Skin nonmelanocytic tumor

• Rare low grade sweat gland carcinoma with nests / strands of atypical epithelial cells floating in lakes of extracellular mucin
• Distinction from metastatic mucinous carcinoma is essential

• 45 year old man presented with asymptomatic mass on left cheek (Int J Dermatol 2024 Jul 4 [Epub ahead of print])
• 60 year old woman presented with asymptomatic scalp lesion 7 years after positive cervical lymph nodes (J Cutan Pathol 2014;41:686)
• 61 year old man presented with 2 eyelid growths and 76 year old man presented with periorbital mass (Arch Craniofac Surg 2024;25:90)
• 68 year old woman presented with slow growing painless pink papules on eyelids (JAAD Case Rep 2021;9:78)
• 72 year old man presented with 2 year history of growing abdominal nodule (Ann Dermatol 2019;31:339)
• 84 year old man presented with blue mass of buccal space (Am J Otolaryngol 2018;39:242)

Contributed by Taylor Novice, M.D., M.B.A. and Paul Harms, M.D., Ph.D.


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• Soft nodule / mass (Dermatol Surg 2020;46:1141)
• May be translucent or cystic (Am J Otolaryngol 2018;39:242, Arch Craniofac Surg 2024;25:90)
• Nonencapsulated and usually poorly circumscribed (Am J Surg Pathol 2005;29:764)

Contributed by Taylor Novice, M.D., M.B.A., Paul Harms, M.D., Ph.D. and Case #413

• Immunohistochemistry (Am J Surg Pathol 2020;44:1005, Dermatol Surg 2023;49:1091, Am J Dermatopathol 2024;46:114)
  • Cytokeratins: low molecular weight cytokeratins, CK7, AE1 / AE3, CAM 5.2
  • EMA, E-cadherin, GATA3, c-MYB (Am J Dermatopathol 2017;39:279, J Cutan Pathol 2017;44:444)
  • ER, PR and GCDFP-15 (BRST2) (Am J Surg Pathol 2005;29:764)
    • Mucinous carcinoma of breast can have same staining profile
  • In situ component (if present): myoepithelial layer positive for p63, p40 or calponin (Am J Surg Pathol 2005;29:764)
  • MUC (Am J Dermatopathol 2024;46:114)
    • MUC1: positive for luminal aspect of cells
    • MUC2: intracytoplasmic positivity
  • CEA: can be positive (variable reports on sensitivity) (Am J Surg Pathol 2005;29:764)
  • Neuroendocrine differentiation in a subset (J Cutan Pathol 2014;41:686)
    • Synaptophysin, chromogranin, CD56 and neurospecific enolase can be expressed, including for noneyelid sites but many cases are negative (Ann Dermatol 2010;22:472, J Cutan Pathol 2014;41:686, Am J Surg Pathol 2005;29:764)
    • Small study (n = 9) of noneyelid primary cutaneous mucinous carcinoma (PCMC) with the more sensitive neuroendocrine marker INSM1 found that the majority were positive (Am J Surg Pathol 2023;47:1186)
    • Endocrine mucin producing sweat gland carcinoma (EMPSGC) associated PCMC proposed to be the neuroendocrine subtype of PCMC (Am J Surg Pathol 2020;44:1005)
      • Frequency and significance of neuroendocrine marker expression in PCMC not associated with EMPSGC is unclear (Am J Surg Pathol 2020;44:1005)
• Special stains
  • Mucin stains
    • Alcian blue (pH 2.5)
    • Colloidal iron
    • Mucicarmine
    • PAS

• Must rule out cutaneous metastasis or direct extension from visceral mucinous carcinoma (Dermatol Surg 2020;46:1141)
  • Presence of in situ component supports cutaneous origin
  • No definitive way to rule out metastasis if in situ component is absent (Dermatol Surg 2020;46:1141)
  • Morphologic features suggestive of metastasis
    • Increased cytologic atypia with or without more mitotic activity (although cutaneous metastasis may also be bland) (Dermatol Surg 2023;49:1091)
    • More clusters of cohesive neoplastic cells (J Pathol Transl Med 2018;52:238)
    • Less mucin (J Pathol Transl Med 2018;52:238)
    • Absence of fibrous septa (J Pathol Transl Med 2018;52:238)
    • Intestinal origin: dirty necrosis, glandular components resembling colonic adenocarcinoma (Am J Surg Pathol 2005;29:764)
  • Immunohistochemistry (Am J Surg Pathol 2005;29:764, J Pathol Transl Med 2018;52:238)
    • In situ component with peripheral myoepithelial cell layer (p63, SMA and calponin): specific but not completely sensitive for cutaneous origin
    • Mucinous carcinoma from intestine:
      • CK20 positive, typically CDX2 positive (some metastatic colorectal may lose CDX2)
    • Mammary mucinous carcinoma:
      • Cannot distinguish on H&E / IHC alone without in situ component
      • Also positive for CK7 and GCDFP-15
      • Chest wall / axilla lesions: mammary carcinoma originating from a lactiferous duct in the dermis can be indistinguishable from a primary cutaneous lesion
  • Workup for metastatic disease (PET scan, CT, mammography, etc.) (Am J Surg Pathol 2005;29:764, Dermatol Surg 2020;46:1141)
• Endocrine mucin producing sweat gland carcinoma (EMPSGC):
  • Proposed precursor lesion for mucinous carcinoma with neuroendocrine differentiation
    • Tumors with areas of both mucinous carcinoma and EMPSGC may be encountered (Am J Surg Pathol 2020;44:1005, J Cutan Pathol 2015;42:578)
    • These are proposed to exist on a clinical and histopathologic spectrum (Dermatol Surg 2023;49:1091, Am J Surg Pathol 1997;21:1501, Am J Surg Pathol 2005;29:1330, Am J Surg Pathol 2020;44:1005)
  • Almost exclusively on eyelids or periorbital skin (rare reports of extrafacial occurrence) (J Cutan Pathol 2014;41:544)
  • Association with benign sweat ducts; in situ carcinoma that spreads between luminal ductal epithelium and myoepithelial layer (Am J Surg Pathol 2005;29:1330, J Cutan Pathol 2015;42:578)
    • Only peripheral layer of myoepithelial cells expresses p63, SMA, calponin
  • Mucin within cystic spaces and epithelial aggregates but not lakes / pools (Am J Surg Pathol 2005;29:1330)
  • Positive for neuroendocrine markers (chromogranin, synaptophysin, neuron specific enolase, INSM1) (Dermatol Surg 2023;49:1091, Am J Surg Pathol 1997;21:1501)
    • Can be focal or even absent on small biopsy (Am J Surg Pathol 2020;44:1005)
  • If invasive component develops within lakes / pools of mucin, considered to have progressed to cutaneous mucinous carcinoma (Am J Surg Pathol 2020;44:1005)
  • Distinction between mucinous carcinoma with more solid areas and EMPSGC can be challenging (Am J Surg Pathol 2020;44:1005, J Cutan Pathol 2015;42:578, Dermatol Surg 2023;49:1091)

• Requena: Cutaneous Adnexal Neoplasms, 1st Edition, 2017, WHO Classification of Tumours Editorial Board: Skin Tumours, 5th Edition, 2022

An 81 year old woman presents with a 1.5 x 2.0 cm, slow growing nodule on the right cheek. An excisional biopsy is performed, which shows the findings in the figure above. Immunohistochemistry is positive for CK7 and GCDFP-15. p63, synaptophysin, chromogranin A, CK20 and CDX2 are diffusely negative. What is the most likely diagnosis?

1. Basal cell carcinoma
2. Cutaneous metastasis of mammary mucinous carcinoma
3. Endocrine mucin producing sweat gland carcinoma
4. Primary cutaneous mucinous carcinoma
5. Unable to distinguish between primary cutaneous mucinous carcinoma and mammary mucinous carcinoma with information provided

E. Unable to distinguish between primary cutaneous mucinous carcinoma and mammary mucinous carcinoma with information provided. Both primary cutaneous mucinous carcinoma and mammary mucinous carcinoma have the characteristic histopathology shown in the figure: basaloid islands floating in pools of mucin, separated by fibrous septa. Without the in situ component (positive for p63), it is impossible to distinguish between these 2 entities. CK20 and CDX2 negativity militates against a gastrointestinal visceral metastasis. Further workup for metastatic disease is essential. Answer A is incorrect because the histopathology and staining profile is not characteristic for basal cell carcinoma (BCC). Stromal mucin is seen in BCC but not pools of mucin characteristic of mucinous carcinoma. GCDFP-15 is negative in basal cell carcinoma. Answers B and D are incorrect because histopathology and immunohistochemistry cannot distinguish between these entities. Answer C is incorrect because endocrine mucin producing sweat gland carcinoma has different histopathologic findings (i.e., not characterized by invasive basaloid islands floating in pools of mucin) and it should stain positive for neuroendocrine markers (e.g., synaptophysin, chromogranin A) and p63 in the myoepithelial layer.

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Reference: Primary cutaneous mucinous carcinoma

Which of the following is true about primary cutaneous mucinous carcinoma?

1. Cutaneous mucinous carcinoma is an aggressive tumor with a high metastatic rate
2. Neuroendocrine differentiation of primary cutaneous mucinous carcinoma is associated with a worse prognosis
3. Primary cutaneous mucinous carcinoma and endocrine mucin producing sweat gland carcinoma are synonymous entities
4. Recurrences are common and complete excision with margin assessment is recommended
5. The scalp is the most common location for primary cutaneous mucinous carcinoma

D. Recurrences are common and complete excision with margin assessment is recommended. Recurrences are common in primary cutaneous mucinous carcinoma (~20 - 30%). This may be a result of small tumor aggregates extending into the deeper dermis / subcutis, far from the main tumor mass. Complete excision with margin assessment is recommended. Answer A is incorrect because primary cutaneous mucinous carcinoma is typically considered a low grade neoplasm with a low metastatic rate. In contrast, metastatic visceral carcinoma to the skin has a worse prognosis. Answer B is incorrect because the association of neuroendocrine differentiation with prognosis is inconclusive. However, reviews by Agni et al. and Au et al. suggest the neuroendocrine subtype of primary cutaneous mucinous carcinoma may have a more indolent behavior and more favorable prognosis (Am J Dermatopathol 2023;45:123). Answer C is incorrect because endocrine mucin producing sweat gland carcinoma is typically considered an in situ precursor to primary cutaneous mucinous carcinoma with neuroendocrine differentiation. Answer E is incorrect because while the head / neck is the most common location for this tumor, ~50% occur on the eyelid. The scalp comprises 17% of cases and nonperiorbital head / neck comprises 20% of cases.

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Reference: Primary cutaneous mucinous carcinoma