Spitz Nevus, Spitzoid Melanoma, and Atypical Spitzoid Neoplasm

3	Spitz Nevus, Spitzoid Melanoma, and Atypical Spitzoid Neoplasm Rossitza Lazova

In 1948, Sophie Spitz, a pathologist from Memorial Hospital in New York City, described the melanoma of childhood for the first time. Dr. Spitz noticed that the cytologic characteristics of these lesions in children were identical to those of melanoma in adults. Hence, at that time, she believed they were juvenile melanomas. However, in her work, she noted that the children with these lesions fared well clinically. After her death, it took about 10 years of clinical pathologic correlation and observation to realize that this lesion, composed of large epithelioid and spindled melanocytes, was one type of benign nevus. In memory of Dr. Spitz, who initially (although erroneously) described this entity as melanoma, the name Spitz nevus was established. Interestingly, it became evident that not all of the 13 patients described in her manuscript had benign nevi. One patient died of metastatic disease and therefore had true melanoma. This illustrates how difficult it may be at times to differentiate benign Spitz nevus from its mimicker, Spitzoid melanoma, which histologically resembles Spitz nevus. Spitzoid melanomas usually arise as new lesions in adults. The microscopic examination reveals a number of atypical features including numerous mitotic figures, atypical mitoses, deep infiltration into the subcutis, and many other features, which make arriving at the diagnosis of Spitzoid melanoma relatively easy. The difficulties come when there are overlapping histopathologic criteria, some in favor of a benign process and others in favor of malignancy. In this case, pathologists have to admit the limitations of criteria-based histopathologic examination, and render a diagnosis conveying uncertainty, using the term atypical Spitzoid neoplasm. This chapter reviews these issues.

SPITZ NEVUS

Definition

Spitz nevus is a type of benign melanocytic nevus composed of large epithelioid, oval, or spindled melanocytes arranged in nests and fascicles.

Synonyms

Spindle and epithelioid cell nevus is a synonym of Spitz nevus. The name Spitz was given to this type of nevus approximately 10 years after the original description of this entity by Sophie Spitz in 1948, initially misconstrued as juvenile melanoma (1).

Epidemiology

Spitz nevi usually arise in children and young adults. However, they may appear at any age (1–6). Congenital Spitz nevi have also been described (7). Spitz nevi account for approximately 1% of excised nevi in children (3). There is a female predominance (6). Spitz nevi may be seen in all racial groups but are more commonly seen in Caucasians. The lower extremities are the most common location, followed by the upper extremities and trunk (6,8–12). The head and neck region, particularly the face, is erroneously listed as the most common anatomic location for Spitz nevus in many textbooks of dermatology (13–15). However, in the largest study of 484 Spitz nevi, the head and neck region was the least common location (6), which was consistent with other studies (9–12).

Clinical Presentation

Spitz nevus usually presents as a single, dome-shaped papule or nodule with a diameter of 8 mm or less (6) (Figure 3.1). The color may vary including nonpigmented, pink, reddish, brown, and black. Spitz nevi commonly appear suddenly and grow rapidly for a period of time, after which they remain stable. Color changes, pruritus, and bleeding may occur. Agminated (grouped) Spitz nevus, as well as disseminated and eruptive Spitz nevi, are unusual clinical variants (16–20).

Dermoscopic Features

Nonpigmented Spitz nevi may demonstrate one of many dermoscopic patterns including starburst, globular, and atypical (11). Dotted vessels and network depigmentation may also be seen. The most suggestive dermoscopic characteristics of pigmented Spitz nevus are (a) a starburst pattern—radial streaks and/or pseudopods, symmetrically disposed in the lesion periphery and (b) a globular pattern—globules symmetrically disposed in the lesion periphery (11,21).

Histopathologic Features

Spitz nevus is composed of a proliferation of large melanocytes with epithelioid and/or spindled shape, organized in nests or fascicles (22). The majority of Spitz nevi are compound, with both intraepidermal and intradermal components (6). They are symmetric, well circumscribed, and often wedge shaped if ample dermal component is present (Figure 3.2A). There are large nests of melanocytes in the epidermis, distributed equidistantly from one another, relatively uniform in size and shape and often vertically oriented (Figure 3.2B). Clefts are seen between the melanocytic nests and the surrounding epidermis. Melanocytes may be seen above the dermal epidermal junction as single units and in nests. The epidermis is hyperplastic, with hypergranulosis and hyperkeratosis. In the dermis, the melanocytes are arranged in fascicles or nests, which become smaller (mature) with their descent toward the deep component of the lesion. The base of the lesion may be flat and single melanocytes may infiltrate in between collagen bundles in the reticular dermis. Mitotic figures are commonly seen but they are not numerous and are not atypical. They are more prevalent in the upper portion of the nevus. Mitoses may be numerous in rapidly growing or traumatized Spitz nevi. However, this feature should not be misconstrued as in favor of malignancy (23).

Figure 3.1 (A) Spitz nevus presenting as a round and smooth pink papule, a few millimeters in diameter, on the right cheek of a 3-year-old child. (B) A reddish/brown 6-mm smooth and relatively symmetric papule, representing a Spitz nevus, near the knee of a 5-year-old child.

Figure 3.2 (A) A low-power view of a Spitz nevus with symmetric distribution of melanocytic nests in the epidermis and in the superficial dermis. (B) The melanocytic nests vary slightly in size and shape. Many are vertically oriented. There are clefts between the nests and the adjacent hyperplastic epidermis, which shows hypergranulosis and hyperkeratosis. (C) The arrows point to two dull pink globules in the epidermis, named Kamino bodies, composed of basement membrane material, necrotic keratinocytes, and melanocytes.

Figure 3.3 (A) An intradermal Spitz nevus presenting as an elevated papule. There is a slightly wedge-shaped symmetric proliferation of small melanocytic nests in the dermis with an overlying hyperplastic epidermis. (B) Irregularly shaped nests and fascicles of large epithelioid melanocytes are noted in the dermis, surrounded by desmoplastic, thickened collagen bundles. The melanocytes are relatively monomorphic and display vesicular nuclei and abundant amphophilic cytoplasm.

The melanocytes of Spitz nevi are plump, with vesicular nuclei, purple nucleoli, and abundant pale cytoplasm. The melanocytes may also contain finely granular melanin pigment in their cytoplasm. Dull pink globules, named Kamino bodies, containing basement membrane material, necrotic melanocytes, and necrotic keratinocytes may be seen in the epidermis (Figure 3.2C). Dilated blood vessels lined by plump endothelial cells are often noted in the dermis. Lymphocytic inflammatory infiltrate may be present around vessels and at the base of the lesion but not in between melanocytes. Developing junctional Spitz nevi may resemble melanoma in situ, depicting mostly single, large melanocytes distributed at all levels of the epidermis. Desmoplastic Spitz nevus is a variant, in which there are small nests and individual melanocytes embedded in fibrotic, hyalinized stroma (Figure 3.3). Angiomatoid, myxoid, and plexiform among others, are different histologic variants of Spitz nevi. Pigmented spindle cell nevus of Reed is considered by some authors as a variant of Spitz nevus. Others consider it a separate entity.

SPITZOID MELANOMA

Definition

Spitzoid melanoma is a melanoma, which histopathologically resembles a Spitz nevus and is composed of large epithelioid melanocytes (4,6,9,11,24–26). Histopathologic criteria in favor of Spitzoid melanoma include (but are not limited to) the following: asymmetry, sheet-like growth pattern, expansile nodular growth, lack of maturation, ulceration of the epidermis, presence of numerous mitotic figures, deep or atypical mitotic figures, deep extension into the subcutis, and large size (>1 cm).

Epidemiology

Spitzoid melanoma usually occurs in older patients. The mean age of patients with Spitzoid melanoma in one study was 55 years (6). There is no gender predilection and the most common location is the lower extremities followed by the trunk, upper extremities, and head and neck (6). Most Spitzoid melanomas develop in adulthood (27,28). However, Spitzoid melanomas may also occur in prepubescent children and adolescents. Approximately 2% of all melanomas occur in patients younger than the age of 20 years. A total of 0.3% to 0.4% of these melanomas occur in prepubescent children and about one-third demonstrate Spitzoid characteristics (27–31).

Clinical Presentation

Spitzoid melanomas are usually larger than Spitz nevi, often with a diameter greater than 10 mm (6). There is great variability in the clinical presentation of Spitzoid melanomas (Figure 3.4). They may present as asymmetric pigmented lesions with variable colors and irregular borders. The color may vary from nonpigmented, to pink, reddish, brown, or black. Spitzoid melanoma may clinically resemble a nevus or a nonmelanocytic skin cancer.

Figure 3.4 Spitzoid melanoma on the thigh of a 16-year-old boy. Note the large size, the irregular surface, the uneven and focally notched border, and the variation in color.

Dermoscopic Features

Clinically and dermoscopically, Spitzoid melanoma is often indistinguishable from conventional melanoma. Melanomas may show striae and/or asymmetric pseudopods, blue-whitish veil, and asymmetric and irregular globules. Atypical vascularity may also be a clue of malignancy, with linear, dotted, corkscrew, or polymorphous vessels.

Histopathologic Features

Spitzoid melanoma is a melanoma with architecture and cytology that resembles a Spitz nevus. It is usually large (>10 mm in diameter), asymmetric, and sometimes extends deep into the subcutaneous fat. There is a dense proliferation of back-to-back nests or sheets of melanocytes with a nodular expansile appearance (Figure 3.5A). The melanocytes are large and epithelioid, which may display polygonal, oval, or elongated shapes. There is a lack of maturation of the melanocytes and the melanocytic nests with their descent into the dermis. Numerous mitotic figures and deep or atypical mitotic figures are often seen (Figure 3.5B). Ulceration of the epidermis may be observed. Features that may be encountered in Spitzoid melanoma but are rarely, if at all, seen in Spitz nevi are (a) consumption of the epidermis, (b) discohesion within the melanocytic nests as opposed to clefting between melanocytic nests and the adjacent epidermis at the periphery of the nests, and (c) horizontal orientation of melanocytic nests unlike the vertical orientation of the nests in Spitz nevi.

Figure 3.5 (A) Spitzoid melanoma from the posterior thigh of a 50-year-old woman. The lesion had been enlarging gradually over the past year and a half. At low power, there is an asymmetric proliferation of melanocytes predominantly in the dermis. The epidermis is markedly hyperplastic and shows hyperkeratosis. The base of the lesion is uneven with small nests and individual melanocytes percolating in between collagen bundles. (B) Numerous mitotic figures (arrows) are seen throughout the lesion including the base.

ATYPICAL SPITZOID NEOPLASM

Definition

The definition of atypical Spitzoid neoplasm is a major source of discrepancy since there are no unified criteria agreed upon among expert dermatopathologists (4,11,24,32–36). We define atypical Spitzoid neoplasms as melanocytic lesions with architectural and cytologic features shared by both Spitz nevi and Spitzoid melanomas, for which a definitive histopathologic diagnosis of either Spitz nevus or Spitzoid melanoma cannot be confidently rendered by an experienced dermatopathologist (25,34). A number of studies have demonstrated that it can be difficult to predict the clinical behavior of atypical Spitzoid neoplasms from assessment of histopathologic features, and the interobserver reproducibility by pathologists for the diagnosis of these tumors is generally poor (1–5).

Atypical Spitzoid neoplasms represent one of the most difficult of all diagnostic areas in dermatopathology. Spitzoid lesions constitute a histologic spectrum. At one end there are “classic” Spitz nevi, whereas at the other end there are melanomas (i.e., Spitzoid melanomas) that histologically resemble Spitz nevi (4,6,9,11,24–26). In between these two well-defined categories at the two ends, there are lesions that cannot be classified precisely as either benign or malignant. Atypical Spitzoid neoplasm is a histopathologic term encompassing lesions that cannot be classified with certainty into the category of Spitz nevus or Spitzoid melanoma by microscopic examination.

This “gray” category of atypical Spitzoid neoplasms is an artificial category; depending on how broadly it is defined, this group will contain some lesions that are either benign, malignant, or of low-grade malignant potential. Currently, based on histopathologic examination and using the available histopathologic criteria, we cannot categorize these cases with certainty and thus predict their behavior. In addition, since they represent a broad category with variable features and criteria, they are difficult to delineate, thus resulting in different definitions and criteria used by different authors (24,25,37–39).

Epidemiology

Atypical Spitzoid neoplasms may occur in young patients as well as in adults. In a recent study, patients ranged from 2 to 83 years (average 32.6) (6). There is no gender predilection, and the most common location is the lower extremities, followed by the trunk, upper extremities, and head and neck (6).

Clinical Presentation

Atypical Spitzoid neoplasms are usually larger than Spitz nevi, often with a diameter greater than 10 mm (6). There is great variability in the clinical presentation of these lesions, which may present as atypical pigmented lesions with variable colors from pink to reddish, brown or black (Figure 3.6). Atypical Spitzoid neoplasms may clinically mimic a nonmelanocytic skin cancer.

Dermoscopic Features

There are not specific features, dermoscopically, that are characteristic of atypical Spitzoid neoplasms. These melanocytic lesions may often show similar dermoscopic features to those seen in melanoma.

Histopathologic Features

The term atypical Spitzoid neoplasm is used for lesions that do not precisely conform to the category of a “typical” Spitz nevus but also do not fulfill the criteria for melanoma. Under this designation is a broad category of lesions also known as atypical Spitz tumors or atypical Spitz nevi (40). It is impossible to precisely define the histopathologic criteria for diagnosis of atypical Spitzoid neoplasm, because this term is used to describe lesions with the architecture and cytomorphology of both Spitz nevus and Spitzoid melanoma, in which a firm histopathologic diagnosis of one or the other cannot be made with absolute certainty. This broad category includes Spitz nevi with atypical features, which deviate slightly or more substantially from the stereotypical depiction of the classic Spitz nevus. It also includes melanocytic lesions that display conflicting histopathologic criteria, that is, some features of benign Spitz nevi and other features of Spitzoid melanoma. Because of the young age of the patients, as well as the fact that melanoma is rare in youngsters and Spitz nevus is quite common, dermatopathologists are sometimes reluctant to make an unequivocal diagnosis of Spitzoid melanoma in children.

Figure 3.6 An atypical Spitzoid neoplasm, more than 10 mm in diameter, with irregular borders and a variegated color from light brown to dark brown.

Atypical Spitzoid neoplasms show architectural asymmetry, lack of circumscription, lack of maturation with descent in the dermis, nuclear and cellular pleomorphism, increased number of mitotic figures, increased cellularity and confluence of growth, deep mitotic figures, atypical mitoses, and, often, deep extension into the subcutaneous fat (Figures 3.7A–C) (2,4,40). Features that may be helpful in the differential diagnosis between Spitz nevus and Spitzoid melanoma are symmetry (or lack thereof), uniformity of nests from side to side, brisk mitotic rate (Figure 3.7D), mitoses at the base, abnormal mitoses (Figure 3.7E), ulceration, and pigment within melanocytes at the base.

Many attempts have been made to better categorize atypical Spitzoid neoplasms into high-risk and low-risk lesions based on several histopathologic criteria. Among these are the presence of ulceration, large size (>1 cm), asymmetry, deep extension, hypercellularity, and high mitotic activity (23,41,42). In a method advocated by Spatz et al. (43), a lesion that cannot be judged as clear-cut Spitz nevus or Spitzoid melanoma is evaluated and scored for lesional diameter, presence of ulceration, mitotic activity, deep extension into the fat, and other features. On the basis of their data from a collection of problematic cases, a progressively greater score indicates a greater risk of metastases. Fat involvement, which correlates with tumor thickness, has been reported to be frequent in patients with metastatic evolution (2,44,45). Other clues that may be helpful in the distinction between Spitz nevus and Spitzoid melanoma, when present, include solar elastosis in Spitzoid melanomas and extensive pagetoid spread of melanocytes in the epidermis, reaching its uppermost levels and lateral borders.

The age of the patient is often heavily relied upon and used as a criterion by dermatopathologists when approaching a borderline melanocytic lesion (46,47). We are faced with the limitations of criteria-based analysis at this time. Although atypical Spitzoid neoplasms have generally been reported to have a good prognosis, very few well-documented cases of metastasis and death exist (2,48,49). It is imperative that the data from the microscopic examination of the lesion is always interpreted along with the clinical information, especially the age of the patient, location of the lesion, history of changes, symptoms, personal and family history of melanoma, and so on (5).

For lesions in the “gray” zone, it is wise to admit the uncertainty and provide a differential diagnosis and microstaging attributes that would apply if the lesion were interpreted as a melanoma (50). Because the malignant potential of these lesions is uncertain, many clinicians and patients make decisions to treat them as if they were melanomas with excision and, often, a sentinel lymph node biopsy (51). Cases of Spitzoid melanoma in this age group usually have a combination of striking atypia, mitoses, pleomorphism, solid sheets growth pattern, and involvement of the subcutis (40,42,52,53).