Pathologic characteristics of melanoma

INTRODUCTION — Melanoma is the most serious form of skin cancer and the sixth most common cancer in North America [1]. Early detection, accurate histopathologic diagnosis, and appropriate management are key factors for improving survival in patients with melanoma.

Here we will review the pathologic features, including its growth phases, major histopathologic subtypes, and rare variants, and the genetic and molecular characterization of cutaneous melanoma [2]. Other aspects of melanoma, including risk factors, clinical presentation and diagnosis, staging, and management, are discussed elsewhere. Spitz melanoma and pediatric melanoma are also discussed separately.

●(See "Melanoma: Epidemiology and risk factors".)

●(See "Inherited susceptibility to melanoma".)

●(See "Melanoma: Clinical features and diagnosis".)

●(See "Tumor, node, metastasis (TNM) staging system and other prognostic factors in cutaneous melanoma".)

●(See "Pathologic evaluation of regional lymph nodes in melanoma".)

●(See "Surgical management of primary cutaneous melanoma or melanoma at other unusual sites".)

●(See "Overview of the management of advanced cutaneous melanoma".)

●(See "Spitz nevus and atypical Spitz tumors" and "Melanoma in children".)

●(See "Spitz nevus and atypical Spitz tumors" and "Melanoma in children".)

OVERVIEW — Melanoma is an aggressive neoplasm that may spread in an unpredictable manner to involve virtually any organ of the body. Therefore, early diagnosis and treatment is the key to minimizing morbidity and mortality. The diagnostic and prognostic information provided by pathologic review of the surgical specimen influences the selection of treatment for patients with melanoma [3]. Recognized prognostic factors for melanoma include the thickness of the primary tumor, ulceration, and presence and extent of metastatic disease [4]. (See "Tumor, node, metastasis (TNM) staging system and other prognostic factors in cutaneous melanoma".)

However, accurate pathologic diagnosis can be challenging, even to the most experienced pathologist, due to variability in cytomorphology and architecture and the similarity of some melanomas to benign, nevomelanocytic lesions [5]. To improve diagnostic accuracy, adjunctive techniques, including immunohistochemical and molecular techniques, are continuously being refined. (See 'Immunohistochemistry' below and 'Genetic and molecular characterization of melanoma' below.)

GROWTH PHASES OF MELANOMA — Most melanomas arise as superficial, indolent tumors that are confined to the epidermis, where they remain for several years. During this stage, known as the horizontal or "radial" growth phase, the melanoma is almost always curable by surgical excision alone. At some point, probably in response to the stepwise accumulation of genetic abnormalities [6], the melanoma is transformed into an expansile nodule that extends beyond the biologic boundary of the basement membrane and invades the dermis.

The Cancer Genome Atlas program analyzed the DNA and RNA of 331 metastatic and primary melanomas and matched peripheral blood [7]. The study resulted in a genomic classification of melanoma in four subtypes, based on the frequency of significantly mutated genes, in decreasing order of frequency: BRAF, RAS, NF1, and the triple wild type. Further studies led to a hypothesis that specific melanoma subtypes and their precursors/benign counterparts develop along distinct evolutionary pathways, driven by mutations in different genes and diverging according to amount and pattern of sun exposure [8]. (See 'Evolutionary pathway classification of melanoma' below.)

Some superficially invasive malignant melanomas (termed "microinvasive radial growth phase" melanomas) remain highly curable with surgery alone, but those that infiltrate deep into the dermis are considered to be in a "vertical" growth phase and have metastatic potential [9]. Biologically, the vertical growth phase melanomas have different cell surface antigen expression, cytogenetic profiles, and growth characteristics that enhance their metastatic propensity [10-13]. Although the molecular changes that accompany melanoma transition from radial growth phase to vertical growth phase are not yet fully elucidated, the technique of comparative genomic hybridization has yielded important insights into the progression of these neoplasms [14]. Gene amplifications at specific loci, especially those encoding proteins involved in cell cycle progression, have been associated with the acquisition of metastatic potential early in the progression of some melanomas, such as acral melanomas [15]. By contrast, these gene amplifications are found less frequently in other histologic subtypes of melanomas, and if present, they arise in later stages of tumor progression [16,17].

Radial growth phase — Radial growth phase melanomas are thin, primarily confined to the epidermis (picture 1), and behave in an indolent fashion. These melanomas are represented by two histopathologic patterns: in situ melanomas and microinvasive melanomas.

Melanoma in situ — Melanoma in situ is a form of radial growth phase melanoma in which the proliferation of malignant melanocytes is restricted to the epidermis. Of the four major subtypes of melanoma, an in situ form exists for superficial spreading, acral lentiginous, and lentigo maligna melanomas, but not for nodular melanomas. (See 'Morphologic classification of melanoma' below.)

In the superficial spreading variant of melanoma in situ, the malignant melanocytes extend away from their normal position along the basal layer throughout the epidermis and even into the stratum corneum, a phenomenon termed "pagetoid spread" (picture 2). Acral lentiginous melanoma in situ is characterized by uniformly atypical, dendritic, single-cell to nested melanocytes that are aligned in a continuous or near-continuous array along the dermoepidermal junction, frequently with poor lateral circumscription.

The lentigo maligna form of melanoma in situ is characterized by an increased number of atypical melanocytes, often spindle shaped, arranged in single cells or in small nests along the dermoepidermal junction, and often extending into the infundibular portion of hair follicles, and the presence of giant cells with multiple nuclei in the intraepidermal component (picture 3A-B). It should be noted that the clear distinction of lentigo maligna from precursor states of atypical, lentiginous, melanocytic proliferations in sun-damaged skin can be challenging. Once the tumor becomes invasive, the lesion is considered lentigo maligna melanoma. (See "Lentigo maligna: Clinical manifestations, diagnosis, and management".)

Microinvasive radial growth phase melanoma — In addition to epidermal involvement, microinvasive melanomas are characterized by microscopic, papillary, dermal extension, and they tend to behave in an indolent fashion (picture 4). By definition, the largest dermal "nest" can be no larger than the largest epidermal nest, and dermal mitoses are not allowed [18]. If a dermal mitosis is found, the tumor is regarded as vertical phase melanoma, regardless of the size of the dermal melanocytic nests. In contrast to more invasive melanomas that involve the dermis, the morphology of the dermal nevomelanocytes is similar to that of the epidermal component. Frequently, a predominantly lymphocytic, inflammatory infiltrate is present.

Vertical growth phase — Most vertical growth phase melanomas are clearly invasive, extending deeply into the dermis (picture 5A-C). Included in the term "vertical growth phase melanoma" are lesions that are associated with an expansile nodule filling the papillary dermis and/or invasion of reticular dermis or fat. These features correspond to the histologic level of invasion (Clark level) III, IV, and V, respectively [9].

Once a melanoma enters the vertical growth phase, it possesses the potential for metastasis. By definition, a vertical growth phase melanoma has at least one dermal mitosis or one dermal nest larger than the largest epidermal nest. These features represent the earliest histologic evidence of progression from a nonmetastatic lesion to a potentially metastatic lesion.

Vertical growth phase melanomas can arise de novo or from a radial growth phase melanoma. It may take decades for some melanomas to reach vertical growth phase, while others develop an early vertical growth phase. Nodular melanomas have no identifiable radial growth phase and enter the vertical growth phase almost from their inception. The probability of metastases with invasive, vertical growth phase melanoma may be predicted by measuring in millimeters the depth of invasion of the vertical growth phase nodule beneath the top of the granular cell layer of the overlying epidermis, as originally described by Breslow [17,19]. (See "Tumor, node, metastasis (TNM) staging system and other prognostic factors in cutaneous melanoma", section on 'Eighth edition AJCC TNM staging'.)

MORPHOLOGIC CLASSIFICATION OF MELANOMA — The traditional clinicopathologic classification of melanoma is based on the morphologic aspects of the growth phase (radial or vertical) of the tumor and distinguishes four main subtypes. In descending order of frequency, these are superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, and acral lentiginous melanoma [20]. A comparison of histopathologic features among the four major subtypes of malignant melanoma is presented in the table (table 1) [17].

Although histologic subtype classification is important for histopathologic recognition and diagnosis in most cases, it is not informative about the biologic behavior of the tumor and is insufficient to inform management, particularly in advanced disease.

Superficial spreading melanoma — Superficial spreading melanoma is the most common subtype, comprising approximately 75 percent of all malignant melanomas. It derives its name from histologic evidence of lateral (radial) growth for a period of time before vertical (invasive) growth occurs.

Superficial spreading melanoma typically presents as a variably pigmented macule or plaque with an irregular border, ranging in size from a few millimeters to several centimeters, often with multiple shades of red, blue, black, gray, and white color (picture 6A-B) (see "Melanoma: Clinical features and diagnosis"). The red zones are thought to represent areas of vessel ectasia and inflammation, and the white and gray regions reflect amelanotic or regressed foci. An asymmetric flare at the lesion periphery represents the advancing border of proliferating, neoplastic melanocytes.

Approximately 30 percent of superficial spreading melanomas are found in association with a pre-existing nevus, such as a dysplastic or congenital nevus, while the majority appear to arise de novo [21].

Histologically, superficial spreading melanomas are asymmetric, poorly circumscribed, and lack cellular maturation (ie, the nests and cells do not become smaller as they descend into the reticular dermis) (picture 7). Typically, the intraepidermal component extends laterally for more than three rete ridges past the confines of the dermal component [9].

In the radial phase of growth, there is haphazard growth of neoplastic melanocytes with single-cell spread throughout the layers of the epidermis (picture 7). This pagetoid spread of neoplastic melanocytes confers an appearance that resembles buckshot scatter. Cytologically, the melanocytes are often epithelioid in morphology, with large, round-to-oval nuclei, prominent eosinophilic nucleoli, and ample eosinophilic to amphophilic cytoplasm that is filled with fine melanin granules. Where neoplastic melanocytes form nests, the nests are often poorly formed and not cohesive.

A lymphocytic infiltrate is sometimes observed in the underlying papillary dermis; the presence of such an infiltrate in the earliest stages may signal incipient transformation into a microinvasive tumor. In the microinvasive radial growth phase of superficial spreading melanoma, both single-cell dispersal and nests of neoplastic melanocytes can be seen in the papillary dermis. The cytomorphology of these cells is similar to that seen with entirely intraepidermal growth, although the cytoplasm is characteristically more abundant and eosinophilic in the microinvasive radial growth phase. When no mitotic figures are identified in the dermal melanocytes, the largest nest in the dermis should not exceed the largest epidermal nest.

Transition to vertical growth phase occurs when the largest nest in the dermis exceeds that in the epidermis or if mitoses become evident within the dermis. Superficial spreading melanomas in the vertical growth phase may be confused with nodular malignant melanoma. The presence of an epidermal component extending three rete ridges beyond the dermal component distinguishes vertical growth phase superficial spreading melanoma from nodular malignant melanoma.

Lentigo maligna melanoma — Lentigo maligna melanoma most commonly arises in sun-damaged areas of the skin in older individuals and begins as a freckle-like, tan-brown macule [22]. The lesion gradually enlarges and develops darker, asymmetric foci (picture 8). When the lesion is confined to the epidermis (melanoma in situ-lentigo maligna type), it presents as a nonpalpable macule. (See "Lentigo maligna: Clinical manifestations, diagnosis, and management".)

Approximately 5 percent of intraepidermal lesions evolve to become clinically palpable, signaling dermal invasion and transformation into lentigo maligna melanoma [23]. Transformation is slow, and the lesion may be present for 10 to 50 years before a vertical growth phase becomes apparent [22].

Partial regression is not uncommon during evolution, a phenomenon that is represented by foci of blue-gray or light gray coloration. Once a lentigo maligna melanoma is fully evolved, color variegation can be striking.

Histologically, neoplastic melanocytes are arrayed along the dermoepidermal junction in a lentiginous pattern against a background of epidermal atrophy and solar elastosis (picture 9). During the radial growth phase, the atypical melanocytes are usually polygonal in shape with hyperchromatic, angulated nuclei, and they are dispersed along the dermoepidermal junction as well as along eccrine ducts and the outer root sheath epithelium of hair follicles. Multinucleated giant melanocytes ("star-burst giant cells") may be present at the basal layer of the epidermis [24]. These multinucleated giant cells can contain up to 30 nuclei, and their atypical morphology is similar to those in the lentiginous array.

As the lesion progresses, poorly cohesive or dyshesive nests are seen along the dermoepidermal junction, and they are aligned parallel to the long axis of the epidermis, forming the "swallow's nest" sign. Pagetoid spread, confluence of melanocytes along the basal layer, and nesting all herald an incipient, invasive phase [25].

The hallmark of the vertical growth phase is the formation of dermal nodules and fascicles that are larger than the epidermal component. The melanocytes are often pleomorphic with variably hyperchromatic nuclei. The cytoplasm of the tumor cells is shrunken and surrounds a pale nucleus with small nucleoli. Numerous mitoses and exuberant pagetoid spread are frequently observed. The lentiginous proliferation extends down the external root sheath of hair follicles, a feature that accounts for the high local recurrence rates when these lesions are superficially ablated. Other accompanying features include a lymphocytic infiltrate and the presence of melanophages.

The invasive dermal component of lentigo maligna melanoma may assume a spindle cell appearance with background desmoplastic stroma [17,26]. (See 'Desmoplastic melanoma' below.)

Acral lentiginous melanoma — Acral lentiginous melanoma is the least common variant of radial growth phase melanomas, comprising fewer than 5 percent of all melanomas. Acral lentiginous melanoma arises most commonly on palmar, plantar, subungual, and, occasionally, mucosal surfaces. The acral lentiginous subtype is the most common type of malignant melanoma among Asians and individuals with darker skin tones and shows a particular predilection for the soles of the feet.

Subungual melanoma arises from the nail matrix and usually presents as a longitudinal, brown or black band, with or without nail dystrophy. The involvement of the proximal nail fold (Hutchinson's sign) is considered a clue to the diagnosis [27]. Sometimes the presentation is that of a subungual mass (with or without pigmentation) with various degrees of ulceration and nail plate destruction (onychodystrophy) [28]. (See "Longitudinal melanonychia" and "Longitudinal melanonychia", section on 'Nail melanoma'.)

Not all melanomas arising in acral sites are acral lentiginous. Approximately 50 percent are acral lentiginous melanoma, followed by superficial spreading melanoma (35 to 40 percent) and nodular melanoma (8 to 20 percent) [29].

Clinically, acral lentiginous melanoma appears as a dark brown to black, unevenly pigmented patch (picture 10) [30]. Areas of regression manifest as foci of gray-white discoloration. If a lesion becomes raised or develops ulceration (picture 11), the likelihood of invasion should be considered. However, some tumors that invade along the perieccrine adventitial dermis may appear flat clinically, even if they have encroached upon subcutaneous adipose tissue.

Histologically, early acral lentiginous melanomas are characterized by a lentiginous array of atypical melanocytes along the dermoepidermal junction, with foci of confluent melanocytic growth (picture 12). With progression, large junctional nests that are composed of atypical melanocytes form, and atypical single cells extend into the epidermis (pagetoid spread) independently of the junctional nests. The confluence of junctional nests frequently heralds microinvasion of single cells into the papillary dermis during the radial growth phase. Invasive lesions are characterized by the presence of neoplastic single cells or nests in the dermis.

Cytologically, the lentiginous array of atypical cells is composed of large, hyperchromatic, angulated melanocytes with scant cytoplasm. Prominent, dendritic processes highlighted by fine melanin granules extend into the stratum spinosum. Single cells that spread upward into the epidermis in a pagetoid fashion appear epithelioid, like those seen in superficial spreading melanomas. The junctional nests are large with marked loss of cohesiveness, and they contain cells of epithelioid or spindle shape and severe nuclear atypia.

In invasive lesions, the morphology of neoplastic single cells or nests is similar to that of the epidermal component, except their cytoplasm is more abundant with fine pigmentation. Two useful histologic features can help with the distinction of acral lentiginous melanomas from benign acral nevi:

●The predominance of a single-cell pattern over a nested pattern; the converse is observed for benign acral nevi.

●The presence of a lichenoid, inflammatory infiltrate composed of lymphocytes admixed with melanophages, a feature that is virtually absent in benign acral nevi.

Nodular melanoma — By definition, nodular melanomas are vertical growth phase melanomas [31]. They constitute 15 to 30 percent of all melanomas. Clinically, a nodular melanoma appears as a darkly pigmented, pedunculated or polypoid nodule (picture 13), although amelanotic variants are infrequently seen [32].

Histologically, dermal growth occurs in isolation or, occasionally, in association with an epidermal component (picture 14A-B). When an epidermal component is present, it must not extend beyond three rete ridges of the dermal component. The neoplastic cells within the dermal growth may appear epithelioid or spindled. Mitoses are frequent and often atypical.

Rare variants — The challenge of correctly diagnosing certain types of melanoma is due, in part, to their mimicry of benign lesions. As many as 17 rare variants of malignant melanoma have been described in the last few decades, and new variants continue to emerge. In this section, we will emphasize nevoid melanoma and desmoplastic melanoma, variants that can escape the attention of even the most skilled pathologist because of their resemblance to nonpathologic conditions.

Nevoid melanoma — Nevoid melanomas are frequently mistaken for benign dermal nevi because of their superficial resemblance to this lesion, both clinically and histologically. However, nevoid melanoma behaves as a variant of malignant melanoma with metastatic potential [33,34]. Clinically, these lesions appear as verrucous or dome-shaped nodules frequently present on the trunk or proximal limbs of young adults [35].

Histologically, nevoid melanoma resembles a dermal nevus in that it lacks a prominent intraepidermal component and has a rather bland dermal component (picture 15A) [36]. However, careful inspection reveals that the dermal component has properties of frank vertical growth phase melanoma. On medium power view, it can be seen that the dermal component has striking hypercellularity and hyperchromasia, and the neoplastic nevoid cells lack true maturation but instead display a phenomenon termed "pseudomaturation" (picture 15B).

With higher power magnification, the nevoid cells appear to become smaller in the deeper dermis (as is observed with true maturation of melanocytes in benign nevi), but the cells are very hyperchromatic and are malignant appearing, with readily observed mitoses. Immunohistochemical studies using proliferation antigens and HMB-45 (uniform or patchy dermal expression, not restricted to the superficial portion of the tumor) can aid in the diagnosis of nevoid melanoma [36]. Fluorescence in situ hybridization (FISH) may also be useful for distinguishing between this variant of melanoma and benign nevi. (See 'Fluorescence in situ hybridization' below.)

Two variants of nevoid melanoma are recognized. One is polypoid, composed of large, epithelioid cells resembling the cells of a Spitz nevus (a red-pink, isolated, dome-shaped papule or nodule that usually occurs in young children and is composed of large, plump cells with pink-blue cytoplasm) [37]. Spitzoid melanoma should be distinguished from melanocytic tumors associated with BAP1 mutations [38]. Telomerase reverse transcriptase (TERT) promoter mutations may aid in stratifying clinical behavior of Spitzoid melanocytic neoplasms [39]. The other variant is most often a slightly raised papule or plaque resembling ordinary nevus; it is composed of small, nevus-like cells. (See "Spitz nevus and atypical Spitz tumors" and "Spitz nevus/tumor in children: Diagnosis and management" and "BAP1-inactivated melanocytoma".)

Desmoplastic melanoma — Desmoplastic melanoma is frequently clinically mistaken for a scar, fibroma, fibromatosis, or basal cell carcinoma because it typically presents as an amelanotic, pale, fleshy nodule or plaque that is reminiscent of a scar [40]. The presence of mucin within the lesion may impart a boggy quality [41]. When present, an important clue to clinical diagnosis is the presence of cutaneous pigmentation over a dermal nodule [42]. Desmoplastic melanomas tend to occur on sun-exposed areas of the head, neck, or upper back of older individuals, in whom they sometimes arise in the context of an associated lentigo maligna. In one series of 33 patients with desmoplastic melanoma, eight (24 percent) were associated with lentigo maligna [43].

Histologic examination reveals a poorly circumscribed vertical growth phase tumor. The spindle-shaped, malignant cells are associated with a marked, fibrogenic (myxoid), stromal response, in which reactive fibroblasts are intimately associated with the malignant melanocytes (picture 16). The malignant cells contain hyperchromatic, elongated nuclei, and their morphology closely resembles that of fibroblasts seen in a scar or fibroma. The hyperchromatic spindle cells form long fascicles that are arranged in acute angles to the horizontal axis of the epidermis. Occasionally, single dispersed spindle cells are also observed [42].

Associated pathologic findings may be helpful in confirming the diagnosis:

●The epidermis may contain lentiginous, melanocytic hyperplasia or even lentigo maligna [44].

●The spindle-shaped, malignant melanocytes may be neurotropic.

●Foci of lymphocytic aggregates and mucin may be seen in the dermis [42].

●Immunohistochemical staining with S-100 and SOX10 are positive. HMB-45 is generally negative. HMB-45 positivity is likely indicative of sclerosing blue nevus and is uncommon in desmoplastic melanoma [45]. (See 'Immunohistochemistry' below.)

Some desmoplastic melanomas fail to stain positively or stain only weakly with S-100 [46-48]. A variable proportion expresses the p75 nerve growth factor receptor (P75 NGF-R) [48-51].

Because the cytomorphology of desmoplastic melanoma mimics benign fibroblasts, inadequate surgical excision may be performed, contributing to a high local recurrence rate. The presence of neurotropism also increases the likelihood of locally recurrent disease, presumably because tumor cells extend along nerves to outside the wide local excision margin [52].

The clinical features of desmoplastic melanoma are discussed separately. (See "Surgical management of primary cutaneous melanoma or melanoma at other unusual sites", section on 'Desmoplastic melanoma'.)

Primary dermal melanoma — Primary dermal melanoma, also called solitary dermal melanoma, is a lesion that is confined to the dermis and/or subcutaneous tissue, without an epidermal component [53-55]. Whether these lesions represent a true primary lesion, a dermal metastasis from an unknown primary melanoma, or a lesion in which the epidermal component has regressed is unknown. Given the significantly better prognosis of primary dermal melanoma compared with cutaneous metastatic melanoma, ancillary molecular testing has been evaluated as a potential discriminating tool, but no distinct molecular profile for dermal melanoma has been identified [53,56]. (See "Tumor, node, metastasis (TNM) staging system and other prognostic factors in cutaneous melanoma".)

A large reported series included 101 patients, which represented 0.8 percent of the melanoma cases seen at a single institution over a 35 year period [53]. Nine of these patients had distant metastases at presentation. Nodal disease was either present at diagnosis or subsequently developed in 21 of the 92 patients (23 percent) who did not have disseminated disease at presentation. The five-year overall survival rates for those with local and regional disease were 73 and 67 percent, respectively. In another series of 49 patients, locoregional recurrence occurred in six patients, and three patients developed distant metastases after an average follow-up time of 26 months [54].

The observed prognosis in these patients is similar to that of intermediate thickness, primary melanomas and suggests that an aggressive approach to initial management, including wide local excision and sentinel lymph node biopsy, is warranted. (See "Surgical management of primary cutaneous melanoma or melanoma at other unusual sites".)

Cutaneous metastases — Clinically, metastatic melanoma involving the skin presents as a dermal nodule or plaque-like lesion, often in close proximity to the primary tumor [57]. (See "Tumor, node, metastasis (TNM) staging system and other prognostic factors in cutaneous melanoma", section on 'Regional involvement'.)

Histologically, cutaneous metastases appear as nodules in the dermis or subcutaneous fat without an epidermal connection (picture 17). The cells comprising the dermal nodules commonly have an epithelioid cytomorphology with hyperchromasia. The degree of cellular atypia is variable and is generally similar to the primary melanoma. A significant inflammatory response is typically absent [58].

Although the majority of cutaneous metastases have no epidermal connection, epidermal involvement may rarely be seen, a phenomenon termed "epidermotropic metastasis" [59]. The distinction between an epidermotropic metastasis and a primary malignant melanoma can be challenging. Correlation with clinical data, especially a careful search for a primary melanoma, is important.

Certain histologic features that are more consistently observed in epidermotropic metastases can help in the differentiation from primary cutaneous melanoma:

●The dermal component of epidermotropic metastases extends laterally beyond the borders of the epidermal involvement, while the opposite is often observed in primary melanomas. The epidermis also tends to be atrophic in metastatic melanomas.

●Although the cytomorphology of malignant melanocytes in the dermis is similar to that of the epidermal component in metastatic lesions, the morphology of cells in the epidermal and dermal components of a primary tumor tend to be more disparate.

●Compared with the frequently observed, lichenoid, inflammatory response in a primary tumor, this response is rarely appreciated in a metastatic tumor, in the absence of immunotherapy [58].

●Although tumor cells within vascular channels may be seen in primary melanoma, lymphovascular invasion supports metastatic melanoma in conjunction with the findings described above.

EVOLUTIONARY PATHWAY CLASSIFICATION OF MELANOMA

Overview — The enormous progress in discovering genetic alterations in melanocytic tumors has led to a reappraisal of the traditional morphologic classification of melanoma. The new classification incorporates clinical, pathologic, and genomic characteristics of the tumor. It is based on the theory that specific melanoma subtypes and their precursors/benign counterparts develop along distinct evolutionary pathways that diverge according to the amount of cumulative sun damage, as assessed by the degree of solar elastosis, and the pattern and sequence of genetic alterations [8,60]. The initiating events in melanomagenesis are gain-of-function mutations in driver oncogenes (eg, BRAF, NRAS, GNAQ, GNA11), while loss-of-function mutations in tumor suppressor genes (eg, CDNK2A, TP53, PTEN, or BAP1) occur as secondary events that mark the progression from benign, melanocytic tumors to specific subtypes of melanoma [6,8,61]. "Intermediate" lesions have some of the progression-related genetic alterations, though insufficient to result in a malignant behavior [8].

The molecular biology of melanoma is discussed in detail elsewhere. (See "The molecular biology of melanoma".)

The 2018 WHO classification — The 2018 World Health Organization (WHO) classification of melanocytic tumors identifies three major categories of melanomas, based on the intensity of chronic ultraviolet radiation exposure/cumulative solar damage, and nine evolutionary pathways, defined by different patterns of genetic alterations that lead to the development of melanoma subtypes as well as benign and intermediate, melanocytic lesions (table 2) [60].

This categorization places superficial spreading melanoma under the "low cumulative solar damage" heading and lentigo maligna and desmoplastic melanoma under the "high cumulative solar damage" heading. Acral lentiginous melanoma as well as other melanoma variants (ie, Spitz melanoma, mucosal melanoma, melanoma in congenital nevi, and melanoma in blue nevi) are placed in the "low to no cumulative solar damage" category. Nodular melanoma is recognized as a subtype that can arise from multiple pathways and is included in both the high and low cumulative solar damage categories. "Melanocytoma" is further offered as an intermediate category of melanocytic entities with low risk of progression to melanoma [26,60,62].

HISTOPATHOLOGIC DIAGNOSIS — Histopathology is the gold standard of diagnosis (table 1). In difficult cases, immunohistochemistry, fluorescence in situ hybridization (FISH), and molecular techniques can be used to support the diagnosis.

Components of the pathology report — In addition to confirming the diagnosis, pathologic evaluation provides important prognostic information that helps management, and this information must be provided to the clinician [3]. Once the diagnosis of malignant melanoma is established, the pathology report must include the subtype and a description of cytomorphology and architecture. Other important prognostic factors should be included, such as the greatest depth (Breslow thickness), level of dermal invasion (Clark's level), presence of ulceration, margin status, and for vertical growth phase lesions, the presence of mitoses, lymphocytic infiltrates, microsatellites, and neural or vascular invasion (table 3). An example of a histology worksheet is presented in the following figure (figure 1). A detailed discussion of prognostic factors in melanoma is provided elsewhere. (See "Tumor, node, metastasis (TNM) staging system and other prognostic factors in cutaneous melanoma".)

Immunohistochemistry — Immunohistochemistry can be helpful in difficult, cutaneous, melanocytic cases or in nodal metastases. Widely used markers of melanocytic differentiation include S-100, MART-1, HMB-45, MITF, SOX10, and preferentially expressed antigen in melanoma (PRAME) (table 4). Beyond corroboration that a given neoplasm is of melanocytic lineage, immunohistochemical stains can support a diagnosis of malignancy based on the following findings:

●HMB-45 expression throughout the dermal component

●Diffuse nuclear PRAME expression [63]

●P16 loss of expression [64]

The role of immunohistochemistry in lymph nodes is discussed separately. (See "Pathologic evaluation of regional lymph nodes in melanoma", section on 'Immunohistochemistry'.)

GENETIC AND MOLECULAR CHARACTERIZATION OF MELANOMA — Based upon a variety of molecular genetic techniques, including polymerase chain reaction (PCR), massively parallel sequencing, fluorescence in situ hybridization (FISH), and comparative genomic hybridization, several chromosomal aberrations and genetic mutations have been recognized as potentially valuable for the diagnosis and management of melanoma (table 5) [65,66]. Telomerase reverse transcriptase (TERT) promoter mutations, for example, are rare in nevi and have been linked with melanoma development [67]. Massively parallel sequencing (next-generation sequencing) has enabled sequencing of multiple cancer-driving genes implicated in melanoma (including BRAF, NRAS, PREX2, GRIN2A, and ERBB4) in a single assay as a first step towards personalized medicine [68].

Fluorescence in situ hybridization — Fluorescence in situ hybridization (FISH) may be a useful technique to support or refute a diagnosis of melanoma in difficult cases [66,69,70]. The procedure provides chromosomal copy number analysis at selected or targeted genomic loci, including 6p25 (RREB1), 6q23 (MYB), 8q24 (MYC), 9p21 (CDKN2A), and 11q13 (CCND1). Practically, FISH is often utilized to help arbitrate histopathologically challenging cases with spitzoid morphology.

Gene expression profiling — Gene expression profiling has been promoted to offer additional, improved diagnostic and prognostic utility for cutaneous melanoma [71]. Utilizing a panel of genes related to melanoma, stratification into risk categories is aimed to predict the likelihood of metastasis beyond conventional clinical and pathologic parameters. While commonly employed for uveal melanoma and promising for cutaneous melanoma, cautions have been expressed about its routine use for skin melanoma [72,73].

HISTOPATHOLOGIC DIFFERENTIAL DIAGNOSIS FOR MELANOMA

Other melanocytic proliferations — The main pathologic differential distinction for primary melanoma concerns other melanocytic proliferations that are not unequivocally benign, including dysplastic nevi, cellular blue nevi, Spitz nevi, deep-penetrating nevi, recurrent or persistent nevi, nevi of special sites, nevi during pregnancy, pigmented epithelioid melanocytoma, and BAP1-negative melanocytic tumors (BAPoma). (See "Atypical (dysplastic) nevi" and "Spitz nevus and atypical Spitz tumors" and "BAP1-inactivated melanocytoma".)

Nonmelanocytic lesions — In certain instances, depending upon its particular cytomorphology and architecture, melanoma can resemble nonmelanocytic lesions as well. For example, epithelioid melanoma can be confused with carcinoma; spindle cell melanoma can be mistaken for neoplasms of fibrohistiocytic, myofibroblastic, neural, or vascular nature; and small cell melanoma can mimic lymphoid proliferations. Even inflammatory dermatoses must be considered in rare cases (eg, desmoplastic melanoma obscured by postsurgical, inflammatory changes and scars).

Clear cell sarcoma is a rare soft tissue sarcoma that for many years, due to the occasional presence of melanin pigment and melanosomes, was thought to be histogenetically related to melanoma [74]. However, clear cell sarcoma bears only a phenotypic resemblance to malignant melanoma. Subsequent genetic studies have demonstrated a characteristic translocation [t(12;22)(q13;q12)] that results in a unique fusion gene (EWSR1/ATF1) that is not found in cutaneous or uveal malignant melanomas but is instead related to those found in some sarcomas [75]. (See "Pathogenetic factors in soft tissue and bone sarcomas", section on 'Clear cell sarcoma'.)

Clear cell sarcoma typically affects young women in their 30s and has a predilection for the lower extremities. Although a potentially aggressive tumor [76], its clinical course is usually more indolent than most malignant melanomas.

Grossly, clear cell sarcoma often appears fleshy and white, bearing more resemblance to a soft tissue sarcoma than a melanoma. Histologic examination reveals large, polygonal cells with clear to eosinophilic cytoplasm and prominent nucleoli. The cells frequently have an eccentrically located nucleus, conferring a "plasmacytoid" appearance; binucleation is also observed.

Although the presence of melanin can be demonstrated by special stains in most cases of clear cell sarcoma, melanin is rarely seen on hematoxylin and eosin-stained sections [77]. Confirmation of the presence of melanin is helpful in distinguishing clear cell sarcoma from other soft tissue sarcomas, especially fibrosarcoma and synovial sarcoma. (See "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma".)

Immunohistochemically, 80 percent of clear cell sarcomas express S-100, while 78 percent are HMB-45 positive, 75 percent are MITF positive, and cytokeratin stains are negative [78,79]. (See 'Immunohistochemistry' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Melanoma screening, prevention, diagnosis, and management".)

SUMMARY

●The pathologic report provides diagnostic and prognostic information that influences the selection of treatment for patients with melanoma (table 3). (See 'Overview' above and 'Components of the pathology report' above.)

●Melanomas exhibit two growth modalities: the radial phase and the vertical phase. In the radial growth phase, proliferation of malignant melanocytes is confined to the epidermis, with occasional involvement of the upper dermis. In the vertical growth phase, malignant melanocytes form nests or nodules in the dermis. (See 'Growth phases of melanoma' above.)

●The traditional clinicopathologic classification of melanoma is based on the morphologic aspects of the growth phase and distinguishes four main subtypes: superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, and acral lentiginous melanoma (table 1). For each subtype, except the nodular, an in situ form exists. (See 'Morphologic classification of melanoma' above.)

●Following the enormous progress in discovering genetic alterations in melanocytic tumors, a new classification has been proposed that is based on the concept that melanoma subtypes develop along distinct evolutionary pathways that diverge according to the amount of chronic ultraviolet radiation exposure. This classification incorporates clinical, pathologic, and genomic characteristics of the tumor (table 2). (See 'Evolutionary pathway classification of melanoma' above and "The molecular biology of melanoma".)

●Superficial spreading melanoma appears as a plaque that is a few millimeters to several centimeters in diameter, with irregular borders and variegated color (picture 18). Malignant melanocytes spread throughout the layers of the epidermis as single cells and nests. In the vertical growth phase, mitoses or nests of malignant melanocytes are observed in the dermis (picture 7). The melanocytes are epithelioid with large nuclei and abundant cytoplasm filled with melanin granules. (See 'Superficial spreading melanoma' above.)

●Lentigo maligna melanomas begin as a nonpalpable, tan or brown macule, enlarging gradually over many years (picture 8). Dermal invasion is signaled by the appearance of palpable areas. Neoplastic melanocytes are polygonal with hyperchromatic nuclei, arrayed along the dermoepidermal junction in a lentiginous pattern (picture 9). A dermal nodule indicates a vertical growth phase. The cells appear pleomorphic, with shrunken cytoplasm, and extend down the external root sheath of hair follicles. Desmoplastic melanoma may arise in conjunction with lentigo maligna. (See 'Lentigo maligna melanoma' above and "Lentigo maligna: Clinical manifestations, diagnosis, and management".)

●Acral lentiginous melanomas arise on palmar, plantar, subungual, and mucosal surfaces (picture 10). Atypical melanocytes are arrayed along the dermoepidermal junction (picture 12). Progression is marked by the presence of large junctional nests of atypical melanocytes, which are large and hyperchromatic with scant cytoplasm. (See 'Acral lentiginous melanoma' above.)

●Nodular melanomas are by definition vertical growth phase melanomas. They present as darkly pigmented nodules, sometimes ulcerated (picture 13). On histology, there is a nodule of neoplastic cells in the dermis, with no recognizable adjacent radial growth phase (picture 14B). The neoplastic melanocytes are epithelioid or spindle cells; mitoses are frequent and often atypical. (See 'Nodular melanoma' above.)

●Rare variants of melanoma include nevoid melanoma (picture 15A-B), desmoplastic melanoma (picture 16), and solitary dermal melanoma. (See 'Rare variants' above.)

●Metastatic melanoma involving the skin appears as a dermal nodule or plaque-like lesion, often in close proximity to the primary tumor. Histologically, cutaneous metastases appear as nodules in the dermis or subcutaneous fat without an epidermal connection (picture 17). (See 'Cutaneous metastases' above.)

●Most melanomas are diagnosed on routine histology. Immunohistochemistry can be helpful in difficult cases or in differentiating nodal metastases from nodal nevi. The most widely used markers include S-100, MART-1, HMB-45, MITF, SOX10, and preferentially expressed antigen in melanoma (PRAME) (table 4). (See "Pathologic evaluation of regional lymph nodes in melanoma", section on 'Immunohistochemistry'.)

●Based upon a variety of molecular genetic techniques, including polymerase chain reaction (PCR), massively parallel sequencing, fluorescence in situ hybridization (FISH), and comparative genomic hybridization, several chromosomal aberrations and genetic mutations have been recognized as potentially valuable for the diagnosis and management of melanoma (table 5). (See 'Genetic and molecular characterization of melanoma' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Martin C Mihm, Jr, MD (deceased), who contributed to earlier versions of this topic review.