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Address for correspondence: Dr Rajiv M. Patel, Department of Dermatopathology, University of Michigan, 2800 Plymouth Rd, Bldg. 35, Ann Arbor, MI 48109, 2800, USA.
Mesenchymal tumours with melanocytic expression can pose a diagnostic challenge because they frequently demonstrate both morphological and immunohistochemical overlap with other cutaneous melanocytic neoplasms. Therefore, they present potential pathological pitfalls that may lead to a misdiagnosis of malignant melanoma. Mesenchymal neoplasms that closely mimic melanoma include malignant melanotic nerve sheath tumour (melanotic schwannoma), epithelioid schwannoma, malignant peripheral nerve sheath, cutaneous syncytial myoepithelioma, clear cell sarcoma of soft tissue, and perivascular epithelioid cell tumour. Awareness of these melanoma mimics is necessary for establishing the correct diagnosis so that the appropriate clinical management can be rendered to the patient. This in-depth review highlights key diagnostic features and molecular genetics and also discusses the differential diagnosis and treatment of mesenchymal tumours that exhibit melanocytic expression.
Mesenchymal neoplasms may exhibit melanocytic expression and frequently pose a diagnostic challenge for dermatopathologists and surgical pathologists. Differentiating mesenchymal tumours from malignant melanoma is crucial and awareness of the mesenchymal neoplasms that mimic melanoma can aid in avoiding misdiagnosis. Such entities include the following: malignant melanotic nerve sheath tumour (melanotic schwannoma), epithelioid schwannoma, malignant peripheral nerve sheath tumour, cutaneous syncytial myoepithelioma, clear cell sarcoma of soft tissue, and perivascular epithelioid cell tumour. This in-depth review discusses the clinical, histological, immunophenotypical, and molecular features of each of these tumours as well as their differential diagnosis and clinical management.
Melanotic schwannomas, also known as malignant melanotic nerve sheath tumours or malignant melanotic schwannian tumours, are a very rare variant of schwannoma that account for less than 1% of all nerve sheath tumours and exhibit true melanocytic differentiation because they have been shown to display ultrastructural evidence of melanosome-like structures.
Melanotic schwannoma is frequently associated with the paraspinal sympathetic chain and gastrointestinal tract, particularly the oesophagus and stomach.
Cases in visceral organs and skin have been reported. Typically, an isolated melanotic schwannoma develops in young adults (average age of 33.2 years) without gender predilection; however, it often develops earlier in patients with Carney complex (mean age of 22.5 years).
While approximately 30% of cases are asymptomatic, the majority of patients present with a painful localised mass associated with neurological symptoms, such as tingling sensation, numbness, and weakness.
Genomic and clinicopathologic characteristics of PRKAR1A-inactivated melanomas: toward genetic distinctions of animal-type melanoma/pigment synthesizing melanoma.
Genomic and clinicopathologic characteristics of PRKAR1A-inactivated melanomas: toward genetic distinctions of animal-type melanoma/pigment synthesizing melanoma.
Despite the absence of established criteria for malignant transformation, worrisome histological features that may be helpful include macronuclei, high mitotic activity and necrosis.
Fig. 1Melanotic schwannoma. (A) Scanning magnification shows a heavily pigmented neoplasm. (B) Medium and high power magnification show epithelioid cells with round nuclei and small nucleoli. (C) Significant melanin pigmentation, occasional multinucleated cells, and nuclear pseudoinclusions are noted as well. (D) The neoplastic cells are diffusely positive for S100.
Melanotic schwannomas strongly and diffusely express melanotic markers such as HMB-45 and Melan-A, but also express neural crest markers like S100 and SOX10.
Melanin pigment can be detected by staining positive for Fontana–Masson. Antibodies to collagen IV and laminin can be expressed in a linear, pericellular pattern within the tumour.
Loss of the protein product of PRKAR1A can be detected through immunohistochemistry, which has diagnostic value, but may be seen in both melanotic schwannomas and PRKAR1A-inactivated melanocytic tumours.
Genomic and clinicopathologic characteristics of PRKAR1A-inactivated melanomas: toward genetic distinctions of animal-type melanoma/pigment synthesizing melanoma.
PRKAR1A-inactivated melanocytic tumours arising from acquired conventional melanocytic naevi may have BRAF V600E mutations; which can be detected using an antibody specific to those mutations, while PRKAR1A alterations are expected to be the only genetic abnormality in melanotic schwannomas.
Genomic and clinicopathologic characteristics of PRKAR1A-inactivated melanomas: toward genetic distinctions of animal-type melanoma/pigment synthesizing melanoma.
If a patient is diagnosed as having Carney complex, a surveillance work-up should be performed to screen for cardiac myxomas with an echocardiogram, as this tumour can lead to significant patient morbidity and mortality. Inactivating mutations in the PRKAR1A gene, which encodes for the type 1A regulatory subunit of protein kinase, are found in 50% of patients with Carney complex.
In addition, melanotic schwannomas also tend to show more prominent pigmentation and stain negative for CD34, while melanotic neurofibromas have less pigment and do exhibit immunoreactivity for CD34.
Pigmented dermatofibrosarcoma protuberans (DFSP), also referred to as Bednar tumours, show plump spindle cells and pigmented dendritic cells arranged in a storiform pattern.
Additionally, the tumour is characterised by a t(17; 22) translocation or a supernumerary ring chromosome that results in the fusion of PDGFB to COL1A1.1
Melanocytoma is a low-grade tumour that originates from leptomeningeal melanocytes and may be associated with a conventional naevus.
While the immunohistochemical profile of melanocytoma overlaps with that of melanotic schwannoma, morphological features can be used to distinguish between the two entities. For example, melanocytoma lacks the psammoma bodies, adipose-like cells, and pericellular basement membrane commonly seen in melanotic schwannoma. Additionally, melanocytoma exhibits hot-spot mutations in GNAQ and GNA11, which can also be seen in uveal melanoma and blue naevi.
Malignant melanoma and melanotic schwannoma share several histological features, including melanin deposition, presence of atypical cells, and expression of melanocytic markers like HMB-45 and Melan-A as well as neural crest markers including S100 and SOX10. However, findings that are suggestive of melanotic schwannoma include a predominantly spindled morphology, heavy melanin pigmentation, psammoma bodies, vacuolated cells, and a relatively low mitotic rate.
Although most cases show a benign clinical course, the tumour can undergo malignant progression in 10–35% of cases. Alexiev et al. reported that malignant tumours recur in 15–35% of cases and metastasise in up to 44% of cases, most commonly to the lung and pleura.
Although no consistently reliable histopathological indicators of malignancy have been identified, pleomorphism and high mitotic activity are typically present in metastatic melanotic schwannomas.
Close long-term clinical follow-up is recommended for all patients diagnosed with this entity.
Epithelioid schwannoma
Clinical presentation
First described by Orosz et al. and Kindblom et al. in the 1990s, epithelioid schwannoma is a benign peripheral nerve sheath tumour composed predominantly of epithelioid Schwann cells.
This tumour typically occurs in the fourth to fifth decades of life with an equal male-to-female ratio and clinically presents as multiple small (<5 cm), circumscribed, dermal and subcutaneous nodules.
Histologically, the tumours are based in the dermis or subcutaneous tissue and are surrounded by a thin perineural capsule (Fig. 2). They consist of tight clusters of epithelioid Schwann cells arranged in sheets, nests, and cords with a myxoid and/or hyalinised stroma.
The Schwann cells typically demonstrate small reniform or convoluted nuclei with pinpoint nucleoli and may occasionally contain nuclear pseudoinclusions.
Nuclear atypia is seen in up to 30% of cases; however, large nuclei with a smudgy appearance may be secondary to degenerative changes. Similar to conventional schwannomas, features like hyalinised ectatic vessels, lymphoid aggregates, and nuclear palisading may be noted.
Fig. 2Epithelioid schwannoma. (A) Scanning magnification shows a well-circumscribed subcutaneous nodule. (B) Medium power magnification demonstrates epithelioid Schwann cells arranged in cords in a myxoid stroma. (C) The Schwann cells have small reniform to convoluted nuclei with a pinpoint nucleoli. Occasional nuclear pseudoinclusions are also appreciated. The tumour cells are diffusely positive for (D) S100 and (E) SOX10.
Cases that display significant nuclear atypia (such as nuclear enlargement with hyperchromasia, prominent nucleoli, or 3-fold nuclear size variability) and mitotic activity (>3/HPF), but fall short of meeting the criteria required for a diagnosis of epithelioid malignant peripheral nerve sheath tumour (MPNST), are referred to as ‘atypical variants’ of epithelioid schwannoma.
Necrosis, extreme anaplasia, atypical mitotic figures, and infiltrative growth seen in epithelioid MPNSTs and other malignancies are absent.
Immunohistochemistry
While epithelioid schwannomas diffusely express neural crest markers like S100 and SOX10, they typically stain negative for other melanocytic markers, including melanocyte inducing transcription factor (MITF), tyrosinase, and HMB-45.
A subset of cases may show glial fibrillary acidic protein (GFAP) expression, and even rarer cases may be focally positive for keratins and/or Melan-A.
Although most sporadic conventional schwannomas retain SMARCB1/INI expression, SMARCB1/INI1 aberrations may play a role in the pathogenesis of a subset of epithelioid schwannomas.
This implies a different biological behaviour from conventional schwannomas, which frequently harbour inactivating mutations of neurofibromatosis type 2 (NF2).
Epithelioid schwannoma of the skin displaying unique histopathological features: a teaching case giving rise to diagnostic difficulties on a morphological examination of a resected specimen, with a brief literature review.
Epithelioid schwannoma of the skin displaying unique histopathological features: a teaching case giving rise to diagnostic difficulties on a morphological examination of a resected specimen, with a brief literature review.
However, epithelioid schwannomas are more superficial and frequently encapsulated, whereas epithelioid MPNSTs are deep and poorly circumscribed. Additionally, features that favour epithelioid MPNSTs over epithelioid schwannomas include the presence of more significant nuclear atypia, atypical mitotic figures, necrosis, infiltrative growth, diffuse nuclear atypia and/or prominent nucleoli.
While epithelioid schwannomas and nodular melanomas both have S100 and SOX10 expression, malignant melanomas frequently express additional melanocytic markers, such as HMB-45, Melan-A, and MITF.
However, cellular neurothekeoma displays a septate architectural appearance, may not be as well-circumscribed due to absence of a capsule, and stain positive for NK1/C3 but are negative for neural-associated markers such as S100.
Myoepitheliomas may show a more spindled cell morphology compared to epithelioid schwannomas and express epithelial markers, including EMA and cytokeratin, in addition to S100.
Complete, yet conservative, excision is the standard treatment, with a reported low local recurrence rate and low rate of malignant transformation to MPNST.
MPNSTs are malignant tumours arising from a peripheral nerve or a pre-existing neurofibroma, the latter of which occurs most often in patients with NF1.
Approximately 30–50% of patients with MPNST have NF1. In comparison, 10% arise following therapeutic radiation therapy and the remaining tumours develop sporadically.
MPNSTs usually occur in deep-seated locations and most commonly involve the proximal extremities and paraspinal region. Patients with NF1 carry a lifetime risk of 2–10% for developing MPNST, usually in the context of pre-existing plexiform neurofibromas.
Conventional MPNSTs are characterised by highly cellular fascicles of spindle cells and a marbling pattern composed of alternating hypocellular and hypercellular areas (Fig. 3). These spindle cells have hyperchromatic, tapering nuclei with some degree of nuclear pleomorphism. Perivascular accentuation and large areas of geographic-like necrosis may be noted as well.
Heterologous differentiation is detected in approximately 10–15% of cases, including chondro-osseous, rhabdomyoblastic (known as malignant Triton tumour), angiosarcomatous, and epithelial/glandular elements.
Fig. 3Malignant peripheral nerve sheath tumour. (A) Low power magnification demonstrates a poorly circumscribed, infiltrative neoplasm. (B) Medium power magnification shows highly cellular fascicles of spindle cells and alternating hypocellular and hypercellular areas. (C) The cells have hyperchromatic nuclei with some degree of nuclear pleomorphism and several mitotic figures. (D) The tumour shows S100 expression and (E) loss of methylation marker.
The epithelioid cells resemble melanoma by showing high-grade cytological features (including large vesicular nuclei and prominent nucleoli). They may be arranged in nests and cord-like patterns with variable stromal myxoid changes.
Epithelioid schwannoma of the skin displaying unique histopathological features: a teaching case giving rise to diagnostic difficulties on a morphological examination of a resected specimen, with a brief literature review.
Loss of H3K27me3 staining is a modestly sensitive, yet highly specific, marker for MPNST and thus can aid in the diagnosis. Furthermore, Prieto-Granada et al. reported the loss of the H3K27me3 in 60% of NF1-related high-grade MPNSTs, 95% of sporadic MPNSTs, and 91% of radiotherapy-related MPNSTs.
Lastly, complete loss of the marker has been demonstrated in 60–80% of intermediate-grade and 85% of high-grade MPNSTs, while it is not seen in low-grade tumours.
Recent studies have identified loss-of-function somatic alterations of polycomb repressive complex 2 (PRC2), EED, or SUZ12 in MPSNTs. Lee et al. reported these genetic aberrations in 92% of sporadic, 70% of NF1-associated, and 90% of radiotherapy-associated MPNSTs.
MPNSTs with PRC2 loss also showed complete loss of trimethylation at H3K27me3 and aberrant transcriptional activation of multiple PRC2-repressed homeobox master regulators, resulting in increased cell growth.
Similar to epithelioid schwannomas, epithelioid MPNSTs typically show inactivating mutations of SMARCB1, which strongly correlate with the loss of INI1.
The differential diagnosis for MPNST is broad and includes melanoma, synovial sarcoma, epithelioid sarcoma, leiomyosarcoma, malignant fibrous histocytoma, spindle cell squamous carcinoma, and dermatofibrosarcoma protuberans with fibrosarcomatous transformation.
Conventional malignant melanomas can resemble epithelioid MPNST; therefore, making the distinction between melanoma and MPNST can be challenging. The presence of a junctional component and/or melanin pigment is more suggestive of melanoma. While both melanoma and epithelioid MPNST express S100 strongly and diffusely, the melanocytic markers Melan-A, HMB-45, and MITF are usually positive in melanomas but negative in epithelioid MPNST. It is important to note that desmoplastic and spindle cell melanomas do not show immunoreactivity with traditional melanocytic markers. It may not be possible to distinguish between these tumours and epithelioid MPNST in the absence of pre-existing and/or concurrent melanocytic lesions. Clinical presentation and loss of INI1 immunohistochemistry therefore are very useful for diagnosing epithelioid MPNSTs, as INI1 should be retained in melanomas.
In contrast to MPNSTs, most synovial sarcomas occur in the skeletal muscle and connective tissue of the extremities, and rarely arise from nerve tissue.
An important histological feature that may help distinguish MPNST from synovial sarcoma is the presence of nuclear pleomorphism, which is absent in synovial sarcoma.
Synovial sarcomas and MPNSTs have different immunohistochemical profiles. Although both entities express low molecular weight cytokeratins and EMA, monophasic synovial sarcomas stain for high molecular weight cytokeratins, which are not expressed in MPNSTs.
Neural crest markers can also help distinguish MPNST from synovial sarcomas, as up to 50% of MPNSTs and up to 90% of epithelioid MPNSTs stain with SOX10, while synovial sarcomas are negative for SOX10. In addition, a history of NF1 and/or a co-existing neurofibroma precursor suggests MPNST.
Demonstration of SS18-SSX1 or SS18-SSX2 gene fusions, resulting from a characteristic (X;18) translocation, is detected in synovial sarcoma and not in MPNST.
Epithelioid MPNSTs are positive for podoplanin in 75% of cases, whereas other sarcomas with epithelioid cells (such as epithelioid sarcoma, epithelioid leiomyosarcoma, and malignant fibrous histiocytoma) may lack podoplanin expression.
Absent cytokeratin expression helps differentiate MPNST from carcinoma and epithelioid sarcoma; however, both epithelioid MPNST and epithelioid sarcoma may show loss of SMARCB1/INI1, which is a potential diagnostic pitfall. While fibrosarcomatous dermatofibrosarcoma protuberans may display morphological overlap with MPNSTs, it demonstrates loss of CD34 and a characteristic (17;22) translocation. These features are not seen in MPNSTs.
Treatment and prognosis
Although complete surgical resection with wide clear margins remains the mainstay of treatment, MPNSTs are aggressive tumours with a high mortality rate.
While there is limited data in the literature on the prognosis of epithelioid MPNSTs, there has been no evidence to suggest that it has a better prognosis than conventional MPNSTs.
Cutaneous syncytial myoepithelioma is a rare variant of cutaneous myoepithelioma with less than 50 reported cases in the literature. It usually presents clinically with a papule or nodule on the extremities of young and middle-aged adults.
On histological examination, the tumour shows syncytial proliferation of spindled, histiocytoid, or epithelioid cells with ovoid monomorphic nuclei and moderately abundant pale eosinophilic cytoplasm (Fig. 4).
Fig. 4Cutaneous syncytial myoepithelioma. (A) Low power magnification shows a well-circumscribed tumour. (B) The tumour shows syncytial growth of uniform ovoid, spindled, and histiocytoid cells. (C) The neoplastic cells contain moderately abundant pale eosinophilic cytoplasm, bland nuclei, and poorly defined cytoplasmic membranes. They are (D) immunoreactive for S100 and (E) EMA.
Cutaneous syncytial myoepitheliomas are immunoreactive for S100 and EMA. Unlike most myoepithelial neoplasms, this entity infrequently stains focally for keratin in up to 10% of cases.
In a series of 38 cases, Jo et al. reported positive immunoreactivity for GFAP in 14 of 33 cases (42.3%), SMA in 9 of 13 cases (69.2%), and p63 in 6 of 11 cases (54.5%).
The differential diagnosis includes epithelioid fibrous histiocytoma, juvenile xanthogranuloma, melanocytic neoplasms, and epithelioid sarcoma.
Epithelioid fibrous histiocytoma is a subtype of fibrous histiocytoma. Similar to cutaneous syncytial myoepithelioma, it is characterised by a well-circumscribed dermal nodule composed of sheets of epithelioid cells with abundant eosinophilic cytoplasm.
Compared to cutaneous syncytial myoepithelioma, epithelioid fibrous histiocytoma has a more significant collagenous stromal component and has binucleated to multinucleated cells.
Both cutaneous syncytial myoepithelioma and epithelioid fibrous histiocytoma express EMA; however, epithelioid fibrous histiocytoma is also positive for ALK expression and factor XIIIa while being negative for S100, GFAP, and p63.
The early stage of juvenile xanthogranuloma can resemble cutaneous syncytial myoepithelioma and shows a proliferation of eosinophilic histiocytic cells without characteristic Touton giant cells and lipidisation.
Juvenile xanthogranuloma most frequently affects children, while cutaneous syncytial myoepithelioma most commonly presents in adolescents and older children. Juvenile xanthogranuloma expresses histiocytic markers like CD163 and CD68, and is negative for myoepithelial markers such as EMA, SMA, and S100.
Melanocytic tumours, such as Spitz naevi, should be considered in the differential diagnosis for cutaneous syncytial myoepithelioma because melanocytes of Spitz naevi may resemble the large eosinophilic cells of cutaneous syncytial myoepitheliomas.
Certain features can be used to distinguish between the two entities. Spitz naevi demonstrate a nested growth pattern with downward maturation, lacking the sheet-like syncytial architecture seen in cutaneous myoepithelioma.
Immunohistochemically, cutaneous syncytial myoepitheliomas and melanocytic neoplasms show positive immunoreactivity for S100; however, only melanocytic lesions may express melanocytic markers (like HMB-45, Melan-A, and MITF) as well.
Epithelioid sarcoma may show some morphological overlap with cutaneous syncytial myoepithelioma and commonly affects young adults on the distal extremities.
Expression of S100 and other typical myoepithelial markers are also absent in epithelioid sarcomas. Additionally, 90% of epithelioid sarcomas are reported to demonstrate loss of nuclear expression of INI1, which is retained in cutaneous syncytial myoepitheliomas.
Clear cell sarcoma, also known as malignant melanoma of soft parts, is a rare soft tissue tumour with melanocytic differentiation. It typically occurs in adolescents and young adults without any gender predilection.
Genomic and clinicopathologic characteristics of PRKAR1A-inactivated melanomas: toward genetic distinctions of animal-type melanoma/pigment synthesizing melanoma.
Genomic and clinicopathologic characteristics of PRKAR1A-inactivated melanomas: toward genetic distinctions of animal-type melanoma/pigment synthesizing melanoma.
Although most cases are present in the soft tissue, it has been documented that the tumour occurs in visceral sites such as the gastrointestinal tract and kidney.
Macroscopically, clear cell sarcoma of soft tissue appears as a tan-grey, firm, and somewhat circumscribed mass that commonly infiltrates into tendons and aponeuroses.
Histological examination reveals a large nodular proliferation of compact nests and fascicles composed of spindled to epithelioid cells, which may be surrounded or separated by thick, hyalinised collagen bundles (Fig. 5).
Fig. 5Clear cell sarcoma. (A) Low power magnification shows a hypercellular neoplasm involving the dermis and subcutaneous tissue. (B,C) The epithelioid tumour cells are arranged in nests and surrounded by hyalinised collagenous stroma. (D) They contain eosinophilic cytoplasm and moderately prominent nucleoli. (E) Melanin pigment and wreath-like multinucleated tumour giant cells are seen as well.
Clear cell sarcoma is characterised by the translocation (12; 22) that results in fusion of the ATF1 gene localised to 12q13 to the EWSR1 gene at 22q12.
The EWSR1-ATF1 protein constitutively induces the expression of melanocyte-specific microphthalmia-associated transcription factor (MITF) in clear cell sarcoma, and plays an important role in melanocytic differentiation and growth of tumour cells.
This t(12;22) translocation can be demonstrated by cytogenetics, reverse transcriptase polymerase chain reaction, and FISH in up to 70–90% of clear cell sarcoma cases.
The differential diagnosis of clear cell sarcoma includes melanoma, epithelioid MPNST, melanotic schwannoma, paraganglioma-like dermal melanocytic tumour, and perivascular epithelioid cell tumour (PEComa).
Although it may be difficult to initially differentiate clear cell sarcoma from melanoma, the two entities have specific histological features that provide helpful clues as to the correct diagnosis. Melanoma has high-grade cytological atypia with prominent pleomorphism and multiple mitoses, which may not necessarily be seen in clear cell sarcoma. Clear cell sarcoma of soft tissue occurs in younger patient populations and is associated with aponeuroses or tendons. Most clear cell sarcomas are associated with a t(12;22) translocation, which has not been identified in melanoma. In addition, the presence of an intraepidermal atypical melanocytic component or patient history of melanoma would strongly favour a diagnosis of melanoma over clear cell sarcoma.
Correlation with the patient's clinical history and molecular studies is often crucial to make the appropriate diagnosis.
Clear cell sarcoma and epithelioid MPNST share both histopathological features and S100 protein immunoreactivity. Compared to clear cell sarcoma, epithelioid MPNST demonstrates more significant pleomorphism and frequent mitosis.
Multinucleated giant cells and melanin pigment are also not observed in MPNST, nor are additional melanocytic markers such as Melan-A and HMB-45 immunoreactive.
PEComa shares histological and immunohistochemical overlap with clear cell sarcoma and therefore should be considered in the differential diagnosis. It is characterised by fascicular and nested proliferation of uniform epithelioid cells and the expression of melanocytic markers.
Complete surgical excision with negative margins is the primary treatment modality with or without radiotherapy; however, studies have not shown evidence of the therapeutic benefits of radiotherapy and chemotherapy.
Indefinite close clinical follow-up in patients with clear cell sarcoma is necessary because of the high rate of recurrence and metastasis associated with the tumour.
This family of tumours includes angiomyolipoma (AML), sugar tumour of the lung, lymphangiomatosis (LAM), and clear cell myomelanocytic tumour of the falciform ligament/ligamentum teres.
Fig. 6Cutaneous PEComa. (A) Low power magnification demonstrates a well-circumscribed neoplasm involving the dermis and subcutaneous. (B,C) Medium power magnification shows the neoplastic cells arranged in nests. A network of branching capillaries is appreciated. (D) The cells have granular eosinophilic cytoplasm without significant cytological atypia. (E) A subset of PEComas displays nuclear staining for TFE3.
Among melanocytic markers, HMB-45 and MART-1/Melan-A are the most sensitive markers and have been reported to be positive in more than 90% and 14–50% of cases, respectively.
While tyrosinase and MITF are also expressed, S100 is typically negative and thus helpful in differentiating PEComas from S100-positive melanocytic lesions.
PEComas are a genetically diverse group of neoplasms. Studies have shown that the family includes tumours that harbour TFE3 gene rearrangements and TSC2 mutations.
PEComas have a broad differential diagnosis, including tumours with either smooth muscle or melanocytic differentiation, such as paraganglioma, clear cell sarcoma, alveolar soft part sarcoma (ASPS), and malignant melanoma.
While both entities share similar overall architecture and growth patterns, paraganglioma does not express melanocytic markers and is instead immunoreactive for neuroendocrine markers and S100 in sustentacular cells.
ASPS and some cases of PEComa exhibit overlapping histopathological features as well as TFE3 immunohistochemical expression and gene rearrangement. PEComa is known to exhibit immunoreactivity for smooth muscle markers, which is absent in ASPS. ASPS also characteristically shows rod-shaped, PAS-D positive intracytoplasmic crystals.
Melanoma may rarely present with clear cytoplasm or balloon cell changes, which may cause confusion with PEComa.
Melanocytic neoplasms can also be distinguished by their lack of smooth muscle marker expression, presence of diffuse S100 protein expression, and detection of a junctional component.
PEComa and melanoma harbour different genetic aberrations. Furthermore, PEComa does not show genetic aberrations associated with melanocytic lesions, including BRAF, GNAS, NRAS, and KIT.
Afrogheh et al. proposed provisional criteria for malignancy, including large size (>5 cm), increased nuclear atypia, necrosis, high mitotic activity (>1/50 HPF), atypical mitotic figures, and infiltrative growth pattern.
Although PEComas are generally resistant to radiation and chemotherapy, neoadjuvant therapy with chemotherapy may be considered for patients with locally advanced or metastatic disease.
Malignant perivascular epithelioid cell tumour (PEComa) of the uterus with late renal and pulmonary metastases: a case report with review of the literature.
In conclusion, mesenchymal neoplasms that display morphological or immunohistochemical evidence of melanocytic expression should be considered in the differential diagnosis of melanocytic tumours. While mesenchymal neoplasms with melanocytic expression may pose a diagnostic challenge, it is crucial to distinguish them from melanoma because they often require different approaches to management and treatment. Attention to the patient's past medical history, careful histopathological and immunohistochemical examination, and ancillary studies will assist in making the correct diagnosis and ensure appropriate subsequent clinical management.
Conflicts of interest and sources of funding
The authors state that there are no conflicts of interest to disclose. No special funding was received by the authors of this review.
Genomic and clinicopathologic characteristics of PRKAR1A-inactivated melanomas: toward genetic distinctions of animal-type melanoma/pigment synthesizing melanoma.
Epithelioid schwannoma of the skin displaying unique histopathological features: a teaching case giving rise to diagnostic difficulties on a morphological examination of a resected specimen, with a brief literature review.
Malignant perivascular epithelioid cell tumour (PEComa) of the uterus with late renal and pulmonary metastases: a case report with review of the literature.
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