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Squamous cell carcinoma of the skin continues to plague the adult population. In transplant patients, these skin cancers are greatly increased and may be difficult to eradicate. In addition, there may be a viral association with some cases caused by Human Papilloma Virus infection.


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Histologic subtyping and malignancy assessment of cutaneous squamous cell carcinoma.

Petter G, Haustein UF.

Department of Dermatology, University of Leipzig, Leipzig, Germany.

Dermatol Surg 2000 Jun;26(6):521-30 Abstract quote

BACKGROUND: Squamous cell carcinomas (SCCs) of the skin have a wide range of histologic subtypes and there are indications of differences in prognosis.

OBJECTIVE: The morphologic variety of SCCs with respect to its biological behavior and the further course of disease is analyzed, with emphasis on histopathologic criteria, briefly quoting the main clinical and pathogenetic aspects.

METHODS: Referring to the international tumor classification of the World Health Organization, histologically different carcinoma variants are presented and discussed, based on a review of the literature regarding each subtype, and also including the desmoplastic SCC type.

RESULTS: Histologically, common invasive SCCs are most frequently found, while metastases mainly occur in tumors of high thickness and poor differentiation. The immature spindle cell carcinoma type resembles sarcoma and may grow rapidly with an aggressive clinical course. Lymphoepithelioma-like carcinoma of the skin is extremely rare and its histogenesis remains to be elucidated. Thus far, one case with metastasis and lethal outcome has been reported. As details determining the progression ability have so far only been scanty and partially contradictory, more investigations are necessary, especially for acantholytic SCCs and invasive SCCs developing from Bowen's disease, whereas verrucous carcinomas can be categorized as low malignancy neoplasms. Desmoplastic SCCs, especially with large tumor thickness, should be separated from other SCC subtypes due to their high risk of local recurrence and metastatic spread.

CONCLUSION: The future outcome of SCCs of the skin is significantly influenced by their histologic grade and tumor thickness. In addition, subtyping represents another valuable histopathologic tool for improving the assessment of malignancy.

Immune status

Arch Dermatol 1986;122:1288-1293
Organ transplant patients are 18-36x more prevalent than in general population

These patients are also at higher risk for lymph node metastasis

Risk is related to degree of immunosuppression

Int J Cancer 1999;81:555-59
An estimated 1200 deaths a year occur from basal cell and squamous cell carcinomas, with the majority occurring with Squamous cell carcinomas
J Eur Acad Dermatol Venereol 1998;11:37-44
3 YRS was 98% if tumor <3.5 mm in depth
84% >3.5 mm in depth
J Am Acad Dermatol 1992;26:976-990
<10% for lesions <2 cm
30% for lesions>2 cm
Tumor grade
Cancer 1983;51:1537
Poorly differentiated tumors have 3x recurrence rate of well-differentiated tumors
Microscopic growth pattern
Small nests, infiltrative pattern, diffuse haphazard growth, isolated strands, and clusters of cells or single cells are at higher risk
Perineural invasion
J Dermatol Surg Oncol 1982;8:589-600
Present in 2.4-14% of tumors
More frequent in recurrences
One study indicated a a 2 year cure rate of only 2% if perineural invasion was found

Tumors with rapid growth rate
Closer to a mucosal surface

>2 cm doubles the recurrence rate and triples the metastatic rate to 30%

Tumor thickness

Surg Oncol Clin N Am 1997;6:625-638

Tumors >Clark's level IV or V or >4 mm had metastatic rate of 45.7%

Previous treatment
Clin Plast Surg 1980;7:361-368
Increased metastatic potential
Risk Factors for Metastasis
J Am Acad Dermatol 1992;26:976-990
  % Risk
Acantholytic histology
Arising in Bowen's disease
Non-sun exposed skin
Arising in Marjolin's ulcer
Perineum and penis

Prognostic factors for metastasis in squamous cell carcinoma of the skin.

Cherpelis BS, Marcusen C, Lang PG.

Department of Dermatology, Medical University of South Carolina, Charleston, South Carolina.


Dermatol Surg 2002 Mar;28(3):268-73 Abstract quote

BACKGROUND: Squamous cell carcinoma (SCC) of the skin exhibits a significant propensity to metastasize. A number of variables have been reported to influence the tendency of SCC to metastasize. Because of the increasing incidence of skin cancer, it is becoming increasingly important to identify those neoplasms which are biologically more aggressive. We report 25 cases of metastatic SCC and compare them to 175 cases of nonmetastasizing SCC treated during the same period.

OBJECTIVE: To characterize tumors with the greatest tendency to metastasize.

METHODS: A tumor registry from the Dermatologic Surgery Unit at the Medical University of South Carolina was accessed to obtain records on 200 patients diagnosed with invasive SCC managed by Mohs surgery from 1988 to 1998. A retrospective analysis was conducted. The characteristics of patients with metastatic SCC and those with nonmetastatic SCC were compared using the chi-squared test and Fisher's exact test.

RESULTS: Of 200 tumors, 25 (12.5%) metastasized. Size, Clark's level, degree of differentiation, the presence of small tumor nests, infiltrative tumor strands, single-cell infiltration, perineural invasion, acantholysis, and recurrence all correlated strongly with metastasis. Location, ulceration, inflammation, and Breslow depth did not correlate with the development of metastasis.

CONCLUSION: Patients with tumors that exhibit certain clinical and histologic features are more likely to metastasize and need close follow-up to detect recurrence and metastasis early, allowing for appropriate life-saving intervention. Sentinel lymph node biopsy should be considered in patients with high-risk SCC.


Metalloproteinase-2 expression correlates with aggressiveness of cutaneous squamous cell carcinomas.

Fundyler O, Khanna M, Smoller BR.

Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
Mod Pathol. 2004 May;17(5):496-502. Abstract quote  

Matrix metalloproteinases compose a family of enzymes involved in degradation of the extracellular matrix. Tumor cells must penetrate the basement membrane and traverse the extracellular matrix in order to invade surrounding structures and metastasize to distant sites. Gelatinases, particularly gelatinase A (matrix metalloproteinase-2), demonstrate degradative activity against components of the basement membrane and may be involved in the progression of in situ squamous cell carcinoma lesions.

Matrix metalloproteinase-2 overexpression has been correlated with tumor invasiveness and metastasis in a wide variety of cancer types, including squamous cell carcinoma arising on mucous membranes. However, correlation between matrix metalloproteinase-2 overexpression and the spread and prognosis of cutaneous squamous cell carcinoma has not been characterized in the literature at present.

In this study, we used immunohistochemical techniques to examine the expression of matrix metalloproteinase-2 in 10 actinic keratosis, 15 in situ, 13 invasive, 13 primary (with documented metastatic disease), 11 metastatic, and 8 recurrent squamous cell carcinoma cases. We found that while the average staining intensity (scale 0-3+, 3+ being strongest) of actinic keratosis and in situ lesions was not statistically significant (0.87-1.3 and 0.75-1.4, respectively), the average staining intensity of invasive squamous cell carcinomas (1.6-2.5) was significantly greater than that of actinic keratosis and in situ lesions. Likewise, while the average staining intensity of primary squamous cell carcinomas and metastatic squamous cell carcinomas was not found to be statistically significant (3.1-3.5 and 3.1-3.8, respectively), the average staining intensity of these lesions was significantly higher than that of invasive lesions.

We also found that the intensity of matrix metalloproteinase-2 staining correlates with cellular atypia, inflammation, neovascularization, and the invasive tumor front, as well as tumor aggressiveness, and may play a role in the pathogenesis, invasion, and metastasis of cutaneous squamous cell carcinoma.

Cutaneous squamous cell carcinoma treated with Mohs micrographic surgery in Australia I. Experience over 10 years.

Leibovitch I, Huilgol SC, Selva D, Hill D, Richards S, Paver R.

Oculoplastic and Orbital Division, Department of Ophthalmology and Visual Sciences, Royal Adelaide Hospital, University of Adelaide, Adelaide, Australia.

J Am Acad Dermatol. 2005 Aug;53(2):253-60. Abstract quote  

BACKGROUND: Only a few reports have been published on the long-term outcome of surgical excision of cutaneous squamous cell carcinoma (SCC).

OBJECTIVE: Our purpose was to report the clinical findings and 5-year recurrence rate of all patients with cutaneous SCC treated with Mohs micrographic surgery (MMS) in Australia between 1993 and 2002.

METHOD: This prospective, multicenter case series included all patients with SCC who were monitored by the Skin and Cancer Foundation. The main outcome measures were patient demographics, reason for referral, duration of tumor, site, preoperative tumor size, postoperative defect size, recurrences before MMS, histological subtypes, and 5-year recurrence after MMS.

RESULTS: The case series comprised 1263 patients (25.7% female and 74.3% male; P < .0001) with a mean age of 66 +/- 13 years. In 61.1% of cases the lesion was a primary tumor, and in 38.9% it was a recurrent tumor. Most of the tumors (96.5%) were on the head and neck area. Recurrent tumors were larger than primary tumors (P < .0001), had a larger postexcision defect (P < .0001), required more levels of excision (P < .0001), and had more cases of subclinical extension (P = .002). Recurrence after MMS was diagnosed in 15 of the 381 patients (3.9%) who completed the 5-year follow-up after MMS. The recurrence rate was 2.6% in patients with primary SCC and 5.9% in patients with previously recurrent SCC (P < .001).

CONCLUSION: This large prospective series of SCC managed by MMS is characterized by a high percentage of high-risk tumors. The low 5-year recurrence rate with MMS emphasizes the importance of margin-controlled excision.
Cutaneous squamous cell carcinoma treated with Mohs micrographic surgery in Australia II. Perineural invasion.

Leibovitch I, Huilgol SC, Selva D, Hill D, Richards S, Paver R.

Oculoplastic and Orbital Division, Department of Ophthalmology and Visual Sciences, Royal Adelaide Hospital, Adelaide, South Australia.

J Am Acad Dermatol. 2005 Aug;53(2):261-6. Abstract quote  

BACKGROUND: Perineural invasion (PNI) is an important histologic factor that plays a significant role in cutaneous tumors' aggressiveness.

OBJECTIVES: We sought to evaluate the incidence, features, and outcomes of cutaneous squamous cell carcinoma with PNI in patients treated with Mohs micrographic surgery (MMS).

METHOD: This prospective, multicenter, case series included all patients in Australia treated with MMS for squamous cell carcinoma with PNI who were monitored by the Skin and Cancer Foundation Australia between 1993 and 2002. The parameters recorded were patient demographics, duration of tumor, site, preoperative tumor size, recurrence before MMS, histologic subtypes, postoperative defect size, and recurrence at 5 years after MMS.

RESULTS: Seventy patients were given a diagnosis of PNI. PNI was more common in men (77.1%) and in previously recurrent tumors (P = .04). The moderately and poorly differentiated histologic subtypes were more likely to be associated with PNI (P < .0001). Tumor sizes before excision, postoperative defect sizes, subclinical extension, and mean number of MMS levels were significantly larger in cases with PNI compared with cases without PNI (P < .0001, P < .0001, P = .002, and P < .0001, respectively). Most patients with PNI (52.9%) were treated with adjunctive radiotherapy. In all, 25 patients completed a 5-year follow-up post-MMS, and two of them (8.0%) were given a diagnosis of recurrence.

CONCLUSION: Although PNI is an uncommon feature of cutaneous squamous cell carcinoma, when present, it is associated with larger, more aggressive tumors, and the risk of recurrence is higher. This emphasizes the importance of tumor excision with margin control and long-term patient monitoring.

Squamous cell carcinoma of the lip treated with Mohs micrographic surgery: outcome at 5 years.

Holmkvist KA, Roenigk RK.

Department of Dermatology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA.

J Am Acad Dermatol 1998 Jun;38(6 Pt 1):960-6 Abstract quote

BACKGROUND: Mohs micrographic surgery (MMS) is believed to be a highly effective treatment of squamous cell carcinoma (SCC) of the lip.

OBJECTIVE: The goals of our study were to determine the long-term (5-year) outcome of patients treated with MMS for SCC of the lip and to identify factors associated with tumor recurrence.

METHODS: Clinical and histopathologic data from 50 consecutive cases of SCC of the lip treated with MMS were retrospectively reviewed.

RESULTS: There were no tumor-related deaths or metastases. Forty-six patients (92%) remained free of disease. Four patients (8%) were diagnosed with SCC at the surgical site after MMS. Recurrent lesions tended to be superficial and occurred in the setting of severe actinic cheilitis. The average time to diagnosis after MMS was 2.5 years. All patients with recurrent disease were treated with further MMS and had successful results. No recurrences were seen among patients who received adjuvant treatment for actinic cheilitis with the carbon dioxide (CO2) laser, had clinical lesions 1 cm or less in diameter, or had post-MMS defects 2 cm or less in diameter.

CONCLUSION: MMS is highly effective for treating both primary and recurrent SCC of the lip. Treatment of coexisting actinic cheilitis may lower the risk for local recurrence after MMS.

A retrospective study of outcome of Mohs' micrographic surgery for cutaneous squamous cell carcinoma using formalin fixed sections.

Turner RJ, Leonard N, Malcolm AJ, Lawrence CM, Dahl MG.

Department of Dermatology and Pathology, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne, NE1 4LP, UK.

Br J Dermatol 2000 Apr;142(4):752-7 Abstract quote

The surgical management of recurrent or large squamous cell carcinoma (SCC) can be challenging as tumours often extend beyond visible margins. Micrographic surgery is a potentially effective method of ensuring complete clearance of tumour.

A retrospective study of all cases of SCC treated by micrographic surgery in this department between 1986 and 1996 has been done. Sixty-one patients were treated using a formalin-fixed paraffin-embedded tissue technique with a median follow-up of 4 years. In two cases there was local recurrence and in three others metastasis to local lymph nodes. The overall cure rate was 92% (56 of 61), which compares favourably with published series using chemosurgery and frozen tissue techniques.

The results show that this technique of micrographic surgery is a satisfactory and cost-effective alternative to conventional frozen section techniques in the treatment of SCC. The formalin-fixed tissue method has the advantage of providing high-quality permanent histological sections using existing conventional pathology services.


Adjuvant radiotherapy after excision of cutaneous squamous cell carcinoma.

Geohas J, Roholt NS, Robinson JK.

Department of Dermatology, Northwestern University Medical School, Chicago, Illinois.

J Am Acad Dermatol 1994 Apr;30(4):633-6 Abstract quote

Most cutaneous squamous cell carcinomas (SCCs) of the trunk and extremities are small enough to be cured by simple surgical excision. Because the risk of metastasis of SCCs of the head and neck arising from mucosal surfaces is higher than the risk of metastasis of SCCs arising from cutaneous surfaces, it may be more appropriate to review case reports of the trunk and extremities separately from those of the head and neck when seeking prognostic indicators. A small group of advanced lesions, however, is more difficult to treat and has an increased risk of local recurrence or metastasis and a poorer prognosis.

We describe a patient with high-risk cutaneous SCC who is disease-free 1 year after adjuvant radiotherapy subsequent to excision by Mohs micrographic surgery. This report discusses prognostic indicators of cutaneous SCC and suggests adjuvant modalities for the treatment of high-risk disease after surgical excision.

Radiotherapy is a rational choice as adjuvant therapy for the treatment of high-risk cutaneous SCC after excision.

Low-dose retinoids in the prevention of cutaneous squamous cell carcinomas in organ transplant recipients: a 16-year retrospective study.

Harwood CA, Leedham-Green M, Leigh IM, Proby CM.

Centre for Cutaneous Research, St Bartholomew's and the Royal London School of Medicine and Dentistry, Queen Mary, University of London, London, England.
Arch Dermatol. 2005 Apr;141(4):456-64. Abstract quote  

OBJECTIVE: To evaluate the long-term efficacy of systemic retinoids in reducing the incidence of cutaneous squamous cell carcinomas (SCCs) in organ transplant recipients (OTRs), who are at greatly increased risk of SCCs.

DESIGN: A retrospective before-after study of OTRs who had received low-dose systemic retinoids during 1 to 16 years for prevention of SCCs.

SETTING: A specialist dermatology clinic for organ transplant recipients at St Bartholomew's and the Royal London Hospital, University of London, London, England.

PATIENTS: Thirty-two OTRs with at least 1 histologically proved SCC.

INTERVENTIONS: Continuous systemic retinoids at dosages of 0.2 to 0.4 mg/kg per day for a minimum of 12 months.

MAIN OUTCOME MEASURES: The mean difference between the number of SCCs developing annually during retinoid treatment and the number during the 12-month pretreatment interval. RESULTS: In 28 continuously treated individuals, the mean number of SCCs in the 12-month pretreatment interval was 2.9. The number of SCCs was significantly reduced, with a mean difference of 1.46 in the first year of treatment (P = .006), 2.20 in the second (P<.001), and 2.14 in the third (P = .02). The numbers of SCCs were also reduced in subsequent years, but this effect was no longer significant because of smaller patient numbers. Six patients in whom retinoid treatment was interrupted subsequently had a significant increase in SCCs.

CONCLUSIONS: Low-dose systemic retinoids significantly reduce SCC development in OTRs for the first 3 years of treatment, and this effect may be sustained for at least 8 years, with a generally well-tolerated side-effect profile. Studies are now required to further optimize their use as a chemopreventive strategy in high-risk OTRs.

Combined sentinel lymphadenectomy and mohs micrographic surgery for high-risk cutaneous squamous cell carcinoma.

Weisberg NK, Bertagnolli MM, Becker DS.

Departments of Dermatology and Surgery, Weill Cornell Medical School, New York, NY 10021, USA.

J Am Acad Dermatol 2000 Sep;43(3):483-8 Abstract quote

BACKGROUND: There are subgroups of cutaneous squamous cell carcinoma (SCC) that have a higher risk for both regional and distant metastasis. When cutaneous SCC does metastasize, it typically spreads first to local nodal groups. Sentinel lymph node (SLN) localization has been successfully used to evaluate nodal metastasis in breast carcinoma, melanoma, and other select tumors. It may also be useful in certain high-risk cutaneous SCCs. Currently, Mohs micrographic surgery is the treatment of choice for these tumors.

METHODS: A patient presented with a high-risk recurrent SCC on the forehead. The regional nodal groups were clinically negative and radiographically negative by computed tomographic scan. Sentinel lymphadenectomy was performed by means of technetium 99m-radiolabeled sulfur colloid. The main tumor was resected with Mohs micrographic surgery.

RESULTS: A left preauricular SLN was localized by lymphoscintigraphy. The SLN was located intraoperatively by means of a gamma probe and excised. Subsequent pathologic evaluation of the SLN was negative for evidence of metastatic SCC by light microscopy with hematoxylin and eosin, and with immunohistochemical stains for cytokeratins AE1 and AE3. The day after SLN excision, the tumor was removed via Mohs micrographic surgery with clear surgical margins after a total of 8 stages. Aggressive subclinical spread by both subcutaneous "skating" and perineural invasion was noted.

CONCLUSION: The combination of Mohs micrographic surgery and sentinel lymphadenectomy is feasible and has theoretical utility in the management of a subset of cutaneous SCCs at high risk for metastasis. The ability of sentinel lymphadenectomy to identify regionally metastatic cutaneous SCC as well as the additive benefit of SLN and Mohs micrographic extirpation in the treatment of high-risk cutaneous SCC remain to be further clarified.

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Last Updated August 15, 2005

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