Uncommon Malignant Tumors of the Skin

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What is an atypical fibroxanthoma (AFX) and what is it relationship to pleomorphic dermal sarcoma (PDS)?

AFX is a malignant neoplasm that occurs chiefly in the elderly, upon sun-damaged skin. These tumors are usually well circumscribed, grow rapidly, and demonstrate an exophytic architecture but are otherwise indistinct ( Fig. 46.1 A,B ). AFX does not invade the deep soft tissue, and in general, it has a favorable prognosis. PDS occurs in a similar population, with cellular morphology similar to AFX, but it manifests more aggressive histological features, such as deep invasion, tumor necrosis, and lymphovascular or perineural invasion. PDS has greater potential for local recurrence and metastasis. Distinguishing AFX from PDS is important due to differences in clinical behavior (see below).

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What are the histologic features of AFX and PDS?

Both AFX and PDS are dermal processes, without an epidermal connection, but often with an epidermal collarette. The tumor is composed of spindle and slightly epithelioid cells arranged in disordered fascicles, with striking nuclear pleomorphism and hyperchromasia, and numerous mitotic figures, including atypical forms (ring mitoses, tripolar mitoses, etc.). Importantly, as AFX and PDS may be confused with other entities, such as spindle-cell squamous cell carcinoma and desmoplastic/spindle-cell melanoma, immunostains are utilized to exclude other entities. In general, AFX/PDS mark affirmatively with immunostains for CD10, CD68, and procollagen I.

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What is the clinical course of AFX and PDS?

Despite high-grade cytologic atypia and a malignant histologic appearance, AFX has a favorable prognosis, typically with complete resolution upon extirpation. However, PDS is also managed surgically but is more often associated with local recurrence and even metastatic behavior. PDS can be particularly problematic in persons with immunosuppression, to include chronic lymphocytic leukemia. The metastatic behavior of PDS is problematic for treatment, but the author (W.A.H.) has had success with programmed death protein-1 (PD-1) inhibitors. Attempts to distinguish between AFX and PDS based upon shallow shave specimens are impossible, as depth of invasion is a key determinate. In such cases, full reevaluation will be necessary upon full surgical extirpation.

Griewank KG, Wiesner T, Murali R, et al. Atypical fibroxanthoma and pleomorphic dermal sarcoma harbor frequent NOTCH1/2 and FAT1 mutations and similar DNA copy number alteration profiles. Mod Pathol . 2018;31:418–428.

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What is a Merkel cell carcinoma (MCC)?

Also known as primary neuroendocrine carcinoma of the skin, MCC is an aggressive skin malignancy. The incidence and mortality of MCC are both increasing. The tumor was originally thought to arise from Merkel cells, which are involved in sensory reception in the skin, but this is not known with certitude and is widely debated.

Kervarrec T, Samimi M, Guyétant S, et al. Histogenesis of Merkel cell carcinoma: a comprehensive review. Front Oncol . 2019;9:451.

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Describe the clinical presentation of MCC

MCC usually presents as a solitary, rapidly growing, painless dermal or subcutaneous nodule with a slight violaceous hue, on the sun-damaged skin of elderly persons. Whites are affected most often. The head and neck ( Fig. 46.2 A ) are high-risk areas, but the extremities and trunk can be involved, on occasion. The mnemonic “ AEIOU + blue ” helps to recollect some of the features of MCC: A symptomatic/lack of tenderness; E xpanding rapidly; I mmune-suppressed persons; O lder than 50 years; U ltraviolet (UV)-exposed skin, and with a slightly “ blue” hue.

Adapted by W.A.H. from: Heath M, Jaimes N, Lemos B, et al. Clinical characteristics of Merkel cell carcinoma at diagnosis in 195 patients: the AEIOU features. J Am Acad Dermatol . 2008;58:375–381.

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What is the pathogenesis of MCC?

MCC is rare before the age of 50 years, but the incidence increases sharply after 65 years of age. This suggests an accumulation of pro-oncogenic events, such as:

• Immunosuppression —patients with chronic lymphocytic leukemia, HIV, acquired immunosuppression, and organ transplantation have higher incidence of MCC.

• UV exposure —most tumors present on sun-exposed areas, and the risk of MCC may be increased by prior psoralen and UV A treatment.

• Merkel cell polyomavirus (MCV) —the pathogenic role of MCV is still under investigation. Although MCV infections in humans may be common, the integration of the virus into the genome is not, and this event is strongly associated with MCC and may play a role in the oncogenesis for most, if not all, cases of MCC.

Amber K, Mcleod MP, Nouri K. The Merkel cell polyomavirus and its involvement in Merkel cell carcinoma. Dermatol Surg. 2013;39:232–238.

Feng H, Shuda M, Chang Y, Moore PS. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science. 2008;319:1096–1100.

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Can any other tumors be microscopically confused with MCC?

Yes. MCC is composed of “ small blue (basaloid) cells ” with hyperchromatic nuclei, scant cytoplasm, and numerous mitoses ( Fig. 46.2 B). It may be confused with metastatic small cell carcinoma of the lung, lymphomas, sweat gland carcinoma, metatypical basal cell carcinoma, metastatic carcinoid tumors, and Ewing sarcoma.

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How can MCC be distinguished from these other tumors?

MCC often has a characteristic paranuclear/perinuclear “dot” with immunostains for cytokeratins, particularly cytokeratin 20 ( Fig. 46.2 B, inset ). Moreover, cytokeratin 20 is not expressed in basal cell carcinoma, lymphomas, or sweat gland carcinoma ( Fig. 46.2 C). MCC also marked with various neuroendocrine markers, such as synaptophysin, chromogranin A, and neuron-specific enolase. Epithelial membrane antigen (EMA) is also expressed in most MCC, as is CD56. Neurofilament is a useful marker for confirming or refuting the diagnosis of MCC. Electron microscopy may demonstrate the dense core neurosecretory granules seen in MCC but is rarely necessary.

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How do you treat MCC?

Wide local excision is necessary for MCC. Margins of 1–2 cm are employed, depending upon the clinical size of the lesion. Sentinel lymph node biopsy (SLNB) is recommended for all patients fit for the procedure (remember, MCC is common in the elderly). As with other skin cancers, SLNB is almost always performed at the time surgery for removal of the primary tumor. For patients with uninvolved lymph nodes, the present position of the National Comprehensive Cancer Network is that it is “unclear how to identify patients with MCC most likely to benefit from postoperative radiotherapy.” Patients with regional lymph node involvement are often treated with lymph node dissection and/or irradiation. Chemotherapy and immunotherapy may be used for unresectable, metastatic, and recurrent MCC. Current immunotherapies employed in MCC include pembrolizumab and nivolizumab (anti-PD-1 agents) and avelumab (an anti-PD-L1 agent).

Bichakjian JCK, Olencki T, Aasi SZ, et al. Merkel cell carcinoma, clinical practice guidelines in oncology. J Natl Compr Canc Netw . 2018;16:742–774.

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Does MCC metastasize, and what is the overall prognosis?

Yes. Up to 75% of patients develop regional lymph node metastases. Distant metastases occur to in 30% to 40%. The prognosis of MCC is related to disease stage, with a 5-year survival rate ranging from 81% in patients with small and localized tumors to 11% in those patients with metastatic disease. More than half of all patients experience recurrence, usually within 1 year of treatment. All patients need close serial surveillance.

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What is a microcystic adnexal carcinoma (MAC)?

MAC is a locally aggressive cutaneous malignancy of sweat duct origin that typically presents as a slow-growing, firm, ill-defined skin-colored or yellow plaque or nodule on the head and neck, most often on the upper lip ( Fig. 46.3 A ). Numbness, paresthesia, burning, discomfort, and rarely pruritus of the affected area may be reported and are caused by a propensity for perineural invasion. Patients are usually Caucasians between 40 and 60 years of age. Because of its innocuous clinical appearance and slow progression, the diagnosis is often delayed.

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What are the histologic features of MAC?

The tumor presents as an epithelial tumor without connection to the overlying epidermis and with infiltrative cords and strands with variable keratinization and/or ductal differentiation ( Fig. 46.3 B). The tumor cells often induce a desmoplastic stroma. Tumor islands become progressively smaller with depth in the dermis. Deep invasion and perineural invasion are characteristic. An adequate biopsy is essential, as a superficial sampling may lead to misdiagnosis. The entity must be distinguished from morpheaform basal cell carcinoma, desmoplastic trichoepithelioma, trichoadenoma, or syringoma.

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