This represents one of the earliest stages of melanoma with the atypical melanocytes limited to the dermal-epidermal junction and with no evidence of dermal involvement. Depending upon the morphology, some dermatopathologists subclassify these melanoma in situs as:
Melanoma in situ, superficial spreading type
Melanoma in situ, acral lentiginous type
A melanoma in situ stage does not exist for a nodular melanoma, which by definition, is in the vertical invasive growth phase. Desmoplastic melanomas, likewise, do not have a recognized precursor in situ lesion. However, lentigo malignas may give rise to this type of melanomas. Because this melanoma is a precursor lesion to a later invasive lesion, complete excision is curative.
Epidemiology Disease Associations Pathogenesis Laboratory/Radiologic/
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DISEASE ASSOCIATIONS CHARACTERIZATION DERMATOFIBROMA
- Melanocytic lesions associated with dermatofibromas: a spectrum of lesions ranging from junctional nevus to malignant melanoma in situ.
King R, Googe PB, Page RN, Mihm MC.
 1Knoxville Dermatopathology Laboratory, Knoxville, TN, USA  2Department of Pathology, University of Tennessee, Knoxville, TN, USA.
Mod Pathol. 2005 Aug;18(8):1043-7. Abstract quote
Dermatofibromas are common lesions that are often associated with epidermal hyperplasia and basal layer hyperpigmentation. A single case of lentiginous melanocytic hyperplasia overlying a dermatofibroma has been reported, however, nevi and melanoma have to the best of our knowledge, not been previously reported.
We present 14 cases of melanocytic lesions associated with dermatofibromas. The clinical data and hematoxylin- and eosin- stained sections were obtained and formalin-fixed, paraffin-embedded tissue was immunostained with antibodies against S-100, Mart-1, Factor XIIIa, and CD117. There were nine females and five males ranging in age from 30 to 64 years and anatomic sites included back (five), arm (six), flank (two), and leg (one). The clinical diagnosis ranged from dermatofibroma to desmoplastic melanoma.
Histologically, the melanocytic lesions included junctional, compound, and dermal nevi, and malignant melanoma in situ. In four cases the dermal component appeared to merge with the dermatofibroma. In the case of the melanoma in situ, the dermatofibroma abutted the epidermis. Immunohistochemically, the melanocytic lesions were S-100/ Mart-1+, FXIIIa-, and the dermatofibromas were S-100/Mart-1-, FXIIIa+. Melanocytic neoplasia may appear in association with dermatofibromas. The fibrohistiocytic proliferation may be misinterpreted as a spindle or pleomorphic melanocytic process.
Awareness of this association will aid in the correct diagnosis, and immunohistochemical studies will help in the differentiation of these two cell populations.
PATHOGENESIS CHARACTERISTICS APOPTOSIS
Differential expression of proliferation- and apoptosis-related markers in lentigo maligna and solar keratosis keratinocytes.
Feinmesser M, Tsabari C, Fichman S, Hodak E, Sulkes J, Okon E.
Am J Dermatopathol. 2003 Aug;25(4):300-7 Abstract quote.
Keratinocytes influence the number, morphology, and proliferation of melanocytes. An interference in the melanocyte-keratinocyte relationship may contribute to melanoma development.
This study examined the expression of apoptotic and proliferative markers in keratinocytes in lentigo maligna to characterize the epidermis permissive to these lesions. Formalin-fixed and paraffin-embedded tissues from 25 samples of lentigo maligna, 20 samples of solar keratoses, and 5 samples each of normal sun-exposed and non-sun-exposed skin (controls) were immunostained with antibodies directed against the proapoptotic markers bax and p53, the antiapoptotic marker bcl-2, and the proliferation marker ki-67. Eight percent of the lentigo maligna samples were positive for keratinocyte expression of bcl-2, 24% were positive for p53, and 76% were positive for bax; respective findings for solar keratoses were 35%, 85%, and 90%.
Comparison with normal sun-exposed skin yielded lower rates of keratinocyte proliferation in 56% of the lentigo maligna samples, similar rates in 36%, and higher rates in 8%; for solar keratoses, proliferation was higher than controls in 60% of samples, similar in 35%, and lower in 5%. All these differences were statistically significant. These findings indicate that there are variable patterns of epidermal reaction to chronic sun exposure. The epidermis in lentigo maligna shows overall low proliferation and an apparently low apoptotic tendency.
The dysfunctional epidermis may be permissive to aberrant melanocyte proliferation in the early stages of melanoma development.
- Concordant loss of heterozygosity of DNA repair gene, hOGG1, in melanoma in situ and atypical melanocytic hyperplasia.
Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
- J Cutan Pathol. 2008 Jun;35(6):525-31 Abstract quote
BACKGROUND: One major risk factor for cutaneous melanoma is chronic sun-exposure and oxidative stress. Among various oxidative DNA damages, 8-oxoquanine is the most abundant and is potentially mutagenic if not sufficiently repaired. The human 8-oxoquanine DNA glycosylase 1 (hOGG1) gene specifically repairs 8-oxoguanine, and this gene shows frequent loss of heterozygosity (LOH) in human tumors. In this study, we investigate whether hOGG1 LOH occurs in melanoma in situ (MIS) and adjacent atypical melanocytic hyperplasia (AMH).
METHODS: Twelve skin biopsies with MIS and adjacent AMH were included. DNA samples derived from manual microdissection of tissues were subjected to polymerase chain reaction amplification using three fluorescent-labeled microsatellite makers, followed by fragment analysis.
RESULTS: Five of 12 cases were informative for both telomeric (3S1297) and centromeric (3S1289 or 3S1300) markers, bordering the hOGG1 locus. Among them, four (80%) MIS and three (60%) AMH showed hOGG1 LOH at both markers.
CONCLUSIONS: These results shows that LOH at hOGG1 gene is associated with MIS and AMH and suggest that the hOGG1 gene may play a role in melanocytic tumor progression.
LABORATORY CHARACTERIZATION DERMOSCOPY
- Early Acral Melanoma In Situ: Correlation Between the Parallel Ridge Pattern on Dermoscopy and Microscopic Features.
Ishihara Y, Saida T, Miyazaki A, Koga H, Taniguchi A, Tsuchida T, Toyama M, Ohara K.
From the *Department of Dermatology, Shinshu University School of Medicine, Matsumoto, Japan; daggerDepartment of Dermatology, Saitama Medical School, Moroyama, Japan; and double daggerDepartment of Dermatology, Toranomon Hospital, Tokyo, Japan.
Am J Dermatopathol. 2006 Feb;28(1):21-27. Abstract quote
In non-white populations, acral skin is the most prevalent site of malignant melanoma. Early melanomas of this anatomic site are often misdiagnosed as melanocytic nevi, which are not uncommon on acral skin. In fact, clinical and/or histopathological features of melanocytic nevi occasionally mimic those of early acral melanoma and vice versa, and thus differentiation of early acral melanoma from melanocytic nevus is sometimes very difficult for clinicians as well as for histopathologists. Our dermoscopic investigation has revealed that the parallel ridge pattern, a band-like pigmentation on the ridges of the skin markings, is highly specific to malignant melanoma in situ on acral volar skin.
In the present study, we reviewed 22 acral melanocytic lesions that showed the parallel ridge pattern on dermoscopy but had very subtle clinical and/or histopathological presentations. We diagnosed 20 of them as early melanoma in situ by careful histopathological examination, which revealed histopathological features very similar to those seen in macular portions of overt acral melanoma, but fundamentally different from features found in melanocytic nevi on acral skin. In correspondence with their dermoscopic pattern, in these early lesions of acral melanomas, proliferation of solitary arranged melanocytes was mainly detected in the crista profunda intermedia, the epidermal rete ridge underlying the ridge of the skin marking.
The two remaining lesions were diagnosed as possible cases of acquired melanocytic nevus because of the formation of well-demarcated nests of melanocytes in the epidermal rete ridges.
We propose that a finding of preferential proliferation of solitary arranged melanocytes in the crista profunda intermedia is an important clue for the histopathological diagnosis of early phases of acral melanoma.
DIGITAL EPILUMINESCENCE MICROSCOPY Use of Digital Epiluminescence Microscopy to Help Define the Edge of Lentigo Maligna June K. Robinson, MD
From the Division of Dermatology, Departments of Medicine and Pathology, Cardinal Bernardin Cancer Center, Loyola University Stritch School of Medicine, Maywood, Ill. Dr Robinson is the Editor, Archives of Dermatology.
Arch Dermatol. 2004;140:1095-1100 Abstract quote Objective To compare identification of the border of lentigo maligna (LM) with digital epiluminescence microscopy (DELM) with clinical and Wood light assessment.
Design The borders of lesions identified clinically with the Wood light, with DELM, and after excision by Mohs micrographic surgery were traced onto plastic sheets. The borders defined on the tracings were compared for congruence and mean surface area.
Setting Cardinal Bernardin Cancer Center for Skin Cancer, Loyola University Health System, Maywood, Ill.
Patients Twenty-six consecutive patients with LM of the head and neck.
Main Outcome Measures Results of the comparison of the outlines of the borders and the mean surface area identified by the 4 methods.
Results The border determined by clinical examination was smaller than that determined with the Wood lamp or by DELM. Most lesions underwent an additional excision 5 mm beyond the DELM-defined border. The DELM pattern of LM with asymmetric follicular openings and dark brown rhomboidal structures changed at the periphery and became a pigmented thin mesh that was associated with the histopathological features of melanoma in situ. More homogeneous pigmented areas extending from the LM were associated with the pathologic features of melanocytic hyperplasia.
Conclusions Visualization of LM by DELM (dermoscopy) helps to guide resection. Because LM arises in sun-damaged skin with melanocytic hyperplasia, determining the tumor-free margin requires the judgment of an experienced physician.
CLINICAL VARIANTS CHARACTERIZATION NAILBED Presentation, Histopathologic Findings, and Clinical Outcomes in 7 Cases of Melanoma In Situ of the Nail Unit Whitney A. High, MD; Robert A. Quirey, MD; David R. Guillén, MD; Gloria Munõz, CHT; R. Stan Taylor, MD
From the Department of Dermatology, The University of Texas Southwestern Medical Center at Dallas. The authors have no relevant financial interest in this article.
Arch Dermatol. 2004;140:1102-1106 Abstract quote Objective To report on the presentation, histopathologic findings, and clinical outcomes for a case series of MIS of the nail apparatus because melanoma in situ (MIS) of the nail unit has not been well characterized in the literature.
Setting A division of a tertiary academic center specializing in micrographic excision of cutaneous neoplasms.
Design Surgical records were searched for cases of MIS of the nail unit for the period of January 1, 1997, to December 31, 2002. The patient demographics and disease presentation, treatment, and clinical course were reviewed.
Results Seven cases of MIS of the nail unit in white patients were identified. Longitudinal melanonychia was present in all cases, but dyspigmentation of the proximal nail fold and onychodystrophy were uncommon. Histopathologic analysis revealed poorly circumscribed proliferations of single cells over nests with variable pagetoid spread. Atypia was variable. Mitotic activity was low. All cases were treated with micrographic surgery. Amputation was avoided in 3 cases and was limited to partial distal interphalangeal amputation in the remainder. Six cases did not recur locally after initial surgical intervention. With an average of 24 months of follow-up, all patients were free of disease.
Conclusions Longitudinal melanonychia in a white patient mandates consideration of MIS of the nail unit. Given the nondescript clinical presentation, the threshold for biopsy should be low. The histopathologic findings appear similar to those of MIS in other areas, with asymmetry and poor circumscription predominating. With additional study and further acceptance, micrographically controlled excision has the potential to minimize morbidity. Further investigation is warranted.
HISTOLOGICAL TYPES CHARACTERIZATION GENERAL
Malignant melanoma in situ.
Department of Dermatology, Massachusetts General Hospital, Boston 02114.
Hum Pathol 1990 Dec;21(12):1199-201 Abstract quote
There is general agreement that there are lesions which should be diagnosed as malignant melanoma in situ. The biologic behavior of the intraepidermal component of superficial spreading melanoma (the radial growth phase) has been demonstrated to have significantly different properties than those of the cells in the vertical growth phase.
The central controversies regarding malignant melanoma in situ relate to the criteria for diagnosing melanoma and whether there are atypical melanocytic lesions which are neither nevi nor melanoma. I propose that reliable and reproducible objective criteria for melanoma have not been developed; rather, dermatopathologists use differing subjective criteria which result in diagnostic agreement in the vast majority of lesions.
The controversy is over those lesions which are classified as melanoma by one set of criteria and not by others. I am also a proponent of the diagnosis of atypical melanocytic lesions, and have suggested an analogy to keratinocytic lesions in which this concept is well established.
Studies of the sensitivity and specificity of the correlation between clinical and histologic features and the biologic behavior of melanocytic lesions are necessary to resolve these issues.
ACRAL LENTIGINOUS MELANOMA IN SITU Acral lentiginous melanoma in situ: a study of nine cases.
Kwon IH, Lee JH, Cho KH.
Department of Dermatology, Seoul National University College of Medicine, Seoul, Korea.
Am J Dermatopathol. 2004 Aug;26(4):285-9. Abstract quote
An acral lentiginous melanoma (ALM) is the most common type of cutaneous melanoma in Asians. However, it is unusual to encounter a patient showing only the histologic features of an ALM in situ.
Here we describe clinical and histologic features of nine cases of ALM in situ including immunohistochemical staining with anti-S100 protein and HMB-45. All the patients had a long clinical history. Clinically, the lesions were characterized by a longitudinal pigmented streak in the nail plates, black pigmentation on the proximal or lateral nail fold, and an irregular border and variegated pigmentation on the sole or thumb. Total resections of the lesions were performed in all patients. All lesions, in both biopsy and excisional specimens demonstrated more melanocytes generally located in the basal layer of the epidermis. There was no dermal invasion.
No recurrence of the disease had occurred in any patient after a follow-up period of between 6 months to 12 years after surgery. These results suggest that ALM can evolve slowly over many years.
AMELANOTIC LENTIGO MALIGNA
Amelanotic lentigo maligna melanoma.
Kaufmann R, Nikelski K, Weber L, Sterry W.
Department of Dermatology, University of Ulm, Germany.
J Am Acad Dermatol 1995 Feb;32(2 Pt 2):339-42 Abstract quote
Only five cases of the amelanotic variant of lentigo maligna melanoma of the face have been reported.
We describe an additional four patients observed within the past 5 years, suggesting a much higher incidence of this variant than previously suspected.
Amelanotic superficial spreading malignant melanoma mimicking Bowen's disease.
Holder JE, Colloby PS, Fletcher A, Camp RD.
Department of Dermatology, Leicester Royal Infirmary, U.K.
Br J Dermatol 1996 Mar;134(3):519-21 Abstract quote
A 67-year-old woman presented with a scaly, erythematous plaque, for which a clinical diagnosis of Bowen's disease was made.
However, incisional biopsy established the diagnosis of amelanotic superficial spreading malignant melanoma. Biopsy thus avoided the use of inappropriate destructive therapy, such as cryotherapy or cautery.
This case illustrates the importance of obtaining a histological diagnosis, prior to treatment, in suspected cases of Bowen's disease.
Amelanotic lentigo maligna melanoma: a diagnostic conundrum-- presentation of four new cases.
Rahbari H, Nabai H, Mehregan AH, Mehregan DA, Mehregan DR, Lipinski J.
Department of Dermatology, Wayne State University School of Medicine, Detroit, Michigan, USA
Cancer 1996 May 15;77(10):2052-7 Abstract quote
BACKGROUND: The clinical appearance of amelanotic lentigo maligna melanoma (ALMM) is quite confusing and usually is not diagnosed prior to histopathologic examination.
METHODS: We have studied four new patients with ALMM whose correct diagnosis was not obtained from any one clinical finding. We arrived at the final diagnosis in an unexpected way, having had biopsied the lesions for diagnoses other than malignant melanoma.
RESULTS: ALMM presents as a nonspecific skin lesion with no single indicative characteristic. A search of the literature confirmed our difficulty in making the diagnosis.
CONCLUSIONS: To diagnose ALMM, one has to be cognizant of this condition and has to consider a constellation of findings that are unusual with melanocytic lesions. Questionable lesions must be biopsied for definitive histopathologic diagnosis.
Amelanotic lentigo maligna melanoma of the face: a case report and review of the literature.
Cliff S, Otter M, Holden CA.
Department of Dermatology, St Helier Hospital, Carshalton, Surrey, UK.
Clin Exp Dermatol 1997 Jul;22(4):177-9 Abstract quote
Amelanotic lentigo maligna melanoma is rare, only 10 cases over the face having been reported to date in the English literature. In none of these was the diagnosis suspected clinically, being made in all cases only after histopathological examination.
We now report an unusual additional case of this uncommon lesion, which quickly progressed from an amelanotic lentigo maligna to an invasive melanoma in a short space of time, and review the literature concerning this condition.
Amelanotic lentigo maligna and amelanotic lentigo maligna melanoma: a report of three cases mimicking intraepidermal squamous carcinoma.
Allan SJ, Dicker AJ, Tidman MJ, McLaren KM, Hunter JA.
Department of Dermatology, Royal Infirmary of Edinburgh NHS Trust, UK.
J Eur Acad Dermatol Venereol 1998 Jul;11(1):78-81 Abstract quote
The clinical diagnosis of amelanotic melanoma may pose diagnostic difficulties.
We report three cases of amelanotic lentigo maligna, two of which developed an invasive component (lentigo maligna melanoma). The clinical appearances in each case mimicked intraepidermal squamous carcinoma.
Amelanotic lentigo maligna melanoma: a unique case presentation.
Conrad N, Jackson B, Goldberg L.
Department of Dermatology, Baylor College of Medicine, Texas, USA.
Dermatol Surg 1999 May;25(5):408-11 Abstract quote
Amelanotic melanomas comprise only 2% of melanomas and are commonly a difficult clinical diagnosis, due to the lack of melanin pigment typically found in melanomas.
Even rarer is the amelanotic lentigo maligna, which may have an unusual clinical presentation, such as erythema, pruritus, or edema. Biopsy is the key to diagnosis.
Multiple therapies for amelanotic lentigo malignas have been tried, but excision, with margin control (Mohs micrographic surgery-frozen or paraffin sections), remains the treatment of choice.
- Contiguous lesions in lentigo maligna.
Dalton SR, Gardner TL, Libow LF, Elston DM.
Department of Pathology, Bassett Army Hospital, Ft. Wainwright, Alaska, USA.
J Am Acad Dermatol. 2005 May;52(5):859-62. Abstract quote
BACKGROUND: Determining the best biopsy technique for a suspected lentigo maligna can be challenging. Because complete excisional biopsy is rarely practical, the physician is left to choose an appropriate area to biopsy. Sampling error can have devastating consequences, especially if the biopsy demonstrates a pigmented lesion that was considered in the clinical differential diagnosis. The presence of a solar lentigo, pigmented actinic keratosis, or reticulated seborrheic keratosis could mislead the pathologist and clinician to the erroneous conclusion that the incisional specimen is representative of the whole, and that no lentigo maligna is present.
OBJECTIVE: We have often observed the presence of a contiguous pigmented lesion adjacent to lentigo maligna. The current study was designed to determine how frequently this phenomenon occurs.
METHODS: We studied Mohs debulking specimens of lentigo maligna, and broad shave biopsy specimens of pigmented lesions on heavily sun-damaged areas of the skin proven to be lentigo maligna.
RESULTS: Contiguous pigmented lesions were present in 48% of the specimens. The most common lesion was a benign solar lentigo (30%), followed by pigmented actinic keratosis (24%).
CONCLUSION: Recognition of this phenomenon may prevent misdiagnosis of lentigo maligna related to sampling error.
Histologic evaluation of lentigo maligna with permanent sections: Implications regarding current guidelines.
Agarwal-Antal N, Bowen GM, Gerwels JW.
Department of Dermatology, University of Utah, Salt Lake City.
J Am Acad Dermatol 2002 Nov;47(5):743-8 Abstract quote
BACKGROUND: Obtaining clear margins of resection of lentigo maligna (LM), a subtype of melanoma in situ, from sun-damaged skin of the head and neck continues to be a surgical challenge. The margins may be uncertain both clinically and histologically, causing difficulty in determining the surgical excision perimeter.
OBJECTIVE: We sought to determine whether the current National Institutes of Health consensus conference (1992) recommendation of 5-mm margins is adequate for the removal of LM and to evaluate at what stage tumor-free margins are ultimately attained by using polygonal, staged excisions.
METHODS: Ninety-two cases of LM were evaluated and treated in a university tertiary care setting. Straight-edge polygonal resections in a staged fashion of LM variants of MIS were evaluated by means of permanent serial histopathologic sections. Each stage of resection used a 5-mm margin. Specimens were color-coded and mapped. Any sites of tumor at resected margins were identified by a dermatopathologist and noted on the map of the excised specimen. Positive margins and areas with markedly atypical melanocytes were further resected, color-coded, mapped, and evaluated as previously described until margins free of tumor were attained.
RESULTS: The patient distribution was 37% female and 63% male, with ages ranging from 24 to 100 years (median age, 70 years). Sixty-nine patients had a biopsy-proven diagnosis of LM involving the head and neck (75%), and 23 patients (25%) had LM elsewhere. Thirty-nine patients (42%) were tumor-free after one stage, 25 (27%) required 2 stages, 14 (15%) required 3 stages, 6 (7%) required 4 stages, and 8 (9%) needed 5 or more stages to achieve tumor-free margins. The central portion of the submitted polygonal excisions revealed an invasive component in 16% of cases.
CONCLUSIONS: Use of polygonal perimeter excisions with serial histopathologic permanent sections in a staged fashion is an accurate and thorough method of evaluating and treating LM. This study demonstrates that the standard recommendation of 5-mm margins is adequate in less than 50% of cases and reiterates the need for the careful evaluation of peripheral margins in LM. Because an invasive component can be present and would alter recommended surgical depths and margins, all of the tumor should be submitted at the first stage rather than peripheral margins only.
Mod Pathol. 2005 Oct;18(10):1397-401. Abstract quote
Atypical lentiginous melanocytic proliferations in elderly patients continue to pose a diagnostic dilemma with lesions variably categorized as dysplastic nevus, atypical junctional nevus, melanoma in situ (early or evolving) and premalignant melanosis.
We present pigmented lesions from 16 patients (seven male and nine female) and with the exception of one case, all were older than 50 years of age. The anatomical sites included trunk (7), head and neck (6) and upper extremity (3). The clinical diagnosis was variable and included lentigo maligna, atypical nevus, pigmented basal cell carcinoma, seborrheic keratosis and lentigo.
The initial biopsies mimicked lentiginous nevus or dysplastic nevus and were characterized by a lentiginous proliferation of melanocytes at the dermoepidermal junction both as single cells and as small nests with areas of confluent growth, extending to the edges of the biopsy. The retiform epidermis was maintained and pagetoid spread of melanocytes was not prominent in hematoxylin- and eosin- stained sections. Dermal fibrosis was variably present and the melanocytic proliferation demonstrated cytological atypia. The subsequent re-excisions demonstrated similar atypical melanocytic proliferation occurring over a broad area flanking the prior biopsy sites.
The diagnosis of melanoma was more easily recognized in the complete excision specimens. Immunohistochemical stains for Mitf and Mart-1 highlighted the extent of the basalar melanocytic proliferation as well as foci of pagetoid spread by melanocytes.
Familiarity with this pattern of early melanoma should facilitate proper classification of lentiginous melanocytic proliferations in biopsies from older adults.
CHARACTERIZATION SPECIAL STAINS IMMUNOPEROXIDASE
Lentigo maligna and superficial spreading melanoma are different in their in situ phase: An immunohistochemical study.
Auslender S, Barzilai A, Goldberg I, Kopolovic J, Trau H.
Department of Dermatology and Institute of Pathology, Sheba Medical Center, Tel-Hashomer, Israel and the Sackler Faculty of Medicine, Tel-Aviv University, Israel.
Hum Pathol 2002 Oct;33(10):1001-5 Abstract quote
Clinical and pathologic observations have prompted the categorization of malignant melanoma into 4 subtypes. Although some authorities challenge the value of this classification, nevertheless it is generally accepted that lentigo maligna (LM), or melanoma on sun-damaged skin, has a different biological behavior than so-called superficial spreading melanoma (SSM), at least in the early stage of its evolution.
To characterize some aspects of this different behavior, the in situ phase of SSM and LM was studied using immunohistochemical methods. Seventeen cases of SSM in situ and 13 cases of LM were chosen for the study. All cases qualified with strict histologic criteria. Sections from these lesions were stained with antibodies against HMB-45 antigen, basic fibroblast growth factor (bFGF), proliferating cell nuclear antigen (PCNA), and factor VIII. Semiquantitative analysis was performed. Cases classified as either LM or SSM corresponded well to the epidemiologic and clinical characteristics as described in the literature; that is, LM appeared in older patients and occurred mostly on the face, whereas SSM occurred mostly on the trunk and lower limbs. Although no difference in HMB-45 stain was observed, melanoctyes of SSM showed greater proliferative activity, as reflected by PCNA stain (P < 0.02) and higher levels of bFGF (P < 0.001), than melanocytes of LM. More blood vessels were counted under SSM than under LM (P < 0.05).
These results are in accordance with the biological behavior of SSM and LM, that is, the longer in situ phase of the latter. bFGF is both a growth factor for melanocytes and an angiogentic factor. The differences in PCNA, a proliferation marker, and blood vessel count may be related to the bFGF effect.
Thus this study reveals some of the biological differences between LM and SSM. Location and sun exposure habits may contribute to these differences, which already exist in the in situ phase.
Immunolabeling pattern of syndecan-1 expression may distinguish pagetoid Bowen's disease, extramammary Paget's disease, and pagetoid malignant melanoma in situ.
Bayer-Garner IB, Reed JA.
Marshfield Clinic, Marshfield, WI, and Baylor College of Medicine, Houston, TX, USA.
J Cutan Pathol. 2004 Feb;31(2):169-73. Abstract quote
The differential diagnosis of pagetoid cells within the epidermis rests primarily between pagetoid Bowen's disease (PBD), extramammary Paget's disease (EPD), and pagetoid malignant melanoma (MIS) in situ. Although morphologic clues are often helpful in differentiating these lesions, the use of immunohistochemistry is often necessary to arrive at the correct diagnosis.
Syndecan-1 is a cell-surface proteoglycan that mediates adhesion between cells and the extracellular matrix, and between cells themselves. Twenty-two cases of PBD, four cases of intraepidermal EPD, and 13 cases of MIS were examined for syndecan-1 immunoreactivity. Cell-membrane syndecan-1 immunoreactivity was evident in PBD, cytoplasmic syndecan-1 immunoreactivity was evident in EPD, whereas immunoreactivity for syndecan-1 was not present in MIS.
The patterns of syndecan-1 immunoreactivity in these lesions may be a useful adjunct in the differentiation of PBD, EPD, and MIS.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES DYSPLASTIC NEVUS
- Histologic similarities between lentigo maligna and dysplastic nevus: importance of clinicopathologic distinction.
Farrahi F, Egbert BM, Swetter SM.
Department of Dermatology, Stanford University Medical Center, Stanford, CA, USA.
J Cutan Pathol. 2005 Jul;32(6):405-12. Abstract quote
Background: Lentigo maligna (LM) can histologically simulate dysplastic nevus (DN). Partial biopsy of LM may lead to misdiagnosis.
Methods: One hundred and fourteen cases of LM and LM melanoma (LMM) were diagnosed at the Veterans Affairs Palo Alto Health Care System (1993-2002). Biopsy and excision specimens for 68 in situ and 28 invasive melanomas were classified as having predominant classical LM features, predominant DN-like morphology, or a mixed pattern.
Results: Biopsy specimens demonstrated a predominant classical pattern in 38% (25/65) LM and 36% (10/28) LMM, predominant DN-like features in 43% (28/65) LM and 25% (7/28) LMM, and mixed pattern in 15% (10/65) LM and 29% (8/28) LMM. Most LM and LMM biopsies were partial. Significant DN-like features were present in 51% LM and 57% LMM excision specimens. Median age was 72 years for LM and 73 years for LMM, mean lesion diameters were 1.3 and 1.7 cm for LM and LMM, respectively, and 85% of LM and 75% of LMM cases were located on heavily sun-exposed sites.
Conclusions: Misdiagnosis of LM or LMM as DN could have devastating results. Large pigmented lesions on sun-damaged skin in elderly individuals should warrant consideration of LM/LMM diagnosis, even in the setting of DN-like features histologically. Excisional biopsy may help to avoid misdiagnosis.
PIGMENTED ACTINIC KERATOSIS
- Immunostaining for MART-1 in the interpretation of problematic intra-epidermal pigmented lesions.
Division of Surgical Pathology and Cytopathology, University of Virginia Health System, Charlottesville, VA, USA.
- J Cutan Pathol. 2007 Aug;34(8):601-5. Abstract quote
The histopathologic distinction between pigmented actinic keratosis (PAK) and atypical junctional melanocytic proliferations (AJMP) is a common problem, and it is one with meaningful clinical significance. Previous publications have suggested that Melanocyte Antigen Related to T-cells-1 (MART-1) - a melanocytic marker related to host immune response - was not useful in making this interpretative separation.
To revisit that assertion, the authors selected 68 specimens that concerned the diagnosis of PAK vs. AJMP. The degree of morphologic difficulty attached to each case was rated semiquantitatively using a three-tiered scale, and interpretative problems were caused by cytologic similarity between atypical keratinocytes and aberrant melanocytes, obscuring lichenoid inflammation, subepidermal fibrosis, and an absence of clearly defined cell nests at the dermoepidermal junction. Each biopsy sample was immunostained for MART-1 (using antibody clone A103) with azure-B counterstaining; the principal criterion for a diagnosis of AJMP was that of confluent cellular positivity over at least 1 high-power (x400) microscopic field, in conjunction with nested cell growth. The specimens were then re-examined diagnostically.
Immunostaining definitely improved interpretative certitude in 65 examples (96% effectiveness); the final diagnosis was that of PAK for 21 lesions and AJMP for 47. Three specimens - all of which represented AJMP - did not benefit by MART-1 staining.
It is concluded that MART-1 immunostaining with azure-B counterstaining is a useful adjunct in the interpretation of problematic intra-epidermal pigmented lesions.
- Melan-A: Not a Helpful Marker in Distinction between Melanoma In Situ on Sun-Damaged Skin and Pigmented Actinic Keratosis.
Shabrawi-Caelen LE, Kerl H, Cerroni L.
Department of Dermatology, University of Graz, Austria.
Am J Dermatopathol. 2004 Oct;26(5):364-6. Abstract quote
Pigmented actinic keratosis is one of the simulators of early melanoma in situ from severely sun-damaged skin. Close scrutiny of the hematoxylin and eosin stained section does not always allow an unequivocal diagnosis, because it is sometimes difficult to distinguish pigmented keratinocytes from melanocytes. Immunohistochemical stains, such as S-100 and HMB-45, are used routinely to address this problem. Melan-A, also known as MART-1, is an additional melanocytic marker and has proved to be useful in identifying metastatic tumors of melanocytic origin. The usefulness of this marker to discriminate pigmented actinic keratosis from early melanoma in situ, however, has not yet been a subject of investigation.
In this study we evaluated Melan-A expression in ten unequivocal cases of pigmented actinic keratosis and compared the staining pattern with that of S-100, HMB-45, and tyrosinase. In all ten cases the number of cells highlighted with Melan-A was by far larger than those labeled with S-100, HMB-45, and tyrosinase. Four cases showed clusters of Melan-A positive cells being suggestive of melanocytic nests. Even areas of normal skin adjacent to the actinic keratosis featured prominent staining of Melan-A, but only inconsistent labeling of intraepidermal melanocytes with S-100, HMB-45, and tyrosinase. We therefore believe that Melan-A is a more sensitive marker for intraepidermal melanocytes than S-100, HMB-45, and tyrosinase. In addition there may be expression of Melan-A in keratinocytes and nonmelanocytic cells.
To avoid an erroneous diagnosis of malignant melanoma one should therefore interpret results obtained from Melan-A stained slides carefully and in the context with other melanocytic markers.
Lichenoid tissue reaction in malignant melanoma: a potential diagnostic pitfall.
Dalton SR, Baptista MA, Libow LF, Elston DM.
Department of Pathology, Brooke Army Medical Center, Ft Sam Houston, TX 78234-3600, USA.
Am J Clin Pathol. 2002 May;117(5):766-70. Abstract quote
Lichenoid tissue reactions can occur in malignant melanoma and may cause partial regression of the lesion. We studied a series of melanomas to determine how frequently lichenoid tissue reaction obscures the diagnosis of malignant melanoma.
We retrospectively reviewed 342 cases of invasive malignant melanoma and melanoma in situ from the head, neck, chest, and back. Of the 342 cases, 23 (6.7%) had a lichenoid tissue reaction obscuring a portion of the lesion. In 6 cases (1.8%), the lichenoid tissue reaction replaced a major portion of the lesion.
Knowledge of this phenomenon can prevent misdiagnosis.
J Am Acad Dermatol. 2006 Jan;54(1):132-5. Abstract quote
BACKGROUND: We observed seborrheic keratoses with many basilar clear cells, creating a microscopic pattern that mimicked a seborrheic keratosis involved by melanoma in situ.
OBJECTIVE: We sought to report a series of these seborrheic keratoses and the immunohistochemical stains used to reach a proper diagnosis.
METHODS: We reviewed 9 cases of seborrheic keratosis that had a distinctive pattern of basal clear cells with ample cytoplasm. All cases were evaluated by conventional microscopy, and Melan-A, S-100, and high molecular weight keratin 903 immunostains.
RESULTS: The basal clear cells failed to react with Melan-A and S-100 protein antisera. In contrast, these cells labeled with an antikeratin antibody in all cases. In all, 7/9 (78%) showed immunopositivity only at the peripheries of cells, creating a pattern that could be mistaken for a negative stain if not examined at high magnification.
LIMITATIONS: This is a retrospective review of cases limited to a large referral dermatopathology service.
CONCLUSIONS: We describe a previously uncharacterized pattern of seborrheic keratosis that can microscopically mimic melanoma in situ. Careful conventional microscopy coupled with a panel of immunostains can allow the proper diagnosis to be reached.
PROGNOSIS CHARACTERIZATION GENERAL Totally curable if completely removed PROGRESSION
Progression to invasive melanoma from malignant melanoma in situ, lentigo maligna type.
Tannous ZS, Lerner LH, Duncan LM, Mihm MC Jr, Flotte TJ.
Massachusetts General Hospital, Harvard Medical School, Boston, USA.
Hum Pathol 2000 Jun;31(6):705-8 Abstract quote
We have previously hypothesized that lesions that have been termed lentigo maligna can be divided into 2 categories: 1 represents a pigmented lesion that is a precursor to melanoma, and the other melanoma in situ.
We and others have hypothesized that there is a progressive acquisition of attributes in pigmented lesions that results in malignant melanoma. Based on these 2 hypotheses, we have predicted that the intraepidermal component of invasive malignant melanomas, lentigo maligna type, should be similar to those lesions that we have termed malignant melanoma in situ, lentigo maligna type rather than lentigo maligna. The intraepidermal component of 42 consecutive cases of invasive malignant melanoma, lentigo maligna type was evaluated by all of the authors. Malignant melanoma in situ, lentigo maligna type is characterized by pagetoid spread, confluence, and nesting of atypical melanocytes. All of the cases evaluated showed features diagnostic of malignant melanoma in situ, lentigo maligna type, in the epidermis overlying the invasive dermal component.
We conclude that invasive lentigo maligna melanoma arises in association with those lesions that we have termed malignant melanoma in situ, lentigo maligna type, which may represent a step in the progression between atypical melanocytic hyperplasia (lentigo maligna) and invasive melanoma. This finding supports the distinction of these entities and may have therapeutic implications.
Aggressive amelanotic lentigo maligna.
Kelly RI, Cook MG, Mortimer PS.
Department of Dermatology, St George's Hospital, London, U.K.
Br J Dermatol 1994 Oct;131(4):562-5 Abstract quote.
A 66-year-old woman had a long-standing, scaly erythematous lesion on her left temple which histologically showed features of amelanotic lentigo maligna. It had recurred on numerous occasions over a period of 17 years, in spite of multiple attempts at curative surgery.
There were also recurrences within a skin graft which, to our knowledge, has not been documented previously with lentigo maligna. In spite of the prolonged course, and extensive intraepidermal melanocytic proliferation amounting to melanoma in situ, there has been no evidence of dermal invasion. The lack of pigmentation in such lesions means that clinical definition of margins is highly inaccurate. In view of the aggressive horizontal growth phase of this lesion, with rapid recurrence following surgery, it was treated with electron beam therapy, and this has resulted in complete clinical remission.
This most unusual case illustrates the potential difficulties in diagnosis and management of amelanotic lentigo maligna.
TREATMENT CHARACTERIZATION GENERAL Simple excision is curative with margins of 5-10 mm
- Variation in the diagnosis, treatment, and management of melanoma in situ: a survey of US dermatologists.
Charles CA, Yee VS, Dusza SW, Marghoob AA, Oliveria SA, Kopf A, Rigel D, Halpern AC.
Division of Dermatology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10022, USA.
Arch Dermatol. 2005 Jun;141(6):723-9. Abstract quote
OBJECTIVE: To assess current practices of US dermatologists regarding the diagnosis, treatment, and management of melanoma in situ (MIS).
PARTICIPANTS: A total of 1200 dermatologists randomly selected from the American Board of Medical Specialists Directory of Board Certified Medical Specialists.
MAIN OUTCOME MEASURES: Results based on 597 questionnaires returned.
RESULTS: The overall response rate was 63% (597 of 945 eligible participants). To aid in clinical assessment, respondents reported using a magnifying lens (57.4%) and dermoscopy (17.4%). Most dermatologists preferred excisional and saucerization biopsies as the method of choice for sampling. A large percentage of physicians (78.9%) preferentially used dermatopathologists for the evaluation of the majority of pigmented lesions. Although most respondents would not unquestioningly accept a benign pathology diagnosis when there was a clinical suspicion of MIS, 16.1% would accept a pathologist's diagnosis without further action. There was no consensus on the appropriate surgical margins or depth of excision for MIS. Of the respondents who characterized MIS as premalignant and malignant, 63.2% and 46.4%, respectively, did not know what percentage of MISs would progress to metastatic disease if left untreated.
CONCLUSIONS: Considerable variability exists in the clinical concept and management of MIS. Dermoscopy is underutilized. The true nature of the evolution of MIS is unknown. Surgical margins and depth of excision need to be standardized to help dermatologists manage disease. Further research in the specific area of MIS is warranted to develop clear guidelines in the management and prevention of further disease.
- Treatment of lentigo maligna (melanoma in situ) with the immune response modifier imiquimod.
Wolf IH, Cerroni L, Kodama K, Kerl H.
Department of Dermatology, Medical University of Graz, Graz, Austria.
Arch Dermatol. 2005 Apr;141(4):510-4. Abstract quote
BACKGROUND: Surgical excision is the treatment of choice for lentigo maligna (LM), or melanoma in situ. Topical application of imiquimod, a local immune response modifier, is a novel therapeutic approach that leads to LM tumor clearance. This pilot, open-label, nonrandomized study evaluates the efficacy of imiquimod in patients with LM and other systemic problems that make them poor surgical risks.
OBSERVATIONS: Six biopsy-proven cases of LM from 5 patients (age range, 67-80 years) in whom standard surgical therapy was contraindicated were enrolled in the study. Five tumors were located on the face and 1 on the right shoulder. Imiquimod was used as a 5% cream once a day for a maximum of 13 weeks. Immediate clinical responses and follow-up, as well as histopathologic changes and immunohistologic parameters (in 2 patients), were analyzed. The complete response rate for all LM cases was 100%. Time to complete clearing varied from 5 to 13 weeks based on both clinical and histopathologic findings. The inflammatory infiltrate following imiquimod treatment consisted of T-helper lymphocytes mixed with a significant number of cytotoxic cells and monocytes or macrophages. These results indicate that imiquimod induces a cytotoxic T-cell-mediated immune response. In all patients, erythema and erosions occurred at the treated area 2 to 4 weeks after initiation of imiquimod therapy. The patients have been followed up for 3 to 18 months without evidence of recurrences.
CONCLUSIONS: Topical imiquimod appears to be an excellent therapeutic option for LM. Close evaluation of patients, including posttherapy histopathologic investigation, is essential. Imiquimod can be added to the list of therapeutic approaches for carefully selected patients with LM.
A retrospective study of 150 patients with lentigo maligna and lentigo maligna melanoma and the efficacy of radiotherapy using Grenz or soft X-rays.
Farshad A, Burg G, Panizzon R, Dummer R.
Department of Dermatology, University Hospital Zurich, Gloriastrasse 31, CH-8091 Zurich, Switzerland.
Br J Dermatol 2002 Jun;146(6):1042-6 Abstract quote
BACKGROUND: Lentigo maligna (LM) and lentigo maligna melanoma (LMM) are the most common melanocytic neoplasms on sun-exposed skin of elderly patients.
OBJECTIVES: To perform a retrospective study of 150 patients with LM and LMM treated with radiotherapy using Grenz or soft X-rays.
METHODS: The information recorded and analysed included gender, age, diagnosis, size of the lesion, localization, X-ray treatment, recurrence rate, other skin malignancies and non-dermatological neoplasms.
RESULTS: The 150 patients comprised 78 women and 72 men (mean age 70 years). Ninety-three patients had LM, 54 had LMM and three had both neoplasms. Ninety per cent of lesions were located on the face. Treatment was with Grenz rays in 96 patients with LM and 11 with LMM (70%) and with soft X-rays in 46 patients with LMM (30%). Three patients were treated using both modalities. One hundred and one patients were followed up for at least 2 years after radiotherapy (mean 8 years). The mean time to recurrence was 45.6 months, and the recurrence rate was 7% (seven of 101). Other skin malignancies were observed in 65 of 150 patients, including basal cell carcinoma in 23 (35%) and actinic keratosis in 20 (31%). Four patients developed internal cancers.
CONCLUSIONS: The study showed that radiotherapy of LM and LMM was curative. In particular, radiotherapy proved to be an excellent treatment for elderly patients. Owing to the high incidence of other skin cancers, LM patients need careful follow-up.
SURGERY Surgical Margins for Lentigo Maligna and Lentigo Maligna Melanoma
The Technique of Mapped Serial Excision
Shyamala C. Huilgol, FACD; Dinesh Selva, FRANZCO; Celia Chen, MBBS; Dudley C. Hill, FACD; Craig L. James, FRCPA; Amanda Gramp, FRCPA; Raman Malhotra, FRCOphth
From the Department of Dermatology (Drs Huilgol and Hill) and Oculoplastic and Orbital Unit, Department of Ophthalmology (Drs Selva, Chen, and Malhotra), Royal Adelaide Hospital, University of Adelaide; Adelaide Pathology Partners (Dr James), Gramp Skin Pathology (Dr Gramp), and Hill Day Surgery, Wakefield Clinic (Drs Huilgol and Hill), Adelaide, Australia. The authors have no relevant financial interest in this article.
Arch Dermatol. 2004;140:1087-1092. Abstract quote
Objectives To assess the margins required for excision of lentigo maligna (LM) and lentigo maligna melanoma (LMM) by the technique of mapped serial excision (MSE), and to assess the efficacy of MSE.
Design An interventional, prospective, noncontrolled case series.
Setting Tertiary referral, dermatologic surgery unit.
Patients Consecutive patients with head and neck LM or LMM who underwent MSE between March 1, 1993, and October 31, 2002.
Intervention The MSE of LM or LMM.
Main Outcome Measures The number of 5-mm levels for excision of LM and LMM and recurrence.
Results One hundred sixty-one LMs or LMMs in 155 patients were treated. Thirty percent (37 of 125) of LMs required more than 5-mm margins. For LMMs less than 1 mm in Breslow thickness, 12% (4/32) required more than 10-mm margins. For primary tumors, 20% of LMs (18 of 91) required more than 5-mm margins, while 10% of LMMs less than 1 mm in Breslow thickness (2 of 21) required more than a 10-mm margin. For recurrent tumors, 56% of LMs (19/34) required more than a 5-mm margin. Mean follow-up of 38 months (range, 5-100 months) showed 4 recurrences (2%) after MSE. The extrapolated recurrence at 5 years was 5.0%.
Conclusions The current recommendations of 5-mm margins for LM and 10-mm margins for LMM less than 1 mm in Breslow thickness are often insufficient. Our results demonstrate the importance of margin-controlled excision, particularly in recurrent lesions. The use of MSE offers a high cure rate, in conjunction with tissue conservation.
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Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fifth Edition. Mosby Elesevier 2008
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