Soft tissue

Peripheral nerve


Malignant melanotic nerve sheath tumor

Last author update: 7 February 2023
Last staff update: 22 January 2024

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PubMed Search: Malignant melanotic nerve sheath tumor

Amna Babar, M.B.B.S.
Nasir Ud Din, M.B.B.S.
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Cite this page: Babar A, Anjum S, Ud Din N. Malignant melanotic nerve sheath tumor. website. Accessed May 20th, 2024.
Definition / general
  • Rare aggressive peripheral nerve sheath tumor uniformly composed of Schwann cells showing melanocytic differentiation, usually arising in association with spinal or visceral autonomic nerves (Adv Anat Pathol 2021;28:44)
  • Previously classified as a benign tumor in the 2013 WHO classification; however, 2020 WHO classification includes this entity as malignant melanotic nerve sheath tumor (MMNST) due to its malignant behavior (World J Clin Cases 2022;10:8735, BMJ Case Rep 2022;15:e252107)
  • Approximately 50% of cases are associated with Carney complex (Adv Anat Pathol 2021;28:44)
Essential features
  • Peripheral nerve sheath tumor neoplasm comprised of Schwann cells showing melanocytic differentiation, commonly in association with spinal or visceral autonomic nerves
  • Fascicular to sheet-like proliferation of heavily pigmented, relatively uniform plump spindle cells
  • Co-expression of S100 / SOX10 and melanocytic markers (HMB45, MelanA)
  • The behavior of MMNST is difficult to predict and metastases can occur in the absence of morphologically malignant features
  • Loss of PRKAR1A expression suggests a link to Carney complex (Am J Surg Pathol 2014;38:94)
  • Preferable: malignant melanotic nerve sheath tumor
  • Acceptable: melanotic schwannoma; psammomatous melanotic schwannoma; malignant melanotic Schwannian tumor
ICD coding
  • ICD-O: 9540/3 - malignant peripheral nerve sheath tumor
  • ICD-11: 2B5E & XH2XP8 - malignant nerve sheath tumor of peripheral nerves or autonomic nervous system, primary site & malignant peripheral nerve sheath tumor
  • Poorly understood, most tumors are sporadic
  • Characterized by a complex karyotype with recurrent monosomy of band 22q, variable whole chromosomal gains and recurrent losses involving chromosomes 1, 21 and 17p
  • 50 - 55% of psammomatous MMNST cases are associated with Carney complex, which shows mutation within chromosome 17 (affecting PRKAR1A / 17q24 band) (Nat Genet 2000;26:89, Genes Chromosomes Cancer 2015;54:463)
  • Recent cytogenetic studies demonstrated trisomy 6p and ring chromosome 11 in MMNST, suggesting that the tumor may share some genetic aberrations with malignant melanoma; however, it lacks BRAF V600E as in malignant melanoma (Arch Pathol Lab Med 2018;142:1517)
  • A missense DDR2 mutation of Q231K has been identified in 1 case report (Case Rep Oncol 2021;14:826)
Clinical features
  • Local mass with associated pain and neurologic symptoms, depending on site and rate of growth or incidental
  • Tumors associated with nerves (35.5% of patients) include motor and sensory abnormalities
  • Pressure symptoms with large tumors
  • Cutaneous lesions can manifest features similar to melanomas
  • Asymptomatic presentations have been noted in 29% of cases
  • Reference: Arch Pathol Lab Med 2018;142:1517
  • Clinical history
  • CT scan / MRI remains the investigation of choice
  • Fluorodeoxyglucose (FDG) PET / CT one stop examination can detect tumors and determine whether they are malignant based on their glucose metabolism before morphological changes occur (Medicine (Baltimore) 2021;100:e24803)
  • Biopsy followed by histopathology
Radiology description
Radiology images

Images hosted on other servers:

PET / CT: extraspinal tumor with strong FDG

Well circumscribed tumor in the Meckel cavum

MET PET / MRI: recurrence with hypermetabolic activity

MRI of cystic mass at the para-aortic region

CT showing left knee irregular mass

Prognostic factors
Case reports
Gross description
  • Most MMNSTs are > 5 cm in diameter (Arch Pathol Lab Med 2018;142:1517)
  • Well circumscribed and covered by a thin fibrous membrane and arising in relation to a nerve
  • Solid cysts can be found on the surface; cut surface has the consistency of tar and varies from gray to pitch black
  • Erosion of the adjacent bone may be seen (Arch Pathol Lab Med 2018;142:1517)
Gross images

Images hosted on other servers:

Well encapsulated, black and fibrotic tumor

Microscopic (histologic) description
  • Circumscribed, unencapsulated lesion with plump spindle and epithelioid cells arranged in interlacing fascicles or nests
  • Accumulation of melanin in neoplastic cells and associated melanophages
  • Round, ovoid or elongated nuclei which contain delicate, evenly distributed chromatin and small distinct nucleoli; some areas may show large and prominent nucleoli
  • Rare mitoses
  • Tumors associated with Carney complex may show sheets of adipose-like cells and psammoma bodies
  • Degenerative nuclear atypia, markedly enlarged, hyperchromatic nuclei, smudgy chromatin and cytoplasmic nuclear inclusions may occasionally be seen
  • Psammoma bodies can be seen; these can be isolated foci or innumerable calcified structures (J Int Med Res 2020;48:300060520947919, Am J Surg Pathol 2014;38:94, Arch Pathol Lab Med 2018;142:1517)
  • Necrosis, when present, is often geographic in pattern
  • Strict criteria of malignancy in MMNST are not well developed, although a combination of worrisome histologic features (large, vesicular nuclei with macronucleoli; brisk, mitotic activity; necrosis) raises concern of aggressive behavior (Arch Pathol Lab Med 2018;142:1517)
Microscopic (histologic) images

Contributed by Nasir Ud Din, M.B.B.S.
Fascicles and nests of pigmented spindle to epithelioid cells

Fascicles, nests of pigmented spindle to epithelioid cells

Cells with remarkable brown pigment

Cells with remarkable brown pigment

Accumulation of melanin in neoplastic cells and melanophages

Melanin in neoplastic cells and melanophages

Epithelioid cell clusters

Epithelioid cell clusters

Ovoid cells, regular nuclei and small nucleoli

Ovoid cells, regular nuclei and small nucleoli

Degenerative nuclear atypia

Degenerative nuclear atypia

Foci of calcifications Foci of calcifications

Foci of calcifications

No significant mitosis and necrosis

No significant mitosis or necrosis

Positive stains
Electron microscopy description
  • Epithelial Schwann cells and pigmented spindle cells are bundle shaped, interleaved and wheel shaped, with round and oval nuclei, obvious nucleoli and rare nuclear division (Medicine (Baltimore) 2021;100:e24803)
  • Numerous elongated tumor cell processes, duplicated basement membrane and melanosomes are observed in all developmental stages (Arch Pathol Lab Med 2018;142:1517)
Molecular / cytogenetics description

MMNST by Dr. Jerad Gardner

Sample pathology report
  • Lumbar spine mass, excision:
    • Malignant melanotic nerve sheath tumor (see comment)
    • Comment: Histology showed a circumscribed, unencapsulated lesion containing plump spindle to epithelioid cells arranged in interlacing fascicles. Individual cells are round to ovoid with regular nuclei and evenly distributed chromatin. No significant mitotic activity or necrosis is identified. These cells exhibit melanin pigment. These tumors can be sporadic or part Carney complex or neurofibromatosis type 1. Clinical correlation is suggested.
Differential diagnosis
  • Malignant melanoma:
    • Occurs in older patients
    • Predilection for cutaneous, mucosal and extracutaneous sites
    • Composed of epithelioid or spindle shaped cells with nuclear pleomorphism, hyperchromasia, coarse irregular chromatin and prominent eosinophilic nucleoli
    • Variable dusty pigmented cytoplasm, frequent mitosis
    • Lacks psammoma bodies, adipose-like cells and pericellular basement membrane synthesis
    • Overlapping positive stains (S100 [nuclear and cytoplasmic], SOX10 [nuclear], MelanA / MART1 [cytoplasmic], HMB45 [cytoplasmic], tyrosinase [cytoplasmic]), Ki67 / MIB1 > 10%
    • Molecular testing for BRAF V600E is positive
  • Pigmented neurofibroma:
    • Occurs in 2 - 61 year old patients (median age of 28 years) (Am J Surg Pathol 2000;24:331)
    • Localized neurofibromas are superficial and evenly disturbed over the body surface
    • Diffuse neurofibromas are usually in the head and neck
    • Plexiform neurofibromas are localized to a major nerve trunk
    • Histologically cells are short and spindle shaped, with wavy scant cytoplasm and occasionally granular, dark brown pigment, small elongated nuclei
    • Intratumoral fat in the form of scattered adipocytes may be seen
    • Lacks psammoma bodies
    • Positive for melanocytic / Schwannian cell markers and CD34
  • Pigmented dermatofibrosarcoma protuberans:
    • Occurs over a wide age range but most commonly in early to mid adulthood
    • Can involve any area of skin but the trunk and extremities are the most common location
    • Histologically plump spindle cells in a storiform pattern, diffuse infiltration of the dermal stroma and subcutis with pigmented dendritic cells dispersed among neoplastic cells
    • Positive for CD34
    • Negative for S100 and other melanocytic markers
    • Dendritic pigmented cells show positivity for Fontana-Masson stain; express S100 protein, MelanA and HMB45; contain premelanosomes and mature melanosomes
    • Characterized by a t(17;22) translocation resulting in the fusion of exon 2 of PDGFB to COL1A1 gene
  • Pigmented epithelioid melanocytoma:
    • Age: median age of 20 - 27 years (Surg Pathol Clin 2021;14:285)
    • Site: extremities (38.3%), head and neck (30.8%) and trunk (30.8%) (Surg Pathol Clin 2021;14:285)
    • Melanocytoma are benign lesions, intermediate grade tumors
    • Histologically heavily pigmented, elongated or polygonal cells with vesicular nuclei and distinct nucleoli
    • Lacks psammoma bodies and pericellular basement membrane and adipose-like cells
    • Often associated with Carney complex or other banal nevi
    • Immunoprofile is similar to MMNST: positive for S100, SOX10, HMB45, MelanA
    • Negative stain: loss of cytoplasmic PRKAR1A
    • Fusions in protein kinase C alpha (PRKCA) or inactivating alterations in protein kinase A regulatory subunit R1 alpha gene (PRKAR1A) with a preceding mutation of BRAF or less frequently, NRAS (J Cutan Pathol 2019;46:878)
  • Reference: Arch Pathol Lab Med 2018;142:1517
Board review style question #1

A 55 year old patient presented with a mass in the lumbar region. After radiologic evaluation, the lesion was excised and histological features are shown in the image. What is the most likely diagnosis?

  1. Germ cell tumor
  2. Lymphoma
  3. Malignant melanotic nerve sheath tumor
  4. Meningioma
  5. Schwannoma
Board review style answer #1
C. Malignant melanotic nerve sheath tumor

Comment Here

Reference: Malignant melanotic nerve sheath tumor
Board review style question #2
Malignant melanotic nerve sheath tumor is associated with which of the following?

  1. Carney syndrome
  2. McCune-Albright syndrome
  3. Neurofibromatosis type 2 (NF2)
  4. Peutz-Jeghers syndrome
  5. Tuberous sclerosis
Board review style answer #2
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