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Uncommon Histopathological Variants of Malignant Melanoma. Part 2

Saggini, Andrea, MD*; Cota, Carlo, MD; Lora, Viviana, MD; Kutzner, Heinz, MD; Rütten, Arno, MD; Sangüeza, Omar, MD§; Requena, Luis, MD; Cerroni, Lorenzo, MD

The American Journal of Dermatopathology: May 2019 - Volume 41 - Issue 5 - p 321–342
doi: 10.1097/DAD.0000000000001226
CME Article
Free

Abstract: Despite new horizons opened by recent advances in molecular pathology, histological evaluation still remains the diagnostic gold standard regarding cutaneous melanocytic neoplasms. Several histological variants of melanoma have been described, and their knowledge is crucial for accurate diagnosis and classification of cases with unusual clinico-pathological features. Uncommon histological variants of melanoma have been described based on a broad constellation of features, including architectural pattern, stromal alterations, cytological attributes, and other morphological properties. This review is aimed at providing an extensive discussion of unusual but distinctive histopathological variants of melanoma.

*Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy;

San Gallicano Dermatological Institute, Rome, Italy;

Dermatopathology Friedrichshafen, Friedrichshafen, Germany;

§Department of Pathology, Wake Forest School of Medicine, Winston Salem, NC;

Department of Dermatology, Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain; and

Research Unit Dermatopathology, Department of Dermatology, Medical University of Graz, Graz, Austria.

Correspondence: Lorenzo Cerroni, MD, Department of Dermatology, Medical University of Graz, Auenbruggerplatz 8, A-8036 Graz, Austria (e-mail: lorenzo.cerroni@medunigraz.at).

All authors and staff in a position to control the content of this CME activity and their spouses/life partners (if any) have disclosed that they have no financial relationships with, or financial interests in, any commercial organizations relevant to this educational activity.

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LEARNING OBJECTIVES

After participating in this activity, the physician should be better able to:

  1. Analyze different types of melanocytic tumors regarding architectural, cytomorphological, and immunohistochemical features.
  2. Assess the histopathological pattern of different types of melanoma with particular regard to specific variants characterized either by presence of peculiar cell types (eg, balloon cells, multinucleated cells, signet-ring cells, etc.), by unconventional morphology (eg, follicular melanoma, bullous melanoma, small melanoma, etc.), or by stromal changes (eg, desmoplasia).
  3. Distinguish between several melanoma variants with peculiar structural features and recognize challenges related to measurement of tumor thickness.

Despite new horizons opened by recent advances in molecular pathology, histological evaluation still remains the diagnostic gold standard regarding cutaneous melanocytic neoplasms.1–3 In addition to main melanoma categories listed in the WHO classification of tumors (Table 1),4 several other histological variants have been described, and their knowledge is crucial for accurate diagnosis and classification of cases with unusual clinico-pathological features.5,6 Uncommon histological variants of melanoma have been described based on a broad constellation of features, including architectural pattern, stromal alterations, cytological attributes, and other morphological properties.7,8

TABLE 1

TABLE 1

This is the second part of a review aimed at providing an extensive discussion of unusual but distinctive histopathological variants of melanoma, as described in the available literature. For practical purposes, histological entities are listed according to alphabetical order.

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MYXOID MELANOMA

Variable amounts of extracellular mucin may be focally observed in conventional melanoma (Fig. 1).8,9 According to the definition by Hitchcock et al,10 the term “myxoid melanoma” should apply to cases with myxoid changes exceeding 15% of the stroma. Prominent myxoid changes in melanoma seem to be related to desmoplastic melanoma and melanoma with neuroid differentiation.8 Although melanocytes have been demonstrated to be able to induce glycosaminoglycan synthesis, reactive mesenchymal cells seem to be the likely culprit of acid mucopolysaccharides production in myxoid melanoma.11,12 Prominent extracellular deposition of mucin may be also observed in melanoma metastases, with primary lesions usually exhibiting a nonmyxoid appearance.13,14 In one case of myxoid melanoma, stromal changes were thought to be related to the effects of prolonged phototherapy applied for over 30 months on an undiagnosed melanocytic neoplasm.15 Of note, a mucinous-like appearance may be the result of marked intratumoral edema, a phenomenon referred to as “pseudo-myxoid” changes.16 The mucinous quality of extracellular material should be confirmed by means of histochemical staining for alcian blue at pH 2.5 and/or colloidal iron.8

FIGURE 1

FIGURE 1

Extensive mucin deposition in melanoma results in a diagnostic challenge, especially in tumors lacking evidence of pigmentation. Myxoid areas in melanoma often feature stellate, spindled, and/or astroglial-like melanocytes, frequently smaller than conventional melanoma cells.8,10,17 Multinucleated or floret-like giant cells may be observed as well. Furthermore, akin to desmoplastic melanoma, melanocytes within myxoid foci may fail to express HMB-45 and/or Mart-1, despite retaining positivity for S100 and Sox-10.18

The differential diagnosis in cases of myxoid melanoma is broad, including several benign and malignant neoplasms with myxoid changes.8 Myxoid changes have been recently described also in Spitz nevi.19 Detection of features of conventional melanoma at the periphery of myxoid areas and/or within the epidermis represents a useful diagnostic clue in challenging cases.9

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NESTED MELANOMA OF THE ELDERLY

Nested melanoma of the elderly is a peculiar variant of superficial melanoma characterized by predominance of large, irregular, confluent nests of melanocytes (Fig. 2).20,21 Given the bland appearance of such lesions and similarity to benign junctional nevi in their growing phase (observed mainly in children), nested melanoma of the elderly may be regarded as part of the heterogeneous spectrum of nevoid melanomas.22 Predictably, in light of histological similarities with nested junctional nevi in children, the corresponding clinico-dermatoscopical features are characterized by an irregular globular pattern.23

FIGURE 2

FIGURE 2

Histopathologically, nested melanoma of the elderly is characterized by a superficial (mainly junctional) proliferation of cells mostly arranged in large, cannonball-like irregular nests strikingly predominating over solitary melanocytes.20,21,24 A key finding favoring a diagnosis of melanoma is presence of actinic elastosis in the dermis.21,22 Indeed, any melanocytic neoplasm with such histological features in an elderly patient should be regarded as strongly suspicious for melanoma.22,24 Important additional clues may include focal pagetoid spread of melanocytes and thinning of epidermal rim surrounding the nests.21 The malignant nature of this variant of melanoma has been confirmed by means of genetic analyses, as indicated by presence of multiple chromosomal aberrations.24

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NEUROTROPIC MELANOMA AND MELANOMA WITH NEURAL DIFFERENTIATION

Development of a neural/neurotropic phenotype in melanoma seems to be closely related to desmoplastic melanoma, as suggested also by the overlapping features of these 2 variants.25–27 The propensity of melanoma for acquisition of neural differentiation is likely linked to the embryological origin of melanocytes from the neural crest, a feature shared with Schwann cells.28 Transcriptional reprogramming with upregulation of neurotropic factors and of proteins involved in extracellular matrix production seems to be responsible for the morphological changes observed in this variant of melanoma.26,28

FIGURE 3

FIGURE 3

FIGURE 4

FIGURE 4

Similarly to desmoplastic melanoma, neurotropic melanoma and melanoma with neural differentiation show a predilection for sun-exposed areas of the head and neck in elderly people.25,27 In neurotropic melanoma, the tumor usually involves the entire dermis exhibiting growth around and/or infiltration of the nerve bundles (Figs. 3 and 4).25,26 The latter are commonly hyperplastic.26,27 At times, neural involvement may be minimal and easily missed, with only slight increase in stromal cellularity surrounding nerve structures along with a sparse lymphoplasmacellular infiltrate.25 Neural differentiation in melanoma is characterized by development of nerve-like structures, simulating neural tumors.26,27 Perineurial29 and ganglioneuroblastic30,31 differentiation have been rarely observed and Homer-Wright rosette-like structures.32 Presence of an intraepidermal in situ component represents a valuable diagnostic clue.25

Immunohistochemical stainings may be helpful in the differential diagnosis between melanoma with neural differentiation and neural neoplasms.25–27 Despite shared expression of S-100 and Sox-10, melanoma with neural differentiation may be at least focally positive for melanosome-associated markers such as HMB-45 and Mart-1, and for MiTF.26,27 A caveat in this regard is aberrant melanocytic differentiation in neural tumors, including pigmented neurofibroma, melanotic schwannoma and malignant peripheral nerve sheath tumor.25–27 Absence of CD34 fingerprint positivity was proposed to be a useful clue for distinguishing desmoplastic/neurotropic melanoma from neurofibroma, but subsequent research has questioned the reliability of this finding.33–35 Recently, p53 positivity has been demonstrated in almost all cases of desmoplastic melanoma but not in neurofibroma.35 Expression of the histone methylation marker H3K27me3 (trimethylation of lysine 27 on histone H3 protein subunit) is usually lost in malignant peripheral nerve sheath tumors, but is retained in desmoplastic, spindle cell and neurotropic melanoma.36

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NEVOID MELANOMA

Nevoid melanoma is a generic term that has been used for different types of melanoma showing histopathological features similar to those of any melanocytic nevus.22,37 Several other terms have been used to refer to the same conceptual problem, such as minimal deviation melanoma, small cell melanoma or spitzoid melanoma among others.22,37 The definition of nevoid melanoma provided by McKee (“a melanoma that I have diagnosed as nevus, and I wish I hadn't”)38 puts the problematic of nevoid melanoma in a nutshell: these malignant melanocytic tumors are deceitfully similar to their benign counterparts.

A precise definition of nevoid melanoma is difficult and subjective, as the histopathological features vary according to the type of simulated melanocytic nevus, and also because many cases of otherwise conventional melanoma may show, at least focally, nevoid features. Historically, 2 major architectural patterns have been traditionally considered typical of nevoid melanoma39: a papillomatous subtype, and the dome-shaped, nonpapillomatous nevoid melanoma. Massi and LeBoit22 added a third pattern, including also the nested melanoma of the elderly in this category (see specific paragraph). For practical purposes, we use the term “nevoid melanoma” for any case of melanoma that shows architectural and/or cytomorphological features similar to those of a melanocytic nevus with the exception of Spitz nevus, as this last may be characterized by atypical cytomorphological features. In fact, “Spitz” melanoma (the term “spitzoid” melanoma has been discouraged in the new WHO classification, whereas Spitz melanoma has been introduced as the malignant end of the group of melanocytic tumors including also Spitz nevus and atypical Spitz tumor) is considered as a distinct variant of melanoma separated by other types of melanomas.4 In addition to Spitz melanoma, some types of melanoma (eg, malignant blue nevus, dermal melanoma, plexiform melanoma, small diameter melanoma, small cell melanoma, and lentiginous melanoma of the elderly) may belong conceptually to the group of nevoid melanoma, but in our opinion are better considered as distinct histopathologic variants, and will be discussed separately in this review. Besides primary cutaneous melanoma, nevoid features may be encountered in metastatic melanoma as well (eg, blue nevus-like metastatic melanoma).40

The clinical features of nevoid melanoma are not specific.22,37 Recently, a multicentric study of the International Dermoscopy Society suggested that atypical vessels and/or irregular dots/globules in a papillomatous lesion should prompt to include nevoid melanoma in the differential diagnosis.41 Parenthetically, the histological resemblance to melanocytic nevi does not have any prognostic value in nevoid melanoma, with prognosis depending on the same criteria valid for “conventional” melanoma.22

Histopathologically, we divide nevoid melanoma into the following 5 main categories according to the simulated benign counterpart: (1) nevoid melanoma with dysplastic nevus-like pattern (Fig. 5); (2) nevoid melanoma with congenital nevus-like pattern (Fig. 6); (3) nevoid melanoma with Reed nevus-like pattern42 (although many authors consider Reed nevus as a variant of pigmented Spitz nevus, unlike “Spitz nevus,” which has become over the years a huge group of completely different lesions, Reed nevus displays morphological features which are very distinctive); (4) nevoid melanoma with dermal nevus-like pattern (papillomatous or dome-shaped) (Fig. 7); and (5) nevoid melanoma with hypermelanotic nevus-like pattern (Fig. 8). It is obvious that, like in all other variants of melanoma, a degree of overlap exists between these types, but this classification may be helpful when assessing a given tumor at the microscope. Valuable clues pointing to a diagnosis of nevoid melanoma include advanced age of patients, large size of the lesion, architectural disarray of nests regarding size, distribution and shape, and even mild spread of single melanocytes above the dermo-epidermal junction.22,37 Presence of actinic elastosis displaced (“pushed down”) by a dermal melanocytic tumor represents a further, important criterion for malignancy.22 Predominantly intradermal subtypes of nevoid melanoma (ie, papillomatous and dome-shaped) will often feature an abnormally increased density of neoplastic melanocytes with “stuffing” of dermal papillae.22 Immunohistochemistry usually does not help in differentiating nevoid melanomas from benign counterparts, although an abnormally increased mitotic activity may be confirmed by staining for Ki67 and phosphorylated histone H3 (pHH3).22,37 Genetic assessment by means of fluorescence in-situ hybridization (FISH) or comparative genomic hybridization (CGH) has been shown to hold diagnostic potential in challenging cases.43,44 Some authors proposed that the pattern of HMB-45 staining may be helpful in differentiating melanocytic nevi from melanoma (strong staining in the entire dermal component of nevoid melanoma as opposed to negativity of the deepest dermal component of melanocytic nevi);45 but in our experience, this immunohistological staining is not reliable in the differential diagnosis of nevoid melanoma.

FIGURE 5

FIGURE 5

FIGURE 6

FIGURE 6

FIGURE 7

FIGURE 7

FIGURE 8

FIGURE 8

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OSTEO-CARTILAGINEOUS MELANOMA

Areas of osteoid and/or chondroid metaplasia can be occasionally found in otherwise conventional melanomas, either primary or metastatic (Fig. 9).8 The metaplastic component may range from purely osteoid or chondroid differentiation to a combination of both.29,46,47 This phenomenon seems to be more frequent on acral skin, particularly the subungueal region, and in mucosal melanomas.29,48

FIGURE 9

FIGURE 9

A history of recurrent trauma is fairly common in osteo-cartilaginous melanoma, pointing to a role for chronic reparative response in the pathogenesis of the chondro-osteoid metaplasia.49 However, the finding of osteo-cartilaginous differentiation also in metastatic melanoma seems to support further pathogenetic hypotheses, including stromal induction of chondroid and/or osteoid metaplasia and mesenchymal dedifferentiation of melanoma cells.48

In most cases, chondro-osteoid differentiation will be limited to only a small percentage of the tumor mass, thus not representing a significant problem in the diagnosis of melanoma.8 Recognition of an intraepithelial component with lentiginous growth and/or pagetoid spread of melanocytes represents an important clue in problematic cases.8 Only rarely acral osteo-cartilaginous melanoma may by misdiagnosed as sarcoma, because of the presence of areas with spindled morphology, desmoplastic stromal response, and neurotropism.49,50 As expected from studies on chondro- and osteosarcomas, nuclear positivity for Sox-9 and SATB2 in sarcomatous foci correlates with histological evidence of chondroid and osteoid metaplasia in osteo-cartilaginous melanoma.51

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PIGMENTED EPITHELIOID MELANOCYTOMA

The term “pigmented epithelioid melanocytoma” (PEM) has been coined to describe a group of pigment synthesizing melanocytic neoplasms similar to the “epithelioid blue nevus” first observed in patients suffering from the Carney complex, a genodermatosis predominantly linked to germline inactivating mutations in PRKAR1A (Figs. 10 and 11).52–54 Most of reported cases of PEM have been described in the general population, in the absence of clinical and genetic evidence of Carney complex.52–54 PEM has been described as a melanocytic tumor of low-grade malignant potential, but follow-up data on the original cases showed that no patient died of melanoma (although liver metastases were found in one case).52,54

FIGURE 10

FIGURE 10

FIGURE 11

FIGURE 11

It has been proposed that PEM should also encompass lesions previously known as animal-type melanoma, or that the denomination of “pigment synthesizing melanocytic tumors” should be used as an umbrella term.53–55 Although acknowledging the possibility of overlapping features, other authors have supported the existence of PEM as a separate entity.56 According to the latter view, histopathological features typical of PEM include smaller size, wedge-shape or rectangular silhouette, regular epidermal hyperplasia, and presence of a heterogeneous epithelioid and spindled population of melanocytes with only limited cytological atypia.56 The proportion of pigmentation seems to be much lower in PEM than in animal-type melanoma, with less than 10% of melanophagic component.56 Cases with a junctional proliferation of melanocytes may be misdiagnosed as junctional blue nevus or blue-nevus like melanoma.56

Recent genetic studies have revealed that the term “PEM” has been actually used for a group of neoplastic lesions with heterogeneous molecular and phenotypic features.57 So-called “pure” PEM (ie, devoid of a combined morphological component) is characterized by MAP2K1 activating mutations associated with PRKAR1A inactivating mutations and immunohistochemical loss of PrkaR1-alpha expression.57 Some “pure” cases of PEM show PRKCA gene fusions, no PRKAR1A inactivating mutations, and immunohistochemical retention of PrkaR1-alpha expression, whereas in others there is no detectable genetic alteration (with either loss or maintenance of PrkaR1-alpha expression at the immunohistochemical level).57 In some cases, evidence of GNAQ Q209P activating mutations, akin to those typical of the blue nevus-family of melanocytic neoplasms, can be observed.57 It is still a matter of debate if the latter subgroup of lesions should be reclassified as blue nevi of uncertain malignant potential based on their genetic status. Finally, some lesions of PEM represent combined nevi with evidence of BRAF V600E activating mutations coupled with PRKAR1A inactivating mutations (ie, fulfilling criteria of a “double-hit” genetic model) and show immunohistochemical loss of PrkaR1-alpha expression.57 The exact biological potential of this category is unclear; as on the one hand, it has been demonstrated that the PEM component represents a “second hit” in the melanocytic population, thus representing a further step toward a malignant phenotype, and on the other decades of clinical observations suggest that combined nevi (including those with PEM features) are completely benign. At the present state of knowledge, in our opinion, combined nevi should be excised completely with narrow margins, but no further treatment is necessary.

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PLASMACYTOID MELANOMA

Plasmacytoid melanoma (also known as “melanoma with plasmacytic features”) is characterized by neoplastic cells with eccentric round nuclei, perinuclear halo, and eosinophilic cytoplasm, thus mimicking plasmacytic elements typical of plasma cell neoplasms (Fig. 12).8 The plasmacytoid morphology, which seems to be likely related to ultrastructural changes of rhabdoid melanoma, is rare in primary cutaneous melanoma and has been observed also in mucosal and metastatic melanoma.58,59

FIGURE 12

FIGURE 12

As in several other unusual variants of melanoma, also in plasmacytoid melanoma, histological diagnosis may be challenging.8 With most of reported cases appearing to be clinically amelanotic, lack of melanin pigment is a frequent feature also in biopsy specimens.58,59 In some cases, the occurrence of necrosis and/or ulceration results in intermingling with a plasma cell-rich inflammatory infiltrate, thus representing a further confounding feature. In this context, it should be also emphasized that plasmacytoid dendritic cells may be a frequent finding within the inflammatory infiltrate in conventional melanoma, exerting a key role in melanoma-associated immune response, and they should not be confused with tumor cells.60 A unique case of plasmacytoid melanoma colonized by monoclonal plasma cells in a patient with plasma cell myeloma has been described.61

Melanoma should be always considered in the differential diagnosis of neoplasms with plasmacytoid appearance, and use of immunohistochemical stainings may be useful in confirming the lineage of neoplastic cells. In this regard, it should be reminded that apparent plasmacytoid differentiation in plasmacytoid melanoma may be suggested by the not infrequent positivity for CD138, MUM1, and/or immunoglobulin light chains, representing a potential pitfall.61 Neoplastic cells of plasmacytoid melanoma, however, are positive as a rule for conventional melanoma markers.

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PLEXIFORM MELANOMA (DEEP PENETRATING NEVUS-LIKE MELANOMA)

The presence of a plexiform growth pattern in melanoma represents a diagnostic challenge, as differentiation from deep penetrating nevus (DPN) may be very difficult if not impossible (Fig. 13).62,63 Indeed, the biological relationship between plexiform melanoma and DPN, and corresponding histopathologic criteria for differential diagnosis are still widely disputed. Clinically, plexiform melanoma is characterized by similar epidemiology and favored anatomic locations as DPN, being mostly reported in young people on the upper half of the body.63 Histopathologically, presence of diffuse pleomorphism and of cytologic atypia, horizontal confluence of the nests in either the superficial or deeper part of the tumor, lack of maturation, increased mitotic activity, and disproportionate thickness have been said to favor a diagnosis of malignancy.63,64 It should be remembered, however, that some degree of atypia and mitotic activity are found in most DPN, and that maturation may be missing as well.62,63 Indeed, the term “deep penetrating nevus-like borderline tumor” has been recently proposed by Magro et al65 to refer to lesions with conflicting, intermediate histopathologic features between DPN and plexiform melanoma. A spectrum of melanocytic lesions with “deep-penetrating” features seems to exist, as corroborated by recent evidence of recurring oncogenic mutations in the APC-beta-catenin pathway.66 In the authors' practice, the working term “deep penetrating tumor” is used for DPN-like tumors, which cannot be confidently classified as benign. For practical purposes, any DPN-like melanocytic neoplasm should be always excised completely with free margins. We do not advocate the use of sentinel lymph node biopsy for borderline DPN-like tumors, though radiological imaging of regional lymph nodes may be suggested.

FIGURE 13

FIGURE 13

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POLYPOID MELANOMA

First described by Vogler et al in 1958,67 polypoid melanoma is defined as a malignant melanocytic tumor with more than half of its vertical diameter protruding above the cutaneous surface (Fig. 14).8 Polypoid melanoma may be either sessile or pedunculated, with an underlying peduncle or stalk and a mushroom-like appearance.68 It is usually regarded as an aggressive presentation of nodular melanoma, characterized by an exclusive vertical growth phase, but rare cases with peripheral radial growth (mimicking superficial spreading melanoma and acral lentiginous melanoma) have also been described.8,69

FIGURE 14

FIGURE 14

Clinically, polypoid melanomas may be misdiagnosed as nodular basal cell carcinoma, fibroepithelial polyp, or several other sessile/pedunculated skin neoplasms of variable biological potential.8 Histopathologically, however, diagnosis is usually straightforward: polypoid melanoma exhibits an exophytic growth pattern featuring sheets of neoplastic cells within a widely expanded papillary dermis, whereas the reticular dermis is only focally infiltrated (if at all).8 The polypoid architectural configuration is thought to favor permeation of blood and lymphatic capillaries by neoplastic cells.69 A junctional in situ component is rarely, if ever present, usually localized at the base of the stalk. Frank cytological atypia and markedly increased mitotic activity are additional features. Areas with more bland neoplastic melanocytes and a nevoid appearance may be observed as well.8

Compared to conventional melanoma, polypoid melanoma is characterized by higher incidence of ulceration and greater thickness, thus being associated with more dismal prognosis.5,68–70

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PSEUDOGLANDULAR MELANOMA

Cases of melanoma in which the dyscohesive pattern typical of bullous/acantholytic melanoma extensively involves the intradermal part of the tumor may exhibit a pseudoglandular appearance with formation of so-called pseudolumina, bearing resemblance to an adenocarcinoma (Fig. 15).8,71 Development of a central pseudolumen may be the result of widespread loss of intercellular junctions within neoplastic nests, extensive cytoplasmic vacuolization of melanocytes, and/or central necrosis of cellular nodules.71,72 Pseudoglandular structures may be observed as a focal component within an otherwise conventional melanoma or, exceptionally, characterize most of the neoplasm; in such cases, detection of the in situ component will serve as a helpful diagnostic clue.8,72 As the above-mentioned pseudoglandular pattern seems to be the result of a morphological artefact rather than of true lineage reprogramming, immunohistochemical staining for melanocytic markers confirms the diagnosis of melanoma in doubtful cases.71 It should be highlighted that rare cases of true adenocarcinomatous transdifferentiation have been reported in advanced metastatic melanoma, accompanied by complete reversal of conventional immunophenotypical features (ie, positivity for cytokeratins and loss of expression of S100 and Sox-10).73,74

FIGURE 15

FIGURE 15

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REGRESSING MELANOMA (MELANOMA WITH COMPLETE REGRESSION)

Three different types of regression have been classically described in cutaneous melanoma: partial (ie, regression of the dermal component with persistence of complexes of melanoma in situ in the overlying epidermis); focal (complete regression of dermal and junctional cells in a given part of melanoma, either within or at one side of the tumor); and complete (regression of all melanoma cells with no remaining melanocytic complexes found in any part of the lesion) (Fig. 16).75 A peculiar subtype of regression is observed in the context of melanoma-associated lichenoid inflammation, as previously discussed (see lichenoid keratosis-like melanoma).76 Partial or focal regression is not uncommon in conventional melanomas, and we will limit our discussion to complete regression only. It should be emphasized that regression is often defined differently in various centers and by individual pathologists, thus hindering a proper comparison of different studies.77

FIGURE 16

FIGURE 16

Despite total disappearance of melanocytic complexes, complete regression of melanoma may still be recognized with confidence in most excisional biopsies. Diagnostic criteria include: (1) patient age (regression of melanocytic nevi does not occur in the elderly, being exceedingly rare in older adults as well); (2) presence of a broad area of regression (often >1 cm); (3) irregular, asymmetrical pattern of regression, with broadened papillary dermis characterized by irregular fibrosis and asymmetrical distribution of pigmented melanophages; (4) presence of actinic elastosis, which may be only subtle, as complete regression frequently occurs on areas of intermittent sun exposure, and the resulting fibrosis may mask the actinic elastosis.76 Importantly, the clinical presentation of such lesions is usually strongly suggestive of a melanoma, and clinicopathological correlation is particularly valuable in this context.

At times, complete regression is seen in melanoma arising in a preexisting melanocytic nevus, resulting in complete disappearance of the melanoma cell population but persistence of bland complexes of the melanocytic nevus in the dermis. Such lesions represent an obvious diagnostic pitfall, being liable to misdiagnosis as benign regressing nevus. According to the authors' experience, patient age is of paramount importance in this setting, as complete regression of melanoma arising in a preexisting nevus only occurs in older adults, thus rendering a diagnosis of benign regressing nevus highly unlikely. In addition, the pattern of regression will show similarly irregular, asymmetrical features as in other completely regressed melanomas.

A peculiar presentation of complete regression is so-called nodular melanosis, defined as nodular, dermal or subcutaneous aggregates of melanophages associated with usually scant inflammation and fibrosis (Fig. 17).78 Nodular melanosis should be regarded as a sign of melanocytic malignancy, being the end-stage of complete regression of either a primary nodular melanoma or a melanoma metastasis. Indeed, purported “nodular melanosis” secondary to epithelial neoplasms invariably showed neoplastic epithelial cells variably admixed with melanophages, thus failing to fulfill the definition of nodular melanosis sensu stricto.79

FIGURE 17

FIGURE 17

The prognostic value of complete regression in primary cutaneous melanoma is yet to be ascertained, but a recent study described a favorable impact on prognosis.80,81 The majority of reported patients presenting with complete regression had advanced, metastatic disease upon complete staging; in this regard, however, a possible caveat is that individuals with metastasis-free completely regressed melanoma may fail to attend any outpatient service, thus being missed by cancer registries. One of the main drawback of most studies on influence on regression in melanoma on prognosis (thus also of the metadata analysis of Gualano et al)81 lies in the definition of regression, which is usually classified differently. In addition, evaluation of regression may be subjective in cases with partial or focal regression.

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RHABDOID MELANOMA

The term “rhabdoid tumor,” initially used for a malignant neoplasm of the kidney regarded as a variant of nephroblastoma, has later been applied to a heterogeneous group of aggressive neoplasms from different anatomical locations sharing similar cytological features82: eccentric nuclei and large, polygonal cytoplasm with strikingly eosinophilic inclusions, imparting a vague resemblance to rhabdomyoblasts (Fig. 18).8,83 According to the available literature, primary rhabdoid melanoma seems to be exceedingly uncommon, with only 9 cases reported so far, whereas development of a rhabdoid morphology seems to be a more frequent occurrence in metastatic melanoma.84–86 Indeed, rhabdoid differentiation in melanoma was first described in 1992 by Bittesini et al85 in a metastasis.

FIGURE 18

FIGURE 18

Clinical presentation of primary rhabdoid melanoma in most of reported cases was unspecific, consisting of a hypomelanotic nodule with no apparent predilection for any body site. Suggested clinical differential diagnoses included basal cell carcinoma, adnexal neoplasms, and infundibular cyst.84,86 Histopathologically, this variant of melanoma is characterized by a variable proportion of rhabdoid cells, with the latter constituting the only cell population in approximately half of reported cases.87 The hypereosinophilic quality of the cytoplasm of rhabdoid melanocytes seems to be the result of exuberant accumulation of intermediate filaments.8 Immunohistochemical markers specific for striated muscle differentiation, including desmin, myogenin, and/or MyoD1 may be positive in rhabdoid melanoma, pointing to a true rhabdomyoblastic phenotype.29,88,89 Melanocytic markers such as S100, Sox-10, and p75NGFR are helpful in challenging cases.84 Presence of rhabdoid differentiation does not seem to be an independent prognostic criterion in melanoma, with most cases usually presenting as nodular lesions at an advanced stage.86

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SARCOMATOID MELANOMA

Sarcomatoid melanoma is a very rare subtype of melanoma characterized by almost complete loss of melanocytic differentiation both morphologically and phenotypically, with the bulk of the tumor being replaced by a spindle cell, sarcomatoid component (Fig. 19).90,91

FIGURE 19

FIGURE 19

Sarcomatoid dedifferentiation may occur at any body site and within any conventional histological variant of melanoma.91 The cellular, pleomorphic, sarcomatoid spindle cell population usually lacks any distinctive features, including pigmentation or nesting, thus bearing resemblance to other primary cutaneous spindle cell neoplasms, including sarcomatoid squamous cell carcinoma, atypical fibroxanthoma/pleomorphic dermal sarcoma, and malignant peripheral nerve sheath tumor among others.90–92 Immunohistochemical analyses may have limited value in this context, as the dedifferentiation process also affects expression of melanocytic markers, with possible loss of positivity for S100 and Sox-10; conversely, sarcomatoid cells may exhibit aberrant expression of nonmelanocytic antigens such as CD10, smooth muscle actin, muscle-specific actin, and desmin.90,91,93

According to limited existing literature, recognition of the biphasic nature of the tumor is a key diagnostic finding.91 Small, often peripheral foci of conventional melanoma are usually found in complete excision specimens, with preserved expression of typical melanocytic markers in these areas. Notwithstanding, a diagnosis of sarcomatoid melanoma may be impossible in partial biopsy samples. Expression of CD56 and WT1 by neoplastic cells has been described as immunohistochemical features suggestive for a melanocytic nature in sarcomatoid neoplasms of the skin.93 Genetic analysis may be a crucial tool in dubious cases, demonstrating copy number variations and mutational patterns typical of melanoma.90

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SIGNET RING CELL MELANOMA

Stereotypical features of signet ring cell may be rarely observed in both benign and malignant melanocytic neoplasms (Fig. 20).94 Histopathologically, neoplastic cells exhibit a single, large intracytoplasmatic vacuole displacing the nucleus at the periphery of the cell.8 As a consequence, signet ring melanocytes feature peripheral, crescent-shaped nuclei with a flattened appearance.8 Ultrastructural studies have showed that solitary vacuoles are the result of intracytoplasmatic accumulation of intermediate vimentin filaments.8,95 In this context, signet ring cell melanoma and rhabdoid melanoma seem to be closely related.95,96

FIGURE 20

FIGURE 20

Presence of a signet ring cell morphology usually does not significantly hinder the histological diagnosis of melanoma, as foci of more conventional melanoma are almost invariably present. Confusion with balloon cell melanoma may be caused by detection of areas with crowding of signet ring cells, thus resulting in an overall clear cell appearance. Solitary vacuoles in signet ring melanoma are variably positive for PAS but always negative for mucin histochemical stains.8,72,97 Furthermore, distinction of signet ring cell melanoma from other signet ring cell neoplasms can be easily achieved by appropriate immunohistochemical staining.72

Initially regarded as a poor prognostic feature more frequently observed in metastatic melanoma,98 the signet ring cell morphology has been subsequently documented also in early-stage primary cutaneous melanomas and in melanocytic nevi.97,98 In fact, presence of a signet ring cell population is currently viewed as devoid of any prognostic significance.97,98

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SMALL CELL MELANOMA

So-called small cell melanoma features a monotonous, “basaloid” cell population characterized by distinctive cytological features such as nuclear hyperchromasia with coarse chromatin and scant cytoplasm, thus resembling lymphomas, Merkel cell carcinoma, Ewing sarcoma, or other aggressive blue round cell tumors (Fig. 21).8,99 Small cell melanomas may be further classified into Merkel cell tumor-like (if a predominance of medium-sized cells is observed) or the non-Merkel cell tumor-like subtype (characterized by smaller cells).8,100,101 Marked cytological atypia, frequent mitoses, solid growth pattern and lack of maturation allow for an easy distinction between small cell melanoma and benign melanocytic nevi. In this context, small-cell melanoma should not be regarded as part of the spectrum of nevoid melanomas.22 Differential diagnosis from nonmelanocytic small round blue cell tumors may be aided by detection of a junctional component, melanin, and/or foci of conventional melanoma, with evidence of a melanocytic immunophenotype playing a key role in dubious cases.8 Importantly, prevalence of small cell melanoma seems to be increased in the pediatric population, with malignant neoplasms occurring either de novo, particularly on the scalp, or in the context of large congenital nevi.8

FIGURE 21

FIGURE 21

The majority of cases of small cell melanoma present as thick nodules in advanced vertical growth phase, being thus associated with poor prognosis. Indeed, it has been suggested that a small cell morphology in melanoma increases the risk of a positive sentinel lymph node biposy.102

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SPINDLE CELL MELANOMA

Melanocytes with spindled shape and elongated nuclei may be seen in any histological presentation of melanoma (Fig. 22). Lesions in which fusiform cells largely predominate have been termed “spindle cell melanomas,” although different histological presentations with diverging features have been lumped under such denomination.103 Predominance of spindle cells with pseudosarcomatous features results in an overlap with the sarcomatoid variant of melanoma (see above).8

FIGURE 22

FIGURE 22

Overall, 2 main histological patterns may fit within the definition of “spindle cell melanoma”: a junctional/compound, Reed nevus-like presentation, and a predominantly intradermal one.42,103 The discussion in this paragraph will focus on the intradermal spindle cell melanoma, as the Reed nevus-like pattern has been discussed briefly in the paragraph on nevoid melanoma.

Spindle cell melanoma seems to have a predilection for anatomical sites where in situ melanoma tends to exhibit a lentiginous growth pattern, namely, chronic sun-exposed skin, palmo-plantar surfaces, and mucous membranes. Histologically, spindle melanocytes are predominantly devoid of pigment and are arranged in fascicles or whorls, often lying within the entire reticular dermis as expansile nodules. Perineural invasion is a not uncommon finding, thus mimicking neural neoplasms. S100, Sox-10, antimicrophthalmia-associated transcription factor antibody, and p75 seem to be the immunohistochemical markers with the highest sensitivity for spindle cell melanoma.104

Spindle cell melanoma sensu stricto should not be confused with desmoplastic melanoma, even though the latter may be viewed as a subtype of the former.105 This distinction is clinically relevant, as spindle cell melanoma seems to carry a worse prognosis than desmoplastic melanoma, often presenting with widespread metastatic disease, and it is associated with higher prevalence of BRAF mutations.106,107 The amount of scar-like tissue is the key parameter in distinguishing between spindle cell melanoma (collagen content <10%) and desmoplastic melanoma (collagen content >90%), with lesions characterized by intermediate collagen content (10%–90%) being referred to as mixed spindle/desmoplastic melanoma.105 A histological algorithm based on staining with Melan-A and Masson's trichrome has been proposed in dubious cases.105

Nonmelanocytic malignant spindle cell neoplasms should always be considered in the differential diagnosis of spindle cell melanoma, and relevant melanocytic markers should be included in any immunohistochemical panel for assessment of such tumors.108,109 Cases of spindle cell melanoma mimicking atypical fibroxanthoma, malignant fibrous histiocytoma, leiomyosarcoma, spindle cell squamous cell carcinoma, dermatofibrosarcoma protuberans, neurofibroma, and malignant peripheral nerve sheath tumor have been reported.33,110 Lack of CD34 fingerprint positivity has been suggested as a useful feature favoring the diagnosis of spindle cell melanoma in cases with a neurofibroma-like pattern, but the applicability of this criterion seems questionable.33,34 As already discussed, p53 seems to be positive in desmoplastic melanoma, but negative in neurofibroma.35 As mentioned for neurotropic melanoma, expression of the histone methylation marker H3K27me3 is usually lost in malignant peripheral nerve sheath tumors, but is retained in spindle cell melanoma.36 Molecular techniques spanning from array comparative genomic hybridization to next-generation sequencing seem to have a potential in the differential diagnosis between spindle cell melanoma and other nonmelanocytic spindle cell neoplasms.

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SYRINGOTROPIC MELANOMA

Involvement of superficial acrosyringia is a well-known phenomenon that may be observed in melanoma on chronic sun-damaged skin and in acral melanoma.111 However, the term “syringotropic melanoma” has been proposed only for cases of melanoma characterized by involvement of eccrine structures and periglandular tissues within the reticular dermis and/or subcutaneous tissue deeper than any other invasive component of the melanoma.111–113 Superficial and partial biopsies may pose particular problems, as the syringotropic features are present in the deep dermis and/or subcutaneous tissue. This peculiar growth pattern of melanoma does not seem to show a predilection for any anatomical site or histopathological variants.111

As in follicular melanoma, also in syringotropic melanoma, evaluation of tumor thickness may be challenging, and there are no studies or guidelines addressing this issue.111 By definition, in syringotropic melanoma, the deepest area of invasion is represented by the syringotropic complexes of malignant melanocytes. Reporting a double measurement has been suggested as a practical solution, including the conventional vertical thickness from the epidermal surface to these complexes and a horizontal measurement from the center of the eccrine gland.111 However, we would suggest to add a third measurement related to the deepest melanoma cells unrelated to the syringotropic complexes.

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VERRUCOUS MELANOMA AND MELANOMA WITH PSEUDOEPITHELIOMATOUS HYPERPLASIA

Rarely, melanoma may be associated with irregular epidermal hyperplasia and/or be characterized by a verrucous, hyperkeratotic surface, clinically simulating a keratotic neoplasm of epithelial origin such as squamous cell carcinoma of the keratoacanthoma type or seborrheic keratosis (Figs. 23 and 24).114,115 Even less common is melanoma presenting as a cutaneous horn, with prominent hyperkeratosis and a hyperplastic, exophytic epidermis.116 Most cases of verrucous melanoma arise on the skin, with a predilection for face and limbs, although pseudoepitheliomatous hyperplasia has been occasionally reported also in oral melanoma.117 The pathogenesis of pseudoepitheliomatous hyperplasia associated with melanoma is unknown; at least in some cases, it may be regarded as a reactive proliferation of follicular or eccrine epithelium.118–120 Histopathologically, 2 different patterns of epithelial hyperplasia may be seen: a conventional pseudoepitheliomatous hyperplasia, characterized by acanthosis, papillomatosis, and irregular cords of epithelial cells extending into the dermis, is detected in most cases of verrucous melanoma, whereas a seborrheic keratosis-like pattern with basaloid acanthosis, orthokeratosis, and keratotic cyst formation has been described more rarely.8,118 The melanocytic proliferation usually shows typical features of superficial spreading melanoma such as asymmetry, lack of circumscription, and irregular nesting, being readily identified as malignant.8 Importantly, nest formation and intraepidermal pagetoid spread of melanocytes seem to be uncommon in this variant of melanoma; filling of papillary stalks with melanocytes accompanied by sheets of neoplastic cells in the underlying dermis may be a valuable diagnostic feature in challenging cases.8

FIGURE 23

FIGURE 23

FIGURE 24

FIGURE 24

Presence of papillations or of marked epithelial hyperplasia in verrucous melanoma may affect the evaluation of tumor thickness, resulting in an overestimation of the Breslow's depth.8 Prognostic studies comparing different methods of measurement of thickness in verrucous lesions are not available. At the present state of knowledge, it is unclear whether measuring the maximal diameter of the tumor from the highest papillation to the deepest complexes in the dermis is an acceptable surrogate of the tumor mass, and whether tumor thickness calculated in this way correlates prognostically with that of conventional melanomas of similar thickness.8

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OTHER RARE MORPHOLOGIC VARIANTS OF MELANOMA

Further variants of melanoma include development of neuroendocrine-like (Fig. 25) and ganglionic/ganglioneuroblastic-like features.8,29

FIGURE 25

FIGURE 25

Neuroendocrine differentiation in melanoma is usually limited to aberrant expression of only 1 or 2 neuroendocrine markers,121 but rare cases of melanoma with true neuroendocrine differentiation (ie, ultrastructural evidence of neuroendocrine granules) have been reported.29,122 In only a minority of cases, small-cell features were observed, and usually a neuroendocrine differentiation could not be inferred based on morphology alone. Even less common seems to be the presence of pseudo-rosetting in neuroendocrine melanoma.123 In this context, the term “carcinoid-like melanoma” has been used to describe cases characterized by neoplastic cells arrangement in trabecules, ribbons, pseudo-rosettes (Fig. 26), and/or small round insular structures, despite no histogenetic or biologic similarities with authentic carcinoids.124

FIGURE 26

FIGURE 26

Ganglioneurobastic features were exceptionally described in one primary melanoma and one metastatic nodal tumor, which recurred subsequently metastasizing with terminal rhabdoid phenotype.30,125 In both instances, large ganglion-like cells were found to be immersed within and surrounded by a pale, pinkish fibrillary material thought to represent neuritic cell processes, admixed with smaller primitive neuroblastic-like cells. The ganglioneuroblastic component was positive for neurofilaments, chromogranin, synaptophysin, and glial fibrillar acidic protein, whereas expression of S-100 and Melan-A could be observed in the divergent cell population. Although the reason for such aberrant differentiation is uncertain, a likely explanation might be related to the shared histogenetic origin from the neural crest of both cellular components.

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CME EXAM INSTRUCTIONS FOR OBTAINING AMA PRA CATEGORY 1 CREDITSTM

The American Journal of Dermatopathology includes CME-certified content that is designed to meet the educational needs of its readers.

An annual total of 12 AMA PRA Category 1 Credits™ is available through the twelve 2019 issues of The American Journal of Dermatopathology. This activity is available for credit through April 30, 2021.

  • Accreditation Statement

Lippincott Continuing Medical Education Institute, Inc., is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

  • Credit Designation Statement

Lippincott Continuing Medical Education Institute, Inc., designates this journal-based CME activity for a maximum of one (1) AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

To earn CME credit, you must read the article in The American Journal of Dermatopathology and complete the quiz, answering at least 80 percent of the questions correctly. Mail the Answer Sheet along with a check or money order for the $15 processing fee, to Lippincott CME Institute, Inc., Wolters Kluwer Health, Two Commerce Square, 2001 Market Street, 3rd Floor, Philadelphia, PA 19103. Only the first entry will be considered for credit and must be postmarked by the expiration date. Answer sheets will be graded and certificates will be mailed to each participant within 6 to 8 weeks of participation. Visit http://cme.lww.com for immediate results, other CME activities, and your personalized CME planner tool.

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CME EXAMINATION May 2019

Please mark your answers on the ANSWER SHEET.

After participating in this activity, the physician should be better able to: 1. Analyze different types of melanocytic tumors regarding architectural, cytomorphological and immunohistochemical features. 2. Assess the histopathological pattern of different types of melanoma with particular regard to specific variants characterized either by presence of peculiar cell types (eg, balloon cells, multinucleated cells, signet-ring cells, etc.), by unconventional morphology (eg, follicular melanoma, bullous melanoma, small melanoma, etc.), or by stromal changes (eg, desmoplasia). 3. Distinguish between several melanoma variants with peculiar structural features, and recognize challenges related to measurement of tumor thickness.

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CME QUESTIONS

  1. Which of the following combinations of findings in a predominantly junctional melanocytic proliferation should be regarded as strongly suspicious for malignancy?
    • a. Confluent nests parallel to the epidermis on genital skin
    • b. Dyscohesive nests of melanocytes with moderate cytological atypia on the umbilicus
    • c. Large nests of melanocytes with abundant pale cytoplasm on the scalp
    • d. Junctional nests arranged at the tip of the rete ridges in the absence of solar elastosis
    • e. Widespread, cannonball-like irregular junctional nests over extensive solar elastosis
  2. Which of the following histological findings is strongly suggestive of a diagnosis of melanoma?
    • a. Actinic elastosis displaced (“pushed down”) by a dermal melanocytic tumor
    • b. Increased density of melanocytes with “stuffing” of dermal papillae
    • c. Broad, flat melanocytic tumor on chronically sun-damaged skin
    • d. Increase in mitotic activity of dermal melanocytes at the base of the tumor
    • e. All of the above
  3. Expression of which of the following markers may be observed in chondroid metaplasia in melanoma?
    • a. Pax-3 and Pax-5
    • b. Pax-3 and Pax-9
    • c. Sox-10
    • d. Sox-9 and SATB2
    • e. Sox-11
  4. Which of the following signaling pathways is frequently involved in the pathogenesis of plexiform melanoma and deep penetrating nevus?
    • a. APC/beta-catenin
    • b. MAPK/ERK
    • c. PIK3/AKT/mTOR
    • d. PKA/CREB/MiTF
    • e. VHL/HIF-1alpha
  5. Morphological changes observed in rhabdoid melanoma are due to:
    • a. Aberrant expression of neuroendocrine markers
    • b. Acquisition of myofibroblastic phenotype
    • c. Epithelial-to-mesenchymal transition
    • d. Intracytoplasmatic accumulation of intermediate filaments
    • e. Polyploidy and complex chromosomal rearrangements
Figure

Figure

Keywords:

melanoma; pigmented epithelioid melanocytoma; animal type melanoma; plexiform melanoma; spitzoid melanoma; balloon cell melanoma

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