Are You Confident of the Diagnosis?
Characteristic findings on physical examination
The most common clinical presentation of Merkel cell carcinoma (MCC) is a rapidly growing, painless, firm, dome-shaped, red nodule. The overlying skin is occasionally ulcerated or smooth and shiny, sometimes exhibiting acneiform or telangiectatic features. The median size of the tumor ranges from 1 to 4 cm in diameter at the initial presentation (Figure 1).
MCC involves predominately sun-exposed areas: head and neck in 50% of cases, with preferential localization on the eyelid and periorbital area (20% of cases), the limbs in 40% of cases, and the trunk in less than 10% of cases. The localization of the tumor does not seem to reflect the density of Merkel cell receptors in the skin, since these mechanoreceptors in humans are more concentrated on limbs, especially fingers and toes.
The tumor has also been reported in the oral mucosa, larynx, esophagus, cervix, and vulva. This leads to a broad clinical differential diagnosis, including basal cell carcinoma, squamous cell carcinoma, sweat gland tumors, pyogenic granuloma, keratoacanthoma, amelanotic melanoma, epidermal or trichilemmal cyst, lymphoma, and metastatic carcinoma to the skin.
A useful rule to remember when suspecting MCC is the “ five vowels rule”: A, asymptomatic; E, expanding rapidly; I, immunosuppression; O, older people; U, ultraviolet (UV) exposure because of its unspecific clinical features, MCC is rarely suspected prior to biopsy.
Expected results of diagnostic studies
Histologically, the tumor arises within the dermis and may extend into the subcutaneous fat and muscles infiltrating lymphatic and blood vessels. The epidermis may be spared or ulcerated. The tumoral cells are small, blue ovoid, hypercromatic cells measuring up to 15 µm in diameter with scanty cytoplasm. A high mitotic index is characteristic. Tumor cells are arranged in dense cohesive sheets with a variable pattern.
The triad of vesicular nuclei, abundant mitosis and apoptosis is considered as pathognomonic. Three main histologic subtypes have been described: small cell, trabecular, and intermediated (Figure 2).
The histological differential diagnosis is very large, ranging from bronchial small cell carcinoma (oat cell carcinoma), amelanotic melanoma, and Ewing sarcoma to medullary carcinoma of the thyroid. Immunohistochemistry (IHC) is essential for diagnosis, and electron microscopy (EM) can be very helpful for the diagnosis
On IHC, MCC shows marked positivity for neuron-specific enolase, synaptophysin, and chromogranin in 100% of cases, ruling out many skin cancers but not carcinoid, oat cell carcinoma, neuroblastoma and melanoma. All MCC also react with cytokeratin markers (cytokeratin 20, anticytokeratin reagent CAM 5.2, and cytokeratin AE1/AE3 used with or instead of CAM5.2). allowing you to exclude lymphoma,undifferentiated carcinoma, and melanoma but not metastatic oat cell carcinoma. Cytokeratin 7 and thyrroid transcription factor 1 (TTF-1), usually found in oat cell carcinoma. are absent in MCC. The negativity for commone leucocyte antigen, vimentin, S-100, and TTF-1 can rule out melanoma.
A useful marker for further diagnostic confirmation is the presence of neurofilament commonly expressed in MCC and not in bronchial small cellcarcinoma (Table I)
EM usually shows Merkel cells with the typical dendritic cytoplasmic processes with actin-like spikes protruding between keratinocytes.They present with peripheral dense core granules bound to cytoplasmic membrane and characteristically are concentrated in the cell periphery or in cytoplasmatic dendritic-like processes.
Who is at Risk for Developing this Disease?
Over the past two decades, the incidence of MCC has tripled in the United States, to 1500 cases per year. The incidence in blacks (0.01 cases per 100,000) seems to be lower than in white people. Both sexes are equally affected, but a slight male predominance has been recorded (2.3:1). It occurs especially in the elderly (sixth to ninth decades), with an average age at the time of diagnosis of 69 years. Less than 5% of cases occur before the age of 50 years. MCC seems to be more common in transplant recipients, and 67 cases reported in the literature showed unusual histological features in these patients.
The tumor has been occasionally reported in association with congenital ectodermal dysplasia, dural ectasia, Cowden disease, and hematological malignancies such as B cell lymphoma and chronic lymphocytic leukemia.
What is the Cause of the Disease?
With regard to its histogenesis, in the past MCC was believed to be a neuroectodermal tumor derived from Merkel cells, the mechanoreceptor cells first described by Friedrich Sigmund Merkel in 1875.
It is currently accepted that the tumor originates from a totipotential stem cell that acquires neuroendocrine features and this may explain the coexistence of MCC and other skin cancers.
The evidence of occurrence on sun-exposed areas, along with data about the geographic distribution of the tumor, supports the relationship with sunlight and ultraviolet (UV) exposure. An association has been reported with other UV light-related skin cancers such as SCC and BCC, and recent studies showed that the common UVB-specific mutations in the p53 and H-Ras gene, found in MCCs and SCC, as well as the shared chromosomal imbalances, may point to a common, environmental derived (e.g,. UVA derived) oxidative damage. A 100-fold increase in patients treated with methoxsalen and UVA for psoriasis has been reported.
The onset in elderly people and in transplant recipients suggests that immunosuppressed individuals present an additional risk for MCC. In renal recipients, the risk of MCC has been estimated at 0.13 per 1,000 person-years whereas the relative risk in MCC in human immunodeficiency virus (HIV) patients is approximately 13.4. Recently a high prevalence of a second neoplasm occurring before, with or after MCC (25-28%) such as haematologic malignancies, breast cancer, ovarian cancer and SCC has been reported. The association with conditions of immunosuppression could be suggestive of an infectious origin.
Recently, studies using molecular investigations and sequence analysis of MCC biopsies led to identification of a previously unknown polyomavirus, called Merkel cell polyomavirus (MCPyv). This new viral DNA was integrated within the tumor in a clonal pattern, suggesting that MCPyv infection and integration precede clonal expansion of the tumour cells. A high prevalence was found in further studies, providing strong evidence of the possible pathogenetic role of these viruses in a specific, clinical subset of MCCS with a worse prognosis. It has also been recently demonstrated that some MCCS are MCPyV-negative; therefore, although most MCCs seem to be associated with MCPyV infection, more work is needed to clarify the role of this virus in the onset and clinical course of MCC.
Systemic Implications and Complications
At presentation, most patients (70-80%) have localized disease, whereas about 9-26% have regional lymph node metastasis and only 1-4% have distant metastasis.The delay in the diagnosis may be due to the absence of symptoms of the primary lesion, and a case with superior vena cava syndrome, owing to the obstruction by a metastazing tumor, has been described. Spontaneous regression of MCC has also been reported, and 20-30% of patients present without a primary lesion that seems to be associated with a better prognosis.
The prognostic factors that have been included in the staging system are the size of the primary tumor, the status of the regional nodal basin, and the presence of distant metastatic disease. The current staging of MCC, developed by the Sloan Kettering Cancer Center investigators and consistent with the American Joint Committee on Cancer, is therefore organized in a four-tiered system Table II.
The crucial impact of nodal involvement on survival and recurrence rates has been largely demonstrated in the past. Nodal involvement can be evaluated by noninvasive procedure or by intraoperative lymphatic mapping with lymphoscintigraphy and sentinel lymph node biopsy (SLNB). Noninvasive techniques are ultrasonography and computed tomography (CT), this last providing a further advantage being able to demonstrate distant metastases in other organs such as lungs and bones; if central nervous system involvement is suspected, magnetic resonance imaging (MRI) should be considered.
SLNB detects MCC spreading in one-third of patients whose tumors would otherwise have been clinically and radiologically understaged. These patients may not have otherwise received treatment to the involvement node bed. The best advantage of SLNB is to overcome the problem of unpredictable lymphatic drainage. It is always to be recommended in cases of tumors larger than 1 cm in diameter. SLNB positivity is strongly predictive of a high short-term risk of recurrence or metastasis, and therapeutic lymph node dissection appears to be effective in preventing short-term regional nodal recurrence.
The available therapeutic options are:
-Surgical excision of the primary lesion,
-Sentinel lymph node biopsy (SLNB)
-Complete lymph node dissection (CLND)
Optimal Therapeutic Approach for this Disease
MCC should be treated early and aggressively with radical surgical excision of the primary lesion. Because of the high risk of local recurrences, complete extirpation of the tumor at the time of the initial resection to achieve clear surgical margins should be the gold standard. Consultation with surgical oncology, radiation oncology, and medical oncology should be requested.
Surgical techniques include excision with wide margins to the fascial layer with complete peripheral margin examination and in certain anatomic areas, Mohs surgery. The size of the tumor can determine the wideness of the margins of excision. Margins of 1 cm are recommended for tumor smaller than 2 cm in diameter, whereas margins of 2 cm are recommended for larger tumors. Mohs micrographic surgery should be suggested mainly for MCC on the head, neck, and extremities. In cases of Mohs xsurgery SNLB cannot be required.
Any surgical approach should be viewed in conjunction with SLNB results. In case of negative SLNB, but also if margins of excision are negative for MCC invasion, and in any case of suspect subclinical disease, radiation therapy (RT) to the primary site plus or minus in-transit lymphatics and/or draining nodal basins, is advocated. MCC is a very radiosensitive malignancy and most studies argued the benefits of postsurgery RT. Irradiation of nodal beds and in-transit lymphatics is added to the irradiation of the primary site of the tumor and also in cases of wide excision performed without SLNB.
RT seems to improve the 5-year overall survival, disease specific survival, and relapse-free survival compared to surgery alone or chemotherapy.The best doses of RT range from a minimum of 45 to a maximum of 66 Gy in 25 to 30 fractions. Adjuvant chemotherapy is usually not recommended in stage I disease.
In stage II, complete lymph node dissection (CLND) is considered the first line and the best treatment for most patients, with low rates of regional lymph node recurrences in several small published series. If massive lymph node involvement is present and CLND cannot be performed, adjiuvant RT should be considered to reduce the nodes before surgical excision. Complete or partial resolution of in-transit MCC metastases have been reported with hyperthermic isolated limb perfusion using tumor necrosis factor alpha, interferon-gamma and/or melphalan.
In stage III, or in case of inoperable disease, a multidisciplinary tumor board consultation to consider any of the following treatments (alone or in combination): surgery, RT and chemotherapy (CHT) is suggested.
MCC is a chemosensitive tumor with an overall response to CHT of 60 to 70%. Several combinations of agents have been reported in the literature. The most used regimens include cisplatin or carboplatin plus etoposide, cyclophoshamide, doxorubicin, epirubicin, vincristine, and 5- fluorouracil. An initial response rate of 100% was recorded with regimes including doxorubicin and cisplatin, of 92% with 5-fluorouracil and 76% with cyclophosphamide, doxorubicin-epirubicin, and vincristine. Single-agent CHT has been reported with topotecan, irinotecan, oral etoposide, taxane and gemicitabine as second-line treatment or first-line treatment in inoperable patients.
Overall the prognosis of patients with stage III MCC is poor, with a mean interval of 8 months between diagnosis and death. The response rates of second- and third-line CHT further decrease to 45 and 20% respectively. No regimen has demonstrated an impact on survival or response longevity in metastatic patients with MCC.
With respect to 5-year survival rate, adjuvant radiotherapy is associated with a marked decrease in local recurrences and a trend to improvement in multiple retrospective studies. A meta-analysis by Lewis (2006) carried out on 1254 MCC cases previously reported in the literature, indicated that local recurrences at 5 years were three times less likely (12% vs39%, p<0.01 if adjuvant radiation was given, a similar association was found for regional recurrences (23% vs 56%, p<0.001).
Data from Surveillance, Epidemiology and End Results (SEER) of the National Cancer Institute collected from 1973 to 2006 in 3870 patients with MCC showed that women (1131) had a greater relative survival rate than men (1642).The survival rate at 10 years for women was 64,8% and for men 50,5% with a statistically significant difference (p<0.001). The overall 10 years survival for patients with MCC, regardless of age, was 57,3%. Stratification by anatomic site showed that MCC of the upper limbs had the best prognosis with 60,7% survival at 10 years. Furthermore MCC tumors of localized stage showed the best prognosis with a 71% survival rate whereas regional, unknown and distant stage were respectively 47.8%, 40.5% and 20.1%.
We propose an Algorithm for the management of patients with MCC.
The scheme is the same regardless of the stage, given the high percentage of recurrences (90%) occurring within 24 months from the diagnosis. The physical examination, including a complete skin and regional lymph node examination, should be performed every 1 to 3 months for the first year, every 3 to 6 months in the second year, and then annually. A self-skin examination should also be suggested because of the greater risk of non melanoma skin cancer.
Unusual Clinical Scenarios to Consider in Patient Management
Toxicity of CHT primarly related to myelosuppression is a concern in the elderly population of patients with MCC, and skin desquamation and tumor lysis syndrome with acute renal failure have been reported.
What is the Evidence?
Heath, M, Jaimes, N, Lemos, B, Mostaghini, A, Wang, LC, Peñas, PF. ” Clinical characteristics of Merkel cell carcinoma at diagnosis in 195 patients: the AEIOU features”. J Am Acad Dermatol. vol. 58. 2008. pp. 375-81. (Outstanding database of nearly 200 Merkel cell carcinomas describing characteristics of the tumors. In this paper, the authors define clinical features that may serve as clues in the diagnosis of MCC. They conducted a cohort study on 195 patients with the diagnosis of MCC between 1980 and 2007 by reviewing medial records. Three or more of the most significant features, summarized in the acronim AEIOU (asymptomatic/lack of tenderness, epanding rapidly, immune suppression, older than 50 years, and ultraviolet-exposed site on a person with fair skin), where present in 89% of primary MCC. Nevertheless no data are reported about improvement of diagnosis in a prospective view or in terms of prognosis.)
Albores-Saavedra, J, Batich, K, Chable-Montero, F, Sagy, N, Schwartz, AM, Henson, DE. “Merkel cell carcinoma demosgraphics, morphology, and survival based on 3870 cases: a population study”. J Cutan Pathol. vol. 37. 2010 Jan. pp. 20-7. (Updated review of Merkel cell carcinoma providing data on 5-year and 10-year survival rates.)
Miller, RW, Rabkin, CS. “Merkel cell carcinoma and melanoma: etiological similarities and differences”. Cancer Epidemiol Biomarkers Prev. vol. 8. 1999. pp. 153-8. (Older review of Merkel cell carcinoma and melanoma. Discusses the factors in common and the uniqueness of each.)
Popp, S, Waltering, S, Herbst, C, Moll, I, Boukamp, P. “UV-B-type mutations and chromosomal imbalances indicate common pathways for the development of Merkel and skin squamous cell carcinoma”. Int J Cancer. vol. 99. 2002. pp. 352-60. (Discusses that ultraviolet light plays a role inthe pathogenesis of merkel and squamous cell carcinoma.In this paper, the authors studied the genetic profile of MCCs comparing it with SCC lines. They concluded that in addition to the common UV-B specific mutation in the p53 and Ha-ras gene, MCCs and SCCs also share chromosomal imbalances that may point to a common environmental-derived oxidative damage.)
Feng, H, Shuda, M, Chang, Y, Moore, PS. “Clonal integration of a polyomavirus in human Merkel cell carcinoma”. Science. vol. 319. 2008. pp. 1096-100. (First report of the Merkel cell polyomavirus. Ten cases reviewed, with 8 having some form of Merkel cell polyomavirus present.)
Henness, S, Vereecken, P. “Management of Merkel tumours: and evidence-based review”. Curr Opin Oncol. vol. 20. 2008. pp. 280-6. (Recent review of the management of Merkel cell carcinoma.)
Gupta, SG, Wang, LC, Peñas, PF, Gellenthin, M, Lee, SJ, Nghiem, P. “Sentinel lymph node biopsy for evaluation and treatment of patients with Merkel cell carcinoma: the Dana-Farber experience and meta-analysis of the literature”. Arch Dermtol. vol. 142. 2006. pp. 685-90. (Discusses the cases of Merkel cell carcinoma treated at this institution and the outcomes.)
Bichakjian, CK, Lowe, L, Lao, CD, Sandler, HM, Bradford, CR, Johnson, TM. “Merkel cell carcinoma: critical review with guidelines for multidisciplinary management”. Cancer. vol. 110. 2007. pp. 1-12. (Gives nice recommendations and guidelines for the multidisciplnary review of merkel cell carcinoma, examining critically the use of adjuvant radiation therapy and adjuvant chemotherapy.)
Guihard, S, Nöel, G. “Merkel cell carcinoma, role of radiotherapy and literature review”. Cancer Radiother. vol. 13. 2009. pp. 47-54. (Reviews the use of adjunctive XRT therapy for the treatment of Merkel cell carcinoma.)
Ruaan, JH, Reeves, M. “A Merkel cell carcinoma treatment Algorithm”. Arch Surg. vol. 144. 2009. pp. 582-5. (Well put-together Algorithm for the treatment and evalution of merkel cell carcinoma.)
Zampetti, A, Feliciani, C, Massi, G, Tulli, A. “Updated review of the pathogenesis and management of Merkel cell carcinoma”. vol. 14. 2010. pp. 51-61. (Reviews the most current knowledge on etiology, treatment, and prognosis of Merkel cell carcinoma.)
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