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Mesenchymal Neoplasms with
Melanocytic Differentiation
By Konstantinos Linos MD, FCAP, FASDP
Bone, Soft Tissue and Dermatopathology
Assistant Professor of Pathology
Dartmouth-Hitchcock Medical Center
Geisel School of Medicine at Dartmouth
Hanover, NH, USA
• Book Royalties
Financial disclosures
• Melanotic Schwannoma
• Perivascular Epithelioid Cell Tumor (PEComa)
• Clear Cell Sarcoma
• Clear Cell Sarcoma-like Tumor of the GI Tract
• Pigmented DFSP
• Melanotic Neuroectodermal Tumor of Infancy
• Malignant Peripheral Nerve Sheath Tumor
• Epithelioid Schwannoma
• Diffuse neurofibromas with melanocytic
differentiation
• Melanocytic schwannoma
• Cutaneous melanocytoneuroma
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Melanotic Schwannoma
• Rare tumor of putative neural crest
origin
• Most often in paraspinal nerve roots
and gastrointestinal tract
• Association with other stigmata of
Carney complex
• Skin pigmentary abnormalities,
myxomas, endocrine
tumors/endocrine hyperactivity
• Mutations in PRKAR1A gene
• Unknown ‘cell of origin”
• Hybrid light microscopic and
ultrastructural features of
Schwann cells and melanocytes
• Unpredictable behavior
• 13-26% metastases including
histologically benign-appearing
tumors
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Myxoid Change “Small cell pattern”
“Rippled pattern”
Bone Invasion Pulmonary Metastasis
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Fontana-Masson
S100-protein SOX10
MelanA
S100-protein HMB45
Loss of PRKAR1A
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Cutaneous Melanotic
Schwannomas
• Tend to arise in the trunk (67%)
• Largely equal gender distribution
• Can be associated with Carney Complex
(56%)
• Melanotic neurofibroma
• Pigmented Epithelioid Melanocytoma (PEM)
• Variants of blue nevi
• Melanoma
Differential Diagnosis
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Melanotic Schwannoma vs
Melanoma• No individual clinicopathologic features
that are completely specific
• Melanotic Schwannoma
• Paravertebral, predominantly spindled, heavy
melanin pigmentation, psammoma bodies,
striking nuclear pleomorphism with low mitotic
activity
• Detailed clinical history
• Careful dermatologic examination
Gene Expression Profiling
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Proposed classification scheme of PEM
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• Mesenchymal tumor composed of perivascular
epithelioid cells (PEC)
• Distinctive neoplastic cell with no known normal
counterpart
• Unique as it shows immunoreactivity for
both melanocytic and smooth muscle
markers
Perivascular Epithelioid Cell
Tumor (PEComa)
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• Group of mesenchymal neoplasms
• Angiomyolipoma
• Clear cell “sugar” tumor of the lung and
extrapulmonary sites
• Lymphangioleiomyomatosis
• Clear cell myomelanocytic tumor of the
falciform ligament/ligamentum teres
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Histologic Features
• Ill-defined dermal proliferation of epithelioid
cells
• Arrangement in nests and trabeculae within an
arborizing network of delicate capillaries
• Uniform round to ovoid vesicular nuclei
• Pink clear or granular cytoplasm
• Nuclei usually bland
• Low-mitotic activity
• Occasional multinucleated giant cells
• Distinct immunophenotype
• Melanocytic
• HMB45, MiTF, Melan-A, tyrosinase
• Smooth muscle
• Desmin, SMA, calponin
• HMB45 the most sensitive
• Primary cutaneous less likely to demonstrate
immunoreactivity for smooth muscle
Immunohistochemistry
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Desmin
MelanAHMB45
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• HMB45- 94%
• MelanA- 35%
• NKI/C3- 100%
• MiTF- 100%
• MSA-17%
• SMA-42%
• Desmin-30%
• Calponin-15%
• Caldesmon-8%
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Differential Diagnosis• Balloon Cell Nevus
• “Clear cell” melanoma
• Clear cell sarcoma
• Lack of strong diffuse positivity for S100-protein
and SOX10
• Dermal Clear Mesenchymal Neoplasm
(DCCMN)
• Metastatic clear cell carcinoma
• Positive for PAX8, RCC, negative for melanocytic
markers (except melanotic Xp11 translocation
renal cell cancer)
• S100-protein and/or SOX10
• MelanA
• HMB45
• SMA
• Desmin
Prognosis
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Clear Cell Sarcoma
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• Usually lesions relatively small (<5cm)
• Primary cutaneous <1cm
• Otherwise similar clinical and pathologic features
• Natural history clinically protracted
• Multiple local recurrences
• Late metastases in lymph nodes, lung, bone
• Wide local excision with adjuvant radiation
S100-Protein Melan-A
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t(12;22)(q13;q12)
EWSR1-ATF1
t(2;22)(q34;q12)
EWSR1-CREB1
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Differential Diagnosis• Melanoma
• Perivascular Epithelioid Cell Neoplasm
(PEComa)
• Cellular Blue Nevus
• Cutaneous Melanocytoma with CRTC1-
TRIM11 Fusion
Cellular Blue Nevus
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Melanoma ex blue nevus
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S100-Protein NTRK1
HMB45 MelanA TRIM11
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• No activating mutations of the MAP-kinase
pathway such as BRAF and NRAS
• No hTERT mutations
• In some cases only a whole gain of
chromosome 7
• No local recurrences or metastatic evolution
(short follow-up)
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SOX-10 MelanA
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• Similar morphologic, immunophenotypic and
molecular genetic features with clear cell
sarcoma of tendons and aponeuroses
• However many lack evidence of melanocytic
differentiation
• EWSR1-CREB1>> or EWSR1-ATF1 fusions
Clear Cell Sarcoma-like Tumor
of the GI Tract
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S100-Protein SOX-10
Synaptophysin CD56
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Dermatofibrosarcoma
Protuberans (DFSP)
• Giant cell
fibroblastoma
• Pigmented DFSP
• DFSP with myoid
nodules
• Fibrosarcomatous
DFSP
• Myxoid DFSP
Pigmented DFSP (Bednar Tumor)
• Rapidly growing pigmented neoplasm
• Typically in infants <1 year-old
• Predominantly involves craniofacial sites
• Biphasic population of melanocytic and
primitive neuroectodermal cells
Melanotic Neuroectodermal
Tumor of Infancy
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Neurospecific enolase Pan Cytokeratin
HMB45 S100
• Defined as an MPNST predominatly localized
in the dermis and/or subcutis
• In contrast to their deep soft tissue and visceral
counterparts rarely a/w with NF1
• Two main subtypes
• Conventional/spindled
• Epithelioid
Cutaneous Malignant
Peripheral Nerve Sheath Tumor
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S100
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S100-protein
INI-1
MelanA
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S100 INI1
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S100 SOX10
EMA INI-1
MelanA
MelanA
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MelanA
HMB45 MITF
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S100 MelanA
EMA Collagen IV
• Email: [email protected]
• @ @ KonstantinosLin
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