with that in a general population. The average number of Mohs layers required for treatment was higher than that reported for standard basal cell carcinoma, an indication of increased subclinical spread.
CONCLUSION: Linear basal cell carcinoma is an uncommonly recognized morphologic variant. Based on the small number of cases, these tumors have more aggressive histologic subtypes. Because of the possibility for increased subclinical spread, Mohs micrographic surgery can be considered for treatment. Further studies are needed to confirm these findings.
NIPPLE Primary basal cell carcinoma of the nipple.
Gupta C, Sheth D, Snower DP.
Deprtment of Pathology, St John Hospital and Medical Center, Detroit, Mich 48236, USA
Arch Pathol Lab Med. 2004 Jul;128(7):792-3. Abstract quote
Basal cell carcinoma arising from the nipple of the breast is an uncommon malignancy, with only a handful of cases reported in the literature.
The diagnosis is, however, important because basal cell carcinoma in this location can mimic breast cancer, may behave aggressively, and there is a relative lack of consensus in its treatment.
A case of basal cell carcinoma of the nipple is described in a 67-year-old man with a brief review of the literature.
Basal cell carcinoma presenting as a large pore.
Benedetto AV, Benedetto EA, Griffin TD.
MCP Hahnemann School of Medicine.
J Am Acad Dermatol 2002 Nov;47(5):727-32 Abstract quote
BACKGROUND: Certain facial lesions clinically appear as large pores, and when examined microscopically, they are found to be basal cell carcinomas (BCCs).
OBJECTIVES: The purposes of this study were to determine the clinical and histologic characteristics of certain large-pore facial lesions, which, on microscopic examination, are found to be BCCs and to identify, if any, a clinical profile of the patients who might be prone to development of such large-pore BCCs.
METHODS: Microscopic examination of biopsy tissue, obtained from patients who presented clinically with characteristic large-pore lesions of the face during the years 1988 to 2000, was performed.
RESULTS: Eleven biopsy specimens from 10 patients who presented with long-standing, gaping pores in the center of the face were shown to be BCCs with features of follicular differentiation and focal keratinization. These patients also had thick, sebaceous skin, and most were users of tobacco.
CONCLUSION: Enlarged pores or pits in the center of the face, present for a long period in patients with thick sebaceous skin, should be examined for evidence of BCC. These large-pore lesions may be BCCs with histologic features of follicular differentiation.
HISTOLOGICAL TYPES CHARACTERIZATION GENERAL
Am J Dermatopathol 2000;22:123-125
The pathologist should always indicate if the tumor is of the micronodular, infiltrative, or sclerosing histologic subtype
These three subtypes follow a much more aggressive course and should be treated more aggressively. In addition, the multifocal superficial type is also more likely to recur.
J Am Acad Dermatol. 2005 Sep;53(3):469-74. Abstract quote
BACKGROUND: There has been no published study estimating the proportion of positive surgical margins that is missed when serial transverse cross-sectioning (bread-loafing) is used to histologically evaluate the surgical margins.
OBJECTIVE: Our purpose was to estimate the accuracy of serial transverse cross-sectioning (bread-loafing) at 4-mm intervals in detecting the presence of residual tumor at the margins of well-defined facial basal cell carcinomas excised as an ellipse with 2-mm surgical margins.
METHODS: Forty-two small (<1 cm), well-defined, primary, nonmorpheaform facial basal cell carcinomas that had been excised as an ellipse with 2-mm margins and that had positive surgical margins utilizing en-face Mohs sections were included. After longitudinal bisection of each ellipse, frozen sections were prepared encompassing the entire surgical margin. Transparencies with parallel lines spaced at 4-mm intervals were superimposed on the histologic slides with the lines perpendicular to the epidermal surface. Areas in which the lines intersected tumor at the surgical margin were noted. The percentage of tumors that would be detected by serial cross sections was calculated on the basis of the percentage of these parallel lines that intersected tumor.
RESULTS: The 42 tumors had a total of 50 positive surgical margins. Overall, the cross-sectional lines intersected tumor 44% of the time (95% confidence interval, 37%-51%). Only 5 (10%) of the residual tumors at the surgical margins exceeded 4 mm in their longitudinal dimension. In the 9 sections containing tumor in the deep margin, tumor intersected the lines 39% of the time.
CONCLUSION: Bread-loafing at 4-mm intervals of elliptical excision specimens from facial basal cell carcinomas excised with 2-mm surgical margins is only 44% sensitive in detecting residual tumor at the surgical margins. We recommend complete histologic margin control by using en face tissue orientation (Mohs technique) to identify residual tumor and reduce the risk of tumor recurrence after elliptical excision of facial basal cell carcinomas.
The heterogenous nature of in vivo basal cell carcinoma.
Jones MS, Maloney ME, Billingsley EM.
Department of Dermatology, Hershey Medical Center, PA 17033, USA.
Dermatol Surg 1998 Aug;24(8):881-4 Abstract quote
BACKGROUND: There have been nearly 70 different histologic subtypes of basal cell carcinoma (BCC) described. Some of the subtypes have been shown to have clinical relevance. The degree to which one type may merge to another, within the same tumor mass, has been poorly studied.
OBJECTIVE: To determine if BCCs maintain biopsy histology throughout the entire architecture of the tumor.
METHOD: Tumors were evaluated with a prospective histologic analysis of all primary BCCs using the Mohs "removal in layers" technique. All BCCs that required more than a single Mohs stage to clear were included in analysis.
RESULTS: One hundred forty-nine tumors were examined. Fourteen of these were of mixed histologic subtype on biopsy and were not included in the analysis. Six biopsy specimens were inadequate to make a subtype diagnosis and were excluded from calculation. Of the remaining 129 tumors 59% maintained their biopsy diagnosis at first Mohs stage, and 49% at the second Mohs stage. Infiltrative tumors were the most likely to maintain their histologic subtype classification. Of the tumors that showed nodular BCC on biopsy, 13% were infiltrative or micronodular at first Mohs stage.
CONCLUSION: While many BCCs demonstrate a single histological subtype, roughly 40% change in their microscopic appearance at the subclinical extension. This finding has the potential to alter therapy
Basal Cell Carcinoma Clues to Its Presence in Histologic Sections When the Initial Slide Is Nondiagnostic
Helen M. Haupt, M.D.; Jere B. Stern, M.D.; Mouta S. Dilaimy, M.D.
From the Pennsylvania Hospital, Philadelphia, PA, U.S.A. (H.M.H.); Dermatopathology Consultation Services, Damascus, Maryland, U.S.A. (J.B.S.); and Quest Diagnostics, Baltimore, Maryland, U.S.A. (J.B.S., M.S.D.).
Am J Surg Pathol 2000;24:1291-1294 Abstract quote
Initial sections of skin biopsies may not be diagnostic of basal cell carcinoma (BCC). Are there histologic predictors of BCC that should prompt deeper sections?
Ninety-four cases in which the clinical diagnosis was BCC or ``rule-out BCC,'' and the initial histologic slides were nondiagnostic, were submitted for deeper sections on three additional slides.
Of the 94 cases, 50 (53%) demonstrated BCC on deeper sections. This relatively high incidence suggests that deeper sections should be taken in all cases of clinically suspected BCCs unless alternate histologic findings adequately account for the clinical lesion.
The results of this study suggest that additional sections are more likely to yield BCC when the initial nondiagnostic slide demonstrates focal epidermal atypia, equivocal adnexae, stromal fibrosis, empty dermal space, and microcalcifications, criteria which may be useful in determining the need to do deeper sections in cases in which BCC is not clinically suspected.
Populated by melanocytes and Langerhan's cells
Am J Dermatopathol 2001;23:24-28
Study of 10 cases
Dendritic melanocytes distributed at periphery (5/10) or evenly throughout the tumor nests (5/10)-no clusters identified
Langerhans cells in 9/10 cases
A case with BCC infiltrated by malignant melanocytes of a melanoma in situ showed a higher melanocyte density and clusters of melanocytes
VARIANTS ADENOID Reticulate pattern, usually in combination with other types BASOSQUAMOUS Areas of squamous differentiation merging with basal cell CLEAR CELL
Basal cell carcinoma with tricholemmal (at the lower portion) differentiation within seborrheic keratosis.
Misago N, Satoh T, Narisawa Y.
Division of Dermatology, Department of Internal Medicine, and Department of Pathology, Saga Medical School, Saga, Japan.
J Cutan Pathol 2003 Mar;30(3):196-201 Abstract quote
BACKGROUND: Recent genetic investigations support the idea that basal cell carcinoma (BCC) is trichoblastic carcinoma. However, it is generally thought that clear cell basal cell carcinoma is a result of degeneration rather than tricholemmal differentiation.
METHODS: We report a case of BCC, with clear cell components, that developed within seborrheic keratosis, with histopathological and immunohistochemical findings.
RESULTS: The clear cell components in the present case showed the following four characteristics: (i) at the periphery of the aggregations, columnar clear cells were aligned in a palisade along a well-defined basement membrane; (ii) the nuclei of the columnar clear cells were at the pole opposite the basement membrane; (iii) the clear cells contained glycogen; (iv) in the aggregations with clear cell components, there was diffuse positive staining for cytokeratin 7 (CK7) (OV/TLR/30), but only the inner region stained positive for CK17. These four characteristics are comparable to those of the lower portion of normal outer root sheath. In addition, the BCC in the present case was partly composed of squamous cells that contained glycogen and were selectively positive for CK17 - features similar to those of squamous cells in normal outer root sheath.
CONCLUSIONS: Some clear cell BCCs are simply the result of degenerative change, but other clear cell BCCs may be the result of tricholemmal (at the lower portion) differentiation.
CYSTIC Central degeneration of the tumor cells GRANULAR
Ber-EP4 and MNF-116 in a Previously Undescribed Morphologic Pattern of Granular Basal Cell Carcinoma
Anna Abraham Hayden, M.D.; H. Nicholas Shamma, M.D.
From the Dermatopathology Laboratory of Central States, and the Division of Dermatology, Wright State University School of Medicine, Dayton, Ohio, U.S.A
Am J Dermatopathol 2001;23:530-532 Abstract quote
Granular basal cell carcinoma (GBCC) is a rare subtype of basal cell carcinoma (BCC) with only seven previously described cases in the literature.
A 65-year-old man presented with a papule on his cheek that was subsequently removed. Histopathologic examination revealed that the neoplasm had no connection to the overlying epidermis and that the neoplasm had two different morphologies; nodules composed solely of granular cells and other nodules with a rim of basaloid cells and central granular cells.
The neoplasm stained for both Ber-EPF4 and MNF-116 thus confirming it as a subtype of BCC. GBCC should be considered in the differential diagnosis of nodular neoplasms containing granular cells.
FIBROEPITHELIOMA OF PINKUS Soft nodular lesion usually on the back or feet with thin anastomosing strands of basaloid cells in loose stroma
- Expression of Androgen Receptor by Fibroepithelioma of Pinkus: Evidence Supporting Classification as a Basal Cell Carcinoma Variant?
From the *Departments of Pathology and Laboratory Medicine; daggerDepartment of Dermatology and double daggerDivision of Biostatistics, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN.
- Am J Dermatopathol. 2007 Feb;29(1):7-12. Abstract quote
The classification of fibroepithelioma of Pinkus as basal cell carcinoma or trichoblastoma remains controversial. Immunohistochemical stains for androgen receptor may be useful in differentiating basal cell carcinoma from trichoepithelioma or trichoblastoma.
We studied androgen receptor expression in 13 fibroepitheliomas of Pinkus, 11 basal cell carcinomas, 12 trichoepitheliomas, and 3 trichoblastomas. Androgen receptor expression was present in 77% (10/13) of fibroepitheliomas of Pinkus, 73% (8/11) of basal cell carcinomas, 17% (2/12) of trichoepitheliomas, and 0% (0/3) of trichoblastomas. Androgen receptor expression was significantly higher in fibroepitheliomas of Pinkus compared with trichoepitheliomas and trichoblastomas (P = .0007), but not basal cell carcinoma (P = 1.00). Tumor-associated Merkel cells, a feature of benign follicular tumors, was identified by cytokeratin 20 stains. Merkel cells were identified in 85% (11/13) of fibroepitheliomas of Pinkus, 27% (3/11) of basal cell carcinoma cases, and 73% (11/15) of benign follicular tumors. Cytokeratin 20 expression was significantly higher in fibroepithelioma of Pinkus and benign follicular tumors compared with basal cell carcinomas (P = 0.0111 and P = 0.025, respectively). No significant difference was found between fibroepitheliomas of Pinkus and trichoepitheliomas and trichoblastomas (P = 1.00).
Similar to basal cell carcinomas, fibroepitheliomas of Pinkus express androgen receptors, potentially supporting classification as a basal cell carcinoma. Conversely, fibroepithelioma of Pinkus demonstrates retention of Merkel cells, a feature of benign follicular tumors.
Immunophenotypic evidence for the classification of fibroepithelioma of Pinkus remains inconclusive. In small, partial biopsy specimens, coexpression of androgen receptor and cytokeratin 20 may aid in the diagnosis of fibroepithelioma of Pinkus.
Fibroepithelioma of pinkus with tumor giant cells.
Val-Bernal JF, Gomez-Ortega JM, Fernandez-Llaca H, Gomez-Roman JJ.
Department of Anatomical Pathology (J.F.V.-B., J.M.G.-O., J.J.G.-R.) and Dermatology Service (H.F.-L.), Marques de Valdecilla University Hospital, Medical Faculty, University of Cantabria, Santander, Spain.
Am J Dermatopathol 2002 Aug;24(4):336-9 Abstract quote
A case of fibroepithelioma of Pinkus with pleomorphic epithelial giant cells is reported. The lesion was an ovoid polypoid nodule measuring 4 mm x 3 mm x 2 mm and was located close to the right axilla in an 86-year-old woman. The immunohistochemical features of the epithelial giant cells indicate that most of these cells are not cycling.
We suggest that these cellular changes may represent a senescent event. Giant cells showed a mean nuclear major diameter more than twice that of small cells. Flow cytometric study of the tumor showed a hypodiploid DNA content and an intermediate grade S-phase fraction of the aneuploid component.
To the best of our knowledge, a pleomorphic variant of Pinkus fibroepithelioma has not been reported to date. In fibroepithelioma of Pinkus, the correct diagnosis depends primarily on the architectural pattern of the tumor rather than on its cytologic features.
FOLLICULAR (INFUNDIBULO-CYSTIC TYPE) Small well circumscribed variant with nests resembling hair follicles
Infundibulocystic basal cell carcinoma: a newly described variant.
Walsh N, Ackerman AB.
Department of Dermatopathology, New York University Medical Center, New York.
Mod Pathol 1990 Sep;3(5):599-608 Abstract quote
A report by Tozawa and Ackerman (Am J Dermatopathol 9(6):474, 1987) upon a distinctive type of basal cell carcinoma with a particular type of follicular differentiation has stimulated lively correspondence in the literature of dermatopathology. The lesion in question presents itself clinically as a basal cell carcinoma on the face and histopathologically as a neoplasm typified by small size, sharp circumscription, and a unique combination of kinds of follicular differentiation, namely, follicular germs and infundibula. The principal point of contention concerning this neoplasm has been whether it is truly a special variant of basal cell carcinoma or whether it is actually a trichoepithelioma. More extensive studies of this singular neoplasm, including its occurrence in patients with nevoid basal cell carcinoma syndrome, and review of the very few portrayals of it in the literature, have consolidated our view that it is indeed a special variant of basal cell carcinoma.
We now present (a) new information about an early stage in the evolution of the neoplasm in point, (b) evidence to validate classification of it as a basal cell carcinoma, and (c) a critical appraisal of other lesions that might pose problems in differential diagnosis. Finally, justification is provided for the designation "infundibulocystic basal cell carcinoma."
Tumors are poorly circumscribed, have an irregular spiky appearance at the edges
Infiltrating nests and cords of basaloid cells with larger islands toward the center and thinner strands toward the periphery
Islands have poorly developed peripheral palisading and scant mucinous retraction
Lacks desmoplastic stroma
Infiltrative basal cell carcinoma: a nonsclerosing subtype.
Siegle RJ, MacMillan J, Pollack SV.
J Dermatol Surg Oncol 1986 Aug;12(8):830-6 Abstract quote
Infiltrative basal cell carcinoma is a distinct histologic subtype of basal cell carcinoma (BCC). Criteria for its diagnosis are presented and its nonsclerotic nature emphasized.
Analysis of 174 consecutive BCCs referred for Mohs micrographic surgery showed the infiltrative subtype (29 tumors) to be significantly more destructive and difficult to treat than the more common nodular BCC.
KERATOTIC Large islands of keratinization MATRICAL
- Basal cell carcinoma with matrical differentiation in a transplant patient: A case report and review of the literature.
Ali F, Brown A, Gottwald L, Thomas J.
Department of Pathology, Division of Dermatology, Medical College of Ohio, OH, USA.
J Cutan Pathol. 2005 Jul;32(6):445-8. Abstract quote
Background: Shadow cells, characterized by basaloid squamous cells with a distinct well-defined border and a central unstained area as a shadow of lost nuclei, are characteristic of pilomatricoma, a distinct neoplasm of hair matrix differentiation. The presence of shadow cells within tumor islands composed of follicular germinative cells of an otherwise classic basal cell carcinoma (BCC) has been considered as a distinct diagnostic category of BCC with matrical differentiation. We present a case of BCC with matrical differentiation in a transplant patient. To our knowledge, only 10 cases [Aloi et al. Am J Dermatopathol 1988; 10: 509; Ambrojo et al. Am J Dermatopathol 1992; 14: 293; Sagol et al. East J Med 1999; 4: 37; Kwittken J. Cutis 2002; 69: 57; Kim et al. Yonsei Med J 2003; 44: 523] of BCC showing matrical differentiation have been reported. None have been reported arising on the background of immunosuppression.
Methods: A 58-year-old male cardiac transplant patient with a nodule on the dorsum of left hand was studied. It arose and enlarged rapidly within a few months, causing irritation and bleeding. The nodule was surgically excised and submitted for histopathologic evaluation. The sections were prepared by hematoxylin and eosin (H&E) method.
Results: The H&E-stained sections of the hand lesion revealed multiple nodular masses of basaloid follicular germinative cells. In some areas, there was peripheral palisading and stromal retraction artifact typical of classic BCC. In these areas, the tumor nodules were connected to the epidermis, whereas in others, it extended deep into the reticular dermis to the subcutaneous fat junction. Elsewhere, the majority of the tumor contained a population of shadow cells, similar to those in pilomatricoma, with basaloid-appearing matrical cells in the periphery. Trichohyaline granules were identified in the cytoplasm of many of the peripheral basaloid cells. These granules are one of the characteristic features of follicular matrix differentiation. Mitoses were rare. Areas of cystic degeneration were present throughout the tumor. There was no evidence of an infiltrating growth pattern, lymphovascular invasion, or sarcomatoid growth pattern.
Conclusion: BCC with matrical differentiation is a distinct pathologic entity and a rare subtype of BCC featuring shadow and matrical cells, typically seen in pilomatricoma, a benign hair matrix neoplasm. This tumor has not yet been reported in an immunosuppressed transplant patient.
- Basal cell carcinoma with matrical differentiation: a case study with analysis of beta-catenin*.
Haskell HD, Haynes HA, McKee PH, Redston M, Granter SR, Lazar AJ.
Department of Pathology, Division of Dermatopathology (H.D.H, P.H.M., M.R., S.R.G., A.J.F.L) and Department of Dermatology (H.A.H), Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
J Cutan Pathol. 2005 Mar;32(3):245-50. Abstract quote
Matrical differentiation in basal cell carcinoma (BCC) is rare. Only nine cases have been described that showed typical diagnostic features of BCC, in addition to shadow cells indicating hair-matrix differentiation.(1-5) These cases often present a diagnostic challenge due to confusion with pilomatrixoma or pilomatrix carcinoma.
We present a case of BCC with matrical differentiation in a 78-year-old man. Immunohistochemical and molecular methods are used to differentiate this lesion from benign or malignant forms of pilomatrixoma.
METATYPICAL Basal cells merge with areas of larger paler cells MICRONODULAR May infiltrate widely through the dermis
Micronodular basal cell carcinoma. A deceptive histologic subtype with frequent clinically undetected tumor extension.
Hendrix JD Jr, Parlette HL.
Department of Dermatology, University of Virginia School of Medicine, Charlottesville.
Arch Dermatol 1996 Mar;132(3):295-8 Abstract quote
BACKGROUND AND DESIGN: Micronodular basal cell carcinoma (BCC) is thought to have a greater potential for clinically surreptitious tumor spread compared with the majority of BCCs that are nodular. However, most supporting data are anecdotal. This study gives objective evidence that micronodular BCCs have wider and deeper tumor extensions than nodular BCCs of similar clinical size. In this retrospective study, 69 cases of micronodular BCC excised by Mohs' micrographic surgery (MMS) were matched to a control group of 69 cases of nodular BCC that were similarly excised. They were paired by site, size, number of recurrences, age, gender, and previous treatment type. The cases were selected and paired by computer from 1070 consecutive BCCs (primary and recurrent) referred for MMS over a 4-year period. The MMS technique allowed us to quantitate and compare the extent of tumor spread using three measurements: the number of surgical stages required for complete removal of the tumor, the width of tissue required to remove subclinical extension of tumor, and the depth of defect at completion of MMS.
RESULTS: Analysis showed the micronodular BCC to have significantly more covert tumor extension, making it more difficult to detect and to eradicate than the nodular BCC. The number of surgical stages required for complete removal of tumor, the width of tissue required to remove subclinical extension of tumor, and the depth of defect at completion of MMS were all greater with micronodular BCCs when compared with nodular BCCs regardless of whether cases were primary or recurrent. These differences were all statistically significant.
CONCLUSIONS: Micronodular BCCs can be significantly more destructive than nodular BCCs because tumor extension is difficult to detect clinically. When treating micronodular BCC, clinicians should keep in mind its potential for clandestine invasion.
MULITFOCAL SUPERFICIAL 10-15% of all cases
Tend to occur in younger patients (57 years vs. 63 years)
Commonly on the trunk and limbs
NODULAR SOLID Most common-70% of cases PIGMENTED Melanin pigment within tumor cells and stroma
Pigmented basal cell carcinoma: investigation of 70 cases.
Maloney ME, Jones DB, Sexton FM.
Department of Medicine, College of Medicine, Pennsylvania State University, Hershey.
J Am Acad Dermatol 1992 Jul;27(1):74-8 Abstract quote
BACKGROUND: Pigmented basal cell carcinoma (PBCC) is a clinical and histologic variant of BCC.
OBJECTIVE: Our purpose was to identify the histologic subtypes of BCC that were most often associated with pigment and to determine whether this correlated with outcome after excision.
METHODS: A series of PBCC was identified and the histologic subtype noted. Margins of all excisions were examined for residual tumor. These results were then compared with a series of nonpigmented BCCs.
RESULTS: In a series of 1039 consecutive BCCs, 70 (6.7%) contained pigment. The histologic growth pattern most frequently associated with pigment was the nodular/micronodular pattern (12.4%) followed by the nodular (7.7%), superficial (7.2%), micronodular (4.0%), and the nodular/micronodular/infiltrative (3.4%) patterns. Margins were examined for evidence of residual tumor in the 40 cases that were excised. In only one case (2.5%) was the margin positive for tumor. This was statistically significant (p less than 0.05) compared with 388 excisions of nonpigmented BCCs with comparable growth patterns in which 69 (17.7%) showed positive margins.
CONCLUSION: PBCC, as a clinical variant, is more frequently excised with adequate margins than are tumors of comparable histologic subtypes that do not contain pigment.
Arch Dermatol 1996;132:320
75-84% of BCCs in Japanese show pigmentation versus less than 10% in Caucasians
J Cutan Pathol 2001;28:34-43
Ultrastructural study identified melanocytes along the basal membrane and also interspersed between tumor cells with large dendrites
Melanocytes in pigmented areas were twice the size of those in non-pigmented basal layer
Melanosomes were almost completely in the apoptotic tumor cells and the phagocytosis of the melanosome-containing apoptotic cells by the neighboring tumor cells followed the formation of melanosome complexes
POLYPOID Polypoid basal cell carcinoma: a new clinicopathological variant.
Department of Dermatology, Heinrich-Heine-University, Moorenstr. 5, 40225 Dusseldorf, Germany.
Br J Dermatol 1999 Apr;140(4):701-3 Abstract quote
Basal cell carcinoma (BCC), the most common malignant neoplasm of the skin, has many different clinical and histological appearances. Four patients with a new distinctive form, polypoid BCC, are described.
Polypoid BCC is clinically distinguished from other types of BCC by being pedunculated and having a stalk that connects it to the skin surface.
Histologically, it is distinctive in that the tumour aggregations are restricted to the exophytic polypoid zone.
- Sarcomatoid Basal Cell Carcinoma-Predilection for Osteosarcomatous Differentiation: A Series of 11 Cases.
*Department of Histopathology, St. James's Hospital, Dublin, Ireland daggerDepartment of Pathology, Singapore General Hospital, Republic of Singapore double daggerAnatomia Patologica, Hospital General de Albacete, Albacete, Spain section signDepartment of Histopathology, Kettering General Hospital, UK parallelDepartment of Dermatopathology, St. John's Institute of Dermatology, St. Thomas' Hospital, London, UK.
- Am J Surg Pathol. 2006 Oct;30(10):1299-1308. Abstract quote
Primary cutaneous carcinomas rarely show heterologous malignant mesenchymal differentiation.
We report 11 cases of sarcomatoid basal cell carcinoma (BCC) with osteosarcomatous differentiation. The patients (7 men and 4 women) ranged in age from 61 to 92 years (median 75 y). The tumors presented as exophytic nodules (0.3 to 7 cm) on the head (n=6), upper limb (n=3), and lower limb (n=2). All lesions were completely excised. Seven patients were alive without evidence of disease (follow-up interval 5 to 24 mo) and 1 patient died of unrelated causes at 7 months without evidence of disease.
On histology, the tumors were dermal in location with 2 cases showing focal subcutaneous involvement. Ten tumors were well-circumscribed and 1 tumor showed focally infiltrative edges. Ten tumors revealed conventional BCC associated with varying proportions of osteosarcomatous and undifferentiated sarcomatous stroma. Transition from neoplastic epithelial to mesenchymal cells was seen in 8 cases. One case showed a purely osteoclastic giant cell rich malignant mesenchyme, interpreted as representing early stages of osteosarcomatous transformation. Previously unreported in sarcomatoid BCC, the mesenchymal component of another two cases displayed predominant malignant giant cell tumor like areas and 1 further case disclosed areas reminiscent of telangiectatic osteosarcoma.
Pancytokeratins (AE1/3 and MNF116) and smooth muscle actin stained occasional undifferentiated sarcomatous cells in 2 and 3 tumors, respectively. MNF116 and EMA were focally positive in osteosarcomatous tumor cells of 1 case. Although the follow-up interval is short, our data suggest an excellent prognosis for polypoid and exophytic sarcomatoid BCC after complete surgical resection.
- Biphasic sarcomatoid basal cell carcinoma (carcinosarcoma): four cases with immunohistochemistry and review of the literature.
Bigby SM, Charlton A, Miller MV, Zwi LJ, Oliver GF.
Department of Pathology, Diagnostic-Medlab, Auckland, New Zealand.
J Cutan Pathol. 2005 Feb;32(2):141-7. Abstract quote
Background: Biphasic sarcomatoid carcinoma (BSC), or carcinosarcoma, is an uncommon biphasic neoplasm that has been reported in diverse anatomical sites. The tumor is composed of a malignant epithelial component intimately associated with a malignant mesenchymal component, which may be homologous or heterologous. Twenty-three cases of primary cutaneous BSC have been reported in the English literature. In only eight of these cases was basal cell carcinoma the epithelial component.
Methods: We report a further four cases of primary cutaneous biphasic basal cell carcinoma, and include the clinical, histological and immunohistochemical features.
Results: The four cases showed basal cell carcinoma associated with a pleomorphic sarcomatous stroma. In addition, myofibroblastic differentiation and foci of osteoid were present in one case, and leiomyosarcomatous areas in another. The epithelial components were positive for several epithelial markers. The mesenchymal components were positive for vimentin and CD99, and negative for epithelial markers. p53 was positive with equal intensity in both epithelial and mesenchymal components. A significantly worse outcome was observed in patients with tumors measuring 40 mm or more at excision.
Conclusions: The sarcomatous component of the tumor is best regarded as a metaplastic transformation of the carcinomatous component. These tumors are potentially aggressive if incompletely excised, and complete resection is recommended.
- Cutaneous spindle cell carcinoma following basal cell carcinoma.
Department of Pathology, the Jikei University School of Medicine, Tokyo, Japan.
Am J Dermatopathol. 2005 Feb;27(1):17-20. Abstract quote
A spindle cell carcinoma arose three years after the seeming excision of a so-called "infiltrative" basal cell carcinoma (IBCC) in the cheek of an 87-year-old Japanese woman. The patent had no history of irradiation. The tumor was composed of short fascicles and whorling arrangements of spindle to polygonal cells without residual IBCC.
Immunohistochemically, the tumor was positive for vimentin, cytokeratin 8 & 18, epithelial membrane antigen, and alpha-smooth muscle actin. Ultrastructurally, the tumor cells had tonofilaments and desmosomes. The patient died after a local recurrence with metastatic lesions in the lung and the neck lymph nodes that were indicated by CT scanning and MRI at nine months after diagnosis.
This case and others support the concept that spindle cell carcinoma can pursue an aggressive clinical course.
SCLEROSING (MORPHEAFORM, DESMOPLASTIC)
5% of all cases with dense stroma surrounding infiltrative nests with angular, spiky appearance
Some distinguish between sclerosing and morpheaform with desmoplastic stroma associated with infiltrative type nests defined as sclerosing and dense sclerotic stroma found around thin tumor cords and single cell strands with poor peripheral palisading and retraction spaces in the morpheaform type
Basal cell carcinoma with sebaceous differentiation.
Misago N, Suse T, Uemura T, Narisawa Y.
Division of Dermatology, Saga Medical School, Nabeshima, Saga, Japan
Am J Dermatopathol. 2004 Aug;26(4):298-303. Abstract quote
Some authors have used sebaceous epithelioma as a synonym for basal cell carcinoma (BCC) with sebaceous differentiation. However, our review of the literature revealed that definite cases of BCC with sebaceous differentiation that provide adequate clinical and histopathologic information are scarce.
We present the case of a 72-year-old woman with a pigmented nodular lesion on her right ala nasi region, clinically diagnosed as pigmented BCC. Histopathologically, this nodular lesion, which was completely excised, showed typical features of BCC. It was noteworthy that within one aggregation of the presented BCC, tiny and small duct-like structures lined by cornified layers with a crenulated inner surface were seen. Vacuolated cells were scattered within a few aggregations, and they had foamy, bubbly cytoplasm and starry nuclei. The vacuolated cells were immunohistochemically positive for epithelial membrane antigen (EMA).
These histopathologic findings demonstrated unquestionable sebaceous differentiation in this BCC, namely BCC with sebaceous differentiation, which should be distinguishable from both sebaceoma and sebaceous carcinoma. The small duct-like structures lined by eosinophilic cuticle, indicating apocrine differentiation, were also observed in this BCC.
Signet Ring Cell Basal Cell Carcinoma A Basal Cell Carcinoma With Myoepithelial Differentiation
You Chan Kim, M.D.; Daniel P. Vandersteen, M.D.; Yoon Jae Chung, M.D.; Na Hye Myong, M.D.
From the Department of Dermatology (Y.C.K.), Plastic Surgery (Y.J.C.), and Pathology (N.H.M.), Dankook University, College of Medicine, Cheonan, Korea; and Department of Pathology (D.P.V.), St. Mary's/Duluth Clinic Health System, Duluth, Minnesota, U.S.A.
Am J Dermatopathol 2001;23:525-529 Abstract quote
Basal cell carcinoma (BCC) can show a variety of routes of differentiation, but myoepithelial differentiation has rarely been described.
We describe a case of BCC showing histologic and immunohistochemical features of myoepithelial differentiation. Histologically, the lesion showed well-demarcated tumor nodules composed of two different components. One component was typical of BCC, and the other component was composed of tumor cells containing abundant cytoplasm, eccentric nuclei, and no peripheral palisading, with scattered signet ring–shaped cells.
Immunohistochemically, the tumor cells in the typical BCC component stained with CKAE1/AE3 and smooth muscle actin (SMA), but not with S-100 protein. They stained weakly with CAM5.2, epithelial membrane antigen, and glial fibrillary acidic protein (GFAP). The tumor cells in the other component stained strongly with CKAE1/AE3 and SMA, moderately with epithelial membrane antigen and GFAP, and weakly with CAM5.2. In a small area, the tumor cells stained with S-100 protein.
CHARACTERIZATION ANDROGEN RECEPTOR
- Androgen receptor expression helps to differentiate basal cell carcinoma from benign trichoblastic tumors.
Izikson L, Bhan A, Zembowicz A.
Department of Dermatology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
Am J Dermatopathol. 2005 Apr;27(2):91-5. Abstract quote
Histologic differentiation between basal cell carcinoma and benign trichoblastic neoplasms such as trichoepithelioma and trichoblastoma can be difficult on small biopsies. Therefore, several attempts have been made to identify immunohistochemical differences between these entities. Recent studies have shown androgen receptor expression in a number of mature epithelial structures in the skin and in epithelial neoplasms including basal cell carcinoma. In contrast, androgen receptor expression was absent in mature hair follicles or the few trichogenic neoplasms studied to date. These findings suggested that androgen receptor expression might be a useful adjunct in the histologic differential diagnosis between basal cell carcinoma and benign trichoblastic neoplasms.
Therefore, we performed immunohistochemical analysis of androgen receptor expression in 32 basal cell carcinomas and 10 benign trichoblastic tumors (6 trichoepitheliomas and 4 trichoblastomas). In our study, at least focal expression of androgen receptor was detected in 78% of basal cell carcinomas. None of the trichoblastic tumors showed any androgen receptor immunoreactivity.
These results confirm the lack of expression of androgen receptor in benign trichoblastic neoplasms and indicate that androgen receptor expression by tumor cells points to basal cell carcinoma as the most likely diagnosis.
J Cutan Pathol. 2006 Feb;33(2):123-8. Abstract quote
Background: Trichoepithelioma (TE) is a benign neoplasm that shares both clinical and histologic features with basal cell carcinoma (BCC). However, it is important to distinguish these neoplasms. Limited immunohistochemical stains are available to separate these two tumors.
- Methods: CD10 protein immunohistochemistry was performed on paraffin-embedded biopsies of 13 TE and 23 BCC diagnosed by routine microscopy. Cases were analyzed for pattern of CD10 expression by tumor cells and surrounding stroma.
- Results: Twelve of 13 (92%) TE showed positive stromal immunoreactivity. Of these, eight cases also demonstrated positivity of the papilla, and two also showed positivity of the basaloid cells. No TE demonstrated epithelial expression alone. On the other hand, expression of CD10 by basaloid cells was identified in 20 (87%) cases of BCC. Stromal positivity was also identified in three cases of BCC. Condensation of CD10-positive stromal cells around basaloid nests was statistically significant in differentiating TE from BCC (p < 0.0001). Conversely, CD10-positive basaloid cells were seen predominantly in BCC (p < 0.0001).
- Conclusions: This study demonstrates a statistically significant difference in CD10 staining pattern between TE and BCC. Thus, CD10 may be a useful adjunct marker in distinguishing these tumors.
- Expression of CD10 in basal cell carcinoma.
Yada K, Kashima K, Daa T, Kitano S, Fujiwara S, Yokoyama S.
Department of Pathology, Faculty of Medicine, Oita University, Oita 879-5593, Japan.
Am J Dermatopathol. 2004 Dec;26(6):463-71. Abstract quote
We investigated the expression of CD10 by an immunohistochemical method in 51 basal cell carcinomas (BCCs), eight pilomatricomas, five trichoblastomas, two trichofolliculomas, three sebaceomas, five sebaceous carcinomas, ten syringomas, two spiradenomas, ten poromas, four porocarcinomas, one eccrine duct carcinoma (not otherwise specified, NOS), six mixed tumors of apocrine origin, and nine squamous cell carcinomas (SCCs).
We detected strong expression of CD10 in tumor cells of BCC (86%), and found that the smaller the number of positive tumor cells, the larger the number of positive stromal cells, in particular in sclerosing BCCs. Spearman's rank correlation test revealed a significant negative correlation in BCCs between the expression of CD10 in tumor cells and that in stromal cells (P = 0.001). In all pilomatricomas (100%) and in four trichoblastomas (80%), strong expression was also detected in tumor cells. There was no detectable expression in trichofolliculomas. One sebaceoma (33%) and two sebaceous carcinomas (40%) expressed CD10 in a similar fashion to BCCs. All tumors of eccrine gland origin, including syringoma, spiradenoma, poroma, porocarcinoma, and eccrine duct carcinoma (NOS), did not express CD10. Five mixed tumors (83%) were immunopositive. In SCC, CD10 was overexpressed only in the stromal cells.
These findings support the hypothesis that BCC is derived from the folliculo-sebaceous apocrine unit, especially having the same origin as trichoblastoma and pilomatricoma. CD10 might be an indicator of tumor invasiveness if it is expressed in stromal cells, while it might be a marker of follicular differentiation if it is expressed in the actual tumor cells of cutaneous epithelial neoplasms.
- Cytokeratin profile in basal cell carcinoma.
Institute of Dermatological Sciences, University of Milan, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan, Italy.
- Am J Dermatopathol. 2008 Jun;30(3):249-55. Abstract quote
Origin of basal cell carcinoma (BCC) is still unclear. We studied the cytokeratin (CK) profile in BCC using monoclonal antibodies against 12 CKs to further investigate the suggested origin of the tumor from follicular matrix cells or from follicular outer root sheath cells and to determine if BCC subtypes can be identified on the basis of their CK profiles. Cases of pilomatricoma and samples of fetal skin served as controls to establish the CK profile in matrical cells and developing follicles during intrauterine life, that of the epidermis and cutaneous adnexa in adult life having been determined in a previous study.
The most significant findings were as follows: (a) CK 5 and CK 17 positivity in all the BCCs studied; (b) CK 7, CK 8, CK 18, and CK 19 positivity in 30/52, 33/52, 42/52, and 14/52 BCCs, respectively; (c) CK 14 negativity in almost all the BCCs studied; and (d) lack of CK 1 expression only in 2/2 morpheiform BCCs and 4/10 nodular BCCs.
The study suggests a tumorous differentiation toward follicular outer root sheath cells and, in most cases, also toward the glandular components of the pilosebaceous-apocrine unit. No significant difference in the CK profile among the BCC subtypes studied was found.
- Immunolabeling pattern of cytokeratin 19 expression may distinguish sebaceous tumors from basal cell carcinomas.
Department of Dermatology, Wayne State University School of Medicine, Detroit, MI, USA.
- J Cutan Pathol. 2008 Jan;35(1):40-5. Abstract quote
Background: Distinction between sebaceous tumors and basal cell carcinomas can often pose diagnostic problems. Recent work with the antibody to cytokeratin 19 (CK 19) has shown that this marker has high specificity for undifferentiated basaloid cells. Our aim was to evaluate the use of CK 19 staining patterns in differentiating between sebaceous tumors and basal cell carcinomas. The sebaceous tumors that were examined in this study included sebaceous adenomas, sebaceous epitheliomas (sebaceomas) and sebaceous carcinomas.
Methods: Thirty-seven cases including 5 sebaceous adenomas, 16 sebaceous epitheliomas, 6 sebaceous carcinomas and 14 basal cell carcinomas (7 being of the morpheaform type and 7 nodular basal cell carcinomas) were tested with a monoclonal mouse antibody to human CK 19.
Results: CK 19 was focally positive in 1/5 (20%) sebaceous adenomas, 8/16 (50%) of sebaceous epitheliomas and 1/6 (17%) of sebaceous carcinomas. Strongly positive expression of CK 19 was not seen in any of the sebaceous adenoma, sebaceous epithelioma or sebaceous carcinoma specimens. CK 19 was found to be strongly positive in 9/14 (64%) and focally positive in 2/14 (14%) of basal cell carcinomas.
Conclusion: CK 19 expression can be helpful in differentiating sebaceous tumors (including sebaceous adenomas, sebaceous epitheliomas and sebaceous carcinomas) from basal cell carcinomas and may be a useful adjunct when these entities are included in the differential diagnosis.
Cytokeratins as Markers of Follicular Differentiation An Immunohistochemical Study of Trichoblastoma and Basal Cell Carcinoma
Hjalmar Kurzen, M.D.; Lorenz Esposito; Lutz Langbein, Ph.D.; Wolfgang Hartschuh, M.D.
From the Department of Dermatology, University of Heidelberg (H.K., L.E., W.H.), and Division of Cell Biology, German Cancer Research Center (L.L.), Heidelberg, Germany
Am J Dermatopathol 2001;23:501-509 Abstract quote
Trichoblastoma(s) (TB) are benign neoplasms of follicular differentiation frequently found in nevus sebaceus. Many morphologic features are shared with nodular basal cell carcinoma(s) (BCC), sometimes rendering the differential diagnosis difficult.
Because both neoplasms can simulate components of mature hair follicles histologically, we attempted to corroborate this by immunohistochemical examination of cytokeratins and hair keratins differentially expressed in the hair follicle. Trichoblastoma(s) and BCC showed homogenous expression of CK14 and CK17. The innermost cells of the tumor nodules in all TB and in 72% of BCC were positive for CK6hf. Using a specific CK15 antibody, 38% of TB showed a focal labeling and all BCC remained negative; 70% of TB and 22% of BCC expressed CK19. CK8 was expressed by numerous Merkel cells present in all TB but in none of the BCC examined. All type I and II hair keratins tested, (especially hHa1, hHa5, and hHa8) remained negative in all tumors examined.
Trichoblastoma(s) and BCC show consistent expression of CK6hf, CK14, and CK17; variable expression of CK15 and CK19; and absence of hair keratins. This indicates a differentiation toward the outer root sheath epithelium or the companion layer and not toward the inner root sheath, matrix, or cortex.
ERp29 (Endoplasmic Reticulum Secretion Factor)
- Expression of ERp29, an Endoplasmic Reticulum Secretion Factor in Basal-Cell Carcinoma.
From the *Dermatologische Klinik, Klinikum Hoyerswerda Akademisches Lehrkrankenhaus an der Technischen Universita t Dresden, Germany; daggerDepartment of Cytopathology, Aretaieion University Hospital; double daggerDepartment of Biological Chemistry, University of Athens Medical School, 115 27 Athens, Greece; and section signDivision of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institute, 171 77 Stockholm, Sweden.
- Am J Dermatopathol. 2006 Oct;28(5):410-412. Abstract quote
The role of endoplasmic reticulum (ER)-stress proteins in the pathogenesis of neoplasia remains obscure. ERp29 encodes for an ER protein that is thought to facilitate the transport of secretory proteins in the early secretory pathway. ERp29 is expressed at varying levels in virtually every tissue tested, yet its precise role remains obscure.
To test if ERp29 is associated with the pathogenesis of skin cancer, in the present study we have assessed the expression of ERp29 in basal-cell carcinoma of the skin. A bank of 104 basal skin carcinoma, including 50 nodular, 29 infiltrating, 15 superficial, 7 sclerosing, 2 fibroepithelial, and 1 pigmented cell carcinoma, were assessed by immunohistochemistry for ERp29 expression.
Thirty-nine (37.5%) of the samples tested expressed ERp29 with the infiltrating carcinomas displaying more intense (++,+++) immunoreactivity (6/29, P < 0.05) and the superficial carcinomas exhibiting the less intense anti-ERp29 staining (1/15, P < 0.05). Collectively our results suggest that ERp29 is expressed in a subset of basal-cell carcinoma of the skin with the infiltrating carcinomas exhibiting the highest incidence of immunopositivity.
The role of ERp29 in the pathogenesis of the disease and its potential diagnostic value should be explored in future investigations.
Expression of p27kip1 in Basal Cell Carcinomas and Trichoepitheliomas.
Cesinaro AM, Migaldi M, Corrado S, Maiorana A.
Section of Pathological Anatomy, Department of Morphologic and Forensic Sciences, University of Modena and Reggio-Emilia, Modena, Italy.
Am J Dermatopathol 2002 Aug;24(4):313-8 Abstract quote
Immunohistochemical analysis was used to evaluate p27kip1 expression in normal hair follicles and in a series of 39 basal cell carcinomas (BCC) (13 of superficial type, 7 infiltrating, 7 morphea-like, 12 nodular) and 20 trichoepitheliomas (TE) (9 of classic type, 9 immature, 2 desmoplastic).
The labeling index (LI) was derived semiautomatically by means of a computer-assisted cellular image analyzer, and statistical analysis was carried out using the Student t test. A positive reaction for p27kip1 was detected in the hair germ papillae, in supramatrical cells, and in the inner pilar sheath, whereas matrical cells and the outer pilar sheath were negative. All BCC and TE cases showed a positive immunoreaction for p27kip1, but the staining pattern was different in the two groups of lesions, being patchy with focal peripheral accentuation in TE and more diffusely dispersed in BCC. The quantitative study showed lower p27kip1 expression in BCC (LI = 27.51 +/- 12.55) than in TE (LI = 45.27 +/- 20.27) (P < 0.0001). Statistically significant differences were also observed between TE subgroups and nodular or infiltrating BCC subtypes.
The occurrence of a wide overlap of LI values hampers the practical application of a p27kip1 LI in the differential diagnosis between BCC and TE in difficult cases, however.
J Cutan Pathol. 2006 Apr;33(4):293-8. Abstract quote
Background: We aim to examine p63 expression in basal cell carcinomas (BCCs) and to investigate association with their histopathological differentiation subtypes.
Methods: Eighty-four BCCs were classified according to the histopathologic differentiation subtypes. Immunohistochemistry using monoclonal antibody against p63 was performed.
Results: In nontumoral skin, p63 expression was consistently seen in basal/suprabasal cells of epidermis, hair matrix cells, and outer root sheath of the hair follicle. In BCCs, the cases were distributed as 47 undifferentiated, 28 differentiated (16 adenoid and 12 keratotic), and nine superficial. The nuclear p63 expression was negative in two cases, whereas 64 BCCs (76.2%) showed homogeneous p63 immunostaining. There was no statistically significant difference between p63 expression and histological differentiation subtypes (p > 0.05). The expression of p63 was found strongly and diffuse in 72.3% of solid undifferentiated and 82.1% differentiated and in 77.8% of superficial type BCCs.
Conclusions: p63 is consistently expressed in epidermal basal/suprabasal and adnexal basal cells. Most BCCs have higher homogeneous p63 expression than nontumoral epidermis, which is not changed according to histological differentiation subtypes. Thus, overexpression of p63 in all histological subtypes may confirm that basaloid progenitor cells are linked tumor-cell lineage and have a role in the tumorigenesis of BCC.
SMOOTH MUSCLE ACTIN
Actin expression in purely nodular versus nodular-infiltrative basal cell carcinoma.
Law AM, Oliveri CV, Pacheco-Quinto X, Horenstein MG.
Department of Pathology, University of South Alabama, Mobile, Alabama, USA.
J Cutan Pathol 2003 Apr;30(4):232-6 Abstract quote
BACKGROUND: The prognosis of basal cell carcinoma (BCC) correlates with its histological subtype. Actin is a microfilament that contributes to cell motility and invasiveness of cancer cells. Actin has been found to be more prominently expressed in the tumor cells and stroma of the more aggressive BCC subtypes. Here we compare actin expression in purely nodular (N-BCC) versus nodular-infiltrative (NI-BCC) tumors.
METHODS: We studied seven cases of N-BCC and 13 cases of NI-BCC with immunohistochemistry for alpha-smooth muscle actin (SMA) and common muscle actin (CMA) within the tumor cells and stroma. A semiquantitative method was used to determine the degree of actin present in the tumor aggregates (on a scale of 0-4).
RESULTS: Actin was present in the nodular component of 2/7 (28%) purely N-BCC and 11/13 (85%) mixed NI-BCC (p = 0.001). Actin was present in the infiltrative component of 13/13 (100%) NI-BCC. The average SMA score was 0.57 within the N-BCC compared with 1.77 within the nodular component of NI-BCC (p = 0.04); and 2.46 within the infiltrative component of the NI-BCC. The CMA score was 0.57 within the N-BCC, 1.54 within the nodular component of NI-BCC, and 1.92 within the infiltrative component of the NI-BCC. Actin was not found in the stroma of any of the N-BCC, while it was present in 8/13 (62%) of the NI-BCC (p = 0.0009).
CONCLUSIONS: Actin expression is more prominent in the nodular component of mixed NI-BCC when compared with purely N-BCC. This suggests that the nodular components of NI-BCC and N-BCC are different, and that actin expression in the nodular component may be associated with potential invasiveness. This finding may be relevant when examining incompletely sampled nodular BCC.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES BASAL CELL NEVUS
- J Cutan Pathol. 2007 Jan;34(1):65-70. Abstract quote
Background: Linear unilateral basal cell nevus represents a linear collection of macules and papules histologically similar to basal cell carcinoma but with benign clinical behavior.
We describe a patient who initially presented at the age of 6 months with a unilateral linear basal cell nevus on the right flank. The differential diagnosis included the nevoid basal cell carcinoma syndrome. Constitutional PTCH mutations are causative of the nevoid basal cell carcinoma syndrome, and somatic PTCH mutations are found in the vast majority of basal cell carcinomas. Somatic SMO mutations have also been found in some basal cell carcinomas.
Methods: Histologic examination of the lesions is performed. Short tandem-repeat molecular analysis at the PTCH locus and sequencing of PTCH and SMO genes is performed.
Results: Histologic examination revealed features initially indistinguishable from basal cell carcinoma. Short tandem-repeat DNA analysis did not reveal loss of heterozygosity at the PTCH locus. DNA sequencing of both the PTCH and the SMO genes from the patient's lesions revealed neither inactivating mutations of PTCH nor activating mutations of SMO.
Conclusion: Molecular examination indicates that the PTCH and SMO genes are not involved in the pathogenesis of the patients' congenital linear unilateral basal cell nevus. Furthermore, we discuss the relationship between linear basal cell nevus and basaloid follicular hamartoma.
BASALOID FOLLICULAR HYPERPLASIA
J Cutan Pathol. 2005 Aug;32(7):491-5. Abstract quote
Background: Basaloid epidermal proliferations (BEP), morphologically resembling basal cell carcinoma (BCC), have been described overlying dermatofibromas. Distinguishing the two is important because of non-aggressiveness of BEP and local aggressiveness of BCC. The aim of this study is to determine whether CK20 antibody staining for Merkel cells can be used as an adjunct method to differentiate BEP from BCC.
Methods: Ten cases of BEP overlying dermatofibromas were selected. Ten cases of BCC were used as control. The two groups were stained with CK20 antibody. Numerical density of CK20 stained Merkel cells in peri-lesional epidermis, BEP and BCC was determined by examining 300 cells at 400X in two separate areas by three independent pathologists. To determine statistical significance, the results were compared using t-test method.
Results: Density of Merkel cells in peri-lesional epidermis was 0.2-0.3%. No merkel cells were detected in the BCC. BEP overlying dermatofibromas showed an obvious increase in CK 20 stained Merkel cells. The difference was statistically significant (P < 0.02)
Conclusions: We report a significant increase in CK20 stained Merkel cells in BEP overlying dermatofibromas as compared to BCC. CK20 antibody staining for Merkel cells can be used as an adjunct method to differentiate BEP overlying dermatofibromas from BCC.
Basaloid/follicular hyperplasia overlying connective tissue/mesenchymal hamartomas simulating basal cell carcinomas
LCDR Mitchell E. Stashower, MC, USNR
Kathleen Smith, MD
David Corbett, DO
Henry G. Skelton, MD
J Am Acad Dermatol 2001;45:886-91 Abstract quote
Background: Basaloid hyperplasia has been described overlying dermatofibromas as well as in the epidermis overlying nevus sebaceus. Although the morphology of these areas may resemble that of basal cell carcinoma (BCC), in the majority of cases aggressive behavior of the proliferation is not seen. In fact, the basaloid proliferation often shows follicular differentiation and may be stimulated and maintained by its relationship with the underlying stromal cells.
Objective: We wanted to determine whether immunohistochemical staining for antibodies, which may suggest differences in pathogenesis, were different in basaloid hyperplasia overlying connective tissue/mesenchymal hamartomas and BCC.
Methods: We report 3 cases of connective tissue/mesenchymal hamartomas with overlying basaloid hyperplasia, in which the areas of the basaloid proliferation showed follicular differentiation. Immunohistochemical stains included Ber-EP4, PCNA, Ki-67, Bcl-2, p53, SM-Actin, CD31, factor XIIIa, KP-1, and CD34.
Results: There was a diffuse positive reaction for Ber-EP4 in all specimens and there was increased nuclear staining for PCNA and Ki-67. There was focal cytoplasmic staining for Bcl-2 in the areas of basaloid hyperplasia. Immunohistochemical staining for p53 showed only scattered positive cells except in a small focus in the areas of basaloid hyperplasia. The connective tissue component of all lesions showed diffuse staining for CD34 surrounding areas of basaloid hyperplasia in the mesenchymal component as well as in abundant S-100+ nerves.
Conclusion: The areas of basaloid hyperplasia in these hamartomas exhibited an immature phenotype similar to that seen in both BCCs and follicular tumors; however, the patterns of proliferation markers, p53, Bcl-2, and the surrounding stromal cell markers were similar to those of benign follicular tumors. Thus the staining pattern for this group of antibodies suggests that areas of basaloid hyperplasia are not BCC.
CD-34 and Ki-67 staining patterns of basaloid follicular hamartoma are different from those in fibroepithelioma of Pinkus and other variants of basal cell carcinoma
J. M. Naeyaert*, C. Pauwels*, M. L. Geerts and P. Verplancke
Department of Dermatology, Ghent University Hospital, Ghent, Belgium
Journal of Cutaneous Pathology 2001;28 (10), 538-541Abstract quote
Background and aims: Basaloid follicular hamartoma is a rare disorder regarded as a developmental malformation. It may be solitary or generalized, linear or regionalized, and is sometimes associated with myasthenia gravis or alopecia. We compared immunohistochemical staining patterns of selected markers in order to differentiate this hamartoma from fibroepithelioma of Pinkus, a basal cell carcinoma variant it can be confused with.
Methods: The expression of three immunohistochemical markers – CD-34, Ki-67, bcl-2 – was studied in a basaloid follicular hamartoma and in a fibroepithelioma of Pinkus. Two basal cell carcinomas, a nodular and a fibrosing type, and a trichoepithelioma were included as controls.
Results: Basaloid follicular hamartoma shows a low proliferation index and an at least focally circumferential expression of CD-34 around the epithelial strands. This compares to the findings in trichoepithelioma. In contrast, fibroepithelial tumor of Pinkus and two other basal cell carcinoma subtypes display a high proliferative index and an absence of CD-34 expression around the epithelium.
These findings support the non-neoplastic nature of basaloid follicular hamartoma.
FIBROUS PAPULE MALIGNANT BASOMELANOCYTIC TUMOR
Am J Surg Pathol. 2006 Jan;30(1):133-136. Abstract quote
We report a case of metastatic melanoma colliding with and colonizing a basal cell carcinoma (BCC) on the head of a 69-year-old man. The man had a prior history of multiple primary BCCs and melanomas. One of his primary melanomas, on the left scalp, recurred locally and resulted in the development of numerous in-transit metastases. A bluish nodule was noted on the postauricular area with clinical features consistent with a pigmented BCC.
Dermoscopy showed some large gray-blue ovoid structures and blood vessels, features also consistent with BCC. However, the histologic features revealed that the nodule consisted of both metastatic melanoma as well as BCC. Melanoma was present adjacent to as well as within the epithelium of the BCC.
The intimate association of melanoma cells within the nodules of BCC simulated the pattern of so-called "malignant basomelanocytic tumor," a recently proposed novel entity. To our knowledge, this is the first description of metastatic melanoma colonizing a BCC.
- Combined High-Grade Basal Cell Carcinoma and Malignant Melanoma of the Skin ("Malignant Basomelanocytic Tumor"): Report of Two Cases and Review of the Literature.
Rodriguez J, Nonaka D, Kuhn E, Reichel M, Rosai J.
From the *Department of Pathology, National Cancer Institute, Milan, Italy; and daggerDepartment of Dermatology, College of Physicians & Surgeons, Columbia University, New York, New York.
Am J Dermatopathol. 2005 Aug;27(4):314-318. Abstract quote
We describe two cases of a malignant cutaneous neoplasm with combined phenotypical features of high-grade basal cell carcinoma and malignant melanoma.
Some tumor cells showed a keratinocytic phenotype (cytokeratins, p63) and others a melanocytic phenotype (HMB-45, MART-1, Melan-A, S100-protein).
We favor the hypothesis of a tumor with bidirectional keratinocytic and melanocytic differentiation, an exceptionally rare event.
MERKEL CELL CARCINOMA
- Merkel cell carcinoma frequently shows histologic features of basal cell carcinoma: a study of 30 cases.
Departments of Pathology and Dermatology, The University of British Columbia and Vancouver General Hospital, Vancouver, British Columbia, Canada.
- J Cutan Pathol. 2007 Aug;34(8):612-9. Abstract quote
Background: Merkel cell carcinoma (MCC) is a basaloid cutaneous neoplasm that may be mistaken for basal cell carcinoma (BCC).
Methods: Thirty MCCs were examined for areas that histologically resembled BCC.
Results: One of the histologic features of BCC (either a mucinous stroma or stromal artifactual retraction) was identified in all MCCs. A mucinous stroma was found in 28 MCCs (93%), stromal artifactual retraction in 27 (90%), mucin-containing gland-like spaces within tumor nests in 8 (27%), focal peripheral palisading in 8 (27%), epidermal involvement in 3 (10%) and dystrophic calcification in 1 MCC (3%). The cytologic features and absence of widespread peripheral palisading were the most reliable discriminators between MCC and BCC on routine sections. Squamous cell carcinoma was identified in four cases (13%). Two cases (7%) contained pagetoid intraepidermal spread (IES) of MCC. In one case, there was IES over the entire epidermal surface associated with intranuclear clearing, resembling the intranuclear cytoplasmic inclusions (INI) common in melanocytic tumors. INI were identified in six MCCs (20%).
Conclusions: MCCs frequently contain areas that histologically resemble BCC and other more common cutaneous malignancies. This can lead to diagnostic errors, particularly in small fragmented curettage specimens or frozen sections.
MICROCYSTIC ADNEXAL CARCINOMA
Institut für Dermatohistologie, Heidelberg, Germany.
- J Cutan Pathol. 2007 Oct;34(10):782-7. Abstract quote
Background: Sclerosing cutaneous neoplasms often represent a diagnostic challenge. The monoclonal antibody Ber-EP4 recognizes two glycopolypeptides found in most human epithelial cells. It is diagnostically highly reliable in the differentiation between basal cell carcinoma and cutaneous squamous cell carcinoma. In this study, we report its application in the differential diagnosis of microcystic adnexal carcinoma, desmoplastic trichoepithelioma and basal cell carcinoma.
Methods: Biopsy samples from 28 sclerosing and infiltrating basal cell carcinomas, 13 microcystic adnexal carcinomas and 16 desmoplastic trichoepitheliomas were examined after immunohistochemical staining with Ber-EP4.
Results: Ber-EP4 did not label any of the microcystic adnexal carcinomas, whereas all 28 basal cell carcinomas were Ber-EP4 positive. Twenty-seven of the 28 showed moderate or strong staining intensity, with the majority being strong. Only one basal cell carcinoma was weakly positive. Twelve of the 16 desmoplastic trichoepitheliomas were immunoreactive with Ber-EP4 and the staining was more variable than those of basal cell carcinomas.
Conclusions: Ber-EP4 reliably differentiates microcystic adnexal carcinoma from basal cell carcinoma to the same extent as it distinguishes the latter tumor from squamous cell carcinoma. While it stains the majority of desmoplastic trichoepitheliomas, these tumors still have to be considered in the differential diagnosis with microcystic adnexal carcinoma, when Ber-EP4 is applied.
Proliferative characterization of basal-cell carcinoma and trichoepithelioma in small biopsy specimens.
Lum CA, Binder SW.
Division of Surgical Pathology, LAC-USC Medical Center, USC-Keck School of Medicine, Los Angeles, CA, USA.
J Cutan Pathol. 2004 Sep;31(8):550-4. Abstract quote
We examined the proliferative characteristics of 20 basal-cell carcinomas (BCCs) and 16 trichoepitheliomas (TEps) in an effort to understand and explore possible differences in their tumorigenic cell-cycle properties. These tumors were first compared for their expression of the nuclear proliferative protein Ki-67 and the tumor suppressor protein p53. We also compared the p53 downstream effector, p21(waf-1/cip-1), an inhibitor of cyclin-dependent kinases. The other p53-dependent, cyclin-dependent kinase inhibitor, p27(kip-1), has shown to be increased in TEps, which is consistent with this benign neoplasm's better-differentiated state.
In our findings, we confirmed through immunohistochemical staining for Ki-67 that BCCs qualitatively showed a greater proliferative fraction compared to TEps (50.0 vs. 13.0%, p < 0.00001) as well as over-expression of p53 (2+ vs. 1+, p < 0.0008). BCCs marked by p21 demonstrated scattered nuclear positivity compared to the virtual absence of staining in the TEps (p < 0.019). In studying their cell-cycle properties, our findings suggest that abnormalities in the p53 pathway allow BCCs to obtain a growth advantage.
We show that Ki-67 and p53 staining both appear useful in resolving challenging differential diagnoses and thereby help in directing appropriate treatment strategies.
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Basal Cell Nevus Syndrome-Syndrome characterized by multiple basal cell carcinomas, odontogenic keratocysts, pits on the palms and soles, skeletal and neurological abnormalities, and ectopic calcifications. There is an early age of onset with autosomal dominant inheritance and high gene penetrance.
Rodent ulcer -Large ulcerating destructive tumor, usually occurring on the face, sometimes measuring 20 cm or more.
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