Spitz Nevi

4  Spitz Nevi Pedram Gerami and Klaus J. Busam

OUTLINE Clinical Findings, 37 Histopathologic Findings, 38 Histopathologic Variants of Spitz Nevi and Related Differential Diagnosis, 40 Angiomatoid Spitz Nevus, 41 Desmoplastic Spitz Nevus, 42 Epithelioid Spitz Nevus, 42 Pagetoid Spitz Nevus, 42 Pigmented Spindle Cell Nevus, 43 Plexiform Spitz Nevus, 45 Other Variants of Spitz Nevus, 45 Molecular Findings and Correlation With Histopathologic Phenotype, 45 HRAS Aberrations, 45 BAP1-Deficient/Inactivated Spitzoid Neoplasms, 45

Spitzoid Neoplasms With Deletions in 6q23, 49 Fusion-Related Spitzoid Neoplasms, 49 Spitz Nevus Versus Atypical Spitz Tumor Versus Spitzoid Melanoma, 56 Spitzoid Melanoma, 56 Atypical Spitz Tumor, 56 Ancillary Methods for Diagnosis, 56 Immunohistochemistry, 56 Cytogenetic Studies, 56 Gene Expression Studies, 56 Mutation Analysis, 57 Prognosis and Treatment, 57

The diagnosis of Spitz nevi and their distinction from melanoma is one of the most difficult tasks in neoplastic dermatopathology. Before a group of melanocytic proliferations was accepted as benign and named Spitz’s nevus, similar lesions in children had been reported as melanoma. Sophie Spitz, after whom this nevus variant was named, published a landmark case series on childhood melanoma in 1948. All but one of the 13 children of her study had an indolent clinical course.1 Sophia Spitz and Arthur Allen subsequently proposed the term “juvenile melanoma” to separate these lesions from adult melanomas. With time it became apparent that histopathologic criteria could be used to differentiate most Spitz nevi from melanoma and that these lesions also occur in adults.2-4 A spitzoid melanocytic neoplasm, for which no definitive distinction between nevus and melanoma can be made even by experts in melanocyte pathology, is generally referred to as “atypical Spitz tumor.”5 Spitz nevi “tumors” and spitzoid melanomas represent a spectrum of melanocytic neoplasms that share distinctive features.2-5 Although pathologists commonly agree on a typical case, there is considerable interobserver variability regarding what set of microscopic findings is needed for a lesion to be designated as “spitzoid” and whether it is clearly benign, malignant, or indeterminate in its biologic potential.5,6 With the benefit of recent genomic aberrations, there is an opportunity to integrate molecular findings for the definition and classification of spitzoid melanocytic neoplasms along with light microscopic and dermoscopic findings.7-12

CLINICAL FINDINGS Spitz nevi may occur at any age and any site but are most commonly found in children and young adults and preferentially affect the lower extremity and the face. In a recent study of 349 patients, the mean and median age at diagnosis was 21 years; 40% of Spitz nevi were diagnosed before the age of 15 years and 80% before the age of 30.3 In 1977 a study from Queensland, Australia, estimated an annual incidence of 1.4 cases per 100,000.4 Spitz nevi constitute approximately 1% of nevi removed during childhood. They can be found in individuals from all ethnic backgrounds. Clinically the lesions usually manifest as dome-shaped papule or small plaque (Figs. 4.1 and 4.2). The color may range from tan, pink, red to light or dark brown. The lesions tend to be symmetric and circumscribed. Most Spitz nevi measure less than 6 mm in diameter. Some have a polypoid and/or verrucous surface. Tumor ulceration is rare, but traumatic excoriation is not uncommon. Most nevi are solitary, but on occasion multiple lesions may be present at the same time—agminated (grouped) (Fig. 4.3) or diffusely and randomly distributed (disseminated). A proliferative spitzoid nodule or multiple Spitz nevi may also develop in a background of a congenital melanocytic nevus. Dermoscopic features of pigmented Spitz nevi include a starburst pattern with pseudopods symmetrically placed around the entire circumference of the lesion, or symmetric radial streaming all around the

37

CHAPTER 4  Spitz Nevi

Keywords spitz spitz nevi pigmented spindle cell nevus desmoplastic spitz nevus spindle and epithelioid cell nevus spitz tumor atypical spitz tumor AST HRAS 11p gain BAP1 9p21 kinase fusions ALK NTRK ROS1 RET MET aCGH SNP array FISH spitzoid melanoma

37.e1

38

A

SECTION I  Benign Cutaneous Melanocytic Proliferations

B

Fig. 4.1  Spitz nevus presenting as erythematous papule on the arm of a 1-year-old child.

Fig. 4.3  Agminated Spitz nevi on the buttocks.

periphery of the lesion. Lesions may also display a granular, globular, or tiered globular pattern or a symmetric inverse pigment pattern. The latter is common in dome-shaped, grossly pink or erythematous papular Spitz nevi.

HISTOPATHOLOGIC FINDINGS

A

B Fig. 4.2  (A) Pigmented Spitz nevus from a 14-year-old girl. (B) Peripheral pseudopods symmetrically placed around the entire perimeter of the lesion on dermoscopy.

The silhouette of a Spitz nevus is fairly symmetric (Fig. 4.4), often displaying an inverted wedge-shaped or superficial plaquelike appearance. The lesions tend to have sharp lateral borders (Figs. 4.4 and 4.5). Associated epidermal hyperplasia is common. Junctional nests often show clefting (i.e., on routinely processed and stained tissue sections, there is a small empty space between the melanocyte nests and the adjacent epidermis) (Figs. 4.5–4.7). The growth pattern is predominantly nested. The nests may be large and cellular. They often vary greatly in size and shape. Large elongated nests arranged parallel to hyperplastic rete ridges have been described as “raining down” or likened to “hanging bananas” (Fig. 4.8). A peculiar finding is the presence of eosinophilic globules (so-called Kamino bodies) (Figs. 4.7, 4.9, and 4.10). They may be small or large. Although small eosinophilic globules can be seen in other nevi or even melanoma, large and/or numerous Kamino bodies are strongly associated with Spitz nevi. Cytologically, Spitz nevi are composed of enlarged spindle and epithelioid melanocytes. The proportion of spindle versus epithelioid cells varies from lesion to lesion. In some nevi, spindle cells may dominate. Other lesions may be nearly exclusively composed of epithelioid melanocytes. Often there is a mixture of both cell types. The spindle cells tend to have polyangular contours (Fig. 4.11). The cytoplasm, especially that of large epithelioid cells, tends to be abundant and opaque, with a “ground-glass” appearance. The nuclei are round to oval or fusiform. The nuclear chromatin pattern is typically finely dispersed. The nucleolus is usually small but distinct. However, in some lesions the nuclei may be hyperchromatic and/or contain pseudoinclusions.

CHAPTER 4  Spitz Nevi

39

B

A

C Fig. 4.4  Compound Spitz Nevus. (A) Small raised papule. (B) Symmetric silhouette and sharp lateral demarcation. (C) Nests of spindle and epithelioid melanocytes.

A

A

B Fig. 4.5  Pigmented Spitz Nevus (Histopathology of the Clinical Lesion of Fig. 4.2). (A) Prominent nested growth with sharp lateral demarcation. (B) Clefts separate large junctional nests of pigmented fusiform melanocytes from the adjacent epidermis.

B Fig. 4.6  Shave Biopsy of a Spitz Nevus. (A) Predominantly nested growth pattern. (B) Clefts are present between junctional nests and adjacent epidermis. The papillary dermis is hypervascular.

40

SECTION I  Benign Cutaneous Melanocytic Proliferations

Fig. 4.7  Junctional Spitz Nevus. Nests of plump spindle and epithelioid melanocytes at the dermoepidermal junction. Small dull pink red globules are present.

Fig. 4.10  Large dull pink hyaline globule and nearby smaller globule.

Fig. 4.11  Acral Spitz nevus with nests of polyangular melanocytes. Fig. 4.8  Compound Spitz Nevus. Fascicles of spindle cells adjacent to thin elongated rete ridges. Some melanocytes resemble hanging bananas.

Multinucleated melanocytes are commonly found (Fig. 4.12). Many lesions are amelanotic or paucimelanotic, but some are pigmented (pigmented Spitz nevus) (Fig. 4.13). Most Spitz nevi show evidence of maturation (i.e., the size of the melanocyte nests decreases from the superficial to deep dermis). At the bottom of a lesion, melanocytes are often displayed in a nondisruptive single cell infiltrative pattern. In some lesions, especially those limited to the superficial dermis, maturation may be limited or absent. The mitotic rate is usually low (≤2 mitoses/mm2). However, in young children a higher mitotic rate is still acceptable for a Spitz nevus. A mild inflammatory cell infiltrate is not uncommon. Lymphocytes are typically dispersed throughout the lesion. Some lesions may be heavily inflamed and/or associated with features of regression (e.g., “halo” Spitz nevi).

HISTOPATHOLOGIC VARIANTS OF SPITZ NEVI AND RELATED DIFFERENTIAL DIAGNOSIS Fig. 4.9  Compound Spitz nevus with several dull pink globules.

The main histopathologic variants of Spitz nevus are shown in Table 4.1 and briefly described in alphabetical order:

CHAPTER 4  Spitz Nevi

41

Angiomatoid Spitz Nevus Angiomatoid Spitz nevus is characterized by the association of usually paucicellular proliferation of spitzoid melanocytes with stromal fibrosis and an increased density of blood vessels of various sizes (Fig. 4.14).13 At low magnification the findings may suggest an angioma. Sometimes the hypervascular stroma may lead to concerns about a regressed melanoma. The spitzoid cytology of the lesional melanocytes in conjunction with the clinical history, small size, and circumscription of the lesion should permit establishing the correct diagnosis of a nevus and avoid confusion with melanoma. Many lesions of angiomatoid Spitz nevus likely represent or may be regarded as a variant of desmoplastic Spitz nevus with stromal hypervascularity.

Fig. 4.12  Compound Spitz nevus with multinucleated melanocytes.

Fig. 4.13  Pigmented junctional Spitz nevus with fine cytoplasmic melanin granules in slender fusiform melanocytes and adjacent keratinocytes.

Fig. 4.14  Angiomatoid Spitz Nevus. Epithelioid melanocytes are located in a fibrous stroma with an increased density of small blood vessels.

TABLE 4.1  Variants of Spitz Nevus Morphologic Variant

Microscopic Findings

Angiomatoid Spitz Nevus Atypical Spitz Nevus Combined Spitz Nevus Desmoplastic Spitz Nevus Epithelioid Spitz Nevusa Granulomatous Spitz Nevus Halo Spitz Nevus Hyalinizing Spitz Nevus Myxoid Spitz Nevus Pagetoid Spitz Nevus Pigmented Spindle Cell Nevus

Spitz nevus associated with vascular proliferation with dilated vessels Spitz nevus with some asymmetry, architectural disorder, and cytologic atypia Spitz nevus associated with another type of nevus (e.g., congenital or common nevus) Spitz nevus associated with prominent stromal sclerosis Spitz nevus characterized by the predominance of large epithelioid melanocytes with open nuclear chromatin pattern Spitz nevus with nodular aggregates simulating granulomas Spitz nevus associated with dense inflammation and clinically a halo phenomenon Spitz nevus with hyalinized stroma Spitz nevus with myxoid stroma Spitz nevus (usually small diameter circumscribed lesion) with several suprabasilar melanocytes Sharply circumscribed pigmented lesion with densely cellular junctional nests of pigmented spindle cells; usually many dermal melanophages Spitz nevus with plexiform growth: fascicles and nests grow along neurovascular bundles Spitz nevus with features of a recurrent nevus Spitz nevus associated with fibrosis and loss of melanocytes Spitz nevus characterized by a predominant fusiform cytology Spitz nevus with tubular arrangement of cells Spitz nevus with verrucous epidermal hyperplasia

Plexiform Spitz Nevus Recurrent Spitz Nevus Regressing Spitz Nevus Spindle cell Spitz Nevus Tubular Spitz Nevus Verrucous Spitz Nevus a

The large epithelioid cell nevus with loss of BAP1 is often listed as a variant of Spitz nevus. It has been argued that because of the frequent presence of BRAF mutations, this lesion is pathomechanistically not a Spitz nevus, but Spitz nevus-like (spitzoid). BAP1, BRCA1-associated protein-1.

42

SECTION I  Benign Cutaneous Melanocytic Proliferations

A A

B Fig. 4.15  Desmoplastic Spitz Nevus. (A) At low magnification the lesion appears pink, reflecting a lesion rich in fibrous stroma and low in cell density. (B) A paucicellular population of epithelioid melanocytes with enlarged nuclei is present in the dermis.

Desmoplastic Spitz Nevus This variant of Spitz nevus is characterized by prominent stromal fibrosis (Fig. 4.15).14 Lesions may be entirely intradermal or may be compound with a usually small junctional component. The silhouette of the nevus may be wedge shaped or broad plaque-like. Most lesions are amelanotic and relatively paucicellular, giving the lesion at low magnification a stroma-rich “pink” fibroma-like appearance. Within the dermal stroma the melanocytes may be arranged in small nests or short fascicles or be distributed as solitary units. Clinically, this variant is more likely to occur in the head and neck region. It is also more likely found in individuals with sun damage compared with other Spitz nevus variants. It is clinically often confused with a fibroma and needs to be distinguished from desmoplastic melanoma. For the distinction of desmoplastic Spitz nevus from desmoplastic melanoma, a number of architectural parameters and cytology features are helpful. In contrast to a desmoplastic melanoma, the silhouette of a desmoplastic Spitz nevus is usually symmetric—shaped like a wedge or as a superficial plaque, with sharp lateral circumscription. In desmoplastic Spitz nevus, nests of melanocytes are usually present and more prominent superficially than deep, thereby displaying zonation (aka “maturation”). The melanocytes in a desmoplastic Spitz nevus are usually plump and display a polygonal shape unlike the fibroblastic-like cells of desmoplastic melanoma. In the latter the nuclei are typically hyperchromatic. In desmoplastic Spitz nevus, the nuclei are round to

B Fig. 4.16  (A) Desmoplastic epithelioid Spitz nevus with lymphocytic aggregate. (B) The lesion is nearly entirely composed of intradermal large epithelioid melanocytes with abundant cytoplasm.

oval or elongated but typically display a finely dispersed chromatin pattern. Both desmoplastic melanoma and desmoplastic Spitz nevi may be associated with lymphoid aggregates (Fig. 4.16). Ancillary methods may help support the diagnosis of a desmoplastic Spitz nevus, such as documentation of HRAS expression by immunohistochemistry (IHC) or an isolated gain of 11p by cytogenetic methods.15 Expression of PReferentially expressed Antigen in MElanoma (PRAME) is only seen in desmoplastic melanoma (albeit with limited sensitivity) but not in desmoplastic Spitz nevus.

Epithelioid Spitz Nevus Epithelioid Spitz nevus includes a spectrum of spitzoid melanocytic nevi with a predominantly epitheloid appearance characterized by enlarged melanocytes with abundant cytoplasm and enlarged round to oval nuclei, often with delicate open chromatin pattern (see Fig. 4.16). Some lesions are flat or form papules. Some may be polypoid (Fig. 4.17).16 Multinucleation is common. A subset of epithelioid/spitzoid melanocytic nevi is associated with inactivation of BRCA1-associated protein 1 (BAP1) (see later). The latter are often seen in association with a combined nevus and typically associated with a lymphocytic infiltrate.

Pagetoid Spitz Nevus Small areas of suprabasilar intraepidermal melanocytes can be seen in various Spitz nevi, especially in association with trauma (Fig. 4.18), in young children, or at acral sites. The term pagetoid Spitz nevus refers

CHAPTER 4  Spitz Nevi

43

B

A

Fig. 4.17  Polypoid Epithelioid Spitz Nevus. (A) Polypoid silhouette. (B) The lesion is composed of intradermal large epithelioid melanocytes. Several of them are multinucleated. There is an associated inflammatory cell infiltrate.

B

A

Fig. 4.18  Compound Spitz Nevus With Focal Pagetoid Melanocytes. (A) Silhouette of a small papule with nested growth and sharp lateral demarcation. (B) The lesional melanocytes display spitzoid cytology. A few small clusters and solitary units of melanocytes are seen in the spinous cell layer.

to a Spitz nevus characterized by prominent pagetoid growth of solitary units and/or nests of melanocytes in the spinous cell layer throughout most of the lesion (Fig. 4.19).17 Caution is needed not to confuse a pagetoid Spitz nevus with superficial spreading melanoma in situ. The presence of spitzoid cytology, occurrence of the lesion in a young patient, small lesional diameter, and sharp circumscription are important parameters for accepting a lesion as a pagetoid Spitz nevus. Furthermore in a pagetoid Spitz nevus the distribution of suprabasilar melanocytes is usually relatively orderly and often confined to the lower half of the epidermis, whereas in melanoma in situ the distribution of melanocytes is more chaotic.

Pigmented Spindle Cell Nevus This melanocytic nevus is characterized by the presence of spindle-shaped melanocytes with heavy melanization (Figs. 4.5, 4.13, and 4.20).18,19 These lesions are mostly superficial (i.e. they are junctional nevi or

compound nevi with often only a small superficial intradermal melanocyte population), but on occasion a pigmented spindle cell nevus may have a more substantial dermal component (Fig. 4.21). The silhouette of this nevus is typically that of a thin cellular pigmented plaque composed of densely packed junctional nests of melanocytes with sharp lateral demarcation. Slight epidermal hyperplasia and clefting between the junctional nests and the adjacent epidermis are common. Lesional melanocytes contain fine cytoplasmic melanin granules. Melanin pigment is often present in adjacent and overlying keratinocytes and even the stratum corneum. A few solitary units of pigmented melanocytes may be present in the spinous cell later. The underlying dermis often displays a band or clusters of melanophages. Lymphocytes are also commonly present. Features of pigmented spindle cell nevi, such as nests of pigmented spindle cells with clefts, can also be seen in association with some melanomas. However, melanoma is distinguished from pigmented

44

SECTION I  Benign Cutaneous Melanocytic Proliferations

Fig. 4.19  Pagetoid Spitz Nevus. Many solitary spitzoid melanocytes are present above the basal cell layer throughout this nevus from a young child.

A

Fig. 4.20  Pigmented Spindle Cell Nevus from a Young Child. (A) Silhouette of a dark slightly raised papular lesion predominantly composed of nests with sharp lateral borders. (B) Junctional nests of melanocytes are composed of slender fusiform melanocytes with fine melanin granules. Melanin pigment is also present in keratinocytes.

B

A

Fig. 4.21  Compound Pigmented Spindle Cell Nevus. (A) Symmetric silhouette of the lesion. (B) Short fascicles of spindle cells are present in the dermis. Melanin pigment is present in melanocytes and melanophages.

B

CHAPTER 4  Spitz Nevi

45

A

Fig. 4.22  Amelanotic Spindle Cell Nevus. (A) Predominantly intradermal spindle cell proliferation on the face of a young boy. (B) The lesion is nearly entirely composed of fusiform melanocytes.

spindle cell nevus by an asymmetric silhouette, usually broader growth (greater horizontal dimension), ill-defined borders, and more prominent and irregular pagetoid spread.

Plexiform Spitz Nevus This variant of Spitz nevus is characterized by a prominent plexiform growth pattern, with nests, short fascicles, or isolated melanocytes following neurovascular bundles, often extending to the deep dermis.20 Most lesions are entirely intradermal. Plexiform Spitz nevus needs to be distinguished from plexiform variants of cellular neurothekeoma and neurotropic melanoma.

Other Variants of Spitz Nevus Some Spitz nevi are nearly exclusively composed of amelanotic spindle cells (amelanotic spindle cell nevus) (Fig. 4.22). Additional rare histopathologic variants may refer to stromal changes, such as the myxoid Spitz nevus (myxoid stroma),21 hyalinizing Spitz nevus (epithelioid Spitz nevus with hyalinized fibrotic stroma, essentially a variant of desmoplastic nevus),22 and tubular Spitz nevus.23 Spitz nevi have also been categorized by associated secondary epidermal changes, such as the Spitz nevus with pseudoepitheliomatous epidermal hyperplasia. Spitz nevi can also be grouped based on their clinical appearance (macular, papular, polypoid, plaque-like), clinical settings (primary vs. recurrent), and the presence of a dense inflammatory cell infiltrate with features of regression (“halo” or “regressing” Spitz nevus)16 or a pseudogranulomatous appearance.24 With regard to their differential diagnosis, Spitz nevi mainly need to be distinguished from melanoma, but they can also be confused with nonmelanocytic lesions, such as cellular neurothekeomas or histiocytomas.

MOLECULAR FINDINGS AND CORRELATION WITH HISTOPATHOLOGIC PHENOTYPE Three different types of molecular events have been identified in Spitz lesions. They include oncogenic mutations, loss of expression of tumor suppressors, and balanced translocations.

B

HRAS Aberrations A subset of Spitz nevi is associated with copy number gains and/or activating mutations in HRAS, which is located at the distal tip of 11p at 11p15.5. In a series of 102 cases assessed for mutations or copy number changes of HRAS, 12 cases (12%) were identified with copy number gains, mostly of the entire p arm of the chromosome.14 Eight of 12 cases also had mutations in HRAS. One case with an activating mutation in HRAS was identified among 21 cases without copy number changes assessed for HRAS mutation. Spitz nevi with this genomic alteration tend to display desmoplastic features (Figs. 4.23 and 4.24), but not all of them are desmoplastic (Fig. 4.25). Most lesions are readily recognized as nevus, but an occasional spitzoid neoplasm with HRAS aberrations may display atypical features such as nuclear pleomorphism and mitotic figures. To date, no progression to melanoma has been reported.

BAP1-Deficient/Inactivated Spitzoid Neoplasms BAP1 is a tumor suppressor gene that acts as a ubiquitin carboxylterminal hydrolase functioning as a deubiquitinizing enzyme. It is a binding partner to BRCA1, as well as to other transcription factors such as HCF1, and is implicated in DNA damage repair and regulation of apoptosis, senescence, and cell cycle regulation. BAP1 also interacts with ATM and ATR proteins, which regulate the DNA damage induced by ultraviolet (UV) radiation. Spitzoid neoplasms associated with a loss of expression of BAP1 are typically predominantly dermal-based tumors with epithelioid cell morphology. Commonly, they are part of a combined nevus (i.e., the spitzoid melanocytic proliferation is associated with a conventional nevus).8,9 Most lesions carry a mutation in BRAF (Fig. 4.26). A few lesions are mutated in NRAS. Because of the presence of BRAF and NRAS driver mutations it has been argued that pathomechanistically, BAP1-deficient epithelioid lesions are spitzoid (Spitz nevus-like) variants of nevi, but not Spitz (or spitzian) neoplasm by molecular definition. Immunohistochemical assessment with BAP1 will show normal nuclear expression in almost all cells in the skin, including the conventional

46

A

SECTION I  Benign Cutaneous Melanocytic Proliferations

B

C Fig. 4.23  Spitz Nevus With Gain of 11p. (A) Plaque-like silhouette of a predominantly intradermal melanocytic nevus. (B) Spindle and epithelioid melanocytes are present in the superficial dermis. The deeper portion of the lesion is predominantly composed of fusiform melanocytes dispersed at low cell density in a fibrous stroma. (C) Single nucleotide polymorphism (SNP) array analysis revealed an isolated gain of 11p (*).

CHAPTER 4  Spitz Nevi

Fig. 4.24  Spitz Nevus With Gain of 11p. Nests of spindle and epithelioid melanocytes with several multinucleated cells are present in the papillary dermis. With descent into the mid and deeper dermis, there is a predominance of solitary units of melanocytes in fibrous stroma. The lesion is inflamed. Single nucleotide polymorphism (SNP) array analysis of this lesion had revealed an isolated gain of 11p but no other genomic aberration (not shown).

A

B

C Fig. 4.25  Compound Spitz Nevus With Gain of 11p Without Significant Desmoplasia. (A) Silhouette of a papillomatous compound Spitz nevus. (B) The tumor cells are immunoreactive for an anti-HRAS antibody. (C) Single nucleotide polymorphism (SNP) array analysis of the tumor cells documented an isolated gain of 11p (*).

47

48

SECTION I  Benign Cutaneous Melanocytic Proliferations

A B

C

E

D

F Fig. 4.26  Combined BRCA1-associated Protein 1 (BAP1)-deficient Epithelioid Melanocytic Nevus from a Patient With Multiple Similar Lesions. (A) There is an expansile intradermal nodular proliferation of large epithelioid melanocytes with small melanocytes at the periphery and focally at the bottom. (B) All lesional melanocytes express BRAFV600E. (C) The main nodular proliferation lacks staining for BAP1. (D) The tumor cells in the center display epithelioid features. (E) Juxtaposition of large epithelioid melanocytes and conventional melanocytes. (F) The epidermis and superficial conventional melanocytes express BAP1. Most of the lesional melanocytes lack nuclear expression of BAP1.

CHAPTER 4  Spitz Nevi

49

B

A

Fig. 4.27  Polypoid BRCA1-associated Protein 1 (BAP1)-deficient Melanocytic Nevus. (A) There is an intradermal epithelioid melanocytic proliferation forming a polypoid nodule. (B) The nevus is composed of a mixed population of large epithelioid and small conventional melanocytes. The lesional melanocytes lacked nuclear expression of BAP1 (not shown).

nevomelanocytes, with loss of nuclear expression in the larger epithelioid melanocytes (see Fig. 4.26). Spitzoid neoplasms with loss of BAP1 typically display a nodular expansile growth and are predominantly composed of amelanotic large epithelioid melanocytes with round to oval nuclei. Lesions may have the silhouette of a small papule (see Fig. 4.26) or polypoid nodule (Figs. 4.27 and 4.28). The nuclear chromatin pattern is open (vesicular). Multinucleation is common. Some lesions display nuclear pleomorphism and may contain a few mitotic figures (Fig. 4.28). Isolated lymphocytes are commonly sprinkled throughout the epithelioid cell population. Some lesions are densely inflamed and associated with regression (Fig. 4.29). BAP1-deficient spitzoid neoplasms may be classified as a nevus or atypical melanocytic tumor, depending on the level of concern and familiarity of the pathologists with the spectrum of cytologic atypia and mitotic activity that can be associated with this lesion. Most have been found to be clinically indolent with follow-up over several years. Progression to melanoma has been observed but is very rare. In our opinion, most spitzoid neoplasms with loss of BAP1 expression are best regarded as melanocytic nevi, but the classification of each lesion needs to be done on a case-by-case basis because some may be better placed into a borderline category or even meet histopathologic and/or genomic criteria for melanoma. We have seen lesions with progression, i.e., frank melanoma associated with a BAP1-deficient nevus, some with a transitional tumor cell population with boderline features.

Spitzoid Neoplasms With Deletions in 6q23 Spitz nevi/tumors with deletions in 6q23 often present with a superficial plaque-like silhouette with prominent expansile junctional nesting. At times, one may see large junctional nests with transepidermal elimination. However, these features are not specific for this genomic aberration.

Fusion-Related Spitzoid Neoplasms Translocations involving tyrosine kinases have been identified in the majority of Spitz lesions. In a study of 102 spitzoid neoplasms,

translocations involving one of the following five tyrosine kinases were found: ROS1, ALK, NTRK1, BRAF, or RET.4 In the meantime, fusions involving MET and NTRK312 have also been identified, and it is likely that additional fusions will be detected. A rearranged kinase may have different fusion partners. The fusion partner replaces the normal regulatory site on the tyrosine kinase, resulting in constitutive activation. Currently, the clinical (diagnostic or prognostic) relevance of the fusions remains to be determined. It is currently not known whether certain translocations are associated with higher probability for progression to (or confusion with) melanoma. Kinase fusions have been found in clinically and histopathologically clearly benign Spitz nevi, as well as atypical Spitz nevi or tumors. They have also been reported to occur in lesions designated as spitzoid melanoma. Some fusions tend to be associated with distinct morphologic findings. ALK-rearranged Spitz nevi or tumors, for example, are characterized by the presence of intersecting fascicles of usually amelanotic spindle cells (Figs. 4.30 and 4.31). Occasional atypical lesions may have a dumbbell-shaped base (Fig. 4.32). ALK-rearranged melanocytic neoplasms can be diagnosed as melanoma based on a combination of atypical architectural and cytologic findings and may be further supported by detection of complex genomic aberrations typical of melanoma (Figs. 4.32 and 4.33). NTRK-rearranged lesions tend to contain melanocytes with oval or slight spindle cell shape with less abundant cytoplasm forming smaller nests (Fig. 4.34). The nests sometimes have a rosettelike arrangement (Fig. 4.35). Kamino bodies are relatively common. However, most fusions associated with Spitz lesions are not known to reflect a distinct morphologic phenotype. As with ALK, NTRK rearrangements can be seen across the spectrum of melanocytic neoplasms histopathologically and/or genomically classified as benign, “borderline,” or malignant. NTRK3 fusions have been identified as the most frequent and characteristic genomic aberration in the pigmented spindle cell nevus Text continued on p. 56

50

SECTION I  Benign Cutaneous Melanocytic Proliferations

A

B

C

D Fig. 4.28  Combined BRCA1-associated Protein 1 (BAP1)-deficient Large Epithelioid Cell and Conventional Melanocytic Nevus. (A) Exophytic silhouette of the lesion. (B) A dominant cell population is characterized by large epithelioid melanocytes with abundant cytoplasm. There is some nuclear pleomorphism. (C) Admixed small conventional melanocytes. (D) The small conventional melanocytes express BAP1 immunohistochemically. The large epithelioid melanocytes of the lesion lack nuclear labeling of BAP1.

CHAPTER 4  Spitz Nevi

B

A

Fig. 4.29  BRCA1-associated Protein 1–deficient Combined Nevus With Partial Regression. (A) Silhouette of a polypoid nevus. One-half of the dermal stroma contains a dense proliferation of epithelioid melanocytes, whereas the other half displays inflammation, edema, and hypervascularity, with a lack of melanocytes suggesting regression. (B) The remaining melanocytes display a large epithelioid morphology and are associated with a lymphocytic infiltrate.

A

B

C Fig. 4.30  ALK-positive Spitz Nevus. (A) Clinical appearance of the lesion from the flank of a 25-year-old man. (B) Symmetric silhouette of a compound nevus. (C) An immunostain for ALK highlights maturation and the presence of intersecting fascicles of spindle cells.

51

52

SECTION I  Benign Cutaneous Melanocytic Proliferations

A

B

C Fig. 4.31  ALK-positive Spitz Nevus. (A) Symmetric silhouette of an amelanotic compound Spitz nevus. (B) There are intersecting fascicles of relatively bland fusiform melanocytes. (C) The tumor is strongly and diffusely immunoreactive for ALK. The immunostain highlights the symmetric wedge-shaped silhouette.

CHAPTER 4  Spitz Nevi

B

A

C Fig. 4.32  ALK-positive Atypical Spitzoid Melanocytic Neoplasm from a 4-year-old Child. (A) There is a proliferation of amelanotic melanocytes in the dermis and subcutis. The subcutaneous portion of the lesion forms a large expansile nodule. (B) The melanocytes within the nodule are mitotically active. (C) The tumor cells strongly and homogenously express ALK. (D) Cytogenetic studies documented the presence of several copy number aberrations. A diagnosis of “spitzoid melanoma of childhood” was favored.

53

54

SECTION I  Benign Cutaneous Melanocytic Proliferations

A

B

C

D

E Fig. 4.33  ALK-positive Pediatric Melanoma from a 6-year-old Child. (A) Large densely cellular tumor nodule. (B) There is broad tumor ulceration and no evidence of maturation. (C) The tumor cells are cytologically atypical and mitotically active. The histopathologic findings are unequivocally malignant. (D) The tumor cells are immunoreactive for ALK. (E) Single nucleotide polymorphism (SNP) array analysis revealed a number of copy number changes at different chromosomes, including segmental losses of 9p (arrow), resulting in homozygous deletions of the CDNK2A gene.

A

Fig. 4.34  NTRK1-positive Spitz Nevus from the Leg of a 17-year-old Female. (A) Sharply circumscribed symmetric compound melanocytic proliferation. (B) The tumor cells strongly express NTRK1. (C) Small Kamino bodies are present. The papillary dermis is hypervascular. The lesional melanocytes display spitzoid cytology.

B

C

A

B

C

D Fig. 4.35  NTRK1-positive Atypical Spitz Tumor. (A) The lesion is a predominantly dermal-based tumor. (B) Relatively small but closely opposed nests of melanocytes. In some areas the nests have a rosettelike arrangement of the cells. (C) The tumors are immunohistochemically positive for NTRK. (D) Fluorescence in situ hybridization assessment for a break-apart in NTRK was positive with separation of the five prime and three prime ends of the gene, as evidenced by the separation of some of red and green dots.

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SECTION I  Benign Cutaneous Melanocytic Proliferations

(PSCN) subtype of Spitz. In a series of 23 cases, over half of cases harbored NTRK3 fusions. Fusions in RET, ROS1, and MERTK were identified in a small proportion of cases. NTRK3-rearranged lesions were more frequent in younger patients and morphologically had more frequent adnexal involvement.24a

SPITZ NEVUS VERSUS ATYPICAL SPITZ TUMOR VERSUS SPITZOID MELANOMA Distinguishing a typical Spitz nevus from a conventional melanoma is not difficult using general guidelines for the distinction of nevus from melanoma. However, the distinction of a Spitz nevus with atypical features from a melanoma closely simulating the appearance of a Spitz nevus (i.e., a nevoid melanoma with spitzoid features) can be very challenging.5,6

Spitzoid Melanoma Spitzoid melanoma is discussed in more detail in Chapter 18. In brief, they include a spectrum of conventional melanomas with Spitz nevus-like features and malignant Spitz tumors, the latter of which harbor genomic aberrations (e.g., kinase fusions) seen in Spitz nevi. Most spitzoid melanomas can be distinguished from a Spitz nevus by light microscopic parameters. In difficult cases, multiple pieces of evidence, using clinical, dermoscopic, routine histopathologic, and immunohistochemical findings, as well as results from genomic analysis, may need to be taken into account to reach the correct diagnosis. For example, using histopathologic findings alone, for a melanocytic neoplasm with spitzoid cytology a combination of marked asymmetry, disordered growth, severe nuclear atypia, absence of maturation, lack of Kamino bodies, and the presence of mitotic figures located at the base of the tumor would favor melanoma. The question, of course, is how many various histopathologic parameters need to deviate from what is acceptable for a nevus with atypical features to warrant a diagnosis of melanoma. This is a gray area with significant interobserver variability among pathologists. A suspected diagnosis of melanoma can be supported by abnormal molecular findings, such as the presence of chromosomal copy number gains typical of melanoma, in particular homozygous deletions of 9p in nearly all tumor cells, or the presence of telomerase reverse transcriptase (TERT) promoter mutations.7,25-29 The presence of the latter two aberrations has been associated with increased risk for clinical recurrence. The term spitzoid melanoma of childhood has been proposed for spitzoid melanocytic neoplasms (i.e., lesions displaying spitzoid cytology and Spitz-associated molecular pathway aberration[s]), which meet microscopic and/or current genomic criteria for melanoma but occur in children. Many, albeit not all, of these tumors tend to have a relatively indolent clinical course and are overall less aggressive than nonspitzoid melanomas of similar thickness. Thus “spitzoid melanoma of childhood” has become the modern-day equivalent of Sophie Spitz’s “juvenile melanoma.”

Atypical Spitz Tumor The term atypical Spitz tumor (AST) is used for a group of spitzoid melanocytic neoplasm that does not meet unequivocal criteria for malignancy but display enough atypical features deviating from a typical Spitz nevus to raise concern about the biologic potential of the lesion (i.e., a possible melanoma) (Fig. 4.36). Thus the term is of practical use because it refers to a diagnostic dilemma: the pathologist is not sure whether the lesion is a benign nevus (or indolent tumor) with unusual or atypical microscopic features or a melanoma deceptively and closely simulating an atypical spitzoid melanocytic nevus. There is significant interobserver variability in the use of the term AST, depending on the

experience and risk tolerance of a pathologist, as well as conceptual thoughts about Spitz lesions. Some pathologists merely use the term pragmatically to report a diagnostic problem. They may use it for a preliminary report while the diagnostic work-up is still under way or as final designation of a tumor when all available tests have failed to reveal definitive diagnostic evidence. Some pathologists use the term AST as a diagnostic “entity” for a biologically indeterminate group of melanocytic neoplasms or a group of “low-grade melanomas” that are often associated with clinically indolent regional lymph node deposits but rarely progress to fully malignant or disseminated metastatic melanoma. In comparison with Spitz nevi, lesions placed into the group of atypical Spitz tumors tend to be larger in horizontal dimension and extend more deeply.5,6,30 They deviate in a number of ways from a typical Spitz nevus. Lesions of AST are less symmetric and less circumscribed. There is more architectural disorder, including pagetoid spread and complex growth of nests and fascicles. The cell density is higher and maturation is less developed. Cytologically, there is more atypia, including nuclear enlargement, hyperchromatism, and prominent nucleoli. Mitotic figures are more easily found, and atypical mitoses may be present. These features overlap with melanoma, and interobserver variability in preference for terminology is accompanied by different diagnostic interpretations: a lesion designated by one pathologist as AST may be accepted by a different pathologist as a Spitz nevus with atypical features or by yet another as spitzoid melanoma.5,6 Given the indolent behavior of many lesions reported as AST, at least in children, it is likely that many of them are not fully malignant melanomas. However, rare lesions classified as initially classified as AST turn out to be melanomas. On occasion a diagnosis of AST needs to be revised to melanoma in light of an adverse clinical event and/or the detection of genomic or gene/ protein expression aberrations typical of or more plausible for melanoma.

ANCILLARY METHODS FOR DIAGNOSIS Immunohistochemistry IHC is of some, but limited, help for the diagnosis of Spitz lesions. It is important to document loss of BAP1 for the diagnosis of a BAP1deficient epithelioid cell nevus or tumor. Furthermore, IHC for HRAS can help to support a suspected diagnosis of a desmoplastic Spitz nevus. IHC for p16 can be used to determine whether further cytogenetic testing is needed. If a Spitz lesion, for example, displays atypical findings and there is complete or near complete loss of p16 expression by IHC, further investigation by fluorescence in situ hybridization (FISH) for the presence of homozygous deletions of 9p would be judicious.

Cytogenetic Studies Cytogenetic studies can be helpful diagnostically for the evaluation of spitzoid neoplasms.7,25-29 The presence of homozygous deletions of 9p in the vast majority of lesional melanocytes should prompt concerns about a possible spitzoid melanoma. The detection of multiple gains or losses of different chromosomes in a spitzoid neoplasm favors melanoma. However, isolated genomic aberrations per se do not imply malignancy (Fig. 4.37). They can be seen in association with benign Spitz nevi and indolent Spitz tumors conceptually placed into an intermediate or borderline category.

Gene Expression Studies The value of gene expression studies for the distinction of a benign or indolent Spitz lesion from malignant melanoma is currently under investigation and has not yet been determined.

CHAPTER 4  Spitz Nevi

57

B

A

C Fig. 4.36  Atypical Spitz Tumor from a Young Child. (A) Wedge-shaped silhouette of the lesion with extension into superficial subcutis. (B) A large Kamino body is present. (C) There is nuclear pleomorphism and lack of maturation.

Mutation Analysis Mutation analysis may provide some diagnostically useful information. The presence of TERT promoter mutations would argue against a Spitz nevus or indolent Spitz tumor and favor melanoma.29 Except for the setting of combined BAP-1-deficient lesions, the detection of BRAF or NRAS mutations generally argues against a classification of a lesion as benign spitzoid. Thus, when one entertains a differential diagnosis of

pagetoid Spitz nevus versus superficial spreading melanoma, the presence of a BRAF mutation would favor the latter.

PROGNOSIS AND TREATMENT Persistent growth and local recurrence following excision is infrequent in Spitz nevi but may occur. Although melanoma can develop in association with a Spitz nevus, such an event appears to be very rare.

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SECTION I  Benign Cutaneous Melanocytic Proliferations

B

A

C Fig. 4.37  Compound Spitz Nevus/Tumor With Isolated Genomic Aberrations (Lesion from an 8-year-old Boy). (A) Fairly symmetric silhouette. (B) Good evidence of maturation. (C) Rare mitotic figure (arrow). This lesion was found to have a partial loss of 9p and gain of 7q. These genomic aberrations in context with the microscopic findings are insufficient for melanoma and in keeping with an indolent Spitz tumor.

Lesions interpreted as Spitz nevus in a child can be followed clinically and do not need to be excised. Consideration should be given to complete excision of partly biopsied lesions of Spitz nevi in adults because recurrent lesion may display more atypical features, leading to possible confusion with melanoma. Any lesion for which a partial biopsy does not yield a definitive diagnosis of a benign Spitz nevus (i.e., if there are atypical findings present and there is related diagnostic uncertainty) should be excised completely, at least when such an excision can easily be performed with no or limited adverse cosmetic or functional consequences. Most cases diagnosed by an experienced dermatopathologist as atypical Spitz tumor in children and adolescents tend to have an indolent clinical course, supporting the use of the term AST to avoid concerns about and possible overtreatment as for malignant melanoma. However, a few cases reported as AST are fully malignant tumors by follow-up and/or genomic analysis. When recurrence occurs, it tends to be localregional. Some of these patients may have long survival despite local

recurrences. Rare cases with distant metastases are spitzoid melanoma, at least in retrospect. In adults, especially middle-aged or elderly individuals, there is a higher risk for a lesion reported as AST to turn out be a malignant melanoma. In a multiinstitutional study that involved several major medical centers across the United States and Australia, only 11 cases of AST were identified with clinical recurrence.25 If assessed in the era of molecular diagnostics, the presence of homozygous deletions of 9p21 may have upgraded some of these lesions to a diagnosis of spitzoid melanoma. Importantly, the same study showed that other copy number aberrations that were previously reported for melanoma, such as an isolated deletion of 6q23 or heterozygous deletions in 9p21, do not infer risk for aggressive behavior in a spitzoid melanocytic neoplasm. Lymph node deposits by Spitz nevi/tumors are common (Fig. 4.38). The reported frequency of lymph node involvement in the setting of a primary AST ranges between 30% and 50% of cases.31,32 Most tumor

CHAPTER 4  Spitz Nevi

59

A

C

B

D Fig. 4.38  Spitzoid Neoplasm With Melanocytes in the Sentinel Lymph Node. (A) Silhouette of a predominantly intradermal spitzoid melanocytic proliferation from the ear of a young adult. (B) There is evidence of maturation. The cytologic findings are relatively bland. (C) The tumor cells express ALK. Analysis of the tumor cells by comparative genomic hybridization failed to reveal any copy number gains or losses. Pathologists who reviewed this lesion interpreted it as either Spitz nevus or atypical Spitz tumor. The surgeon performed nonetheless a sentinel lymph node biopsy. (D) Melanocytes were present in the fibrous tissue of the lymph node capsule (arrow) and as a small cluster in the subcapsular sinus (arrow). The presence of these melanocytes in the lymph node does not require a reinterpretation of the primary tumor. The findings are in keeping with an indolent neoplasm.

deposits are small microdeposits (<1 mm in diameter, often identified only after the use of IHC), but occasional large tumor deposits may be detected. Unlike in conventional melanoma, the presence of small microscopic spitzoid melanocyte deposits does not have prognostic significance.32 Large deposits leading to a clinically palpable node likely reflect metastatic melanoma. Whether or not a tumor deposit represents malignant melanoma or an indolent melanocyte deposit needs to be assessed case by case, taking into account the clinical setting, the histopathologic and genomic features of the primary tumor, and the volume, distribution, cytology, and immunophenotype of the intranodal melanocytes.

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5. Barnhill RL. The Spitzoid lesion: rethinking Spitz tumors, atypical variants, ‘Spitzoid melanoma’ and risk assessment. Mod Pathol. 2006;19(suppl 2):S21–S33. 6. Barnhill RL, et al. Atypical Spitz nevi/tumors: lack of consensus for diagnosis, discrimination from melanoma, and prediction of outcome. Hum Pathol. 1999;30:513–520. 7. Bastian BC, et al. Molecular cytogenetic analysis of Spitz nevi shows clear differences to melanoma. J Invest Dermatol. 1999;113:1065–1069. 8. Wiesner TOA, et al. Germline mutations in BAP1 predispose to melanocytic tumors. Nat Genet. 2011;43:1018–1021. 9. Wiesner T, et al. A distinct subset of atypical Spitz tumors is characterized by BRAF mutation and loss of BAP1 expression. Am J Surg Pathol. 2012;36:818–830. 10. Wiesner T, et al. Kinase fusions are frequent in Spitz tumours and spitzoid melanomas. Nat Commun. 2014;5:3116. 11. Yeh I, et al. Clinical, histopathologic, and genomic features of Spitz tumors with ALK fusions. Am J Surg Pathol. 2015;39:581–591. 12. Yeh I, et al. NTRK3 kinase fusions in Spitz tumours. J Pathol. 2016;240:282–290. 13. Diaz-Cascajo C, Borghi S, Weyers W. Angiomatoid Spitz nevus: a distinctvariant of desmoplastic Spitz nevus with prominent vasculature. Am J Dermatopathol. 2000;22:135–139. 14. Barr RJ, Morales RV, Graham JH. Desmoplastic nevus: a distinct histologic variant of mixed spindle cell and epithelioid cell nevus. Cancer. 1980;46:557–564. 15. Bastian BC, LeBoit PE, Pinkel D. Mutations and copy number increase of HRAS in Spitz nevi with distinctive histopathological features. Am J Pathol. 2000;157:967–972. 16. Akiyama M, et al. Spitz naevus with a predominant epithelioid cell component and halo reaction. Histopathology. 1997;31:292–293. 17. Busam KJ, Barnhill RL. Pagetoid Spitz nevus. Intraepidermal Spitz tumor withprominent pagetoid spread. Am J Surg Pathol. 1995;19:1061–1067. 18. Sau P, Graham JH, Helwig EB. Pigmented spindle cell nevus: a clinicopathologic analysis of ninety-five cases. J Am Acad Dermatol. 1993;28:565–571. 19. Barnhill RL, Mihm MC Jr. Pigmented spindle cell naevus and its variants: distinction from melanoma. Br J Dermatol. 1989;121:717–725. 20. Spatz A, et al. Plexiform spitz nevus: an intradermal spitz nevus with plexiform growth pattern. Am J Dermatopathol. 1999;21:542–546.

21. Cramer SF. Prominent mast cells in myxoid Spitz nevus. Arch Pathol Lab Med. 1990;114:1191–1192. Erratum in: Arch Pathol Lab Med 1991;115:371. 22. Liu J, Cohen PR, Farhood A. Hyalinizing Spitz nevus: spindle and epithelioid cell nevus with paucicellular collagenous stroma. South Med J. 2004;97:102–106. 23. Soyer HP, et al. Tubular’ structures within melanocyticproliferations: a distinctive morphologic finding not restricted to Spitz nevi. J Cutan Pathol. 1999;26:315–317. 24. Sabater Marco V, et al. Pseudogranulomatous Spitz nevus: a variant of Spitz nevus with heavy inflammatory infiltrate mimicking a granulomatous dermatitis. J Cutan Pathol. 2013;40:330–335. 24a.  VandenBoom T, et al. Genomic fusions in pigmented spindle cell nevus of Reed. Am J Surg Pathol. 2018; in press. 25. Gerami P, et al. Risk assessment for atypical spitzoid melanocytic neoplasms using FISH to identify chromosomal copy number aberrations. Am J Surg Pathol. 2013;37:676–684. 26. Gerami P, et al. A highly specific and discriminatory FISH assay for distinguishing between benign and malignant melanocytic neoplasms. Am J Surg Pathol. 2012;36:808–817. 27. Gerami P, et al. Outcomes of atypical spitz tumors with chromosomal copy number aberrations and conventional melanomas in children. Am J Surg Pathol. 2013;37:1387–1394. 28. North JP, et al. Fluorescence in situ hybridization as an ancillary tool in the diagnosis of ambiguous melanocytic neoplasms: a review of 804 cases. Am J Surg Pathol. 2014;38:824–831. 29. Lee S, et al. TERT Promoter Mutations Are Predictive of Aggressive Clinical Behavior in Patients with Spitzoid Melanocytic Neoplasms. Sci Rep. 2015;5:11200. 30. Massi D, et al. Atypical Spitz tumors in patients younger than 18 years. J Am Acad Dermatol. 2015;72:37–46. 31. Lohmann CM, et al. Sentinel lymph node biopsy in patients with diagnostically controversial spitzoid melanocytic tumors. Am J Surg Pathol. 2002;26:47–55. 32. Hung T, et al. Sentinel lymph node metastasis is not predictive of poor outcome in patients with problematic spitzoid melanocytic tumors. Hum Pathol. 2013;44:87–94.