Classic and atypical Spitz nevi: review of the literature

Both classic and atypical Spitz nevi are uncommon melanocytic lesions usually presenting in children and adolescents. The classic Spitz nevus typically is benign and has characteristic clinical and histologic features. In contrast, the atypical Spitz nevus has an unknown clinical prognosis, and its clinical and histologic traits are loosely defined. Melanoma can have similar features to both classic and atypical Spitz nevi and must be ruled out in all cases. We review the literature on classic and atypical Spitz nevi, advances in differentiating both types of nevi from melanoma, and treatment options.     

Spitz样肿瘤320例临床及组织病理分析

【摘要】 目的 总结Spitz样肿瘤的临床及组织病理特征。方法 回顾2005年1月至2020年1月西京皮肤医院确诊的320例Spitz样肿瘤患者的临床及病理资料。结果 320例患者中,男141例,女179例,年龄0 ~ 65（12.5 ± 11.7）岁,病程1个月至30年;其中,Spitz痣307例,不典型Spitz肿瘤（AST）8例,Spitz痣样黑素瘤（SM）5例。皮损多为单发,可见于头面部、躯干和四肢,边界均清楚。307例Spitz痣皮损以黑色（132例,43.0%）和红色（108例,35.1%）为主,多数色素均匀（262例,85.3%）且表面平滑（272例,88.6%）。Spitz痣存在特殊临床亚型,11例 （3.6%）发生在斑痣上,11例 （3.6%）呈簇发性,6例（2.0%）播散性,7例（2.3%）结节性,1例（0.3%）为瘢痕疙瘩样。Spitz痣特征性病理表现包括表皮内痣细胞呈Paget样扩散（123例,40.1%）,真表皮交界处出现Kamino小体（74例,24.1%）,痣细胞呈水平带状（177例,57.8%）及楔形分布（118例,38.4%）,痣细胞巢周围出现裂隙（177例,57.8%）,可见生理性核分裂象（117例,38.1%）,核染色质均细腻。根据特殊组织病理表现,Spitz痣又分为色素性上皮样Spitz痣（9例,2.9%）、结缔组织增生性Spitz痣（13例,4.2%）、血管瘤样Spitz痣（8例,2.6%）、疣状Spitz痣（12例,3.9%）、黏液样Spitz痣（10例,3.3%）、晕痣样Spitz痣（4例,1.3%） 等。4例AST皮损为黑色,7例色素均匀,3例皮损表面粗糙;特征病理表现包括细胞均有轻度至中度的异型性,均可见核分裂象（7例为2 ~ 6个/mm2）,5例核染色质粗糙。3例SM皮损呈红色,4例色素不均匀,3例表面粗糙;特征病理表现包括黑素细胞呈Paget样扩散（3例）,瘤细胞呈无极性浸润性生长且均未见成熟现象,均有明显异型性,并可见病理性核分裂象（3例, > 6个/mm2）,核染色质均粗糙且核膜明显着色。结论 Spitz样肿瘤的临床及组织病理表现具有特征性,Spitz痣的临床及病理亚型繁多,AST同时具有Spitz痣和黑素瘤的临床及组织学特征。     

Spitz nevi arising in speckled lentiginous nevus: clinical, histologic, and molecular evaluation of two cases

Spitz nevi are small dome-shaped nodules that sometimes arise in areas of preexisting hyperpigmentation, such as a speckled lentiginous nevus (nevus spilus), where they present a diagnostic dilemma. We report clinical, histopathological, and molecular findings of two cases of multiple Spitz nevi arising in a speckled lentiginous nevus. We used immunohistochemistry to assess expression of Ki-67, epidermal growth factor receptor, vascular endothelial growth factor, and RelA in two cases of Spitz nevi arising in a speckled lentiginous nevus. We observed rare staining for the proliferative marker Ki-67, but positive staining for the growth and antiapoptotic factors epidermal growth factor receptor, vascular endothelial growth factor, and RelA. Characterization of the molecular phenotype of Spitz nevi arising in speckled lentiginous nevi may provide a useful adjunct to long-term monitoring in this rare but difficult clinical presentation.     

Multiple agminated Spitz nevi arising on a café au lait macule: review of the literature with contribution of another case

The majority of Spitz nevi are acquired solitary lesions. Multiple Spitz nevi are rare and may develop on hyperpigmented skin. We report a 16-year-old girl with multiple Spitz nevi arranged on a café au lait macule. Immunohistochemistry showed positivity for S-100 and HMB-45. Of interest, expression of Polo-like kinase (PLK), a novel proliferation marker that recently proved to be positive in up to 98% of malignant melanoma cells, showed positivity in 40% of the nevus cells. The clinical development of multiple Spitz nevi is not yet clear, as they are preferentially excised. Reviewing 70 cases in the literature we found that multiple agminated Spitz nevi occur more frequently than reported previously. In about one-third of these cases Spitz nevi arose on congenitally hyperpigmented skin.     

Management of Spitz nevi: a survey of dermatologists in the United States

BACKGROUND: There is no consensus concerning management of Spitz nevi. OBJECTIVE: This study was carried out to ascertain how dermatologists manage Spitz nevi. METHODS: A questionnaire was sent to 997 fellows of the American Academy of Dermatology, 284 pediatric dermatologists, and 27 directors of pigmented-lesion clinics. The results are based on the 381 questionnaires returned. RESULTS: The vast majority of responding dermatologists (93%) recommend biopsies of suspected Spitz nevi. Of this group, 43% recommend total biopsies and 55% recommend partial biopsies; 2% would recommend either total or partial biopsies, depending on the clinical situation. Sixty-nine percent of physicians would completely excise a lesion that was histologically diagnosed as an incompletely removed Spitz nevus. Seventy percent of general dermatologists and 80% of pediatric dermatologists would recommend excision with a 1- to 2-mm margin of normal-appearing skin around a Spitz nevus. Nine percent of general dermatologists would recommend margins of 4 mm or more; however, all pediatric dermatologists surveyed would recommend margins less than 4 mm. Physicians were less likely to monitor patients whose Spitz nevi were completely removed. Three fourths (74%) of respondents believe Spitz nevi are entirely benign, 4% believe they are precursors to melanoma, and 22% are not sure. Seven percent of general dermatologists and 4% of pediatric dermatologists have seen metastatic melanomas arise at sites of lesions initially diagnosed histologically as Spitz nevi; 40% of pigmented-lesion clinic directors have seen such lesions. CONCLUSIONS: We believe that the lack of consensus, both in our survey and in the medical literature, reflects to some extent the lack of certainty in the histologic differentiation of Spitz nevi from melanomas and that concern about melanoma influences management. At the pigmented-lesion clinic of the New York University Skin and Cancer Unit, because of this concern about melanoma, it is usually recommended that Spitz nevi be completely excised.     

Linear arrangement of multiple deep penetrating nevi: report of first case and review of literature

BACKGROUND: Deep penetrating nevus is a recently described variant of melanocytic nevi with clinical and histopathological features that may be confused with malignant melanoma, blue nevus, pigmented Spitz nevus, or congenital melanocytic nevus. We report a case with linear arrangement of multiple deep penetrating nevi. To our knowledge, such presentation has never been reported in the literature. OBSERVATIONS: We describe a patient with multiple darkly pigmented lesions in the right periauricular area, above and behind the ear. The histopathological features of these lesions were consistent with deep penetrating nevus. CONCLUSIONS: To our knowledge, this is the first report of linear arrangement of multiple deep penetrating nevi. We consider this case a unique presentation of deep penetrating nevus.     

Proliferation, apoptosis, and survivin expression in a spectrum of melanocytic nevi

BACKGROUND: Apoptosis is important for maintenance of tissue homeostasis and often dysregulated in cutaneous neoplasms. The apoptosis inhibitor survivin is expressed in melanoma and non-melanoma skin cancers and benign keratinocytic lesions. Its expression has not been studied in melanocytic nevi. OBJECTIVE: We determined the expression pattern of survivin in benign melanocytic nevi in comparison to markers of proliferation and apoptosis. METHODS: Six cases of each of the following melanocytic nevi were retrieved from a dermatopathology archive: compound dysplastic nevus, intradermal nevus, compound nevus, neurotized intradermal nevus, and Spitz nevus. Survivin expression was evaluated by in situ hybridization. Apoptotic and proliferation indices were calculated by counting immunoreactive cells in terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling and proliferating cell nuclear antigen immunostained sections, respectively. RESULTS: All nevi, regardless of histologic type, expressed survivin. Compound melanocytic lesions expressed survivin in both epidermal and dermal compartments. The apoptotic rate was low for dysplastic, compound, and Spitz nevi, and apoptotic cells were not identified in any neurotized nevus. The proliferative index was highest for Spitz nevi, while all other nevi demonstrated rare positive cells. CONCLUSIONS: Survivin is consistently expressed in benign melanocytic lesions, while apoptotic cells are rarely identified, suggesting the dysregulation of apoptotic pathways with the accumulation of cells in these neoplasms.     

Expression of activated Akt in benign nevi, Spitz nevi and melanomas

BACKGROUND: Activated Akt expression (p-Akt) is reportedly increased in many melanomas as compared with benign nevi. The purpose of this study was to evaluate and compare p-Akt immunohistological staining in benign nevi, Spitz nevi and primary melanomas. METHODS: Immunostaining for phosphorylated Akt was performed in 41 melanocytic lesions previously classified as benign intradermal nevus (14 lesions), Spitz nevus (9 lesions) or melanoma (18 lesions). Lesions were graded for intensity of p-Akt staining by two independent observers (0, no staining; 1, slightly positive; 2, moderately positive; 3, highly positive). Scores were averaged, and statistical analyses were performed. RESULTS: Benign nevi showed less staining (mean score 1.18) compared with Spitz nevi (mean score 2.11) and melanomas (mean score 2.19). This difference was statistically significant between benign nevi and melanomas (p = 0.0047) and benign nevi and Spitz nevi (p = 0.0271). No statistical difference was detected in staining between Spitz nevi and melanomas (p = 0.8309). CONCLUSIONS: Activated Akt expression is increased in Spitz nevi and melanomas as compared with benign intradermal nevi, but is unlikely to prove useful in differentiating between the former.     

Nevo de Spitz y otros tumores spitzoides en la infancia. Parte 1: aspectos clínicos,histológicos e inmunohistoquímicos

A Spitz nevus is a melanocytic neoplasm of epithelioid and/or spindle cells that usually appears in childhood. These lesions are by nature benign, but their features can sometimes make them difficult to distinguish from melanomas. Spitzoid melanocytic lesions have been grouped into 3 types in recent decades: Spitz nevi, atypical Spitz tumors, and spitzoid melanomas. Atypical Spitz tumors are spitzoid melanocytic proliferations that have atypical histopathologic features that are insufficient to support a diagnosis of melanoma. The malignant potential of these lesions is at present uncertain. This review examines the clinical, dermoscopic, and histopathologic features of this group of lesions.     

Melanocytic nevi with features of Spitz nevi and Clark's/dysplastic nevi ("Spark's" nevi)

Background: Nevi with cytologic characteristics of Spitz nevus and architectural features of Clark's/dysplastic nevus are not well recognized in the literature.
Methods: Twenty-seven nevi with characteristics of Spitz nevus and Clark's/dysplastic nevus are reviewed.
Results: The patients' mean age was 33 years, and 17/27(63%) patients were female. Lesions were most frequent on the trunk and lower extremities. Histopathologically, these nevi were composed of large, monomorphous spindled and/or epithelioid melanocytes. Spindle cells were often oriented parallel to the epidermis, with fused rete and lamellar fibroplasias. Lateral extension of the junctional component was a feature of compound lesions. An average of 10 years of clinical follow up in 12 patients revealed no recurrence or metastasis.
Conclusions: Recognition of this type of nevus is important to avoid confusion with malignant melanoma.     

The spectrum of Spitz nevi: a clinicopathologic study of 83 cases

OBJECTIVE: To achieve a clinicopathologic classification of Spitz nevi by comparing their clinical, dermoscopic, and histopathologic features. DESIGN: Eighty-three cases were independently reviewed by 3 histopathologists and preliminarily classified into classic or desmoplastic Spitz nevus (CDSN, n = 11), pigmented Spitz nevus (PSN, n = 14), Reed nevus (RN, n = 16), or atypical Spitz nevus (ASN, n = 14); the remaining 28 cases were then placed into an intermediate category (pigmented Spitz-Reed nevus, PSRN) because a unanimous diagnosis of either PSN or RN was not reached. SETTING: University dermatology and pathology departments and general hospital pathology departments. PATIENTS: A sample of subjects with excised melanocytic lesions. MAIN OUTCOME MEASURE: Frequency of dermoscopic patterns within the different histopathologic subtypes of Spitz nevi. RESULTS: Overlapping clinical, dermoscopic, and histopathologic findings were observed among PSN, RN, and PSRN, thereby justifying their inclusion into the single PSRN diagnostic category. Asymmetry was the most frequent indicator of histopathologic ASN (79%; n = 11); in only 4 cases did dermoscopic asymmetry show no histopathologic counterpart, and in those cases the discrepancy was probably the result of an artifact of the gross sampling technique carried out with no attention to the dermoscopic features. CONCLUSIONS: Among Spitz nevi, histopathologic distinction between PSN and RN is difficult, not reproducible, and may be clinically useless. A simple clinicopathologic classification of these neoplasms might therefore be structured as CDSN, PSRN, and ASN. Asymmetry should be assessed using both dermoscopic and histopathologic analysis, and reliability in histopathologic diagnosis may be enhanced by the simultaneous evaluation of the corresponding dermoscopic images.     

Spitz nevus is relatively frequent in adults: a clinico-pathologic study of 247 cases related to patient's age

Spitz nevus is a clinico-pathologic entity that can cause diagnostic concern, particularly in adults. Many studies have been performed to establish reliable histologic criteria, in the attempt to differentiate this lesion from melanoma. A series of 247 Spitz nevi, 6 of which were formerly classified as melanomas, were reviewed for clinical and histopathological parameters. Patients older than 20 comprised 66% of cases, with a predominance of women. The lower extremity was more affected in females of any age, whereas the trunk was more frequently involved in men over 40. Histopathologic examination showed the following differences among Spitz nevi related to age: acanthosis, parakeratosis, pagetoid infiltration, and Kamino bodies were more frequent in young people, whereas multinucleated melanocytes were more frequent in adults. The latter also had lesions that were less pigmented, with less maturation and more desmoplasia. At a mean follow-up of 94 months (range 52-172), recurrence at the site of biopsy or metastases were absent. In our study, a greater proportion of Spitz nevi occurred in adults than in previous series. Moreover, the relative incidence of Spitz nevus compared with melanoma in our population was higher than in other studies. Histopathologic criteria elaborated to diagnose Spitz nevus, applied to our cases, appeared reliable, allowing a correct diagnosis, even in adults.     

Multiple Agminated Spitz Nevi: Report of Two Cases and Review of the Literature

Abstract: Spitz nevus is most commonly a benign solitary lesion. Multiple lesions arranged in clusters (agminated) are very rare. Malignant degeneration has not been reported. Although spontaneous involution may occur, the nevi are frequently treated by surgical excision. We describe two preschool girls with multiple agminated Spitz nevi, and review the current world literature on multiple Spitz nevi.     

A case of multiple disseminated eruptive Spitz nevi

Spitz nevus is usually a solitary lesion. However, multiple Spitz nevi do arise and can be divided into two variants, agminated (grouped) or disseminated. We report an interesting case of multiple disseminated eruptive Spitz nevi with an unusual feature. The appearance of most of the nevi resembled that of melanocytic nevi, and clinically it was impossible to distinguish these multiple disseminated eruptive Spitz nevi from eruptive melanocytic one.     

Expression of c-kit (CD117) in Spitz nevus and malignant melanoma

BACKGROUND: CD117, the receptor for kit-ligand, which is a growth factor for melanocyte migration and proliferation, has shown differential staining in various benign and malignant melanocytic lesions. The purpose of this study is to compare CD117 immunohistological staining in Spitz nevus versus malignant melanoma, to determine whether CD117 can aid in the diagnosis of these two lesions. METHODS: CD-117 immunohistological staining was performed in 22 clinically and pathologically diagnosed pigmented lesions including 9 cases of Spitz nevus, 10 cases of primary MM and 3 cases of metastatic melanoma. RESULTS: There was no significant difference in CD117 staining in either epidermis or dermis between Spitz nevi and primary melanomas. However staining of metastatic melanomas is less than dermal staining of primary MM and Spitz nevus. CONCLUSIONS: CD117 is unlikely a useful diagnostic tool in differentiating Spitz nevus from primary MM. On the other hand, CD 117 may be useful in differentiating metastatic melanoma from primary melanoma in patients who had a history of melanoma and who present with new dermal lesions.     

Significant melanocytic lesions in infancy, childhood, and adolescence

Malignant melanoma is diagnosed yearly in approximately 300 persons under age 20 in the United States. Relatively recent advances in dermatology include the recognition of lesions felt to be potential precursors of malignant melanoma. Small congenital melanocytic nevi, present in 1 per cent of all newborn infants, may have a small but definite potential for developing malignant melanoma. Furthermore, despite inconclusive data, many leading dermatologists now advocate removal of these small congenital lesions. Giant congenital melanocytic nevi, with their strong predilection for undergoing malignant change, are removed surgically at an early age, often in multistaged procedures. Dermabrasion, once felt to have a role in the treatment of giant congenital nevi, does not remove the malignant potential of these lesions. The dysplastic nevus syndrome, recognized in 1976, identifies individuals at increased risk for developing melanoma. Adolescents who have the dysplastic nevus syndrome or who are members of families with the syndrome require close medical supervision and patient education. The benign Spitz nevus, with its histologic similarity to malignant melanoma, continues to challenge the dermatopathologist and clinician. These lesions--the Spitz nevus, dysplastic nevus, congenital melanocytic nevus, and malignant melanoma--must all be actively considered when regarding the many other benign melanocytic lesions found in infancy, childhood, and adolescence.     

Use of DAPI cytofluorometric analysis of cellular DNA content to differentiate Spitz nevus from malignant melanoma

Cellular DNA content was measured for the purpose of differentiating Spitz nevus from malignant melanoma using the cytofluorometric technique. DNA was stained by 4',6-diamidino-2-phenylindole, and measured by microfluorometer. Among 20 Spitz nevi examined, 18 of them showed a diploid DNA distribution histographic pattern similar to that of acquired pigmented nevi. The other two Spitz nevi had a few polyploid cells with the major population of cells containing diploid DNA content. In contrast, all malignant melanomas showed an aneuploid DNA distribution histographic pattern. The DNA index values of cells from Spitz nevi distributed in the similar range to that of acquired pigmented nevi and separated from those of malignant melanomas distributed in a much higher range. Our results suggest that cytofluorometric analysis of cellular DNA content reflects the biologic behavior more sensitively than do conventional clinical or histologic criteria, and that it serves as a useful aid for the differentiation of Spitz nevus from malignant melanoma.     

Polypoid Spitz nevus: two cases evaluated with genetic technique, prolonged follow up, and sentinel lymph node biopsy

Polypoid Spitz nevus represents a spitzoid melanocytic neoplasm that frequently has worrying and challenging histopathological details. Distinction from polypoid melanoma may not be straightforward. Two cases of polypoid Spitz nevus with striking histopathological features were studied. One case had prolonged follow up (Case 1) and one patient had undergone sentinel lymph node biopsy (Case 2), and fluorescence in situ hybridization (FISH) analysis was also completed (both cases). Follow up and genetic analysis of three control cases of polypoid melanoma is also presented. Our clinical and genetic results suggest that both the polypoid Spitz nevi were benign. The patients are alive with no evidence of disease. FISH analysis did not show abnormalities with probes tested. This is in sharp contrast with the control cases of polypoid melanoma, wherein genomic alterations were detectable. Our data indicate that the two polypoid lesions presented here are most probably benign, despite their worrying histopathological features. More cases with long-term follow up and greater numbers of DNA probes are necessary to extend this conclusion to other ambiguous melanocytic tumors.     

Pediatric "STUMP" lesions: evaluation and management of difficult atypical Spitzoid lesions in children

Spitz nevi represent a distinct type of melanocytic nevi more commonly seen in childhood. Although typically benign, a subset of Spitz lesions raise concern and create a diagnostic dilemma as a result of confusing histology that involves characteristics of classic Spitz nevi intermixed with features of cutaneous melanoma. Such atypical Spitz lesions, or Spitzoid tumors of uncertain malignant potential, are difficult to classify and their biologic potential is uncertain. Nonetheless, these are critical tasks for both prognosis and clinical management. New tools, such as immunohistochemical stains, comparative genomic hybridization, and fluorescence in situ hybridization, have been used to provide further insight into these controversial lesions and to aid in their evaluation. In this review, we present our experience managing 6 cases of Spitzoid tumor of uncertain malignant potential and discuss the potential use of various diagnostic modalities, including sentinel lymph node biopsy, immunostaining, and molecular analysis.