# Merkel Cell Carcinoma and Rare Cutaneous Malignancies

## Merkel Cell Carcinoma (MCC)

### Epidemiology

Merkel cell carcinoma is a rare but aggressive neuroendocrine carcinoma of the skin with approximately 3,000 cases per year in the United States. Its incidence has risen rapidly, increasing 95 percent from 2000 to 2013. The median age at diagnosis is 75 to 80 years, and there is a strong male predominance (2:1). Risk factors include UV exposure, fair skin, and immunosuppression, with HIV, organ transplant, and CLL patients facing a 10- to 30-fold increased risk.

### Pathogenesis

**Merkel cell polyomavirus (MCPyV)** is clonally integrated in approximately 80 percent of MCC tumors. The viral genome harbors truncating mutations in the large T antigen, while the small T antigen maintains cell proliferation. Virus-positive MCC has fewer somatic mutations, tends to occur in younger patients, and carries a better prognosis. **Virus-negative MCC**, accounting for approximately 20 percent of cases, has a high UV mutational burden with TP53 and RB1 mutations, higher tumor mutational burden, and a worse prognosis.

### Clinical Features

The clinical features are captured by the **AEIOU mnemonic**: **A**symptomatic, **E**xpanding rapidly, **I**mmunosuppression, **O**lder than 50, and **U**V-exposed site. MCC typically presents as a firm, dome-shaped, violaceous or red-blue nodule, most commonly on the head and neck (50 percent) or extremities. It is frequently misdiagnosed as a cyst, BCC, or lymphoma at presentation. At diagnosis, 25 to 30 percent of patients have nodal involvement and approximately 5 percent have distant metastases.

### Histopathology

MCC is a **small round blue cell tumor** within the dermis that must be differentiated from other small blue cell tumors. Histologic patterns include trabecular, intermediate, and small cell types. The characteristic immunohistochemical finding is **paranuclear dot-like CK20 positivity**, present in approximately 95 percent of cases. Additional markers include synaptophysin, chromogranin, and neuron-specific enolase. Critically, MCC is **negative for TTF-1** (distinguishing it from small cell lung cancer), S100, and LCA.

### Staging (AJCC 8th Edition)

Stage I encompasses tumors of 2 cm or less that are node-negative. Stage II includes tumors greater than 2 cm without nodal involvement. Stage III includes regional nodal involvement, and Stage IV represents distant metastasis. Clinical staging (without pathologic node assessment) carries a worse prognosis than pathologic staging.

### Management

The primary tumor is managed with **wide local excision** with 1 to 2 cm margins (Mohs surgery is controversial but used at some centers). **Sentinel lymph node biopsy** is recommended for all clinically node-negative patients, with positivity rates of 25 to 35 percent; SLN status is the strongest predictor of survival. **Adjuvant radiation** to the primary site and regional nodes is recommended, reducing local and regional recurrence by approximately 50 percent, as MCC is highly radiosensitive. For advanced or metastatic MCC, **avelumab** (anti-PD-L1) is FDA-approved with overall response rates of approximately 33 percent in second-line and 62 percent in first-line settings, with durable responses. **Pembrolizumab** achieves an overall response rate of approximately 56 percent in treatment-naive patients. Both virus-negative MCC (through high TMB) and virus-positive MCC (through viral antigen expression) are responsive to immunotherapy. Chemotherapy with cisplatin and etoposide achieves a high initial response rate of approximately 60 percent but responses are short-lived with no overall survival benefit; it is reserved for checkpoint inhibitor failures.

### Prognosis

Five-year overall survival rates are approximately 62 percent for Stage I, 35 percent for Stage II, 28 percent for Stage III, and 14 percent for Stage IV. The recurrence rate is approximately 40 percent within 2 years, necessitating close surveillance with clinical examination and imaging every 3 to 6 months for 3 years.

| MCC Stage | Definition | 5-Year OS |
|-----------|-----------|-----------|
| I | Tumor ≤ 2 cm, node-negative | ~62% |
| II | Tumor > 2 cm, node-negative | ~35% |
| III | Regional nodal involvement | ~28% |
| IV | Distant metastasis | ~14% |

<image>Clinical photograph of Merkel cell carcinoma presenting as a violaceous dome-shaped nodule on the face of an elderly patient alongside histopathology showing small round blue cells with paranuclear dot-like CK20 immunostaining</image>

## Dermatofibrosarcoma Protuberans (DFSP)

### Key Features

DFSP is a low-to-intermediate grade fibrohistiocytic tumor arising in the dermis and subcutis. Its incidence is 0.8 to 5 per million per year, affecting young to middle-aged adults with a slight predominance in Black patients. The molecular hallmark is the **t(17;22) translocation** fusing COL1A1 to PDGFB, present in over 90 percent of cases, resulting in constitutive PDGFB signaling. Clinically, DFSP presents as a slow-growing, indurated, skin-colored to reddish-brown plaque on the trunk (most common site) or proximal extremities. A nodular or protuberant component may develop after years of indolent growth.

### Histopathology

DFSP shows spindle cells arranged in a **storiform ("cartwheel") pattern** infiltrating the dermis and subcutaneous fat. It is **CD34-positive** (in over 90 percent) and **Factor XIIIa-negative**, distinguishing it from dermatofibroma (which is Factor XIIIa-positive and CD34-negative). Fibrosarcomatous transformation (DFSP-FS) produces higher-grade areas with a herringbone pattern and carries increased recurrence and metastatic potential.

### Management

**Mohs micrographic surgery** is the treatment of choice with a cure rate of approximately 98 percent, compared to approximately 80 percent with standard excision. Extensive subclinical extension is common, explaining the high recurrence rate with conventional margins. If Mohs is unavailable, wide local excision with 2 to 3 cm margins is recommended. **Imatinib**, a PDGFR inhibitor, is FDA-approved for unresectable or metastatic DFSP, targeting the COL1A1-PDGFB fusion with an overall response rate of approximately 50 percent. The translocation should be confirmed before starting imatinib, as fibrosarcomatous variants may lose the target. Metastasis is rare (less than 5 percent) except in fibrosarcomatous transformation.

<image>Clinical photograph of dermatofibrosarcoma protuberans showing a multinodular protuberant mass on the trunk, and corresponding histopathology with storiform pattern and CD34 immunostaining</image>

## Microcystic Adnexal Carcinoma (MAC)

### Key Features

MAC is a low-grade sweat gland carcinoma with a propensity for perineural invasion. It occurs most commonly on the upper lip and perioral area of middle-aged to elderly adults. It presents as a slow-growing, firm, skin-colored to yellowish plaque or nodule and is often clinically mistaken for morpheaform BCC, scar, or desmoplastic trichoepithelioma.

### Histopathology

MAC demonstrates biphasic differentiation with superficial keratin-filled cysts (reflecting follicular differentiation) and deep ductal or glandular structures. The growth pattern is deeply infiltrative, extending into subcutis, muscle, and periosteum. Perineural invasion is present in 60 to 80 percent of cases. The stroma is sclerotic with bland cytology and a low mitotic rate.

### Management

**Mohs micrographic surgery** is the treatment of choice due to extensive subclinical spread. The recurrence rate is 40 to 60 percent after standard excision but less than 5 percent after Mohs. Radiation is reserved for inoperable tumors with some role as adjuvant therapy for perineural invasion. Metastasis is exceedingly rare (less than 1 percent).

## Sebaceous Carcinoma

### Key Features

Sebaceous carcinoma is an aggressive adnexal tumor, with 75 percent arising on the eyelid (periocular). The median age is 60 to 70 years with a slight female predominance for ocular lesions. **Muir-Torre syndrome** must be considered: the association of sebaceous neoplasms with visceral malignancies (especially colorectal and genitourinary) results from **mismatch repair gene mutations** (MSH2, MLH1) and represents a variant of Lynch syndrome. Tumor screening with MMR immunohistochemistry and consideration of microsatellite instability testing is recommended.

### Clinical Features

**Periocular** sebaceous carcinoma frequently masquerades as a chalazion or chronic blepharoconjunctivitis, often delaying diagnosis. It favors the upper eyelid over the lower eyelid. Pagetoid spread along the conjunctival epithelium is common, and map biopsies are recommended. **Extraocular** sebaceous carcinoma presents as a firm, yellowish papule or nodule on any sebaceous-rich area, most commonly the head and neck.

### Histopathology

The tumor shows a lobulated growth pattern with sebaceous differentiation manifested by foamy, vacuolated cytoplasm. Pagetoid intraepidermal spread is common, especially in ocular lesions. Immunohistochemistry shows positivity for EMA, adipophilin, and androgen receptor. Loss of MMR proteins indicates Muir-Torre syndrome.

### Management

**Mohs surgery** with en face frozen sections (or excision with wide margins of 5 to 6 mm) is the primary treatment. Map biopsies of the conjunctiva assess pagetoid spread in periocular tumors. SLNB should be considered for tumors larger than 2 cm or with high-risk features, with positivity rates of 10 to 20 percent. Adjuvant radiation is used for large tumors, positive margins, or orbital involvement. The 5-year recurrence rate is 11 to 30 percent, and the metastatic rate is 10 to 25 percent, with higher rates for periocular tumors.

## Atypical Fibroxanthoma (AFX) and Pleomorphic Dermal Sarcoma (PDS)

### Key Features

**AFX** presents as a rapidly growing, dome-shaped nodule on sun-damaged skin of the head and neck in elderly patients. It is a superficial lesion confined to the dermis and is considered a diagnosis of exclusion. **PDS** is the deeper, more aggressive variant with subcutaneous invasion, necrosis, and lymphovascular or perineural invasion. Histologically, both show atypical spindle and pleomorphic cells with numerous mitoses and bizarre giant cells. The diagnosis requires ruling out SCC, melanoma, and leiomyosarcoma with an immunohistochemistry panel: AFX and PDS are negative for keratins, S100, desmin, and SMA, and are CD10-positive and CD68-positive (though these are non-specific).

### Management

AFX is treated with excision with clear margins (Mohs or 1 to 2 cm wide local excision) and carries an excellent prognosis with metastasis being exceedingly rare. PDS requires wider excision or Mohs with consideration of adjuvant radiation, has a 10 to 20 percent recurrence rate, and has rare metastatic potential.

| Rare Cutaneous Malignancy | Molecular Hallmark | Key IHC | Treatment of Choice | Metastatic Risk |
|--------------------------|-------------------|---------|-------------------|-----------------|
| MCC | MCPyV (80%); UV mutations (20%) | CK20+ (paranuclear dot), TTF-1− | WLE + SLNB + RT; immunotherapy for advanced | High |
| DFSP | t(17;22) COL1A1-PDGFB | CD34+, Factor XIIIa− | Mohs surgery; imatinib for unresectable | Low (<5%) |
| MAC | None specific | — | Mohs surgery | Very low (<1%) |
| Sebaceous carcinoma | MMR loss (Muir-Torre) | EMA+, adipophilin+ | Mohs + map biopsies; SLNB for large | Moderate (10–25%) |
| AFX/PDS | UV-driven; diagnosis of exclusion | CD10+; keratin−, S100−, desmin− | Excision (AFX); wide excision ± RT (PDS) | Rare (AFX); low (PDS) |

## Angiosarcoma

### Key Features

Angiosarcoma is an aggressive vascular malignancy with a poor prognosis and 5-year overall survival of approximately 30 to 40 percent. It occurs in three clinical settings: **head and neck angiosarcoma of the elderly** (the most common cutaneous form), presenting as a bruise-like macule or plaque expanding on the scalp or face; **chronic lymphedema-associated angiosarcoma** (Stewart-Treves syndrome), typically occurring in the upper extremity after mastectomy; and **radiation-associated angiosarcoma**, arising in a prior radiation field (breast, chest wall) with a latency of 5 to 10 years.

Histologically, angiosarcoma shows irregular vascular channels lined by atypical endothelial cells infiltrating the dermis. Well-differentiated tumors can be difficult to distinguish from benign vascular proliferations. Immunohistochemistry shows positivity for CD31, CD34, ERG, D2-40 (in some cases), and FLI-1.

### Management

Wide excision with generous margins is the primary treatment, though it is often difficult due to multifocal or ill-defined growth. Adjuvant radiation is recommended. Systemic options include paclitaxel (most commonly used) and doxorubicin, though responses are limited. Anti-angiogenic therapy (bevacizumab, pazopanib) has shown some activity, and checkpoint inhibitors have emerging data showing responses in some cases. The prognosis remains poor regardless of treatment, with a median survival of 15 to 20 months.

<image>Clinical photographs comparing rare cutaneous malignancies: angiosarcoma of the scalp (bruise-like expanding plaque), sebaceous carcinoma of the eyelid (yellowish nodule mimicking chalazion), and microcystic adnexal carcinoma of the upper lip (skin-colored firm plaque)</image>

## Clinical Pearls

Merkel cell carcinoma follows the AEIOU mnemonic -- any rapidly growing, asymptomatic, violaceous nodule in an elderly or immunosuppressed patient on a sun-exposed site should raise suspicion. CK20 paranuclear dot staining is the immunohistochemical hallmark of MCC and distinguishes it from small cell lung cancer (which is TTF-1-positive and CK20-negative). DFSP has notoriously extensive subclinical spread, and Mohs surgery is strongly preferred over standard excision due to the high recurrence rate with conventional margins. A recurrent "chalazion" that does not respond to standard treatment should be biopsied to exclude sebaceous carcinoma, and testing for Muir-Torre syndrome (MMR immunohistochemistry) is essential. Angiosarcoma of the scalp in elderly patients often presents as a "bruise that won't heal" -- a high index of suspicion and early biopsy are critical for this highly lethal malignancy.

## References
- Becker JC, et al. Merkel cell carcinoma. Nat Rev Dis Primers. 2017;3:17077
- Harms PW, et al. The biology and treatment of Merkel cell carcinoma: current understanding and research priorities. Nat Rev Clin Oncol. 2018;15(12):763-776
- D'Angelo SP, et al. Efficacy and safety of first-line avelumab treatment in patients with stage IV metastatic Merkel cell carcinoma (JAVELIN Merkel 200). JAMA Oncol. 2018;4(9):e180077
- Llombart B, et al. Dermatofibrosarcoma protuberans: a comprehensive review. Curr Opin Oncol. 2019;31(2):141-149
- Owen JL, et al. Sebaceous carcinoma: evidence-based clinical practice guidelines. Lancet Oncol. 2019;20(12):e699-e714