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Are You Confident of the Diagnosis?
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Spitz nevus
Spitz nevus, also known as spindle and epithelioid cell nevus, is a benign melanocytic neoplasm seen predominantly in children and adolescents, although they may also develop in adults.
Sophie Spitz first described these nevi as “benign juvenile melanomas” on the basis of their histologic resemblance to melanoma, but having a benign clinical course (although one of the thirteen children described in her initial case series did succumb to metastatic melanoma, a poignant reminder that there was and still is diagnostic confusion between benign Spitz nevi and Spitzoid melanoma).
These so-called atypical Spitz tumors or spitzoid neoplasms of uncertain malignant potential remain one of the most challenging areas in the realm of pigmented lesions for both clinicians and dermatopathologists.
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Characteristic findings on physical examination
Most Spitz nevi develop during the first 2 decades of life. Congenital Spitz nevi have also been reported. The classic presentation is the sudden development of a pink papule on the face, although they may develop anywhere (Figure 1). Pigmented Spitz nevi may also occur and typically resemble a lentigo or acquired junctional melanocytic nevus (Figure 2).
Figure 1.
Typical Spitz nevus.
Figure 2.
Pigmented Spitz nevus.
Most Spitz nevi are 6mm or less in diameter. Spitz nevi may grow rapidly for several months and may rarely ulcerate; ulceration is most often seen in nevi that are greater than 1cm in diameter. Agminated Spitz nevi and eruptive Spitz nevi are peculiar variants that manifest by the development of multiple localized or disseminated Spitz nevi, respectively.
Dermoscopy may be helpful in distinguishing Spitz nevi from non-melanocytic lesions. Pigmented Spitz nevi typically manifest a symmetric starburst pattern, while non-pigmented Spitz nevi typically manifest dotted vessels and white lines, although non-specific or multicomponent patterns may also be noted (Figure 3). However, dermoscopy cannot reliably differentiate a benign Spitz nevus from an atypical Spitz nevus as there is significant overlap in the frequency of additional dermatoscopic features such as linear and polymorphous vessels and blue-white veil.
Figure 3.
Typical histology of a Spitz nevus (H&E).
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Expected results of diagnostic studies
Most Spitz nevi are compound proliferations, although purely junctional or dermal proliferations may be seen. Histologically, Spitz nevi typically are symmetric, well-circumscribed, and well-demarcated, with a wedge-shaped distribution of large epithelioid and/or spindled melanocytes, typically arranged in uniform nests or fascicles that demonstrate maturation with depth (Figure 4).
Figure 4.
Dermoscopy of a pigmented Spitz nevus demonstrating characteristic starburst pigment network.
Pagetoid spread of melanocytes may be seen, but is not typically prominent. Artifactual clefts between melanocytic nests and the adjacent epidermis may also be seen. The epidermis often demonstrates acanthosis, hypergranulosis, and hyperkeratosis. Kamino bodies are a hallmark of the Spitz nevus and appear as pink amorphic Periodic acid-Schiff (PAS)-positive globules within the epidermis.
Diagnosis confirmation
Clinically, the differential diagnosis of a Spitz nevus includes dermal nevus, pyogenic granuloma, verruca vulgaris, juvenile xanthogranuloma, and amelanotic melanoma.
Dermal nevi are typically light brown in color, and may demonstrate associated hypertrichosis.
Pyogenic granulomas are friable, acquired vascular lesions that frequently bleed spontaneously.
Verrucae often have demonstrable epidermal changes manifested by hyperkeratosis; dermoscopy may highlight the presence of numerous minute blood vessels within the verruca.
Juvenile xanthogranulomas usually have a more yellow-orange hue, and lack a discernible pigment network under dermoscopy.
Amelanotic melanoma may be clinically indistinguishable from a Spitz nevus, but fortunately is exceedingly rare in children. Pigmented Spitz nevi may resemble a small congenital melanocytic nevus, an acquired melanocytic nevus, or a superficial spreading malignant melanoma. Dermoscopy may be helpful in differentiating between these melanocytic neoplasms.
Where indicated or when the diagnosis is in question, histopathology will confirm the diagnosis.
Who is at Risk for Developing this Disease?
Predominantly seen in children and adolescents, Spitz nevi are diagnosed in about 1% of all melanocytic nevi biopsied or excised in children, and the vast majority are believed to arise during childhood. They are seen more commonly in fair-skinned Caucasians, but may be seen in patients of many skin types and ethnicities. There is no known gender prevalence.
Spitz nevi usually arise de novo, but rarely can arise within a pre-existing melanocytic nevus or nevus spilus.
What is the Cause of the Disease?
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Etiology
Spitz nevi are benign melanocytic proliferations; atypical Spitzoid tumors are melanocytic proliferations of indeterminate biological behaviour.
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Pathophysiology
The pathophysiology of Spitz nevi and Spitzoid tumors remains unknown. However, certain genetic aberrations have been noted in these tumors, suggesting that serial accumulation of specific genetic anomalies is important in the genesis of these proliferations.
Spitzoid neoplasms, including Spitz nevi, atypical Spitzoid tumors, and Spitzoid melanoma, have been demonstrated to carry a high prevalence of activating kinase fusion mutations in genes such as RET, ROS1, ALK, and NTRK1, which have been reported to occur in 55% of Spitz nevi, 56% of atypical Spitz tumors, and 39% of Spitzoid melanomas.
Other mutations that have been observed in Spitz tumors include BAP1 loss of function mutations (often in association with BRAF mutation) and NRAS mutation.
Systemic Implications and Complications
Spitz nevi are benign melanocytic proliferations and, as such, have no invasive or metastatic potential. If histopathologic confirmation of a benign Spitz nevus has been confirmed, no further evaluation is required.
The biological behaviour of atypical Spitzoid tumors is unpredictable, although the majority likely represent benign tumors. A small percentage of atypical Spitzoid tumors may represent evolving Spitzoid melanoma with metastatic potential.
Treatment Options
Treatment options are summarized in Table I.
Table I.
| Medical Treatment | Surgical Procedures | Physical Modalities |
|---|---|---|
| Not applicable | Excision |
Not applicable |
Optimal Therapeutic Approach for this Disease
Although controversial, many experts recommend complete excision of all Spitz nevi. Although Spitz nevi are benign neoplasms, proponents of complete excision point out that malignant melanoma cannot be distinguished from Spitz nevus on the basis of clinical examination alone, and that even though exceedingly rare in children, melanoma does occur. In addition, incompletely excised Spitz nevi, such as can be seen when the lesion is initially biopsied via a shave procedure, can recur and create diagnostic confusion with an evolving melanoma.
Atypical Spitz tumors should be completely excised with clear margins.
Patient Management
At a minimum, all suspected Spitz nevi should be followed clinically. When there are worrisome or atypical clinical features, biopsy of a suspected Spitz nevus is warranted. Concerning features include diameter greater than 1cm, presence of bleeding or ulceration, asymmetry in morphology or pigmentation, and associated pain or pruritus. Partial biopsy should be avoided in order to allow for complete histopathologic evaluation.
Patients with a history of a Spitz nevus should have regular skin examinations, focusing on any signs of recurrence after excision and on the development of any atypical melanocytic nevi. There is epidemiologic evidence that persons with a history of a Spitzoid neoplasm are at increased risk for the development of a separate de novo invasive melanoma.
Education should stress the importance of self-examination of all nevi (with the assistance of a caregiver, if necessary), as well as the importance of sun safety (including sun protection with the use of protective clothing and routine use of sunscreen) and avoidance of excessive sun exposure.
Unusual Clinical Scenarios to Consider in Patient Management
The atypical Spitz tumor or Spitzoid tumor of uncertain malignant potential is a diagnostic and therapeutic challenge.
This terminology is used to refer to a melanocytic neoplasm that manifests one or more atypical histologic features but does not fulfill the diagnostic criteria for melanoma. There may be significant discordance in histopathologic diagnosis among even expert dermatopathologists.
There are currently no molecular or genetic markers that can reliably differentiate between a benign Spitz nevus and a Spitzoid melanoma.
Ancillary genomic analysis through the use of fluorescent in-situ hybridization (FISH) or comparative genomic hybridization (CGH) are of benefit in the analysis of Spitzoid tumors, though they are most helpful with regards to differentiating benign from malignant tumors and are less useful in classifying atypical Spitzoid tumors.
CGH studies have demonstrated a high frequency of duplications at chromosome 11p in Spitz nevi, although the majority of Spitz nevi have no detectable chromosomal aberrations on CGH. CGH and/or FISH may help to differentiate Spitz nevi from melanoma, as cutaneous melanoma has been reported to manifest frequent partial gains or losses of chromosomes 6,7,9, and 10, none of which have been reported in Spitz nevi.
Both heterozygous and homozygous deletions involving chromosome 9p21 have been reported in atypical Spitzoid tumors, with evidence suggesting that tumors with homozygous deletion associated with loss of p16 expression are more worrisome histopathologic features. The presence of homozygous 9p21 deletions in atypical Spitzoid tumors is also associated with metastatic disease.
Mutations in the BRAF oncogene, which are seen in a significant proportion of malignant melanomas, are seen with variable frequency in Spitz nevi, and are therefore of no diagnostic significance.
Important considerations with regard to the management of an atypical Spitz tumor include the clinical history, age of the patient, and histological characteristics of the tumor.
Larger tumors, particularly when associated with ulceration, are more concerning for malignancy. Spitz nevi typically arise in childhood and are rare in adults; therefore, an atypical Spitz tumor arising in an adult is more worrisome for an evolving melanoma. Worrisome histological features include a sheet-like dermal growth pattern, architectural asymmetry, lack of maturation, ulceration, extension into the deep dermis and subcutis, significant nuclear pleomorphism, and mitoses (particularly atypical mitoses or those involving the deep dermis).
On the basis of review of the clinical and histological features of a series of atypical Spitz tumors in children, Spatz has suggested that the following features are correlated with an increased risk for metastasis: age more than 10 years at diagnosis, tumor diameter greater than 10mm, involvement of the subcutis, ulceration, and a mitotic count greater than 6/mm2.
The clinical prognosis for most atypical Spitz tumors appears very good, with most case series of adults and children demonstrating minimal to no evidence of fatal disease, even in the setting of a positive sentinel lymph node biopsy, at least over several months to years of clinical follow-up. However, there are documented cases of fatal metastatic disease in patients diagnosed with an atypical Spitz tumor, although some experts argue that these patients by definition had melanoma that was initially misdiagnosed.
The use of sentinel lymph node biopsy in the evaluation of patients with atypical Spitz tumors is also controversial, as many studies document a high rate of positive sentinel nodes (approximately 40%), yet overall a very good prognosis. A recent systematic review of published reports failed to show any prognostic benefit for sentinel lymph node biopsy in patients with atypical Spitzoid tumors, as positive sentinel lymph node results did not predict a poorer clinical outcome.
The presence of small foci of melanocytes within the lymph nodes in the primary nodal basin, in particular subcapsular, does not a priori indicate malignancy, although most experts would agree that the presence of large number of melanocytes within a lymph node, in particular if there was parenchymal involvement, is highly suggestive of metastatic melanoma.
What is the Evidence?
Barnhill, RL. “The Spitzoid lesion: rethinking Spitz tumors, atypical variants, 'Spitzoid melanoma' and risk assessment”. Mod Pathol. vol. 19. 2006. pp. S21-33. (Excellent commentary on the diagnostic and prognostic controversies concerning atypical Spitz tumors and Spitzoid melanoma.)
Busam, KJ, Murali, R, Pulitzer, M, McCarthy, SW, Thompson, JF, Shaw, HM. “Atypical spitzoid melanocytic tumors with positive sentinel lymph nodes in children and teenagers, and comparison with histologically unambiguous and lethal melanomas”. Am J Surg Pathol. vol. 33. 2009. pp. 1386-95. (Comparison of small numbers of children with atypical Spitz tumors with those with unambiguous melanoma suggests that children with atypical Spitz tumors and positive sentinel lymph nodes have a significantly better prognosis; all six patients with atypical Spitz tumors and positive sentinel lymph nodes were alive, while two of five patients with metastatic melanoma died of disease.)
Busam, KJ, Pulitzer, M. “Sentinel lymph node biopsy for patients with diagnostically controversial Spitzoid melanocytic tumors”. Adv Anat Pathol. vol. 15. 2008. pp. 253-62. (Excellent overview of the controversies surrounding the use of sentinel lymph node biopsy in patients with atypical Spitz tumors.)
Dahlstrom, JE, Scolyer, RA, Thompson, JF, Jain, S. “Spitz naevus: diagnostic problems and their management implications”. Pathology. vol. 36. 2004. pp. 452-7. (An excellent discussion of the histologic features that aid in differentiation of benign Spitz nevi from Spitzoid melanomas.)
Lallas, A, Kyrgidis, A, Ferrara, G, Kittler, H, Apalla, Z, Castagnetti, F, Longo, C, Moscarella, E, Piana, S, Zalaudek, I, Argenziano, G. “Atypical Spitz tumours and sentinel lymph node biopsy: a systematic review”. Lancet Oncol. vol. 15. 2014 Apr. pp. e178-83. (A systemic review of published data that concludes that the routine use of sentinel lymph node biopsy in the evaluation of atypical Spitzoid tumors has no prognostic benefit.)
Ludgate, MW, Fullen, DR, Lee, J, Lowe, L, Bradford, C, Geiger, J. “The atypical Spitz tumor of uncertain biologic potential: a series of 67 patients from a single institution”. Cancer. vol. 115. 2009. pp. 631-41. (Large case series of sixty-seven adults and children undergoing evaluation for atypical Spitz tumors; demonstrated the high prevalence of positive sentinel lymph node biopsies but an overall favorable prognosis.)
Miteva, M, Lazova, R. “Spitz nevus and atypical Spitzoid neoplasm”. Semin Cutan Med Surg. vol. 29. 2010 Sep. pp. 165-73. (An excellent review of the clinical and diagnostic features of Spitz nevi, atypical Spitz tumors, and Spitzoid melanoma.)
Moscarella, E, Lallas, A, Kyrgidis, A, Ferrara, G. “Clinical and dermoscopic features of atypical Spitz tumors: A multicenter, retrospective, case-control study”. J Am Acad Dermatol. vol. 73. 2015 Nov. pp. 777-84. (The authors review the dermatoscopic and clinical features of a series of 55 atypical Spitz tumors and 110 Spitz nevi.)
North, JP, Garrido, MC, Kolaitis, NA, LeBoit, PE. “Fluorescence in situ hybridization as an ancillary tool in the diagnosis of ambiguous melanocytic neoplasms: a review of 804 cases”. Am J Surg Pathol. vol. 38. 2014 Jun. pp. 824-31. (A review of the use of FISH in the evaluation of Spitzoid tumors and other ambiguous melanocytic tumors.)
Sepehr, A1, Chao, E, Trefrey, B, Blackford, A, Duncan, LM, Flotte, TJ, Sober, A, Mihm, MC, Tsao, H. “Long-term outcome of Spitz-type melanocytic tumors”. Arch Dermatol. vol. 147. 2011 Oct. pp. 1173-9. (The authors demonstrate an 8-fold increase in the observed incidence of invasive melanoma among a cohort of patients with a history of a Spitz nevus, atypical Spitzoid tumor, or Spitzoid melanoma.)
Spatz, A, Calonje, E, Handfield-Jones, S, Barnhill, RL. “Spitz tumors in children:a grading system for risk stratification”. Arch Dermatol. vol. 135. 1999 Mar. pp. 282-5. (A small retrospective case series of the clinical features and outcomes of atypical Spitz nevi in children; using this data, the authors propose a grading system for risk stratification for metastatic disease based on clinical and histologic data.)
Wiesner, T, He, J, Yelensky, R, Esteve-Puig, R, Botton, T, Yeh, I, Lipson, D, Otto, G, Brennan, K, Murali, R, Garrido, M, Miller, VA, Ross, JS, Berger, MF, Sparatta, A, Palmedo, G, Cerroni, L, Busam, KJ, Kutzner, H, Cronin, MT, Stephens, PJ, Bastian, BC. “Kinase fusions are frequent in Spitz tumours and spitzoid melanomas”. Nat Commun.. vol. 5. 2014. pp. 3116(Important publication demonstrating that activating kinase fusions are an important finding in Spitzoid tumors.)
Wiesner, T, Kutzner, H, Cerroni, L, Mihm, MC, Busam, KJ, Murali, R. “Genomic aberrations in spitzoid melanocytic tumours and their implications for diagnosis, prognosis and therapy”. Pathology. vol. 48. 2016 Feb. pp. 113-31. (Excellent overview of the genomic aberrations associated with Spitzoid tumors.)
Yazdan, P, Cooper, C, Sholl, LM, Busam, K, Rademaker, A, Weitner, BB, Obregon, R, Guitart, J, Gerami, P. “Comparative analysis of atypical spitz tumors with heterozygous versus homozygous 9p21 deletions for clinical outcomes, histomorphology, BRAF mutation, and p16 expression”. Am J Surg Pathol. vol. 38. 2014 May. pp. 638-45. (An clinical, histological and genetic comparison of atypical Spitzoid tumors with heterozygous or homozygous 9p21 mutation).
Wiesner, T1, Murali, R, Fried, I, Cerroni, L, Busam, K, Kutzner, H, Bastian, BC. “A distinct subset of atypical Spitz tumors is characterized by BRAF mutation and loss of BAP1 expression”. Am J Surg Pathol. vol. 36. 2012 Jun. pp. 818-30. (Evaluation of loss of BAP1 expression in atypical Spitzoid tumors).
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