Pathology of Spitz Nevi 

Spitz nevus is named after Dr. Sophie Spitz, who in 1948 reported a case series of "melanomas of childhood."^{[1, 2]} Nearly all of Spitz’s original series of 13 cases are now regarded as representing Spitz nevi, only 1 case having proved to be a melanoma resulting in metastasis and death.

Spitz nevus is a clinically and histologically distinct variant of melanocytic nevus composed of spindled and/or epithelioid melanocytes (in the configuration of a benign tumor). Synonyms include Spitz’s nevus, Spitz tumor, and spindle and epithelioid cell nevus.

The spectrum of Spitz nevi includes junctional, compound (most common), and intradermal variants. Pigmented spindle cell nevus (Reed nevus) has been regarded by many authorities as a clinically and histologically distinct variant of Spitz nevus.^[3] Many other clinical and histologic variants have been described.

Historically, Spitz nevus has also been described under the headings of juvenile melanoma, benign juvenile melanoma, and prepubertal melanoma. As these synonyms imply, the differential diagnosis of Spitz nevus and spitzoid melanoma can be among the most challenging in dermatopathology.

See Spitz Nevus and Melanocytic Nevi for more information.

Spitz nevus usually represents a solitary, acquired nevus. Rare congenital Spitz nevi have been documented.

The pathogenesis of Spitz nevi, like that of melanocytic nevi in general, has not been fully elucidated. However, there is evidence that cell proliferation in Spitz nevi, as in other types of nevi and in melanoma, is mediated by activating mutations affecting genes in the RAS-RAF-MEK-ERK-MAP kinase pathway.

Uniquely, many Spitz nevi (approximately 20-30%) exhibit HRAS mutations, reflected by an isolated gain of chromosome 11p as a characteristic DNA copy number alteration. HRAS-positive Spitz nevi exhibit increased immunohistochemical expression of p16 and cyclinD1.^{[4, 5]} To date, HRAS mutations have not been identified in spitzoid melanoma.^[6]

Spitz nevus has been characterized as relatively uncommon: it is estimated to account for only about 1% of surgically removed nevi.^[7] Spitz nevus affects males and females, and the majority arise before the age 20 years.

Spitz nevus most commonly arises on the skin of the head and neck or the extremities (more commonly on the lower extremities than on the upper). Involvement of the central face (eg, nose, cheek) is classic (see the image below). However, it is prudent generally to be skeptical about a diagnosis of Spitz nevi on skin with severe solar elastosis or in elderly individuals.

Spitz nevus typically presents as a solitary, soft, well-demarcated, nonulcerated, dome-shaped papule that is usually less than 6-10 mm in diameter (rarely up to 3 cm) and contains a fairly even degree of pigmentation anywhere within the pink-red-tan–light brown–dark brown color spectrum (see the image below).

A self-limited period of rapid growth over weeks to months, followed by stability in size, is often noted; however, pigmentary changes may continue to occur over time. Halo, congenital, or agminated (grouped) or disseminated Spitz nevi represent uncommon clinical variants (see the image below).

Dermoscopic (dermatoscopic) evaluation may reveal distinctive features of the nevi.

Pigmented spindle cell nevus (Reed nevus) is a uniformly heavily pigmented (dark brown-black), well-defined, round macule or minimally elevated papule, usually less than 6 mm in diameter (see the image below). Involvement of the proximal extremity of a woman is classic. Head and neck involvement is very unusual and should raise concerns about possible melanoma,^[8] especially in adults.

Because this lesion is a variant of melanocytic nevus, there is no staging classification for a correctly diagnosed Spitz nevus.

The differential diagnosis includes the following:

• Juvenile Xanthogranuloma
• Malignant Melanoma
• Melanocytic Nevi
• Pyogenic Granuloma

Other conditions to consider include the following:

• Hemangioma
• Melanoma arising in association with melanocytic nevus
• Nonmelanocytic tumors (eg, epithelioid histiocytoma, reticulohistiocytoma)

Gross inspection of a formalin-fixed specimen containing a Spitz nevus parallels its clinical appearance and does not yield diagnostically useful information.

As of 2010, short of evaluation of biologic behavior (eg, long-term follow-up, metastasis), histologic assessment remains the practical gold standard for diagnosis of all melanocytic tumors, including Spitz nevi.

By definition, Spitz nevi are composed of spindled or epithelioid melanocytes or both; the proportion of spindled versus epithelioid cells varies from case to case.^[9] The melanocytes in Spitz nevi are generally larger than those in other forms of nevi. The nuclei are generally round, vesicular, and centrally situated. Cytologic details of the melanocytes may also vary somewhat, but the melanocytes of Spitz nevi generally display uniform features within each tumor.

Multinucleation may occur, nuclear pseudoinclusions may be prominent, and the nucleoli may be enlarged and eosinophilic. However, eosinophilic nucleoli represent a common feature of Spitz nevus and melanoma. Cytoplasm is abundant and ranges from eosinophilic (most common) to slightly basophilic.

As a variant of melanocytic nevus, Spitz nevus fulfills all major histologic criteria for the diagnosis of melanocytic nevus, with one or more additional features that distinguish it as Spitz nevus. The least common denominators for the diagnosis of melanocytic nevus include the following:

• Symmetrical profile at scanning magnification (including the lymphocytic host response, if present)
• Circumscription: Sharp lateral demarcation, usually ending as a nest rather than single melanocytes
• "Orderly" distribution of single and nested melanocytes exhibiting fairly uniform cytologic features
• Evidence of dermal zonation/maturation: A gradual transition from predominantly larger nests of melanocytes in the superficial dermal component to smaller melanocytes disposed within smaller nests, dispersed aggregates (often including single file strands), and single units within the deep dermal component, often aggregating around adnexal structures (hair follicles, sweat ducts, blood vessels, nerve fibers, arrector pili).

Architecturally, Spitz nevi exhibit a domed, flat-bottomed profile at scanning magnification (see the image below). With the exception of Spitz nevi undergoing halo reactions, the lymphocytic host response is typically sparse.

Junctional or compound Spitz nevus

Junctional or compound Spitz nevi exhibit distinctive epidermal changes, including epidermal hyperplasia. The junctional nests are typically vertically oriented, as are the spindled melanocytes within them, which resemble banana clusters (see the image below). Retraction artifacts or clefts typically surround the junctional nests.

Pale eosinophilic globules known as Kamino bodies (after Dr. Hideko Kamino, the lead author of the group that first described them^[10] ) are usually present at the basement membrane zone (dermal-epidermal junction) of Spitz nevi (see the images below). Kamino bodies contain periodic acid-Schiff/periodic acid-Schiff, digested stain (PAS/PASD)-positive basement membrane constituents, including laminin and type IV collagen.

Kamino bodies are specific for Spitz nevi but may rarely be seen in melanomas. When present in Spitz nevi, Kamino bodies are classically large, coalescent, and numerous. When present in melanomas, Kamino bodies are usually small and few in number and are often PAS negative; such characteristics suggest that these structures actually represent apoptotic cells.

Intradermal Spitz nevus

Intradermal Spitz nevi often lack distinctive epidermal changes but often display a fibrotic/desmoplastic stromal reaction and may then be classified as a desmoplastic Spitz nevus or desmoplastic nevus (see the images below).^{[11, 12]}

Other histologic variants include polypoid, plexiform, angiomatoid, hyperpigmented, combined, halo Spitz nevus, and recurrent Spitz nevus.

Pigmented spindle cell nevus (Reed nevus)

Pigmented spindle cell nevus (Reed nevus) is either a junctional or a superficial compound proliferation. By definition, the melanocytes are predominantly or exclusively spindled and pigmented (see the image below). The lymphohistiocytic host response contains numerous heavily pigmented melanophages.

Notoriously, in all forms of Spitz nevi, features that overlap with those of melanoma may be present, as follows.^{[13, 14]}

Small numbers of large marked, severe, or strikingly atypical epithelioid melanocytes may be seen. The nuclei of these cells are more often vesicular than hyperchromatic (see the image below).

Pagetoid intraepithelial growth may occur, but if such growth is present, it is ideally most prominent in the central portion of the tumor and often manifests as transepidermal elimination or expulsion of nests of melanocytes rather than single cells; this manifestation must be distinguished from so-called consumption of the epidermis, a phrase used to describe the thinned epithelium overlying junctional nests that favors melanoma over Spitz nevus.^[15]

The degree of pagetoid growth of single melanocytes in Reed nevus, particularly in children, may be greater than that seen in some examples of melanoma in situ (see the image below).

Mitotic figures within junctional or dermal melanocytes are often present (see the image below). The rules for assessing mitoses are the same as those for all melanocytic tumors. That is, mitotic figures in nevi are generally sparse and not clustered, not atypical in appearance, and confined to the dermal epidermal junction and superficial dermal component. Conversely, high numbers or "hot spots" of mitoses, atypical forms, deep mitoses, or suprabasilar mitoses may represent evidence of melanoma.

However, because Spitz nevi often exhibit a rapid growth phase, the presence of numerous typical mitoses within the superficial dermal component of an otherwise classic Spitz nevus does not specifically suggest melanoma.

Because Spitz nevi usually arise in children and young adults, solar elastosis is usually absent. Thus, spitzoid proliferations, especially pure spindle cell or pure epithelioid cell melanocytic proliferations on skin with severe solar elastosis usually represent melanoma.

The recognition of atypical Spitz variants is controversial and reflects the fact that some melanocytic proliferations exhibit microscopic features that are intermediate between or overlapping with those of Spitz nevi and melanoma. The designation "metastasizing Spitz nevus/tumor" reflects the fact that some lesions diagnosed as Spitz nevi have been associated with regional lymph node involvement—but without widespread metastasis or death after a reasonable follow-up period.

Comprehensive discussion of these topics are beyond the scope of this article (see Prognosis and Predictive Factors).

In cases in which the tumor cell lineage is uncertain on hematoxylin-eosin (H&E) staining, melanocytic markers may be used to stain Spitz nevi. The most sensitive marker is polyclonal S100. Other melanocytic markers include Melan-A (MART-1), HMB-45, tyrosinase, NKI/C3, and MiTF.

However, immunohistochemical (IHC) studies are not routinely or consistently employed in the diagnosis of Spitz nevi, and practices and institutions differ regarding the extent to which IHC is employed in selected cases when the differential diagnosis includes spitzoid melanoma.^[8] In such cases, IHC studies include the following:

• Assessment of the staining pattern of melanocytic markers, such as HMB-45 (staining of the deep dermal component of melanoma vs loss of staining in the deep dermal component of nevi)^[16] or S100A6 (strong, diffuse immunopositivity in Spitz nevi; often absent or weak staining in melanoma)^[17]
• Assessment of cell proliferation, as measured by cell proliferation markers such as Ki-67

As a variant of melanocytic nevus, Spitz nevus is a benign neoplasm. A minority of Spitz nevi will persist or recur at the biopsy site, sometimes manifesting clinically 1 or more years after the original biopsy. In the evaluation of a recurrent tumor with spitzoid features, it is imperative to compare the findings with those from the original biopsy, because recurrent nevi (pseudomelanoma), particularly Spitz nevi, often exhibit a microscopic appearance that is similar to, if not indistinguishable from, melanoma.^[18]

Missed melanoma represents a leading cause of medical malpractice cases; many of these are initially misdiagnosed as Spitz nevi.^[8] Clinically, melanoma is curable if caught early, but it is consistently fatal if left untreated, and it frequently affects younger individuals. Histologically, in a small percentage of cases, the distinction between nevus and melanoma is difficult or impossible.

Spitz nevi and other spitzoid melanocytic proliferations designated "atypical" for various reasons (including atypical Spitz nevi, atypical Spitz tumor, metastasizing Spitz nevi) represent a controversial and heterogeneous group of tumors (that is, heterogeneous insofar as they include both nevi and melanoma), thorough discussion of which is beyond the scope of this article.^{[19, 20, 21, 22]} Each "atypical" case must be judged on its own attributes, in the context of the degree of diagnostic confidence and competence.^[14]

Regional lymph node involvement by large, unusual/atypical, cutaneous spitzoid tumors has been documented, often in children. Despite the presence of metastatic disease, in many of these cases, the follow-up to date has been more favorable than would be expected in comparison with conventional melanomas of similar tumor burden.

Thus, although each case must be evaluated individually and comprehensively, clinical experience suggests that there is a differential diagnosis for regional lymphatic involvement by melanocytes that includes spitzoid melanoma (possibly divisible into prognostically distinct subsets—for example, spitzoid melanoma of childhood),^[23] other forms of melanoma, and nodal nevus.^[24]

Whenever feasible, obtaining one or more additional opinions on the pathologic diagnosis and following an interdisciplinary management approach are prudent in these problematic cases.