Spitz nevus, atypical Spitz tumor (Spitz melanocytoma), and Spitz melanoma

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 melanocytomas 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 melanocytoma".)

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 are termed "atypical Spitz tumors."

The World Health Organization (WHO) Classification of Skin Tumours 5^th edition has recommended that "Spitz melanocytoma" should replace "atypical Spitz tumors" [4]. However, "atypical Spitz tumors" is widely accepted by many in the field.

Atypical Spitz tumors, characterized by particular high-risk criteria [5,6], are often suspicious for melanoma and, thus, are uncertain entities (see 'Spitz melanoma' below). Some have called such tumors "melanocytic tumor with uncertain malignant potential" (MELTUMP) or "spitzoid tumor or atypical Spitz tumor with uncertain malignant potential" (STUMP).

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, including those with uncertain malignant potential, 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 occur in all ethnic groups. Males and females are approximately equally affected, although there may be a female predominance in young adults [8-11].

They typically occur in the first two decades of life but may also develop in adults [9,10]. In a cohort of 1260 Spitz neoplasms, the proportion of spitzoid neoplasms was similar in each of the first four decades of life, ranging from 16 to 22 percent of all melanocytic tumors, with a significant drop to 12 and 6 percent in the fifth and sixth decades, respectively [12]. However, the molecular analysis of 286 Spitzoid neoplasms using next-generation sequencing demonstrated that this decrease was less precipitous and that nearly one-fifth of all Spitz neoplasms occur in individuals older than 50 years [12].

Congenital cases of Spitz tumor are exceedingly rare [13-15].

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 and table 2). At one end of the spectrum, the Spitz nevus 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 extremely rare Spitz melanomas. Between these two extremes, there is an intermediate and 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 on the utilization of strict criteria for diagnosis, there is accumulating evidence for trends in overdiagnosis of Spitz nevi as either atypical Spitz tumor or Spitz melanoma and, especially, overdiagnosis of atypical Spitz tumor as Spitz melanoma [4].

Based on clinical, histopathologic, and genetic characteristics, three provisional categories of Spitz tumors can be delineated [5,16-19]:

●Spitz nevus – The prototypic Spitz nevus is an amelanotic melanocytic lesion with a unique cellular phenotype that suggests a distinctive benign or low-grade melanocytic neoplasm distinct from conventional melanocytic nevi (picture 1). Spitz nevi are generally small (<5 to 6 mm in diameter), symmetric, and sharply circumscribed. A subset of Spitz nevi with a predominant pigmented spindle cell phenotype are termed "pigmented spindle cell nevus" (nevus of Reed) or simply "pigmented Spitz nevus."

On histology, Spitz nevus shows a regular architecture, zonation, and maturation; absence of or few dermal mitoses; and lack of significant cytologic atypia (table 2). (See 'Spitz nevus' below.)

●Atypical Spitz tumor (Spitz melanocytoma) – The terms "atypical Spitz tumor" and "Spitz melanocytoma" refer 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) [16]. Corresponding atypical variants of pigmented spindle cell nevus are termed "atypical pigmented spindle cell tumor."

Atypical Spitz tumors, including atypical pigmented spindle cell variants, are usually larger than Spitz tumors (>6 mm and sometimes >10 mm) and have 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 2). (See 'Atypical Spitz tumor' below.)

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

The terms "spitzoid melanoma" and "melanoma with spitzoid morphology" have 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, NRAS, NF1 mutations or germline mutations associated with familial melanoma such as CDKN2A, CDK4, POT1, TERF2IP) [20,21].

Thus, the term "spitzoid melanoma" should be used judiciously until more rigorous clinical, histopathologic, and molecular criteria are developed for this entity.

PATHOGENESIS — 

The etiology and pathogenesis of Spitz tumors are unknown. Eruptive Spitz tumors have been documented during pregnancy and puberty, suggesting a potential role for hormonal activation [22,23].

Up to 30 percent of Spitz tumors may exhibit activating HRAS mutations, which are rare or absent in melanoma [24]. In contrast to conventional melanomas, mutations in BRAF and NRAS have not been identified in Spitz tumors [25,26].

Chromosomal rearrangement-induced fusions involving ROS1, NTRK1, NTRK2, NTRK3, ALK, BRAF, MET, 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 Spitz nevi, 75 percent of atypical Spitz tumors, and in rare, true Spitz melanomas [27]. New gene fusions continue to be reported in Spitz tumors. (See 'Mutational analysis' below.)

CLINICAL FEATURES

Age of onset — Spitz tumors typically develop in young individuals, usually before the age of 20 years. Although there is some overlap in the age distributions of Spitz nevus, atypical Spitz tumors, and Spitz melanoma, lesions with Spitz morphology in patients older than 20 to 30 have an increased risk of being atypical or malignant than those in younger patients. (See 'Risk stratification for atypical Spitz tumors' below.)

Spitz nevus

●Age – Spitz nevi are usually seen in children, adolescents, and young adults.

●Lesion appearance – Spitz nevi typically present as a pink or reddish, symmetric, dome-shaped papule or plaque (picture 1). 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 <5 to 6 mm in diameter. The borders are well defined, and the surface is smooth and sometimes glistening. Ulceration is an infrequent finding, although traumatic excoriation is common in children.

●Clinical variants – Variants include polypoid, plaque type, desmoplastic (firm or indurated), pigmented, and halo Spitz nevi (picture 2 and table 3). Multiple Spitz nevi arising within a nevus spilus or speckled lentiginous nevus have also been reported (picture 3) [28-31]. Rarely, multiple Spitz nevi may develop in an eruptive fashion in weeks or months [32-34].

●Location – Spitz nevi may occur on any site. However, the most common locations are the head and neck (especially 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 [15,32,35-40].

Atypical Spitz tumor/Spitz melanoma

●Age – Atypical Spitz tumors and Spitz melanomas, which are extremely rare, are generally seen in adolescents and adults.

●Lesion appearance – Atypical Spitz tumors present as dome-shaped, reddish or brown/black papules or nodules often >1 cm in diameter. It is not possible to distinguish an atypical Spitz tumor from melanoma on clinical grounds in most cases since both lesions share atypical findings, such as a large diameter (>6 mm, especially >1 cm), asymmetry, border irregularity, or color variegation (table 2). (See "Melanoma in children and adolescents", section on 'Clinical presentation'.)

●Regional lymph node involvement – On occasion, palpable lymph nodes may develop in association with atypical Spitz tumors due to deposits of atypical melanocytes. However, the biologic significance of such sentinel lymph node deposits in atypical Spitz tumors is usually not indicative of malignancy and requires further study.

•In a systematic review that included 756 patients with atypical Spitz tumors, 54 percent underwent sentinel lymph node biopsy (SLNB), 35 percent of whom had positive sentinel lymph nodes [41]. The overall survival rates ranged from 93 to 100 percent and was 100 percent among patients who underwent SLNB.

•Another 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 [42]. The survival rate 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.

DERMOSCOPIC FEATURES — 

On dermoscopy, the prototypic amelanotic Spitz nevus exhibits little or no pigmentation and a dotted vascular pattern with or without a so-called inverse network [43]. Pigmented Spitz nevi (or pigmented spindle cell nevi) typically exhibit a "starburst" or "peripheral globular" pattern (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 (picture 4) [44].

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

Cases with an atypical pattern may be indistinguishable from melanoma [43,45].

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 (51, 19, and 17 percent, respectively) [46]. Nine percent of the lesions presented a multicomponent/atypical pattern.

Evolution of dermoscopic patterns of Spitz nevi over time has been documented.

●In a study of 70 patients with Spitz nevi, the most common dermoscopic patterns were globular (50 percent), starburst (34 percent), reticular (11 percent), and homogeneous (4 percent) [47]. On follow-up images that were available for 27 patients, 21 lesions (78 percent) demonstrated evolution to a homogeneous pattern and/or involution, whereas a stable pattern (no evolution) was noted in 6 lesions (22 percent).

●In a retrospective study of 31 pigmented Spitz nevi with starburst pattern, 21 (68 percent) evolved to a pattern characterized by a delicate, brown network at the periphery and a central, structureless or reticular, hyperpigmented area [48].

NATURAL HISTORY — 

The natural history of Spitz nevi, Spitz tumors, and Spitz melanoma is not well documented. Most Spitz nevi usually undergo a period of rapid growth, lasting from three to six months, and then stabilize. It is believed that many Spitz nevi may regress completely over a period of approximately two to three years; however, some lesions may persist indefinitely [47,49].

HISTOPATHOLOGIC FEATURES

Spitz nevus

●Architectural features – Spitz nevi are symmetric and sharply demarcated with papillomatous/polypoid, dome-shaped, or relatively flat, plaque-type silhouettes. They often display nests of large epithelioid cells, spindle cells, or both, usually extending from the epidermis into the dermis with a well-defined horizontal base or a wedge configuration in the reticular dermis (picture 5A and table 2). The closely apposed, vertically oriented 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 [50].

Additional findings include junctional clefting with discohesive junctional melanocytic nests and perivascular lymphoid infiltrates. If present, pagetoid spread (upward spread of cells in the epidermis) is focal, sparsely cellular, and limited to the center of the lesion and the lower half of the epidermis [51].

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 the 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 [51]. This process results in a nondisruptive infiltration of involuted small melanocytes among the dermal collagen bundles [16].

●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 usually <2 per mm². Mitoses are rare or absent in the deep dermis.

Atypical Spitz tumor

●Architectural features – Atypical Spitz tumors are commonly larger in diameter (eg, >6 mm or even >10 mm) compared with Spitz nevi. Atypical Spitz tumors may extend deeply into the dermis to the subcutaneous fat, are often asymmetric, are not well circumscribed, and may be ulcerated (picture 6C and table 2). 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 patterns involving the upper layers of the epidermis. However, such pagetoid spread is often focal and does not extend peripherally beyond the junctional component. 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) [16]. 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 [52-55]. Angiotropism may be a predictor of risk of metastasis in melanoma and may explain regional tumor spread occurring in atypical Spitz tumors [52,53,56,57].

●Cytologic features – Cytologic features of atypical Spitz lesions include cellular and nuclear pleomorphism, increasingly coarse chromatin patterns, high nuclear to cytoplasmic ratio, hyperchromatic nuclei, and large eosinophilic nucleoli (picture 6A-B and table 4) [16].

●Mitotic activity – In atypical Spitz tumors, the mitotic rate may be increased, generally 2 to 6 per mm² or higher. High mitotic rates and mitoses located in the deep dermal or subcutaneous tissue raise concern for malignancy [58]. Situations in which mitotic rate may not reflect malignant transformation include very young age, tumors that are growing, or traumatized or inflamed lesions [16].

●Proliferative index – The proliferative index, as measured by Ki-67 immunohistochemical staining, may be a useful adjunct in the evaluation of the mitotic activity of Spitz tumors. A proliferative index of 2 to 10 percent suggests an atypical or biologically indeterminate Spitz tumor; higher indices (especially >20 percent) suggest melanoma [59]. (See 'Immunostaining' below.)

Spitz melanoma — Spitz melanomas exhibit the morphologic and cytologic features of atypical Spitz tumors (see 'Atypical Spitz tumor' above). Additional features may include asymmetry, poor circumscription, effacement of the epidermis, ulceration, large and confluent nests, and pagetoid spread [19]. There is high-grade cytologic atypia with large and pleomorphic nuclei, hyperchromatism, and enlarged nucleoli. The mitotic rate is increased.

Immunostaining — Spitz tumors have been evaluated with a variety of melanocytic markers [60-66]. Their value in predicting the biologic behavior of atypical Spitz tumors has not been established. Nonetheless, these and other immunomarkers may provide additional information in facilitating the classification and management of some spitzoid neoplasms.

●BRAF V600E, RASQ61R, ROS1, ALK, panTRK – Evaluation of a spitzoid neoplasm by immunohistochemistry for a BRAF mutation may be useful in confirming a non-Spitz phenotype or, alternatively, in suggesting a true Spitz phenotype if negative. ROS1, ALK, and panTRK antibodies can aide in confirming or excluding a Spitz phenotype. The antibody RASQ61R does not discriminate NRAS from HRAS mutations but may still be useful in the appropriate context.

●Ki-67 – Ki-67 is a nuclear protein involved in cell cycle regulation that is 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 [67]. 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 [59].

●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 [60,61,66].

●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 [68].

●p16 – p16, a protein product of the tumor suppressor gene CDKN2A, is a cyclin-dependent kinase inhibitor promoting G1 cell cycle arrest. In general, most Spitz nevi are reported to retain p16 expression [69], although, in one series of Spitz nevi, 17 percent lost p16 [70]. In one study, 26 percent of atypical Spitz tumors and 16 percent of spitzoid melanomas lost expression of this marker [69]. p16 expression shows a diffuse or an equivalent "diffuse-mosaic" (or "checkerboard" [ie, a discontinuous loss of expression among melanocytes in nests]) positivity pattern versus a diffuse loss in the entire tumor or in part of the tumor. Complete or partial (nonmosaic) loss of expression of p16 is abnormal and merits further evaluation of a tumor but is not diagnostic of melanoma.

●PRAME – PRAME (preferentially expressed antigen in melanoma) immunohistochemical staining has been demonstrated to be helpful in the diagnosis of melanoma [71]. However, Because Spitz nevi and atypical Spitz tumors can infrequently express PRAME diffusely, this marker should be used with caution in spitzoid lesions to avoid overdiagnosis of melanoma. (See "Spitz nevus/tumor in children: Diagnosis and management".)

•In a retrospective case series of children and adolescents younger than 16 years with melanoma, atypical spitzoid tumor, or benign nevi, the immunohistochemical expression of PRAME was negative in most cases [72]. 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.

•Another study demonstrated that most Spitz nevi (15 of 20) and atypical Spitz tumors (10 of 13) entirely lacked PRAME expression, whereas nonspitzoid melanomas (23 of 24 [96 percent]) demonstrated diffuse PRAME expression [73]. One Spitz nevus, one atypical Spitz tumor, and one spitzoid melanoma (one of two), however, demonstrated diffuse PRAME expression.

•In another study, fluorescence in situ hybridization (FISH) testing was compared with PRAME staining in 83 diagnostically challenging lesions with spitzoid histologic features [74]. A low sensitivity (29.6 percent) and a high specificity (76.8 percent) was observed for PRAME staining as compared with genomic testing with FISH.

GENOMIC ALTERATIONS

Comparative genomic hybridization — Whole genome analysis for deoxyribonucleic acid (DNA) gains or losses by array comparative genomic hybridization can improve the classification of spitzoid melanocytic lesions [75]. (See "Tools for genetics and genomics: Cytogenetics and molecular genetics", section on 'Array comparative genomic hybridization'.)

Several studies have shown amplification of chromosome 11p (a genome area that contains the HRAS gene) in approximately 20 percent of Spitz tumors [76-79]. The 11p amplification is characteristic of Spitz tumors and is not commonly seen in melanoma.

Next-generation DNA and RNA sequencing — The implementation of next-generation sequencing for both DNA and ribonucleic acid (RNA) facilitates the analysis of virtually all of the genetic alterations observed in Spitz and spitzoid neoplasms and related melanomas. (See "Next-generation DNA sequencing (NGS): Principles and clinical applications".)

Spitz tumors demonstrate genomic aberrations that are rarely observed in other melanocytic lesions. The accumulation of genetic mutations may be progressive, leading to a biologic and morphologic spectrum of lesions, as witnessed by progressively increased clinical risk and histopathologic atypia. 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

●RAF1 fusions

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 [27,80-83]. 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 [84]. 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.

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 (table 5) [81,85]. 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 [27,86]. ALK fusions have been described in anaplastic large cell lymphoma [87]. 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 (table 5) [86,88].

The most prominent ALK fusion partners are TPM3 and DCTN1 [88]. Less common fusion partners with ALK include NPM1, TPR, CLIP1, GTF3C2, EEF2, MYO5A, KANK1, EHBP1, and rarely MLPH [89,90]. MLPH encodes melanophilin, a protein involved in melanosome transportation by interacting with RAB27A and myosin Va.

There is a report of two patients with ALK-positive, atypical Spitz tumors with 9p21 homozygous deletion [91]. Fluorescence in situ hybridization (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 CDKN2A tumor suppressor activity.

●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 [27]. 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 (table 5) [92].

●RAF1 fusions – RAF1 fusions have been described in melanomas, congenital nevi, and BAP1-inactivated melanocytomas (see "BAP1-inactivated melanocytoma"). RAF1 fusions, including CTDSPL::RAF1, PPAP2B::RAF1, and ATP2B4::RAF1 fusions, have been described in two Spitz nevi and one Spitz melanoma [93].

●ROS1 fusions – ROS1 fusions are seen in up to 10 percent of Spitz tumors, often located on the extremities of patients aged between 1 and 59 years [27]. These tumors may have an agminated appearance. Studies of tumors expressing ROS1 fusions with various fusion partners in melanocytes revealed activation of the MAPK/ERK and PI3K/AKT/MTOR pathways [27].

In a series of 11 Spitz tumors positive for ROS1 immunostaining, FISH analysis showed all cases to be rearranged [94]. RNA next-generation sequencing analysis revealed specific fusions of ROS1 in four cases (two with PWWP2A, one with PPFIBP1, and one with ZCCHC8). A GOPC-ROS1 mosaicism was identified in agminated Spitz nevi on the lower limb of two young adults [95]. ROS1 fusions with LIMA1, LRRFIP2, ZCCHC8, ATP2B4, and MPZL1 have also been described [89,96].

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 [97].

●NTRK1 fusions – TRK fusions have been identified in a variety of cancers. (See "TRK fusion-positive cancers and TRK inhibitor therapy".)

NTRK1 fusions have been detected in 11 percent of Spitz nevi, 25 percent of atypical Spitz tumors, and 21 percent of Spitz melanomas [27]. On histopathology, Spitz tumors with NTRK1 fusions frequently have distinctive features, including 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 (table 5) [98].

●NTRK2 fusions – A single NTRK2 (TFG-NTRK2) fusion has been reported in a patient with a pigmented Spitz nevus [99]. SQSTM1::NTRK2 fusions have been identified in a series of five Spitz tumors [100] and in a case with spindled cell features [101].

●NTRK3 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 with those of melanocytic nevi and melanoma [102]. 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) (table 5) [103].

●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 [27]. A novel MYO5A::RET fusion was described using a hybridization-based capture next-generation sequencing [89]. In mice, RET overexpression results in melanocytic proliferation, nevus formation, and progression to melanoma [104].

●MET fusions – Genomic rearrangements that fuse the MET kinase domain to fusion partners have been described in Spitz tumors [80]. 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 [105]. These lesions were compound melanocytic proliferations (eight predominantly dermal and three predominantly junctional). Epithelioid melanocytes were the predominant cell type. They 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).

In another study of 33 melanocytic proliferations harboring a gene fusion of MAP3K8, the fusion gene encoded the intact kinase domain of MAP3K8 but not the inhibitory domain at the C-terminus [106]. 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 diagnosed as Spitz nevus (5), atypical Spitz tumor (13), and malignant Spitz tumor (15). They occurred predominantly in young adults (median age = 18) and involved the lower limbs in one-half of the cases. Atypical and malignant lesions more commonly occurred in younger patients and showed epidermal ulceration, a dermal component with giant multinucleated cells, and clusters of pigmented cells in the dermis in one-third of the cases. 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.

TERT-p mutations — TERT promoter (TERT-p) mutations have been identified in aggressive cutaneous conventional melanoma. In a large cohort of 56 patients diagnosed with atypical Spitz tumor or spitzoid melanoma, TERT-p mutations were identified in all tumors from the four patients who developed distant metastasis but in none of the tumors from patients who had favorable outcomes [6]. The presence of TERT-p "hotspot" mutations (c.-124C>T, c.-146C>T, or c.-138/-139 CC>TT) was the most significant predictor of widespread dissemination and death among the variables analyzed and identified a clinically high-risk subset of patients with spitzoid tumors [6,81].

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 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 [107]. 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.

Methylation — Methylation profiling may be a helpful adjunct to predict the risk level of atypical Spitz tumors and clinical outcomes [108]. Spitz nevi, atypical Spitz tumors, and spitzoid melanomas were examined using reduced representation bisulfite sequencing in a series of genome-wide methylation profiles [109]. A proposed diagnostic algorithm based on the methylation status of seven CG sites located in TETK4P2, MYO1D, and PMF1-BGLAP was able to distinguish Spitz nevi from melanomas and classify atypical Spitz tumors based on similarity of methylation levels with those of Spitz nevi or melanomas.

Novel promoter mutations — A novel promoter utilizing an ALK-C2orf42 rearrangement was identified in a metastatic Spitz melanoma from a prepubescent male [110]. The lesions showed atypical histology and abnormal cytogenetic findings.

Fluorescence in situ hybridization — With the increasing availability of comparative genomic hybridization and, especially, next-generation sequencing of DNA and RNA (see 'Next-generation DNA and RNA sequencing' above), FISH and mutational analysis have almost no application in the evaluation of Spitz tumors. On occasion, however, these techniques can be utilized in order to target specific mutations, or specific FISH probes can be used for specific fusions, such as EWSR1::ATF1 or CRTC1::TRIM11.

A study of 75 atypical Spitz tumors suggested that homozygous deletions of 9p21 may be predictive of aggressive behavior and fatal outcome [111]. However, the role of homozygous 9p21 deletion as a marker of aggressive behavior has not been proven since, in most instances, concomitant TERT-p hotspot mutations or other TERT aberrations may account for the aggressive phenotype or fatal outcome [6,112]. (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 [77,113]. In a study of 93 Spitz nevi and 77 Spitz tumors, 7 of 24 lesions harboring HRAS mutations were initially diagnosed as melanoma [113]. 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 [114-117]. Studies of conventional Spitz tumors and spitzoid melanomas did not find activating hotspot mutations in NRAS or BRAF [118,119].

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). 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 (also known as pigmented spindle cell nevus). (See 'Dermoscopic features' above.)

The definitive diagnosis of Spitz tumors is based on histopathologic evaluation and risk stratification of the excised lesion (table 2 and table 4) [5]. However, the reproducibility of the histologic diagnosis of Spitz tumors is poor [120].

Diagnostic approach

●Histopathologic examination – The initial steps in diagnosis are histopathologic examination and risk stratification (table 4) of the excised tumor to determine whether a clear-cut Spitz nevus or melanoma is present. In general, Spitz tumors should be assessed by a pathologist with expertise in spitzoid neoplasms for the presence of the following high-risk features [5,6]:

•Age at diagnosis >10 years

•Clinical lesion diameter >1 cm

•Ulceration

•Involvement of the subcutaneous fat

•Mitotic rate ≥6/mm²

•Dermal expansile nodule

•High-grade cytologic atypia

All, or nearly all, of the above criteria have been observed in true Spitz melanomas. Thus, their presence strongly suggests the diagnosis of Spitz or spitzoid melanoma.

●Molecular analysis – For lesions suspicious for melanoma, it is recommended to perform immediate investigation by next-generation DNA and RNA sequencing for genetic alterations (see 'Next-generation DNA and RNA sequencing' above), in particular TERT-p hotspot mutations but also other mutations (eg, BRAF, HRAS, NRAS, NF1) and translocations indicative of a true Spitz phenotype or other potentially aggressive tumors that may mimic atypical Spitz tumors. (See 'Atypical Spitz tumors' below.)

●Immunostaining – Immunohistochemical evaluation may also provide additional information in the classification of spitzoid tumors (table 2). (See 'Immunostaining' above.)

Spitz nevus — The diagnosis of Spitz nevus is based upon a constellation of morphologic features (table 2).

●Clinical features – Spitz nevi are generally <5 to 6 mm in diameter, sharply circumscribed, and occur most frequently in prepubertal children.

●Pathology – Lesions are symmetric and show epidermal hyperplasia with "clefting" around 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 absent or low in number (<2 mitoses per mm²), particularly in the deep dermis (picture 5A-B). Coalescent Kamino bodies are often present. (See 'Spitz nevus' above.)

●Genetic alterations – 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 [19]. (See 'Mutational analysis' above.)

●Immunostaining – 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 Melan-A/Mart-1 or SOX10 stain the lesion diffusely. (See 'Immunostaining' above.)

Atypical Spitz tumors — Atypical Spitz tumors have one or more abnormal morphologic features that correlate with potentially aggressive behavior and melanoma (table 2). They usually occur in patients older than 10 years (postpubertal).

●Pathology – Morphologic high-risk features of atypical Spitz tumors include large diameter (≥10 mm), expansile dermal nodule, ulceration, extension into the subcutis, high-grade cytologic atypia, and mitotic rate >6/mm² (picture 6A-C) [5,6]. Other parameters potentially of value include asymmetry, heterogeneity of the cell population, melanocytic confluence, lack of melanocyte maturation in the deeper areas of the dermis, and deeply located mitoses. However, because of the rarity of 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.)

●Genetic alterations – 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) [19]. Increasing DNA copy number alterations correlate with increasing likelihood of melanoma. (See 'Kinase fusions' above and 'Comparative genomic hybridization' above.)

●Immunostaining – 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 'Immunostaining' above.)

Spitz melanoma — The gold standard for diagnosis of true Spitz melanoma is distant metastasis and death. Clinical (palpable) lymph node involvement (but not sentinel lymph node positivity) probably also correlates with true Spitz melanoma.

●High-risk features – All, or almost all, of the following high-risk features are associated with a high probability of melanoma [121]:

•Patient age >10 years

•Tumor diameter >1 cm

•Ulceration

•Involvement of subcutaneous fat

•>6 mitoses per mm²

•An expansile dermal nodule

•High-grade cytologic atypia (picture 7B)

●Pathology – The diagnosis of true Spitz melanoma is made by a pathologist with expertise in this area based on the presence of all, or almost all, of the high-risk morphologic features in individuals >10 years of age (picture 7A-B) (see 'Spitz melanoma' above). Such diagnosis should be supplemented by genetic alterations confirming the Spitz phenotype and, if possible, by TERT promoter (TERT-p) hotspot mutations or TERT gene rearrangements. Various other less important atypical morphologic features may also be present in Spitz melanomas.

●Genetic alterations – With the possible exception of TERT-p hotspot mutations, there are no clear-cut genetic alterations that distinguish atypical Spitz tumors from Spitz melanoma (picture 7A and table 2). TERT-p hotspot mutations or a TERT gene rearrangement provide the greatest evidence for a likely diagnosis of Spitz melanoma [6,105]. Other mutations, such as BRAF, HRAS, NRAS, or NF1, which are associated with conventional "spitzoid" melanoma as well as gene fusions (translocations) indicative of other potentially aggressive tumors that mimic atypical Spitz tumors, may help in distinguishing these non-Spitz neoplasms from true Spitz melanoma. (See 'Next-generation DNA and RNA sequencing' above.)

With array comparative genomic hybridization analysis, 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 a benign lesion. In contrast, the demonstration of multiple (often >3) chromosomal alterations characteristic of conventional melanoma (including deletions in 9p and 10q and gains in chromosome 7) raises concern for melanoma [122-124]. However, it must be emphasized that many exceptions to the latter criteria for comparative genomic hybridization, and especially fluorescence in situ hybridization (FISH) results, exist.

●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, mutational analysis, or next-generation sequencing is worthwhile. Confirmation of a BRAF mutation provides evidence for a conventional (possibly "spitzoid") melanoma.

●Ciliation index – The loss of primary cilia on melanocytes is a useful biomarker for the distinction of melanoma from conventional melanocytic nevi [125]. The ciliation index was measured in 68 cases of spitzoid tumors, including Spitz nevi, atypical Spitz tumors, and spitzoid melanoma [126]. Spitzoid melanomas demonstrated a significant decrease compared with Spitz nevi or atypical Spitz tumors. In addition, a low ciliation index 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 (ciliation index, asymmetry, hyperchromatism, and cytologic atypia) outperformed standard histologic assessment in an independent validation cohort of 56 additional cases. Thus, ciliation index 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 [127].

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 particular architectural features, such as vertically oriented junctional nests, clefting around nests, a wedge-shaped dermal configuration, characteristic enlarged epithelioid and spindled melanocytes, and Kamino bodies. (See "Acquired melanocytic nevi (moles)", section on 'Common acquired melanocytic nevi'.)

Melanoma and other neoplasms with spitzoid morphology — The differentiation of Spitz tumors from melanoma is one of the most difficult problems in dermatopathology. It is largely based on utilization of clinical features; histopathologic parameters; and increasingly ancillary techniques, including immunohistochemistry and molecular studies (table 6 and table 2).

Age is considered an important (but not absolute) criterion to discriminate Spitz tumors from melanoma since melanoma is extremely rare in children <10 years, whereas most Spitz nevi occur in children <10 years.

●Melanomas with spitzoid morphology ("spitzoid" melanoma) – The terms "melanoma with spitzoid morphology" and "spitzoid" melanoma have been used to indicate a subset of melanomas often, but not exclusively, seen in adults that have a morphologic resemblance to Spitz tumors. However, many of these melanomas labeled as "spitzoid" have no relationship to Spitz tumors. Many or most such "spitzoid" melanomas probably represent conventional melanomas (eg, melanomas with BRAF, NRAS, or NF1 mutations) or melanomas with other genetic aberrations (eg, germline mutations in CDKN2a, CDK4, and POT1 or germline variants of telomere maintenance genes in familial melanoma) [20,21].

●BAP1-inactivated melanocytomas – 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 [128,129]. On immunohistochemistry, BAP1-inactivated melanocytomas show nuclear loss of BAP1 expression, whereas BAP1 is expressed in Spitz tumors. (See "BAP1-inactivated melanocytoma".)

●BRAF-mutated spitzoid tumors – Rare melanocytic tumors with BRAF V600E and V600K mutations can show varying degrees of morphologic overlap with Spitz tumors, and a subset can be indistinguishable from Spitz tumors. Features seen more commonly in BRAF-mutated tumors include greater pigmentation, often greater heterogeneity, and more frequent conventional nevoid components in the dermis, often suggesting a "combined nevus." Morphologic evaluation to exclude melanoma is necessary [130,131].

●NRAS-mutated spitzoid tumors – Rare melanocytic tumors with point mutations and amplification in NRAS may exhibit spitzoid morphology. Among seven tumors reported, the median age was 20 years, and there was striking predilection for the helix of the ear (four cases) [132]. These tumors were well-circumscribed cellular tumors, either compound or dermal, and often with deep extension of tumor cells in plexiform fascicles into the deep reticular dermis and subcutaneous fat. The melanocytes were epithelioid to spindled with moderate amounts of cytoplasm and conspicuous nucleoli. They were arranged in short fascicles, nests, and cords. Some cases had occasional pleomorphic and multinucleated melanocytes. Rare dermal mitotic figures were detected in all cases.

●Melanocytic tumors with MAP2K1 activating mutations – Benign and intermediate-grade melanocytic lesions with MAP2K1 activating mutations may demonstrate spitzoid morphology. In a cohort of 16 cases with MAP2K1 mutations, the morphologic diagnosis was Spitz nevus (8 of 16), atypical Spitz tumors (6 of 16), and deep penetrating nevus (2 of 16) [133]. Common architectural patterns included a plaque-like silhouette with fibroplasia around the rete, reminiscent of a dysplastic nevus, or a wedge-shaped pattern with plexiform arrangements of nests surrounding adnexa. MAP2K1-mutated neoplasms occurred in an older age group as compared with spitzoid tumors. The MAP2K1-mutated tumors also demonstrated pagetoid scatter and a lower mitotic count. Benign and intermediate-grade MAP2K1-mutated tumors are the result of in-frame deletions, whereas missense mutations are more common in melanomas.

●CRTC1::TRIM11-rearranged cutaneous tumor – This is a distinctive dermal tumor comprised of epithelioid and spindled cells [134]. It exhibits partial melanocytic differentiation and is defined by a CRTC1::TRIM11 fusion gene. This specific genetic marker has not been identified in other tumor entities. It generally presents as a discrete, slowly growing, skin-colored nodule without pigmentation. The tumor has a broad anatomic distribution with a higher prevalence on the limbs compared with the trunk and head. The tumor is composed of anastomosing nests and fascicles of ovoid, epithelioid, and spindled cells. The tumor appears to behave less aggressively than melanoma and clear cell sarcoma, with limited cases showing regional or distant metastasis. Additionally, this fusion retains an interaction site with CREB1, potentially accounting for the expression of microphthalmia transcription factor (MITF), which acts like an oncogene.

●MED15::ATF1-rearranged cutaneous tumor – The MED15::ATF1-rearranged tumor is another cutaneous tumor with melanocytic differentiation and spitzoid morphology. This tumor type was identified in three children aged 5 to 16 years who presented with tumors suggesting a cutaneous melanocytic tumor with CRTC1::TRIM11 translocation but were found to have a different genetic fusion (ie, MED15::ATF1). One case has shown progressive metastatic disease [135].

The clinical presentation and behavior of these tumors are still under investigation. They primarily occur in the head and neck region of pediatric patients. Histopathologically, these tumors are bulky, cellular, dermal-based tumors comprised of spitzoid spindle and epithelioid cells with increased mitotic rate.

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'.)

●Pyogenic granuloma (lobular capillary hemangioma) – Pyogenic granulomas (lobular capillary hemangiomas) 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 nevi and 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. (See "Spitz nevus/tumor in children: Diagnosis and management".)

The management of lesions that have undergone change(s) over time, including spontaneous regression, should be decided on a case-by-case basis. The clinician may consider biopsy sampling the site to obtain additional information about the nature of the lesion and the changes present. At their discretion, clinicians 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 lesion 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 2 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 [136].

Excision of the entire lesion allows complete histopathologic examination and reduces the risk of persistence, recurrence, and neoplastic progression [136]. 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 [137]. 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 2 to 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 — As a general rule, sentinel lymph node biopsy (SLNB) is no longer recommended for patients, especially pediatric patients, with atypical Spitz tumors [42].

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 [42]. In this review, SLNB was performed in 303 patients (56 percent) and was positive in 119 patients (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 patients (4 percent) with positive SLNB and 11 of 238 patients (5 percent) treated with wide excision alone had regional recurrence during follow-up.

However, for severely atypical spitzoid melanocytic neoplasms with uncertain malignant potential, the decision to perform an SLNB should be made on a case-by-case basis. Clinically involved lymph nodes that are palpable or radiographically evident (macrometastatic disease) are concerning for melanoma and should be further evaluated with tissue sampling and/or imaging.

Patients with a positive SLNB showing a virtually macrometastatic deposit or one highly concerning for melanoma may be considered for completion lymphadenectomy and adjuvant therapy as if they have stage III melanoma. (See "Evaluation and management of regional nodes in primary cutaneous melanoma".)

FOLLOW-UP

●There is no specific protocol of follow-up for children, adolescents, and young adults after excision of 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 scoring system based on the patient's age and tumor morphologic characteristics has been introduced to help clinicians determine whether an atypical Spitz tumor is at low, intermediate, or high risk for metastasis (table 4) [5,6]. Age and the same high-risk morphologic criteria have been confirmed in another study of 56 patients, which included adults [7].

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. However, true Spitz melanoma is virtually nonexistent in prepubertal patients and extremely rare in postpubertal patients of all ages. Although the importance of age cannot be overstated, pathologists must remain pragmatic and utilize the high-risk morphologic features (table 2 and table 4) in assessing atypical Spitz tumors for the likelihood of melanoma.

Additional ancillary techniques, including immunomarkers (eg, p16, BRAF, Ki-67 gradients) and molecular studies (in particular next-generation sequencing for TERT promoter [TERT-p] mutations and RNA sequencing for gene fusions), provide additional information for risk stratification. (See 'Immunostaining' above and 'Genomic alterations' 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.

●A large retrospective study evaluated the outcome of 595 children and adolescents (age <20 years) with 622 spitzoid lesions (512 Spitz nevi, 107 atypical Spitz tumors, and 3 Spitz melanomas) with a median follow-up of 4.1 years [138]. Only five recurrences (two Spitz nevi and three atypical Spitz tumors [0.8 percent of the 622 spitzoid lesions]) were documented without any subsequent morbidity or deaths among the entire cohort directly related to these tumors. No recurrences or deaths were associated with the three Spitz melanomas.

●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 [139]. 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) [140]. No positive sentinel lymph nodes 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 [141]. 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 morphologic and biologic spectrum of melanocytic lesions composed of large epithelioid and/or spindled cells ranging from benign or low-grade melanocytic neoplasms to Spitz melanoma/malignant Spitz tumors. Based on clinical, histopathologic, and genetic characteristics, three categories of Spitz tumors have been delineated: Spitz nevus, atypical Spitz tumor (Spitz melanocytoma), and Spitz melanoma (table 1 and table 2). (See 'Classification' above.)

●Epidemiology – Spitz tumors represent approximately 1 percent of the nevi excised in children. They typically occur in the first two decades of life but may also develop in adults. Males and females of all ethnic groups are approximately equally affected. (See 'Epidemiology' above.)

●Clinical features – 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). 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 on clinical, histologic, and genetic features (table 2). Immunohistochemistry and molecular analysis are helpful in problematic cases. (See 'Diagnostic approach' above.)

•Spitz nevi 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). (See '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 2 to 6/mm² or greater (picture 6A-C and table 7). (See 'Atypical Spitz tumors' above.)

•The presence of all, or nearly all, of the following high-risk criteria strongly favors a diagnosis of Spitz melanoma:

-Age at diagnosis >10 years

-Clinical lesion diameter >1 cm

-Ulceration

-Involvement of the subcutaneous fat

-Mitotic rate ≥6/mm²

-Dermal expansile nodule

-High-grade cytologic atypia

The detection of TERT promoter (TERT-p) hotspot mutations provides additional strong support for the diagnosis of true Spitz melanoma. (See 'Spitz melanoma' above.)

●Management

•Spitz nevi and 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. (See 'Monitoring' above and "Spitz nevus/tumor in children: Diagnosis and management".)

•For lesions with clinical features that are concerning for atypical Spitz tumor or melanoma (table 2), we suggest surgical excision rather than observation (Grade 2C). Margins of approximately 2 to 5 mm are appropriate in most cases. (See 'Surgical excision' above.)

•Atypical Spitz tumors with positive margins should undergo re-excision to achieve clear margins. Severely atypical Spitz tumors that are suspicious for 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".)