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Address for correspondence: Lori Lowe, MD, University of Michigan, Department of Pathology, 2800 Plymouth Road, NCRC Bldg. 35, Ann Arbor, MI 48109, USA.
The histopathological diagnosis of melanoma is fraught with potential pitfalls. In the setting of cutaneous metastatic melanoma, it is important to recognise the various histological patterns that can be encountered from the more common to the rare, including epidermotropic, folliculotropic, naevoid, and blue naevus-like. In addition, melanoma is notorious for phenotypic plasticity. Thus, there are many different subtypes and cytomorphological variations that can be difficult to recognise as melanoma, particularly in the recurrent or metastatic setting. Select melanoma variants including primary dermal, clear cell, plasmacytoid, signet ring cell, small cell, myxoid, rhabdoid, and dedifferentiated melanoma will be discussed, in addition to composite melanocytic neoplasms. This review is intended to remind the practitioner of key concepts of metastatic disease and select rare melanoma variants, while providing practical guidelines for accurate diagnosis.
The accurate histopathological diagnosis of melanoma in the skin can be challenging. Metastatic melanoma may have a varied presentation and be difficult to discern from primary melanoma. In addition, there are unusual cytomorphological and phenotypical variants of melanoma that may cause diagnostic confusion with neoplasms derived from different lineages. In this review article, key concepts of metastatic disease will be reviewed and select rare morphological variants of melanoma highlighted in an effort to help the practising pathologist in daily practice and reinforce the many faces of melanoma.
Metastatic melanoma in the skin
Metastatic melanoma is melanoma that has spread to other body sites. The skin represents the number one site of involvement occurring in 56% of cases. In 5% of patients, metastatic melanoma may be the first presentation of disease.
The vast majority (up to 80%) of cutaneous melanoma metastases are locoregional in distribution, whereas distant metastases are identified in the remaining 20%. The most common mechanism of metastasis is lymphatic spread.
While metastatic melanoma may present on any cutaneous site, the leg and scalp have the reported highest incidence of 18% and 15%, respectively. The vast majority (>90%) of cutaneous melanoma metastases present as a solitary dermal nodule ranging from 0.8 cm to 3.0 cm.
In the remaining 10% of cases, however, the clinical presentation can be very heterogeneous. Cutaneous metastases can also manifest as multiple dermal or subcutaneous nodules, erythematous patches and plaques, blue naevus-like eruptive papules, erysipelas-like plaque, sclerodermoid ‘en cuirasse’ indurated plaque, zosteriform, telangiectatic papulovesicles, and purpuric plaques simulating vasculitis.
By definition, a satellite metastasis develops within 2 cm of the primary site and in-transit metastasis refers to metastatic disease that develops greater than 2 cm from the primary site and within the region of the locoregional draining basin. Microsatellitosis is defined as a microscopic focus of metastatic tumour clearly discontinuous from the primary tumour.
Multiple step sections through a tumour may be necessary to confirm microsatellitosis and exclude contiguous periadnexal tracking of the primary tumour. Identification of metastatic disease is important as it alters staging of the patient and is associated with a worse prognosis. Non-nodal locoregional metastasis (microsatellite, satellite, and in-transit metastasis) represents stage III disease and modifies the N category according to American Joint Commission on Cancer (AJCC) staging guidelines. Distant cutaneous metastasis involves the skin or subcutis anywhere beyond the draining regional lymph basin and is stage IV disease.
The accurate histopathological diagnosis of cutaneous melanoma metastasis often requires clinical correlation. One of the common pitfalls in daily practice is that the pathologist is not given the relevant clinical information of a prior history of melanoma. Melanoma metastasis is then erroneously diagnosed as primary melanoma. When the more common histological features are present, the diagnosis is straightforward and the findings readily suspected to be a cutaneous melanoma metastasis, particularly if there is a known prior history of melanoma. The most common histological features include a well-circumscribed, unencapsulated, dermal nodule composed of atypical melanocytes demonstrating compact, sheet-like to expansile growth, mitotic activity, and often a cytomorphological resemblance to the primary melanoma (Fig. 1A). There is often attenuation of the overlying epidermis. There is usually no inflammatory infiltrate, no surrounding fibrosis, no junctional activity, and no associated naevus.
The absence of these features can help distinguish cutaneous melanoma metastasis from primary nodular melanoma and melanoma arising within a pre-existing naevus. Subcutaneous melanoma metastasis has similar features except it is located in the deeper dermis/subcutis (Fig 1B). Immunohistochemical stains such as S100, Melan-A/Mart1, or Sox-10 may be necessary to confirm melanocytic lineage. If the primary melanoma were positive for PReferentially expressed Antigen in Melanoma (PRAME), PRAME immunostaining could be a helpful adjunct in confirming metastatic melanoma.
Fig. 1In transit cutaneous melanoma metastasis. (A) Well circumscribed nodular aggregates of melanoma in dermis with no epidermal connection and scant inflammation. (B) In transit metastasis involving subcutis. (C) Epidermotropic and dermal melanoma metastasis mimicking primary melanoma with junctional component extending beyond the dermal component.
Epidermotropic metastatic melanoma occurs in up to 5% of cutaneous metastases and closely mimics primary melanoma. Helpful histological features that favour epidermotropic metastasis over primary melanoma include small size, dermal component broader than the junctional component, absence of adnexal involvement, and fibrotic dermal stroma.
While these are general guidelines, they are not hard and fast. Exceptions are not uncommon. Involvement of the epidermis beyond the dermal component and adnexal extension can be seen in epidermotropic and dermal melanoma metastases (Fig 1C).
Clearly in such cases, clinical history is imperative to distinguish primary melanoma from cutaneous melanoma metastasis. Similarly, when epidermotropic metastatic melanoma is exclusively intraepidermal it can be impossible to differentiate from melanoma in situ.
It is unlikely that histological criteria alone can differentiate between epidermotropic metastatic melanoma and primary melanoma. A prior history of melanoma and new onset of one or multiple lesions developing in the same locoregional area should make one consider epidermotropic metastasis. Folliculotropic cutaneous melanoma metastasis is an unusual and only recently recognised histological pattern. While the cohort of reported cases is small, it tends to be seen in advanced locoregional and distant disease. The folliculotropic metastases are small in size and usually multiple in number.
Naevoid metastatic melanoma demonstrates an overall naevoid silhouette with symmetry, circumscription, and pseudomaturation. Cytologically, the infiltrate is monomorphous with a naevoid appearance at first glance, yet demonstrates varying degrees of atypia, nuclear hyperchromasia, and mitotic activity. Expansile dermal growth and/or lymphovascular invasion suggest metastasis.
However, intradermal naevus and primary nodular melanoma enter into the histological differential diagnosis. Clinical history, a high index of suspicion, and careful scrutiny of cytological features are necessary for accurate diagnosis. Blue naevus-like melanoma metastasis clinically and histologically simulates blue naevus. As with the majority of cutaneous melanoma metastases, lesions tend to occur in the same locoregional distribution as the primary melanoma. There is often a clinical history of showering of multiple new lesions. Histologically, blue naevus-like metastatic melanoma may be impossible to distinguish from common blue or epithelioid blue naevus. Helpful histological clues favouring metastasis over blue naevus include atypical epithelioid cytomorphology, mitotic figures, and an inflammatory infiltrate at the periphery (Fig. 2).
Fig. 2Blue naevus-like melanoma metastasis. (A) Small focus of pigmented melanocytes in dermis with inflammatory infiltrate at periphery. (B) Melanocytes have an atypical epithelioid cytomorphology with prominent nucleoli.
By definition, it is histologically indistinguishable from metastatic melanoma. Thus, this melanoma variant should be considered in patients with cutaneous metastatic melanoma of unknown primary.
Histologically, there is a circumscribed nodular or multinodular melanocytic tumour confined to the dermis and/or subcutis. The cytomorphology may be spindled, epithelioid, rhabdoid, or pleomorphic. Mitotic activity is common and there may be variable necrosis (Fig. 3). There should be no evidence of an intraepidermal (in situ) component or follicular connection, nor evidence of ulceration or regression that could suggest a primary melanoma in which the epidermal component has been effaced or regressed. There should be no pre-existing melanocytic naevus to suggest a possible precursor lesion. Lastly, there should be no prior history of melanoma or evidence of distant disease with imaging studies to exclude a dermal or subcutaneous metastasis from an unknown primary lesion.
In the original series of primary dermal melanoma, while these lesions were histologically concerning for metastatic melanoma, there was a higher survival rate than expected for AJCC stage IV disease. Thus, primary dermal melanoma was considered to be a subtype of primary melanoma that is less aggressive than conventional melanoma of similar Breslow depth. Since then, additional series have confirmed a variable, yet overall favourable, 5-year survival rate of 73–100%.
These initial observations predated routine use of ancillary molecular pathology testing. Since that time, there have been limited molecular studies of this unique melanoma variant. While there is some heterogeneity, thus far the mutational profile does appear to be similar to conventional melanoma.
Therefore, patients should be staged and treated using the same criteria as primary cutaneous melanoma. The histogenesis of this rare variant is uncertain. Proposed theories include that the neoplasm arises de novo from non-epidermal melanocytes or from melanocytic remnants arrested during embryological migration to the epidermis.
Fig. 3Primary dermal melanoma. (A) Well circumscribed multinodular proliferation centered in the dermis without epidermal connection. (B) Higher magnification demonstrating compact, sheet-like growth, cytological atypia, and focal necrosis. (C) Ki-67/Mart dual stain confirms an elevated proliferation of approximately 20%. (D) PRAME immunohistochemical stain is strongly and diffusely positive.
The differential diagnosis of primary dermal melanoma includes cellular blue naevus, malignant blue naevus, nodular melanoma, metastatic melanoma, clear cell sarcoma, and melanocytoma/cutaneous tumour with CRTC1-TRIM11 rearrangement.
Cutaneous clear cell sarcoma: a clinicopathologic, immunohistochemical, and molecular analysis of 12 cases emphasizing its distinction from dermal melanoma.
Accurate diagnosis requires clinicopathological correlation and, in select cases, additional molecular studies. For example, identifying conventional melanoma driver mutations such as BRAF or NRAS would support a diagnosis of primary dermal melanoma whereas GNAQ/GNA11 mutations would suggest the blue category of melanocytic tumours.
Molecular diagnosis of clear cell sarcoma: detection of EWS-ATF1 and MITF-M transcripts and histopathological and ultrastructural analysis of 12 cases.
It is likely that a subset of lesions that fit the criteria for primary dermal melanoma on clinical and morphological grounds may represent melanocytomas or indeterminant melanocytic tumours with novel rearrangements or fusions yet to be described when analysed more comprehensively with next generation or RNA sequencing.
Clear cell melanoma
Clear cell melanoma is a unique and rare melanoma variant that demonstrates large round or polygonal cells with abundant cytoplasm and clear cell change secondary to the accumulation of glycogen.
Glycogen-rich malignant melanomas and glycogen-rich balloon cell malignant melanomas: frequency and pattern of PAS positivity in primary and metastatic melanomas.
Lesions often have a polypoid configuration. The nuclei can be centrally located, eccentric, or occasionally scalloped with nuclear hyperchromasia and pleomorphism (Fig. 4).
Balloon cell malignant melanoma of the skin. A clinicopathologic study of 34 cases with histochemical, immunohistochemical, and ultrastructural observations.
Clear cell change may be focal or diffuse and can cause diagnostic confusion in primary melanoma in the absence of a junctional component or melanin pigment and in metastatic melanoma. The differential diagnosis of clear cell melanoma is broad and may include clear cell/balloon cell naevus, metastatic renal cell carcinoma and other clear cell carcinoma, clear cell sarcoma, and perivascular epithelioid cell tumour (PEComa).
Distinction of balloon cell naevus from clear cell/balloon cell melanoma should rely on the well known and accepted histomorphological criteria that separate benign naevi from melanoma such as aberrant dermal growth, atypical cytological features, and increased dermal mitoses in the latter. Metastatic renal cell carcinoma should lack an epidermal connection and may be cytologically deceptively bland, composed of clusters and nodules of large polygonal clear cells. Conspicuous ‘chicken wire’ vasculature, associated haemorrhage, absence of staining with melanocytic markers, and positive staining with PAX8 and RCC suggest metastatic renal cell carcinoma.
Clear cell sarcoma may cause considerable diagnostic confusion with melanocytic tumours in general, and clear cell melanoma, in particular. While usually a deeply situated multilobular soft tissue tumour, clear cell sarcoma may occur in the dermis and exceptionally demonstrate an epidermal connection, termed epidermotropic or compound clear cell sarcoma, further simulating a melanocytic tumour.
Tumour cells contain clear to eosinophilic cytoplasm arranged in nests and fascicles. Multinucleate wreath-like giant cells are more common in clear cell sarcoma but can be present in melanoma. There also may be melanin pigment. Immunohistochemistry is of limited utility in distinguishing clear cell sarcoma from melanoma as conventional melanocytic markers are routinely positive [HMB-45 (90%), MiTF (71%), S100 (64%), and Melan-A (43%)].
As mentioned previously, the gold standard in diagnosis of clear cell sarcoma remains identifying an EWSR1 gene rearrangement, usually EWSR1-ATF1 (>90%) or rarely EWSR1-CREB1.
Molecular diagnosis of clear cell sarcoma: detection of EWS-ATF1 and MITF-M transcripts and histopathological and ultrastructural analysis of 12 cases.
Lastly, cutaneous perivascular epithelioid cell tumour (PEComa) is a mesenchymal neoplasm that characteristically demonstrates epithelioid cells with clear to granular cytoplasm and myomelanocytic differentiation immunohistochemically. Rarely, melanin pigment may be present. Most cutaneous PEComas express HMB-45 and Melan-A; however, S100 is negative. Desmin, caldesmon, calponin, and less commonly, smooth muscle actin can be positive, consistent with smooth muscle differentiation, and militates against clear cell melanoma.
Fig. 4Metastatic clear cell melanoma. (A) Well circumscribed polypoid to nodular collection of tumour cells with clear cytoplasm. (B) Higher magnification illustrating nuclear pleomorphism and clear to finely vacuolated cytoplasm.
Plasmacytoid melanoma is a rare melanoma variant that demonstrates focal or diffuse plasmacytoid cytomorphology. There is abundant cytoplasm that may be amphophilic, an eccentric nucleus with coarse chromatin, inconspicuous nucleoli, and pale paranuclear zone (Fig. 5). This morphology may be seen in primary cutaneous and mucosal melanoma and in metastatic disease.
In the absence of a junctional component in primary plasmacytoid melanoma and in the setting of metastasis, immunohistochemistry is necessary to confirm melanocytic lineage and exclude other malignancies that may have plasmacytoid morphology such as plasma cell neoplasms, other lymphoproliferative disorders, carcinoma and sarcoma. A high index of suspicion should be maintained, particularly in the setting of metastatic disease. Rarely, the plasma cell marker CD138 can be spuriously positive in plasmacytoid melanoma and lead to the erroneous diagnosis of plasma cell neoplasm if melanocytic markers are not also specifically obtained.
Plasmacytoid melanoma of the urinary bladder and lymph nodes with immunohistochemical expression of plasma cell markers revealing primary esophageal melanoma.
The signet ring cell variant of melanoma is rare, occurring in less than 0.5% of cases. It is more commonly seen in metastatic or recurrent lesions. Cytomorphologically, the cells may be small or large. The nucleus has a semi-lunar or crescenteric shape as it is compressed to the periphery of the cell due to the cytoplasmic accumulation of intermediate filaments, particularly vimentin, imparting a signet-ring configuration to the nucleus.
Signet-ring change may be present focally or diffusely within the melanoma. As this rare melanoma variant is usually metastatic or recurrent, there is typically no junctional component to suggest melanoma. In addition, dedifferentiation has been reported with this phenotype, making immunohistochemistry for melanocytic lineage potentially less reliable. For instance, S100 negative signet-ring cell melanomas have been described.
Nonetheless, immunohistochemistry in an attempt to confirm melanocytic lineage and exclude other neoplasms, is the first step. Signet-ring cell morphology occurs in a variety of other neoplasms and the differential diagnosis is broad. Most importantly, the differential diagnosis includes metastatic signet-ring adenocarcinoma, signet-ring lymphoma, and liposarcoma.
Small cell melanoma demonstrates small, monomorphous, round to oval cells with hyperchromatic nuclei, finely dispersed chromatin, usually inconspicuous nucleoli, scant cytoplasm, and an increased nuclear to cytoplasmic ratio.
Nuclear molding, angulated nuclei, or a dyscohesive pattern of growth have been described (Fig. 6A,B). Lesions are often amelanotic. This phenotype is more common in melanoma arising in congenital naevi and mucosal melanoma including sinonasal and anorectal melanoma.
If there is no junctional component to suggest a melanocytic lesion, or in the context of metastatic melanoma, the differential diagnosis includes the other small round cell tumours including lymphoblastic lymphoma, Merkel cell carcinoma, metastatic small cell carcinoma, Ewing sarcoma, and peripheral neuroectodermal tumour.
Immunohistochemistry to confirm melanocytic lineage and exclude other small cell tumours and clinical correlation remain essential to accurate diagnosis.
Fig. 6Small cell and myxoid melanoma. (A) Primary small cell melanoma with atypical dyscohesive junctional component. (B) Higher magnification demonstrating small cell cytomorphology with small, monomorphous, round tumour cells and scant cytoplasm. (Case courtesy of David Arps, MD.) (C) Myxoid melanoma with a small amount of myxoid stroma. (D) Myxoid melanoma with greater mucinous stroma, small pools of mucin and early stellate configuration to the melanoma cells.
Myxoid melanoma is a rare melanoma variant that is usually seen in the setting of metastatic or recurrent disease. Primary cutaneous and mucosal myxoid melanoma have been exceptionally reported.
Histologically, amelanotic melanoma cells that are small, stellate, or spindled and arrayed singly or in cords are admixed within a mucinous stroma (Fig. 6C,D). The neoplasm may have rounded, pushing borders composed of individual lobules with surrounding fibrovascular septa. This background mucinous stroma is secondary to increased production of dermal hyaluronic acid and regarded to be a response of the stromal cells to tumour. Occasionally pools of mucin are present.
When the myxoid stroma is greater than 50%, it becomes diagnostically challenging, especially in the context of melanoma metastasis. A high index of suspicion is necessary to even consider melanoma in the differential diagnosis. Immunohistochemical stains are often necessary to confirm melanocytic lineage. The differential diagnosis of myxoid melanoma is broad and includes benign and malignant myxoid neoplasms of soft tissue including myxoid liposarcoma, myxoid malignant fibrous histiocytoma, low-grade fibromyxoid sarcoma, extraskeletal myxoid chondrosarcoma, myxoid peripheral nerve sheath tumour, dermatofibrosarcoma protuberans, and metastatic mucinous adenocarcinoma.
Rhabdoid melanoma is a rare, dedifferentiated melanoma variant that is usually metastatic or recurrent. Histologically, there are sheets or nests of large, amelanotic, polygonal tumour cells, abundant cytoplasm with glassy eosinophilic inclusions, large vesicular eccentric nucleus, and prominent nucleoli. The inclusions are secondary to the accumulation of whorls of intermediate filaments, similar to signet-ring cell melanoma.
Foci of necrosis are typical. The extent of the rhabdoid phenotype is variable. Immunohistochemistry is less reliable with rhabdoid melanoma as there is often a component of dedifferentiation.
In the setting of primary rhabdoid melanoma, positive PRAME expression is a helpful diagnostic tool, particularly if conventional melanocytic immunohistochemical stains are inconsistent.
When metastatic, clinical history of prior melanoma and molecular studies may be necessary to arrive at the diagnosis. It is important to distinguish rhabdoid melanoma from rhabdomyosarcoma, other sarcoma, and other small round cell tumours. MyoD1 and myogenin immunohistochemical stains are negative in rhabdoid melanoma and reasonably exclude rhabdomyosarcoma.
Dedifferentiated melanoma is an under-recognised and aggressive variant of melanoma that is often misdiagnosed as undifferentiated sarcoma or carcinoma. In dedifferentiated melanoma, there is loss of conventional melanoma histological features and loss of expression of melanocytic immunohistochemical markers. The term ‘dedifferentiated’ infers loss of some melanocytic markers, while ‘undifferentiated’ is used when there is complete loss of all markers. As dedifferentiation occurs more commonly in the setting of recurrent and metastatic disease, the usual sites of presentation include the axillary and inguinal lymph nodes, soft tissue, bone, and lung. It has been suggested that a diagnosis of undifferentiated sarcoma, occurring at sites common for metastatic melanoma such as the axillary or inguinal basin in a patient with a known history of melanoma, should be made with extreme caution as some of these are likely metastatic undifferentiated melanoma.
Metastatic malignant melanoma with complete loss of differentiation markers (undifferentiated/dedifferentiated melanoma): analysis of 14 patients emphasizing phenotypic plasticity and the value of molecular testing as surrogate diagnostic marker.
Primary dedifferentiated cutaneous melanoma is rare but may occur. Histologically, these lesions demonstrate high-grade, atypical histological features. Tumour cells have an epithelioid, sarcomatoid, rhabdoid, or pleomorphic cytomorphology (Fig. 7). In addition, there may be development of non-melanocytic heterologous features with expression of aberrant markers such as muscle markers or cytokeratins, leading to further diagnostic confusion and uncertainty.
Metastatic malignant melanoma with complete loss of differentiation markers (undifferentiated/dedifferentiated melanoma): analysis of 14 patients emphasizing phenotypic plasticity and the value of molecular testing as surrogate diagnostic marker.
Metastatic malignant melanoma with complete loss of differentiation markers (undifferentiated/dedifferentiated melanoma): analysis of 14 patients emphasizing phenotypic plasticity and the value of molecular testing as surrogate diagnostic marker.
Accurate histological diagnosis of dedifferentiated melanoma is challenging. Identifying focal melanocytic differentiation histologically and immunohistochemically is helpful. A prior history of primary melanoma and/or the presence of multifocal disease more characteristic of metastatic melanoma are also helpful. In the context of an undifferentiated neoplasm, PRAME positivity might support a diagnosis of melanoma but should be interpreted with caution. PRAME is also positive in numerous other malignant neoplasms, including myxoid liposarcoma,
Metastatic malignant melanoma with complete loss of differentiation markers (undifferentiated/dedifferentiated melanoma): analysis of 14 patients emphasizing phenotypic plasticity and the value of molecular testing as surrogate diagnostic marker.
Fig. 7Dedifferentiated melanoma. (A) Large ulcerated amelanotic spindle cell neoplasm. (B) Peripheral edge of lesion demonstrates a pigmented melanocytic junctional component that merges with the dermal spindle cell proliferation. (C) Higher magnification of the dermal spindle cell component demonstrating dense cellularity, cytologic atypia, and sarcomatoid features. (D) SOX-10 immunostain highlights only a portion of the tumour cells with loss of staining in the dedifferentiated component. (E) CD10 decorates the dedifferentiated sarcomatoid area that no longer expresses SOX-10, S100, Melan-A, or HMB-45.
The term ‘composite’ is used when there are two phenotypically distinct populations that comprise a neoplasm. The most common composite melanocytic neoplasms are squamomelanocytic tumour/squamomelanoma and basomelanocytic tumour/basomelanoma.
The melanocytic component within the neoplasm can range from a minor population of increased benign dendritic melanocytes to frank melanoma admixed with another epithelial lesion that similarly may be benign, indeterminant, or malignant. For instance, squamomelanocytic tumour demonstrates an admixture of melanocytes, often dendritic, within a squamous epithelial lesion, yet the melanocytic component does not classify as melanoma. Squamomelanoma demonstrates bona fide areas of melanoma with an intimately associated squamous epithelial lesion. Similarly, basomelanocytic tumour refers to a composite neoplasm with an admixture of melanocytes, usually dendritic, within a basaloid epithelial lesion. Whereas basomelanoma demonstrates areas of conventional melanoma with closely associated basaloid tumour islands (Fig. 8).
Lastly, melanocytic matricoma should be briefly mentioned. First described by Carlson et al. in 1999 lesions tend to be a well circumscribed nodular dermal tumour comprised of an epithelial component of matrical and supramatrical cells surrounding shadow cells and a melanocytic component that is usually pigmented and dendritic.
An unusual composite pilomatrix carcinoma with intralesional melanocytes: differential diagnosis, immunohistochemical evaluation, and review of the literature.
Fig. 8Composite melanocytic neoplasm (basomelanoma). (A) Melanoma, predominantly in situ, with involvement of the basaloid neoplasm in dermis. (B) SOX-10 highlights the extent of melanoma and its prominent involvement of the basaloid component. (C) PRAME immunostain is strongly positive. (D) Pancytokeratin immunostain stains the basaloid neoplasm. Note the large, atypical melanocytes of the melanoma in situ are negative.
There are various proposed pathogenic mechanisms for composite melanocytic lesions. While not clearly understood, colonisation, combined, and biphenotypic are the descriptors used to explain the most likely mechanisms.
Colonisation occurs when the second neoplasm permeates within the first. A combined neoplasm refers to when two phenotypically different, yet closely intertwined, populations of tumour cells coexist. Biphenotypic tumours arise from a common stem cell and undergo divergent differentiation.
Exceptional cases of squamomelanocytic tumour have been described in which ultrastructural studies demonstrate both melanocytic differentiation (melanosomes) and squamous differentiation (cytoplasmic tonofilaments and desmosomes) in the same tumour cells supporting a biphenotypic or divergent aetiopathogenesis.
Additionally, the rare identification of 11q13 gains in both the epithelial and melanocytic components supports the theory of differentiation from a common progenitor cell.
Lesions are predominantly located in the head and neck area, leading some to speculate that ultraviolet exposure is a contributory factor and supports a field cancerisation theory.
On rare occasions, these composite neoplasms may be confused with collision tumours in which two distinct and separate neoplastic proliferations ‘collide’ and focally overlap or impinge upon each other. As composite neoplasms are rare, their biological behaviour is unclear and often indeterminant. In one retrospective study, distant metastases were uncommon and outcomes favourable, leading the authors to suggest that composite tumours with a melanoma component may have a better prognosis compared to conventional melanoma similarly staged.
It seems reasonable that treatment should be guided by the most atypical component. At a minimum, complete removal with clinical monitoring of the site is suggested. If melanoma is present, it is recommended that the lesion be treated as a melanoma variant with the excision margins and need for additional staging studies based on standard guidelines.
Conclusion
Recognition of the many histological patterns of melanoma metastases and rare melanoma variants is critical for accurate diagnosis and expeditious patient management and treatment. Cutaneous metastatic disease can closely simulate primary melanoma, particularly if adequate clinical history is not provided. Metastatic melanoma should be a diagnostic consideration if new lesion(s) arise in the same locoregional distribution as a prior melanoma. There are many histological phenotypic variants of melanoma that can mimic other non-melanocytic neoplasms, especially in the setting of recurrent or metastatic melanoma. Correlation with clinical history and low threshold for use of melanocytic immunohistochemical stains in the absence of melanoma-specific histological features are essential. In the setting of undifferentiated melanoma, the use of ancillary molecular techniques to identify somatic mutations of established melanoma drivers may be necessary.
Acknowledgement
The author wishes to thank Dr Noah Smith for his technical assistance with the manuscript.
Conflicts of interest and sources of funding
The author states that there are no conflicts of interest to disclose. No special funding was received by the author of this review.
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Cutaneous metastases of malignant melanoma: a clinicopathologic study of 192 cases with emphasis on the morphologic spectrum.
Cutaneous clear cell sarcoma: a clinicopathologic, immunohistochemical, and molecular analysis of 12 cases emphasizing its distinction from dermal melanoma.
Molecular diagnosis of clear cell sarcoma: detection of EWS-ATF1 and MITF-M transcripts and histopathological and ultrastructural analysis of 12 cases.
Glycogen-rich malignant melanomas and glycogen-rich balloon cell malignant melanomas: frequency and pattern of PAS positivity in primary and metastatic melanomas.
Balloon cell malignant melanoma of the skin. A clinicopathologic study of 34 cases with histochemical, immunohistochemical, and ultrastructural observations.
Plasmacytoid melanoma of the urinary bladder and lymph nodes with immunohistochemical expression of plasma cell markers revealing primary esophageal melanoma.
Metastatic malignant melanoma with complete loss of differentiation markers (undifferentiated/dedifferentiated melanoma): analysis of 14 patients emphasizing phenotypic plasticity and the value of molecular testing as surrogate diagnostic marker.
An unusual composite pilomatrix carcinoma with intralesional melanocytes: differential diagnosis, immunohistochemical evaluation, and review of the literature.
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