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Spitz nevus and atypical Spitz tumors

Spitz nevus and atypical Spitz tumors
Literature review current through: Aug 2023.
This topic last updated: Jul 21, 2022.

INTRODUCTION — Spitz nevus (or Spitz tumor) is an uncommon melanocytic lesion composed of large epithelioid and/or spindled cells. It typically presents in childhood or adolescence as a sharply circumscribed, dome-shaped, pink-red papule or plaque most commonly located on the face or lower extremities (picture 1). The clinical relevance of Spitz tumor lies in its close histologic resemblance to melanoma. In some cases, differentiating Spitz tumors from melanoma may be difficult or impossible even for the expert pathologist. Spitz lesions are often not classified in any standardized way, evoke uncertainty in diagnosis by pathologists, and elicit variability in treatment recommendations [1].

The classification, epidemiology, clinical manifestations, diagnosis, and management of Spitz tumors will be discussed here. The diagnosis and management of Spitz nevus in children are discussed separately. Congenital nevi, acquired melanocytic nevi, and atypical nevi are discussed separately. BAP1-inactivated melanocytic tumors (BIMTs) are also discussed separately.

(See "Spitz nevus/tumor in children: Diagnosis and management".)

(See "Congenital melanocytic nevi".)

(See "Acquired melanocytic nevi (moles)".)

(See "Atypical (dysplastic) nevi".)

(See "BAP1-inactivated melanocytic tumors".)

TERMINOLOGY AND HISTORICAL BACKGROUND — Spitz tumors were first described by Darier and Civatte in 1910 [2]. In 1948 Sophie Spitz articulated for the first time criteria for this unusual group of childhood melanocytic lesions that histologically resembled melanomas but did not demonstrate the typical aggressive clinical behavior commonly associated with adult melanomas [3]. Of interest, 1 of Spitz's original 13 cases resulted in metastasis and death of the patient. These lesions were termed "juvenile melanomas" to distinguish them from adult melanoma and benign nevi of childhood. Subsequently, various terms have been used for this group of lesions including "Spitz nevus," "Spitz tumor," and "spindle and epithelioid cell nevus."

Atypical variants of Spitz tumors have been termed "atypical Spitz tumors," "spindle and epithelioid cell nevus with atypia and metastasis," "melanocytic tumor of unknown malignant potential," or "spitzoid tumor of uncertain malignant potential" [4-6].

In this topic we will use the term "Spitz tumor" as a general term for all types of Spitz lesions. Spitz lesions with one or more atypical features and those with indeterminate biologic behavior will be referred to as "atypical Spitz tumors." (See 'Classification' below.)

EPIDEMIOLOGY — Spitz tumors represent approximately 1 percent of the nevi excised in children [7]. They typically occur in the first two decades of life, but also may develop in adults [8,9]. In a series of 342 Spitz tumors, 40 percent of tumors were found in patients <15 years and 76 percent in patients <30 years. Congenital cases of Spitz tumor are exceedingly rare [10-12].

Spitz tumors occur in all ethnic groups. Males and females are approximately equally affected, although there may be a female predominance in young adults [8,9,13,14].

CLASSIFICATION — Spitz tumors include a morphologic and biologic spectrum ranging from benign or low-grade melanocytic neoplasms to Spitz melanoma/malignant Spitz tumors (table 1). On one end of the spectrum, the conventional Spitz nevus (Spitz tumor) is recognized as a benign or indolent melanocyte proliferation that most commonly develops in children, adolescents, and young adults. On the other end of the spectrum are rare, malignant Spitz tumors/Spitz melanoma. Between these two extremes, there is a heterogeneous group of Spitz tumors with varying degrees of atypia, including lesions with extensive pleomorphic features that may be difficult or impossible to distinguish from melanoma without additional information and that are considered to have uncertain malignant potential.

Based upon clinical, histopathologic, and genetic characteristics, three provisional categories of Spitz tumors can be delineated [4,15-17]:

Spitz nevus/Spitz tumor – The conventional or prototypic Spitz nevus is a melanocytic lesion with a unique cellular phenotype that suggests a distinctive benign or low-grade melanocytic neoplasm distinct from conventional melanocytic nevi (picture 1). Conventional Spitz nevi are generally small (<5 to 6 mm in diameter), symmetric, and sharply circumscribed. On histology, they show a regular architecture, zonation and maturation, absence of or few dermal mitoses, and lack significant cytologic atypia (table 2). (See 'Spitz nevus' below.)

Atypical Spitz tumor – The term "atypical Spitz tumor" refers to lesions that have one or more atypical features and often an indeterminate biologic potential (ie, lesions difficult to classify as unequivocally benign or malignant) [4]. Atypical Spitz tumors usually have larger size than conventional Spitz tumors (>6 mm and often >10 mm), abnormal gross morphologic features, including irregular borders, irregular topography, or ulceration. On histology, atypical Spitz tumors may show asymmetry, ulceration, pagetoid melanocytosis, lack of zonation and maturation, conspicuous cellular density of the dermal component including nodule formation, irregular or deep melanin, involvement of the subcutis, dermal mitoses, deep mitoses, and significant degrees of cytologic atypia (table 3). (See 'Atypical Spitz tumor' below.)

Spitz melanoma/malignant Spitz tumor – The term "Spitz melanoma" is reserved for melanomas with histologic features and characteristic genetic alterations of Spitz tumors, such as activating HRAS mutations or kinase fusions.

The term "spitzoid melanoma" has been used to indicate a subset of melanomas often, but not exclusively, seen in adults that have a close morphologic resemblance to Spitz tumors. However, many of these melanomas labeled as "spitzoid" have no relationship to the family of Spitz tumors and probably represent conventional melanomas (eg, melanomas with BRAF mutations). Thus, the term "spitzoid melanoma" should be used judiciously until more rigorous clinical, histopathologic, and molecular criteria are developed for this hypothetical entity.

PATHOGENESIS — The etiology and pathogenesis of Spitz tumors are unknown. Eruptive Spitz tumors have been documented during pregnancy or puberty, suggesting a potential role for hormonal activation [18,19].

Up to 30 percent of Spitz tumors may exhibit HRAS mutations, which are rare or absent in melanoma [20]. In contrast to melanoma, mutations in BRAF and NRAS have not been consistently identified in Spitz tumors [21,22]. Chromosomal rearrangement-induced fusions involving ROS1; NTRK1, NTRK2, and NTRK3; ALK; BRAF; RET; and MAP3K8, resulting in chimeric proteins involved in the activation of oncogenic signaling pathways, have been identified in a mutually exclusive pattern in 60 percent of conventional Spitz nevi and 75 percent of atypical Spitz tumors [23]. (See 'Mutational analysis' below.)

CLINICAL FEATURES — Spitz nevi develop in young individuals, usually before the age of 20 years. Conventional Spitz nevi usually are seen in children <10 years. Although there is overlap in the age distributions of Spitz nevus and Spitz melanoma, Spitz tumors in patients older than 20 to 30 have an increased risk of developing malignancy than those in younger patients. (See 'Risk stratification for atypical Spitz tumors' below.)

Conventional Spitz nevi — Conventional Spitz nevi typically present as a pink or reddish, symmetric, dome-shaped papule or plaque on the face or lower extremities (picture 1 and table 2). Some lesions are so erythematous that the clinical impression is that of a hemangioma. Brown/black papules or plaques are a more common presentation in adults, although heavily pigmented Spitz nevi may also be seen in children (picture 2).

Lesions are usually <6 mm in diameter. The borders are well defined, and the surface is smooth. Ulceration is an infrequent finding, although traumatic excoriation is common in children. Variants include plaque-type, desmoplastic (firm or indurated), pigmented, and halo Spitz nevi (picture 2 and table 4). Multiple Spitz nevi arising within a nevus spilus or speckled lentiginous nevus have also been reported (picture 3) [24-27].

Spitz nevi may occur on any site. However, the most common locations are the face or lower extremities in children and the trunk or extremities in adults. Spitz nevi are typically solitary, but agminated (grouped) Spitz nevi may occur in single or multiple areas [12,28-34]. Lesions usually undergo a period of rapid growth lasting three to six months and then stabilize. Rarely, multiple Spitz nevi may develop in an eruptive fashion in weeks or months [19,35-37].

Atypical Spitz tumors — Atypical Spitz tumors are generally seen in adolescents and young adults. In most cases, it is not possible to distinguish an atypical Spitz tumor from melanoma on clinical grounds, since both lesions share atypical findings such as a large diameter (>6 mm, especially >1 cm), asymmetry, border irregularity, or color variegation. (See "Melanoma in children", section on 'Clinical features'.)

Regional lymph node involvement by atypical Spitz tumors — Palpable lymph nodes may develop, on occasion, in association with atypical Spitz tumors due to deposits of atypical melanocytes. With the development of sentinel lymph node biopsy (SLNB), it has been observed that up to 50 percent of patients with atypical Spitz tumors may show sentinel lymph node involvement [38-46]. However, the biologic significance of such sentinel lymph node deposits in atypical Spitz tumors is not entirely clear and requires further study.

A systematic review of 24 observational studies including 541 patients with atypical Spitz tumors, of whom 303 underwent SLNB, found an overall survival rate of 99 percent at a mean follow-up of 59 months. The survival was similar for 119 patients with a positive SLNB, suggesting that the vast majority of these tumors have a low risk for disease progression and a favorable prognosis, independent from the sentinel lymph node status [47].

DERMOSCOPIC FEATURES — On dermoscopy, conventional Spitz nevus exhibits little or no pigmentation and a dotted vascular pattern with or without a so-called inverse network [48]. Pigmented Spitz tumors typically exhibit a "starburst" or "peripheral globular" pattern (picture 4) (see "Dermoscopic evaluation of skin lesions"):

The starburst pattern is characterized by diffuse blue to black pigmentation that extends into radial streaks at the periphery of the lesion, contributing to a stellate appearance [49].

The peripheral globular pattern consists of prominent brown to gray-blue pigmentation bordered by a peripheral rim of discrete pigment globules.

Dermoscopic identification of a characteristic starburst or peripheral globular pattern may assist in the diagnosis of pigmented conventional Spitz nevus [50-52]. Cases with an atypical pattern may be indistinguishable from melanoma [48,53].

In a review of dermoscopic features of 896 Spitz tumors, the starburst pattern was the most frequently observed, followed by the dotted vessels and the globular pattern (152 of 896, 17 percent) (51, 19, and 17 percent, respectively) [54]. Nine percent of the lesions presented a multicomponent/atypical pattern.

In another study with clinical follow-up data, the most common dermoscopic patterns of Spitz nevi were globular (n = 35 [50 percent]), starburst (n = 24 [34 percent]), reticular (n = 8 [11 percent]), and homogeneous (n = 3 [4 percent]); on follow-up images, 21 of 27 (78 percent) demonstrated evolution of the dermoscopic pattern, whereas a stable pattern (no evolution) was noted in 6 (22 percent) [55].

Evolution over time of the starburst dermoscopic pattern was demonstrated in a retrospective study of 31 pigmented Spitz nevi; of these, 21 (68 percent) evolved to a repetitive pattern characterized by a delicate, brown network at the periphery and a central, structureless or reticular, hyperpigmented area [56].

The dermoscopic features of BAP1-inactivated melanocytic tumors (BIMTs) include pink to tan, structureless areas; brown, irregular dots and globules; serpentine or dotted vessels; and atypical network [57]. Of note, in a series of 47 BIMTs, a pattern of pink to tan, structureless areas with irregular dots-globules was more frequently seen in cases harboring a BAP1 germline mutation [57].

HISTOPATHOLOGY — The histopathologic features of conventional Spitz nevi, atypical Spitz tumors, and Spitz melanoma are summarized in the table (table 5).

Spitz nevus

Architectural features – Spitz nevi are symmetric and sharply demarcated and display nests of large epithelioid cells, spindle cells, or both, usually extending from the epidermis into the reticular dermis in an inverted-wedge configuration (picture 5A and table 2). The closely apposed nests of cells within a uniformly hyperplastic epidermis often contribute to a so-called "raining-down" appearance. Kamino bodies (eosinophilic hyaline globules) are present in most Spitz nevi [58].

Additional findings include junctional clefting with discohesive junctional melanocytic nests and perivascular lymphoid infiltrates. Pagetoid spread (upward spread of cells in the epidermis), if present, is focal, sparsely cellular, and limited to the center of the lesion and the lower half of the epidermis [59].

Spitz nevi exhibit zonation and maturation. Zonation refers to the uniform organization of melanocytes across a horizontal axis of the lesion. Maturation involves the progressive decrease in size of melanocytic nests and individual melanocytes with increasing dermal depth. Melanocytes are organized in relatively prominent junctional nests and vertically oriented fascicles that progressively give place to smaller nests and eventually to single cells in the dermis [59]. This process results in a nondisruptive infiltration of involuted small melanocytes among the dermal collagen bundles [4].

Cytologic features – Spitz nevus is composed of enlarged, relatively uniform spindle and/or epithelioid melanocytes with polyangular contours, opaque or "ground glass" cytoplasm, nuclei with delicately dispersed or vesicular chromatin, and only occasional cellular pleomorphism (picture 5B and table 2).

Mitotic activity – In Spitz nevi, the mitotic rate is low, usually <2 per mm2. Mitoses are rare or absent in the deep dermis.

Atypical Spitz tumor

Architectural features – Atypical Spitz tumors may extend deeply into the dermis to the subcutaneous fat, are often asymmetric, not well-circumscribed, and may be ulcerated (picture 6C and table 3). These lesions display high cellular density with confluence of melanocytes in cellular aggregates or nodules that replace the dermis without maturation.

Atypical Spitz tumors may uncommonly exhibit extensive pagetoid scatter in single cell or small nest pattern involving the upper layers of the epidermis. However, external trauma associated with overlying parakeratosis may also result in pagetoid spread in benign lesions.

Atypical Spitz tumors may lack zonation (uniform organization of melanocytes across a horizontal axis of the lesion) and maturation (progressive reduction in the size of melanocyte nests and individual melanocytes with increasing dermal depth) [4]. A nonuniform organization of the lesion observed when the lesion is scanned side-to-side across a horizontal axis and the persistence of melanocytic nests and fascicles of similar sizes within the deep dermis are abnormal features and may indicate a potentially aggressive biologic behavior. Kamino bodies (eosinophilic, hyaline globules) are rare or absent.

Angiotropism refers to the microscopic finding of melanocytes closely apposed to the external surfaces of vascular channels, as a result of melanocytic migration along the vascular channels (extravascular migratory metastasis). Angiotropism has been found in melanomas and other melanocytic neoplasms, including congenital nevi and atypical Spitz tumors [60-63]. Angiotropism may be a predictor of risk of metastasis in melanoma and may explain regional tumor spread occurring in atypical Spitz tumors [60,61,64,65].

Cytologic features – Cytologic features of atypical Spitz lesions include cellular and nuclear pleomorphism, high nuclear to cytoplasmic ratio, hyperchromatic nuclei, and large eosinophilic nucleoli (picture 6A-B and table 3) [4].

Mitotic activity – In atypical Spitz tumors, the mitotic rate may be increased, generally 2 to 6 per mm2 or higher. Mitoses located in the deep dermal or subcutaneous tissue may be a sign of malignancy [66]. Situations in which mitotic rate may not reflect malignant transformation include very young age, tumors that are growing, or traumatized or inflamed lesions [4].

Proliferative index – The proliferative index, as measured by Ki-67 immunohistochemical staining, may be a useful adjunct in the evaluation of mitotic activity of Spitz tumors. A proliferative index of 2 to 10 percent suggests an atypical or biologically indeterminate Spitz tumor; higher indices suggest melanoma [67]. (See 'Immunohistochemistry' below.)

Spitz melanoma — There are no clear-cut histopathologic features that distinguish atypical Spitz tumors from melanoma. The architectural and cytologic features of melanomas are substantially similar to those of atypical Spitz tumors (picture 7A and table 5).

However, the probability of an aggressive phenotype or melanoma increases with the increase in the number and severity of atypical features, such as increased lesional diameter (especially >1 cm), asymmetry, ulceration, involvement of subcutaneous fat, cytologic pleomorphism, and high dermal mitotic rate (picture 7B) [68]. (See "Pathologic characteristics of melanoma".)

IMMUNOHISTOCHEMISTRY — Spitz tumors have been evaluated with a variety of melanocytic markers, including Ki-67, S-100, Melan-A/Mart-1, HMB-45, cyclin D1, p16, and preferentially expressed antigen in melanoma (PRAME) [69-75]. Their value in predicting the biologic behavior of atypical Spitz tumors is uncertain and needs to be evaluated in larger studies with long-term follow-up. Nonetheless, they may be used in combination with clinical and histologic features in difficult cases:

Ki-67 – Ki-67 is a nuclear protein involved in cell cycle regulation expressed at peak level during mitosis. In a study evaluating the role of Ki-67 staining in the differential diagnosis of Spitz tumors and melanoma, the mean Ki-67 labeling index was 5 percent in conventional Spitz nevi, 10 percent in atypical Spitz tumors, 37 percent in adult invasive melanomas, and 0.5 percent in common compound nevi [76]. In a mathematical model developed to estimate the probability of a Spitz tumor according to its proliferative index, values <2 percent favor a conventional Spitz nevus, values between 2 to 10 percent suggest an atypical or biologically indeterminate Spitz tumor, and values >15 to 20 percent suggest melanoma [67].

HMB-45 – HMB-45 is a melanogenesis-related protein that can be used to assess a lesion's maturation with depth. Typically, expression of this protein decreases toward the base of Spitz lesions whereas melanoma tends to demonstrate a more uniform and scattered distribution of this marker [69,70,75].

Cyclin D1 – Cyclin D1 demonstrate a staining pattern similar to HMB-45 in Spitz tumors, reflecting a decreased cellular proliferation with increasing depth of the dermal component [77]. Fatty acid synthase demonstrates an increasing expression from common nevi to atypical Spitz lesions to melanoma [76].

PRAME – PRAME immunohistochemical staining has been demonstrated to be helpful in the diagnosis of melanoma:

Immunohistochemical expression of PRAME in 400 melanocytic tumors, including 155 primary and 100 metastatic melanomas, and in 145 melanocytic nevi demonstrated diffuse nuclear immunoreactivity for PRAME in 87 percent of metastatic melanomas and 83 percent of primary melanomas [78]. Among melanoma subtypes, PRAME was diffusely expressed in 94 percent of acral melanomas, 93 percent of superficial spreading melanomas, 90 percent of nodular melanomas, 89 percent of lentigo maligna melanomas, and 35 percent of desmoplastic melanomas. In contrast, 86 percent of the 140 cutaneous melanocytic nevi were completely negative for PRAME.

Interestingly, in a retrospective case series comprised of malignant melanoma, atypical spitzoid tumor, and benign nevi in children and adolescents aged less than 16 years, the immunohistochemical expression of PRAME was negative in most cases. Focal and slight positivity (from 1 to 5 percent of the neoplastic cells) was observed in four cases (two Spitz nevi and two atypical Spitz tumors). A moderate positivity in 25 percent of the neoplastic cells was observed in one case of atypical Spitz tumor [79].

Another study demonstrated that nonspitzoid melanomas (23 of 24 [96 percent]) demonstrated diffuse PRAME expression, whereas most Spitz nevi (15 of 20) and atypical Spitz tumors (10 of 13) entirely lacked PRAME expression [80]. One Spitz nevus, one atypical Spitz tumor, and one spitzoid melanoma (one of two), however, demonstrated diffuse PRAME expression.

Because benign Spitz nevi and atypical Spitz tumors can infrequently express diffuse PRAME, utilization of this marker in spitzoid lesions should be used with caution. Larger case studies are required to further establish the utility of this marker in pediatric Spitz tumors and melanoma. (See "Spitz nevus/tumor in children: Diagnosis and management".)

MOLECULAR ANALYSIS

Comparative genomic hybridization — Whole genome analysis for deoxyribonucleic acid (DNA) gains or losses by comparative genomic hybridization (CGH) revealed amplification of chromosome 11p (a genome area that contains the HRAS gene) in approximately 20 percent of Spitz tumors [81-83]. The 11p amplification is characteristic of Spitz tumors and is not commonly seen in melanoma. A study of 16 atypical Spitz tumors with array CGH showed that almost all chromosomal aberrations present in these lesions were not those commonly seen in conventional melanoma. These findings provide support for atypical Spitz tumor as a group of lesions distinct from both conventional Spitz nevi and conventional melanoma [84]. (See "Tools for genetics and genomics: Cytogenetics and molecular genetics", section on 'Array comparative genomic hybridization'.)

Fluorescence in situ hybridization — In contrast with CGH, which investigates the whole genome, fluorescent in situ hybridization (FISH) can investigate one to three loci per experiment. A 4-probe FISH analysis, including RREB1 (6p25), MYB (6q23), 6 centromere, and CCND1 (11q13) demonstrated correct classification of conventional melanoma in 87 percent of cases [85]. However, the utility of FISH in the evaluation of atypical Spitz tumors has not been definitively established and is increasingly discouraged [86]. In a study including 29 Spitz tumors, FISH probes targeting chromosome 6p25, 6q23, 6 centromere, and 11q13 failed to identify one melanoma and one fatal metastatic atypical Spitz tumor [84].

A subsequent study of 75 atypical Spitz tumors demonstrated that homozygous deletions of 9p21 in atypical Spitz tumors may be predictive of aggressive behavior and a fatal outcome [87]. However, the role of homozygous 9p21 deletion as a marker of aggressive behavior is still controversial [88,89]. Furthermore, atypical Spitz tumors with gains in 6p25 or 11q13 also may have increased risk for aggressive behavior. Nonetheless, analysis of a larger cohort of atypical Spitz tumors with gains in 6p25 or 11q13, careful delineation of their histologic characteristics versus those of conventional melanoma, correlation with adverse outcomes, and long-term follow-up are needed to validate these results. (See "Tools for genetics and genomics: Cytogenetics and molecular genetics", section on 'Fluorescence in situ hybridization'.)

Mutational analysis — Oncogenic mutations of HRAS, which are typically absent in melanoma, have been found in subgroups of Spitz tumors, specifically those with a copy number increase of chromosome 11p [82,90]. In a study of 170 Spitz tumors and atypical Spitz tumors, 7 of 24 lesions harboring HRAS mutations were initially diagnosed as melanoma [90]. However, none of the patients developed recurrences or metastases after a median follow-up of 10 years.

NRAS and BRAF mutations are mutually exclusive and occur in approximately 20 and 70 percent of melanomas, respectively, and in a variable proportion of acquired and congenital melanocytic nevi [91-94]. Studies of conventional Spitz tumors and spitzoid melanomas did not find activating hotspot mutations in NRAS or BRAF [95,96].

Next-generation DNA and RNA sequencing — Spitz tumors demonstrate genomic aberrations that are rarely observed in other melanocytic lesions. Genomic rearrangements include the following translocations:

ALK fusions

ROS1 fusions

NTRK1, NTRK2, and NTRK3 fusions

RET fusions

MET fusions

MAP3K8 fusions and truncations

BRAF fusions and amplification

Kinase fusions — Kinase fusions of various receptor tyrosine kinase genes, including ALK, ROS1, NTRK1, NTRK2, NTRK3, RET, and MET, or the serine-threonine kinase BRAF and MAP3K8 are observed in more than 50 percent of Spitz tumors [23,97-100]. Patients with fusion-positive Spitz tumors are younger than those whose tumors lack translocations. Interestingly, 57 percent (13 of 23) of pigmented spindle cell nevus of Reed, a morphologic variant of Spitz nevus, demonstrated NTRK3 fusions with 5' partners ETV6 (12p13) in two cases and MYO5A (15q21) in 11 cases [101]. Other minor fusions identified in pigmented spindle cell nevus of Reed included MYO5A-MERTK in two cases, MYO5A-ROS1, MYO5A-RET, and ETV6-PITX3, leading to a total of 78 percent with fusions [101].

These genomic rearrangements fuse the intact kinase domains to various partner genes, leading to high expression of chimeric fusion proteins. Unique kinase fusions continue to be described in Spitz tumors [98,102]. Kinase fusions are not detected in tumors with HRAS mutations or BAP1 inactivation:

ALK fusions ALK fusions occur in up to 15 percent of Spitz tumors [23,103]. ALK fusions have been described in anaplastic large cell lymphoma [104]. ALK-positive Spitz tumors are typically solitary, dome-shaped lesions and occur slightly more frequently on the extremities. A prominent histopathologic characteristic is a plexiform architecture [103,105]. The most prominent ALK fusion partners are TPM3 and DCTN1 [105]. There is a report of two patients with ALK-positive, atypical Spitz tumors with 9p21 homozygous deletion [106]. FISH analysis showed homozygous deletion of 9p21 and gain of 6p25. In one case, the sentinel lymph node biopsy (SLNB) revealed small subcapsular foci of tumor. In the second case, FISH analysis showed homozygous deletion of 9p21 and gains of 6p25 and 11q13. The cases suggest that transformation of tumors produced by an activating kinase fusion gene (ALK) occur through secondary genetic changes, including loss of tumor suppressor activity (CDKN2A) [106].

BRAF fusions – In the initial study of gene fusions, BRAF fusions were reported to occur in approximately 5 percent of Spitz tumors, including Spitz nevi, atypical Spitz tumors, and Spitz melanoma [23]. Accumulating experience indicates that BRAF fusions are seen most frequently in atypical Spitz tumors and Spitz melanomas. Such tumors may frequently present with an epithelioid cell phenotype, sheet-like arrangements of tumor cells, desmoplasia (commonly near the base), and conspicuous cytologic atypia [107].

ROS1 fusionsROS1 fusions are seen in up to 10 percent of Spitz tumors, which often occur on the extremities in patients aged between 1 and 59 years [23]. ROS1 fusions have also been described in other malignancies and results in fusion of an intact tyrosine kinase coding sequence of ROS1 to various fusion partners. A GOPC-ROS1 mosaicism was identified in agminated Spitz nevi on the lower limb of two young adults [108].

In a study of 35 spitzoid tumors, 11 were positive for ROS1 immunostaining [109]. Four patterns of immunostaining were observed: cytoplasmic, granular, diffuse (n = 6); sparse, cytoplasmic granules (n = 3); paranuclear dots (n = 1); and nuclear (n = 1). FISH analysis showed all cases to be rearranged, and ribonucleic acid (RNA) next-generation sequencing analysis showed specific fusions of ROS1 in four cases (two with PWWP2A, one with PPFIBP1, and one with ZCCHC8). Interestingly, most of the lesions (8 of 11) were localized on the lower extremities.

Spitz tumors with ROS1 fusions present with a varied histopathologic configuration. They may be plaque-like, dome-shaped or nodular, well-circumscribed, melanocytic, compound proliferations with irregular epidermal hyperplasia, often with densely cellular intraepidermal melanocyte proliferation, frequent pagetoid spread, spindle cell phenotype, and low-grade atypia [110].

Functional studies expressing ROS1 fusions in melanocytes revealed activation of the MAPK/ERK and PI3K/AKT/MTOR pathways [23].

NTRK1 fusions TRK fusions have been identified in a variety of cancers. NTRK1 fusions have been detected in 11 percent of Spitz nevi, 25 percent of atypical Spitz tumors, and 21 percent of Spitz melanomas [23]. Histopathologically, Spitz tumors with NTRK1 fusions frequently have distinctive histopathologic features characterized by elongated, thin, and branched epidermal retia (a "filigree-like" pattern); rosette-like arrangements of melanocytes; and striking maturation of melanocytes with depth descent in the dermis [111]. Tumors with NTRK1 fusions show strong staining for NTRK1 in immunohistochemistry, which helps to identify cases with NTRK1 fusions. NTRK3 fusion kinases were detected with low frequency (0.7 percent) in a series of 1202 diagnostically challenging melanocytic tumors with histopathologic features overlapping those of melanocytic nevi and melanoma [112]. (See "TRK fusion-positive cancers and TRK inhibitor therapy".)

NTRK2 fusions – A single NTRK2 (TFG-NTRK2) fusion has been reported in a patient with a pigmented spindle cell nevus variant of Spitz tumor [113].

NTRK3 fusions – Spitz tumors with NTRK3 fusions have been reported to show distinctive features that are linked to the partners ETV6 (younger patients with epithelioid cell phenotype) and MYO5A (spindle cell-predominant tumors with Schwannian differentiation and Verocay-like structures) [114].

RET fusions – Genomic rearrangements of RET are seen in less than 5 percent of Spitz tumors and have been demonstrated to involve fusion partners KIF5B and GOLGA5 [23]. In mice, RET overexpression results in melanocytic proliferation, nevus formation, and progression to melanoma [115].

MET fusions – Genomic rearrangements that fuse the MET kinase domain to fusion partners have been described in Spitz tumors [97]. MET fusions constitutively activate the MAPK/ERK and PI3K/AKT/MTOR pathways.

MAP3K8 fusions and truncations – An analysis of 49 spitzoid tumors including both atypical Spitz tumors and Spitz melanomas by RNA sequencing established, for the first time, in-frame gene fusions or C-terminal truncations of MAP3K8 in 33 percent of cases [116]. Both gene fusions and truncated genes, all containing MAP3K8, were found. These lesions were compound, melanocytic proliferations, among which eight were predominantly dermal and three predominantly junctional. The predominant cell type was epithelioid (94 percent of cases). The epithelioid melanocytes were generally amelanotic; monomorphous; and arranged in expansile, confluent, hypercellular nests or enlarged, syncytial nodules in the dermis. Ulceration was present in 9 of 17 tumors (53 percent), and deep, mitotic figures were seen in 15 of 17 tumors (88 percent). The tumors ranged in thickness from 1.5 to 13.4 mm (median 3.1 mm) [116].

Another study demonstrated 33 melanocytic proliferations harboring a gene fusion of the MAP3K8 gene, which encodes a serine/threonine kinase [117]. The fusion genes encoded the intact kinase domain of MAP3K8 but not the inhibitory domain at the C-terminus. In 13 of the sequenced cases (46 percent), the 3' fusion partner was SVIL. Other recurrent 3' partners were DIP2C and UBL3. The lesions were present mainly in young adults (median age = 18) and most commonly involving the lower limbs (55 percent). The cases were diagnosed as Spitz nevus (5), atypical Spitz tumor (13), and malignant Spitz tumor (15). Atypical and malignant cases more commonly occurred in younger patients and tended to show epidermal ulceration (32 percent), a dermal component with giant multinucleated cells (32 percent), and clusters of pigmented cells in the dermis (32 percent). Clinical follow-up revealed regional nodal involvement in two of six cases in which SLNB was performed, but there was no distant metastatic disease after a median follow-up time of six months [117].

TERT mutations — TERT promoter (TERT-p) mutations have been identified in aggressive cutaneous conventional melanoma. A large cohort of 56 patients with clinical follow-up data were tested for the association of TERT-p mutations, biallelic CDKN2A deletion, biallelic PTEN deletion, kinase fusions, BRAF/NRAS mutations, nodal status, and histopathologic parameters with risk of hematogenous metastasis. Interestingly, TERT-p mutations were identified in biopsies from the four patients who developed distant metastasis but in none of the tumors from patients who had favorable outcomes [88]. The presence of TERT-p mutations was the most significant predictor of widespread dissemination among the variables analyzed and identified a clinically high-risk subset of patients with spitzoid tumors [88].

In a prospective, pediatric study of 70 children with 37 atypical Spitz tumors/Spitz melanomas, 17 conventional melanomas, 4 melanomas arising in a giant congenital nevus, and 12 with other atypical melanocytic proliferations, patients with atypical Spitz tumors/Spitz melanomas were younger (median age seven years), and their tumor most commonly arose in the extremities and trunk [118]. The most common gene rearrangements included MAP3K8 and ALK. None of the 33 patients who underwent a TERT-p mutation analysis had a mutation, and all patients were alive.

Novel promoter mutations — A novel promoter utilizing an ALK-C2orf42 rearrangement was identified in a case of a prepubescent male who developed a spitzoid melanoma with atypical histology, clinically apparent metastatic disease, and abnormal cytogenetic findings [119]. These findings suggest that as the molecular biology of spitzoid melanocytic lesions evolves, classification with detailed molecular analysis and prolonged clinical follow-up is essential for accurate prognostication and therapeutic management.

DIAGNOSIS

General principles — The diagnosis of Spitz tumor is suspected in a child or young adult presenting with a firm, dome-shaped red or reddish-brown papule or nodule located on the face or lower extremities (picture 1 and table 2). Patients typically report a history of rapid growth over three to six months followed by stabilization. (See 'Clinical features' above.)

Dermoscopy has limited value in the evaluation of conventional amelanotic Spitz tumors. The finding of a "starburst" or "peripheral globular" pattern (picture 4) suggests a pigmented Spitz tumor. (See 'Dermoscopic features' above.)

The definitive diagnosis of Spitz tumors is based upon histopathologic evaluation of the excised lesion. However, the reproducibility of the histologic diagnosis of Spitz tumors is poor [120]. In difficult cases, ancillary studies, including immunohistochemistry and molecular analysis, are performed, although none of the markers currently used are highly sensitive and specific in discriminating atypical Spitz lesions from melanoma.

Diagnostic approach — The initial step in diagnosis is histopathologic examination of the excised tumor to determine whether a clear-cut Spitz tumor or melanoma is present. Atypical lesions should be systematically evaluated for histopathologic and immunohistochemical features (table 5). (See 'Immunohistochemistry' above.)

For ambiguous lesions, investigation of genetic aberrations by comparative genomic hybridization or next-generation sequencing may be performed if available. (See 'Comparative genomic hybridization' above.)

Conventional Spitz nevus — The diagnosis of conventional Spitz nevus is based upon a constellation of morphologic features (table 2). Spitz nevi generally are <6 mm in diameter, sharply circumscribed, symmetric, and show epidermal hyperplasia with "clefting" near junctional nests and maturation with depth. A uniform population of enlarged epithelioid cells, spindle cells, or both with abundant, ground-glass (opaque) cytoplasms; rhomboidal or polyangular contours; and enlarged, round or oval nuclei with dispersed (vesicular) chromatin and nucleoli characterize these tumors. Dermal mitoses are usually low in number (<2 mitoses per mm2) or absent, particularly in the deep dermis (picture 5A-B). Coalescent Kamino bodies are often present. (See 'Spitz nevus' above.)

Ki-67 immunostaining is low or absent. Both Ki-67 and HMB-45 staining typically diminish toward the base of the lesion, but exceptions occur, whereas S-100 and Melan-A/Mart-1 stain the lesion diffusely. (See 'Immunohistochemistry' above.)

Spitz nevi, by definition, usually exhibit only a single genetic alteration (ie, the presence of an activating HRAS mutation or kinase fusion). DNA copy number alterations are usually absent [17]. (See 'Mutational analysis' above.)

Atypical Spitz tumors — Atypical Spitz tumors have one or more abnormal morphologic features (table 3). Objective parameters that correlate with potentially aggressive behavior include patient age >10 years (postpubertal), large diameter (≥10 mm), ulceration, extension into the subcutis, and mitotic rate >6/mm2 (picture 6A-C and table 3) [16,88]. Other variables potentially of value to record include asymmetry, heterogeneity of the cell population, melanocytic confluence, lack of melanocyte maturation in the deeper areas of the dermis, and high-grade cytologic atypia. However, because of the rarity of atypical Spitz tumors and bona fide Spitz melanomas and the lack of long-term follow-up studies, the prognostic significance of morphologic abnormalities requires ongoing study. (See 'Atypical Spitz tumor' above.)

The Ki-67 labeling index is variable (5 to 10 percent), and generally higher in the upper dermis and at the dermoepidermal junction. Because of an overlap in proliferative indices of atypical Spitz tumors and melanoma, the ability of Ki-67 staining to discriminate atypical lesions from melanoma is limited and false positive or negative results may occur. (See 'Immunohistochemistry' above.)

Atypical Spitz tumors by definition exhibit at least two genetic alterations (ie, the presence of a kinase fusion plus a DNA copy number change or monoallelic or biallelic deletion of CDKN2A) [17]. Increasing DNA copy number alterations correlate with increasing likelihood of melanoma. (See 'Kinase fusions' above and 'Comparative genomic hybridization' above.)

Atypical Spitz tumors versus melanoma — There are no clear-cut histopathologic criteria to distinguish atypical Spitz tumors from melanoma, and not infrequently, a firm diagnosis cannot be made on pathologic grounds (table 5). The likelihood of melanoma increases with the increase in number and severity of architectural and cytologic abnormalities (picture 7A-B) (see "Pathologic characteristics of melanoma", section on 'Histopathologic diagnosis'):

Immunostaining – Immunostaining may be helpful in the evaluation of ambiguous lesions. Ki-67 labeling in the deepest part of the lesion and/or a labeling index >20 percent favors melanoma, although considerable overlap exists between atypical Spitz tumors and melanoma. Because of potential confusion of an atypical Spitz tumor/melanoma with conventional melanoma, evaluation for a BRAF mutation by immunohistochemistry or mutational analysis is worthwhile. Confirmation of a BRAF mutation provides evidence for a conventional (possibly "spitzoid") melanoma.

Molecular analysis – Molecular analysis with comparative genomic hybridization (CGH) or, preferably, next-generation sequencing can be performed if the diagnosis remains uncertain. The absence of genetic aberrations or the demonstration of a single genetic alteration (eg, a kinase fusion) or an isolated copy gain in chromosome 11p favors a diagnosis of benign lesion. In contrast, the demonstration of multiple (often three or more) chromosomal alterations characteristic of conventional melanoma (including deletions in 9p and 10q, gains in chromosome 7, and TERT promoter mutations) suggest malignancy [121-123]. However, it must be emphasized that many exceptions to latter guidelines exist, particularly with respect to fluorescent in situ hybridization (FISH) testing.

Ciliation index – The loss of primary cilia on melanocytes is a useful biomarker for the distinction of melanoma from conventional melanocytic nevi [124]. The ciliation index (CI) was measured in 68 cases of spitzoid tumors, including Spitz nevi, atypical Spitz tumors, and spitzoid melanoma [125]. Spitzoid melanomas demonstrated a significant decrease compared with Spitz nevi or atypical Spitz tumors. In addition, a low CI was consistently ranked as a top predictive feature in the diagnosis of malignancy using a machine learning-based algorithm. Predictive models trained on only the top four predictive features (CI, asymmetry, hyperchromatism, and cytologic atypia) outperformed standard histologic assessment in an independent validation cohort of 56 additional cases [125]. Thus, CI is a promising ancillary diagnostic test.

Consultation — The histopathologic misdiagnosis of melanoma as a benign Spitz tumor or vice versa can result in excessively aggressive or inadequate treatment, with serious consequences for the patient. For difficult Spitz tumors, obtaining a consultation with a second recognized and highly experienced expert dermatopathologist is recommended.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of Spitz tumors includes melanocytic and nonmelanocytic lesions.

Melanocytic lesions

Compound or intradermal nevi – Compound nevi are pigmented papules, sometimes dome-shaped or papillomatous, and tan to brown in color (picture 8). Intradermal nevi are usually skin-colored to tan papules that are dome-shaped, papillomatous, or pedunculated with a soft, rubbery texture (picture 9). Histologically, these lesions lack vertically oriented spindle or epithelioid melanocytic nests and Kamino bodies. (See "Acquired melanocytic nevi (moles)", section on 'Common acquired melanocytic nevi'.)

Melanoma – The histologic differentiation of Spitz tumors from melanoma is one of the most difficult problems in dermatopathology. It is largely based on utilization of all clinical features, histopathologic parameters, and, increasingly, molecular test results (table 5). Age is considered an important (but not absolute) criterion to discriminate conventional Spitz tumors from melanoma, since melanoma is extremely rare in children <10 years whereas most conventional Spitz nevi occur in children <10 years. (See "Pathologic characteristics of melanoma", section on 'Histopathologic diagnosis'.)

The term "spitzoid melanoma" has been used to indicate a subset of melanomas often, but not exclusively, seen in adults that have a close morphologic resemblance to Spitz tumors. However, many of these melanomas labeled as "spitzoid" have no relationship to the family of Spitz tumors, and many or most such "spitzoid" melanomas probably represent conventional melanomas (eg, melanomas with BRAF mutations).

BAP1-inactivated melanocytic tumors – Individuals affected by the BAP1 tumor predisposition syndrome (MIM #614327) have multiple cutaneous melanocytic neoplasms resembling atypical Spitz tumors (picture 10A-B) and are at increased risk of developing cutaneous and uveal melanoma [126,127]. On immunohistochemistry, BAP1-inactivated melanocytic tumors (BIMTs) show nuclear loss of BAP1 expression, whereas BAP1 is expressed in Spitz tumors. (See "BAP1-inactivated melanocytic tumors".)

Nonmelanocytic lesions — A variety of nonmelanocytic skin lesions share clinical features with Spitz tumors. The histopathologic diagnosis is usually straightforward for most of these lesions, which include:

Solitary (juvenile) xanthogranuloma Solitary (juvenile) xanthogranuloma typically presents as red-yellow papules or nodules on the face, neck, or upper trunk of infants and children (picture 11A-C). Histopathologic findings include a well-circumscribed sheet-like aggregate of foam cells, histiocytes, and Touton-type giant cells. The lesional cells lack immunohistochemical reactivity for melanocytic markers (eg, S-100, HMB-45, Melan-A). (See "Juvenile xanthogranuloma (JXG)", section on 'Diagnosis'.)

Lobular capillary hemangioma (pyogenic granuloma) – Lobular capillary hemangiomas (pyogenic granulomas) typically present as rapidly growing red exophytic papules that frequently ulcerate and bleed (picture 12A-B). Histology shows a compact vascular proliferation within the superficial and deep dermis (picture 13A-B). (See "Pyogenic granuloma (lobular capillary hemangioma)", section on 'Diagnosis'.)

Molluscum contagiosum – Molluscum contagiosum presents as dome-shaped papules with shiny surfaces and central umbilications (picture 14). Histology reveals keratinocytes containing eosinophilic cytoplasmic inclusion bodies (also known as molluscum bodies or Henderson-Paterson bodies) (picture 15). (See "Molluscum contagiosum", section on 'Diagnosis'.)

Hemangioma – Histologically, hemangiomas are vascular proliferations within the dermis that are usually well-circumscribed. The endothelial cells are mature and bland. (See "Infantile hemangiomas: Epidemiology, pathogenesis, clinical features, and complications", section on 'Clinical presentation'.)

Dermatofibroma – Dermatofibromas are papules or nodules sometimes hyperpigmented seen on the legs, arms, or trunk of young to middle aged adults (picture 16). Histology shows a well-circumscribed dermal proliferation of fibrohistiocytic cells that entrap coarse collagen. (See "Overview of benign lesions of the skin" and "Overview of benign lesions of the skin", section on 'Dermatofibroma'.)

Solitary mastocytoma – Solitary mastocytoma presents as a red-brown macule, papule, or nodule in infants and neonates (picture 17). Stroking the lesions results in mast cell degranulation and the subsequent development of an urticarial wheal (Darier sign). On histology, the lesions consist of a perivascular or diffuse infiltrate of monotonous mast cells within the upper dermis. (See "Mastocytosis (cutaneous and systemic) in children: Epidemiology, clinical manifestations, evaluation, and diagnosis".)

MANAGEMENT

Monitoring — Spitz tumors that do not show atypical clinical or dermoscopic features may be monitored clinically, especially in prepubertal children. The frequency of monitoring should be decided on a case-by-case basis and can vary from every 3 to every 12 months. Patients should be instructed to return promptly for a visit at any time if they notice a change in the lesion. Providing a baseline photograph of the lesion to the patient or parents/caregivers may be of help in detecting a clinical change.

The management of lesions that underwent a change over time, including spontaneous regression, should be decided on a case-by-case basis. The clinician may consider biopsy sampling of the site in order to obtain additional information about the nature of the lesion and the changes present. At her/his discretion, the clinician may consider following up with the patient every 3, 6, or 12 months, for example, for a period of two to three years, with less frequent follow-up over time if the patient remains completely unchanged.

Surgical excision — Skin lesions with clinical features of Spitz tumors should be removed by simple excision if there is concern for an atypical melanocytic lesion or melanoma. We suggest margins of approximately 3 to 5 mm. In a retrospective study of 89 Spitz tumors, punch or shave biopsy or excision with narrow margins (1 to 3 mm) were associated with positive histologic margins in more than 20 percent of cases [128].

Excision of the entire lesion allows complete histopathologic examination and reduces the risk of recurrence [128]. Incomplete excision may result in persistent/recurrent Spitz tumors, which have more atypical and worrisome morphologic features than the original lesions and may simulate melanoma [129]. In rare instances, recurrent Spitz tumors have shown progression to malignancy and death [120].

Atypical Spitz tumors with positive margins should undergo re-excision to achieve clear margins given the difficulty in definitively distinguishing atypical Spitz tumors from melanoma. The optimal re-excision margins for atypical Spitz tumors have not been evaluated in randomized trials, and there is no consensus about the extent of margin to achieve clearance. Such lesions should be managed on a case-by-case basis. For many relatively low-risk lesions, margins <5 mm appear adequate. For high-risk lesions that are difficult to distinguish from melanoma, margins of approximately 1 cm are considered adequate by most experts. However, a full 1 cm margin may not be possible for lesions occurring in children or in cosmetically sensitive areas.

Severely atypical Spitz tumors that are impossible to distinguish from melanoma should be managed on a case-by-case basis and many will require management as melanomas. (See "Surgical management of primary cutaneous melanoma or melanoma at other unusual sites" and "Staging work-up and surveillance of cutaneous melanoma".)

Sentinel lymph node biopsy — Sentinel lymph node biopsy (SLNB) in patients with atypical Spitz tumors is controversial. At one time, SLNB was suggested for patients with ambiguous melanocytic tumors of >1 mm thickness and deep dermal involvement to help determine the benign or malignant nature of the lesions [130]. Given the difficulty in differentiating atypical Spitz tumors from melanoma, patients with a positive SLNB often are treated with completion lymphadenectomy and adjuvant therapy as if they have stage III melanoma. (See "Evaluation and treatment of regional lymph nodes in melanoma".)

However, the survival benefit of this approach has not been evaluated in randomized trials and remains undetermined. For severely atypical spitzoid melanocytic neoplasms with uncertain malignant potential, discussion of SLNB may be considered on a case-by-case basis.

Data from a systematic review of 24 observational studies including a total of 541 patients with atypical Spitz tumors indicate that SLNB followed by completion lymph node dissection does not improve the prognosis for these patients [47]. In this review, SLNB was performed in 303 (56 percent) patients and was positive in 119 (39 percent), 97 of whom underwent completion lymph node dissection. After an average follow-up time of 59 months, the survival rates among 119 patients with positive SLNB and 238 patients who were treated with wide excision alone were similar (99 and 98 percent, respectively). Four of 119 (4 percent) patients with positive SLNB and 11 (5 percent) of 238 treated with wide excision alone had regional recurrence during follow-up.

FOLLOW-UP

There is no specific protocol of follow-up for children, adolescents, and young adults after excision of conventional Spitz nevi. Some clinicians have them return if problems develop (eg, local recurrence); others provide annual follow-up for three to five years.

Patients with atypical Spitz tumors are monitored for recurrence and metastasis. The optimal frequency of skin examinations has not been determined. Based upon clinical experience, examinations are generally performed at intervals of 6 to 12 months. The frequency of follow-up may be tailored based upon the age of the patient, tumor diameter, tumor thickness, number of mitoses, presence of ulceration, and genetic alterations, if available.

For patients with Spitz or "spitzoid" melanoma, staging work-up and surveillance after surgical excision of the primary lesion are performed as for conventional melanoma. (See "Staging work-up and surveillance of cutaneous melanoma".)

PROGNOSIS

Risk stratification for atypical Spitz tumors — A grading system based upon patient's age and a subset of morphologic characteristics has been proposed to help clinicians determine whether an atypical Spitz tumor is at low, intermediate, or high risk for metastasis (table 6) [16,88]. In general, age <10 years (prepubertal) is accepted as a very important criterion to discriminate Spitz tumors with indolent behavior from atypical Spitz tumors with greater risk for neoplastic progression and melanoma. Nonetheless, the importance of age should not be too overstated since pathologists may have a propensity to diagnose atypical Spitz tumors as benign variants in children and as melanoma in older individuals. Additional ancillary techniques, including immunomarkers (eg, Ki-67 and HMB-45 gradients) and molecular studies (particularly array comparative genomic hybridization [CGH], TERT promoter [TERT-p] mutation analysis, next-generation sequencing, including RNA sequencing for gene fusions), may provide additional information about risk stratification. (See 'Immunohistochemistry' above and 'Molecular analysis' above.)

Long-term outcome — There is a paucity of data on the long-term outcome of patients with atypical Spitz tumors. However, the available evidence indicates that atypical Spitz tumors generally have a favorable prognosis, as illustrated below. Nonetheless, larger studies with more precise classification of Spitz tumors and long-term follow-up (≥15 years) may be needed to truly understand the biology of this neoplastic system:

In a study involving 144 adult patients with conventional Spitz tumors or atypical Spitz tumors, none developed metastases after a median follow-up of nine years [131]. However, 6 of 144 patients developed a separate conventional melanoma, suggesting that Spitz tumors may be associated with an increased risk of melanoma.

Another study evaluated the outcome of 40 patients with atypical Spitz tumors treated with wide local excision and sentinel lymph node biopsy (SLNB) [132]. No positive SLN were found. All patients were alive and without evidence of regional or distant recurrence after a median follow-up time of 46 months.

A retrospective study evaluated the long-term outcome of 29 children with atypical Spitz tumors excised with clear margins without SLNB [133]. None of the 14 children who completed a clinical outcome survey reported local or regional recurrence or distant metastases after a mean follow-up time of eight years. For 10 children who could not complete the survey, no recurrences were reported in their medical records between the excision of the primary lesion and the last follow-up visit (mean follow-up time 2.8 years).

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

SUMMARY AND RECOMMENDATIONS

Definition and classification – Spitz tumors include a spectrum of melanocytic lesions composed of large epithelioid and/or spindled cells. Based upon clinical, histopathologic, and genetic characteristics, three provisional categories of Spitz tumors have been delineated: conventional Spitz nevus, atypical Spitz tumor, and malignant Spitz tumor/Spitz melanoma (table 1). (See 'Classification' above.)

Clinical relevance – The clinical relevance of Spitz tumors lies on the frequent inability to differentiate histologically these lesions from melanoma and predict their biologic behavior.

Clinical features – Conventional Spitz nevi typically present in children, adolescents, and young adults as small, pink or reddish, dome-shaped papules or plaques on the head and neck region (picture 1 and table 2). Atypical Spitz tumors and extremely rare Spitz melanomas are often larger than conventional Spitz tumors and may show asymmetry, ulceration, border irregularity, and color variegation. (See 'Clinical features' above.)

Diagnosis – The diagnosis of Spitz tumors is based upon clinical, histologic (table 5), and genetic features. Immunohistochemistry and molecular analysis may be helpful in problematic cases (see 'Diagnosis' above and 'Histopathology' above and 'Immunohistochemistry' above and 'Molecular analysis' above):

Conventional Spitz tumors generally are sharply circumscribed, <6 mm in diameter, symmetric, and show on histology zonation and maturation. The cell population is uniform, and mitoses are usually low in number or absent (picture 5A-B and table 2). (See 'Conventional Spitz nevus' above.)

Atypical Spitz tumors are usually >6 mm and may be ulcerated, asymmetric, and lack zonation and maturation. The cell population may show cytologic atypia, and the mitotic rate is increased, often >6/mm2 (picture 6A-C and table 3). (See 'Atypical Spitz tumors' above.)

There are no clear-cut histopathologic criteria to distinguish atypical Spitz tumors from melanoma, and not infrequently, a firm diagnosis cannot be made on pathologic grounds (table 5). A large number of architectural and cytologic abnormalities (picture 7A-B), a high proliferative index, and the presence of three or more genetic aberrations favor the diagnosis of melanoma. The presence of specific genetic alterations, such as HRAS mutations or kinase fusions, support the diagnosis of Spitz melanoma. In contrast, the identification of BRAF mutations provides evidence for a conventional melanoma. (See 'Atypical Spitz tumors versus melanoma' above.)

Management:

Spitz tumors that do not show atypical clinical or dermoscopic features may be monitored clinically, especially in prepubertal children. The frequency of monitoring should be decided on a case-by-case basis and can vary from every 3 to 12 months. (See 'Monitoring' above.)

Skin lesions with clinical features of Spitz tumors should be removed by simple excision if there is concern for an atypical melanocytic lesion or melanoma. We generally recommend margins of approximately 3 mm. Atypical Spitz tumors with positive margins should undergo re-excision to achieve clear margins, given the difficulty in definitively distinguishing atypical Spitz tumors from melanoma. For many relatively low-risk lesions, margins <5 mm appear adequate. For high-risk lesions difficult to distinguish from melanoma, margins of approximately 1 cm are considered adequate by most experts. (See 'Surgical excision' above.)

Severely atypical Spitz tumors that are impossible to distinguish from melanoma should be managed on a case-by-case basis and many will require management as melanomas. (See "Surgical management of primary cutaneous melanoma or melanoma at other unusual sites" and "Staging work-up and surveillance of cutaneous melanoma".)

Follow-up – After surgical excision of the primary lesion, patients with atypical Spitz tumors are monitored for recurrence and metastasis with examinations performed at intervals of 6 to 12 months. For patients with Spitz or "spitzoid" melanoma, staging work-up and surveillance are performed as for conventional melanoma. (See 'Follow-up' above and "Staging work-up and surveillance of cutaneous melanoma".)

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Topic 13523 Version 23.0

References

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