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。     

Angiomatoid and desmoplastic Spitz nevus presenting as a keloidal nodule

Angiomatoid and desmoplastic Spitz nevi are rare histologic variants of Spitz nevi that present most frequently on the extremities of children and young adults. Although Spitz nevi are clinically heterogeneous, one presenting as a keloidal nodule has not been previously published. We present a case of an angiomatoid and desmoplastic Spitz nevus clinically akin to a keloid on an African‐American teenager and describe its unique histopathologic features.     

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.     

Congenital agminated Spitz nevi: immunoreactivity with a melanoma-associated monoclonal antibody

Agminated, or grouped Spitz nevi are a curious expression of nevomelanocytic growth; and represent an uncommon manifestation of these nevi. We encountered an example of agminated Spitz nevi present at birth, which showed progression and rapid growth over months. All showed histologic Spitz nevus features. Avidin-biotin immunohistochemical techniques using anti S-100 protein, neuron-specific enolase (NSE), and melanoma-specific monoclonal antibody, HMB-45 labelled the nevi as follows: diffuse S-100 and NSE staining in most and HMB-45 positivity in sporadic cells deep in the dermis. HMB-45 reactivity occurred in both spindle cells and epithelioid forms.     

Oncogenic BRAF and the tumor suppressor IGFBP7 in the genesis of atypical spitzoid nevomelanocytic proliferations

Rare reports indicate that the frequency of BRAFV600E mutations is high in atypical Spitz nevi. The purpose of this study was to ascertain the utility of the RAF/RAS mutational status as a diagnostic adjunct in lesions with histologic features that deviate from a typical Spitz nevus and, to examine expression of Insulin growth factor binding protein 7 (IGFBP7), a tumor suppressor acting through autocrine/paracrine pathways to inhibit BRAF‐MEK‐ERK signaling, in the same. Genomic DNA for genotyping was isolated from 6 regular Spitz nevi and 14 atypical spitzoid nevomelanocytic proliferations (including 1 melanoma with spitzoid histomorphology). NRAS1, NRAS2 and KRAS were analyzed, in addition to BRAFV600E. A mutation in BRAFV600E was noted in only one case–that of a regular Spitz nevus. IGFBP7 expression appeared to be maintained in this case, but was absent in 7/17 cases, which included 5 atypical spitzoid nevomelanocytic proliferations. Lack of expression of IGFBP7 in atypical spitzoid nevomelanocytic proliferations with histologically concerning features but BRAF‐WT indicates that the evolutionary path in atypical spitzoid nevomelanocytic proliferations is genetically distinct from that of IGFBP7‐negative BRAF‐positive melanoma. From an oncogenic BRAF perspective, our findings suggest that the majority of ‘atypical’ spitzoid nevomelanocytic proliferations are probably no different from conventional Spitz nevi. Emley A, Yang S, Wajapeyee N, Green MR, Mahalingam M. Oncogenic BRAF and the tumor suppressor IGFBP7 in the genesis of atypical spitzoid nevomelanocytic proliferations.     

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.     

Spitz nevus and atypical spitzoid neoplasm

Spitz nevus (SN) and Spitzoid malignant melanoma (SMM) represent benign and malignant counterparts at both ends of the spectrum of Spitzoid lesions. Atypical Spitzoid neoplasm (ASN) is a poorly defined and characterized category of melanocytic tumors with histologic features of both benign Spitz nevi and malignant melanomas. The group of ASN represents a mixture of Spitz nevi with atypical features and Spitzoid melanomas. However, at the current moment in time, histopathologists are not capable of differentiating between the 2 in some cases and are forced to place them in this ambiguous category, where the behavior of these lesions cannot be predicted with certainty. Because this group encompasses both benign and malignant lesions, and perhaps also a separate category of melanocytic tumors that behave better than conventional melanomas, some of these neoplasms can metastasize and kill patients, whereas others have no metastatic potential, and yet others might only metastasize to regional lymph nodes. Although diagnostic accuracy has improved over the years, many of these lesions remain controversial, and there is still poor interobserver agreement in classifying problematic Spitzoid lesions among experienced dermatopathologists. The objective of this review article is to summarize the most relevant information about SN and ASNs. At this time histologic examination remains the golden standard for diagnosing these melanocytic neoplasms. We therefore concentrate on the histopathologic, clinical, and dermoscopic aspects of these lesions. We also review the most recent advances in immunohistochemical and molecular diagnostics as well as discuss the controversies and dilemma regarding whether to consider sentinel lymph node biopsy for diagnostically ambiguous melanocytic neoplasms.     

Congenital Spitz nevus clinically mimicking melanoma

The differentiation between atypical variants of Spitz nevus and melanoma is often difficult given the many clinical and histopathologic similarities between the two. We report a case of an infant with a congenital scalp lesion exhibiting clinical features of melanoma, including variegation and regression of pigmentation and a rapidly changing appearance. Histologic examination of the excised lesion revealed a benign congenital Spitz nevus. This case emphasizes the need for clinical and histologic correlation in determining the benign or malignant nature of atypical pigmented lesions in infants.     

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.     

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.     

Spitz Nevi and Other Spitzoid Neoplasms in Children: Overview of Incidence Data and Diagnostic Criteria

Spitz nevi are benign melanocytic neoplasms characterized by epithelioid or spindle melanocytes or both. In some rare cases their presentation overlaps with the clinical and histopathologic features of malignant melanoma, so a differential diagnosis can be difficult to make. Intermediate forms between Spitz nevi and malignant melanoma, with unpredictable behavior, have been called atypical Spitz tumors. A literature search was performed to review the clinical, dermoscopic, genetic, and histopathologic aspects of spitzoid tumors. Spitz nevi mainly occur in children, with no predilection for sex, and in young women. Common sites are the head and lower arms, where Spitz nevi present as pink nodules or hyperpigmented plaques. Spitzoid lesions may have diverse dermoscopic patterns: vascular, starburst, globular, atypical, reticular, negative homogeneous, or targetoid. The management of spitzoid lesions can be invasive or conservative; surgical excision is usually reserved for those with doubtful features, whereas clinical and dermoscopic follow‐up is preferred for typical pediatric Spitz nevi. The role of sentinel lymph node biopsy in atypical Spitz tumors is debated. Immunohistochemistry and new molecular techniques such as comparative genomic hybridization, polymerase chain reaction, and fluorescence in situ hybridization offer new diagnostic perspectives, investigating genetic alterations that are specific for malignant melanoma or for Spitz nevi.     

Acral pigmented Spitz nevus in a child with transepidermal migration of melanocytes: Dermoscopic and reflectance confocal microscopic features

Acral pigmented Spitz nevi are seldom reported in the literature. We report a new case on the palm of a 4‐year‐old girl that demonstrated correlation between features observed on dermoscopy and reflectance confocal microscopy (RCM). Histopathology revealed a benign intraepidermal Spitz nevus with transepidermal elimination of melanocytes that showed on RCM as focal atypical bright cells concerning for malignancy. This case is one of few reports in the literature combining dermoscopy, reflectance confocal microscopy, and histology for an acral Spitz nevi, which are rarely evaluated by RCM given the thickness of the stratum corneum in acral sites.     

Atypical histologic features in melanocytic nevi

The atypical histologic features considered to be specific to dysplastic (atypical) nevi have been reported to occur in nevi that are common nevi by all other clinical and histologic features. The distribution and mutual relations among such features in nevi need to be further studied. Six histologic features (dimension > 5 mm, lentiginous proliferation, disordered nested pattern, melanocytic dyskaryosis, dermal lymphocytic infiltrate, suprabasal melanocytes) were analyzed in 253 melanocytic nevi with different clinical appearances. Atypical histologic features, found in 72% of nevi, occurred singly or formed numerous and highly variable combinations. Nevi formed a complex histologic spectrum comprising lesions showing a progressively increasing incidence of atypical features rather than two classes (common and dysplastic nevi). To divide the investigated lesions in objectively defined groups, we used a scoring system. In each nevus, a numeric value of 1 was assigned when each of the studied parameters was present and a value of 0 was assigned when each of these parameters was absent; on the basis of the final scores, nevi were divided in six different classes (classes 0-5). Diagnostic categories such as dysplastic nevi and common nevi seem to be inappropriate, as they do not reflect the real histologic complexity of such lesions.     

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.     

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.     

Spitz nevus: follow-up study of 8 cases of childhood starburst type and proposal for management

Spitz nevus is an uncommon, benign melanocytic neoplasm that shares many clinical and histological features with melanoma. It presents clinical ambiguity that makes the diagnosis and management of the patient difficult. We present our experience in the management of Spitz nevus by rigorous dermoscopic long-term follow-up of 8 Spitz nevi in patients younger than 12 years. Dermoscopic images, acquired every 6 months, show evolution and modifications of these lesions. The aim of this paper is to better understand the long-term modifications of nevi with starburst pattern to avoid surgical excision of these lesions in the pediatric age group.     

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.     

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.     

Amelanotic blue nevus: a variant of blue nevus.

Blue nevi are typically heavily melanized. We report a variant of blue nevus that is minimally pigmented. Of the 1,358 blue nevi seen in our laboratory during the last 6 years, 38 (2.7%) were selected that had scant or absent melanin. We refer to these blue nevi as the amelanotic type. Approximately half of the cases in clinical diagnosis were nevus of some type, whereas other differential diagnoses were basal cell carcinoma, dermatofibroma, and lesion. Histologically all specimens were characterized by the spindle-shaped cells seen in blue nevi, but with very little or no obvious melanin. Some lesions were markedly cellular, resembling the features of cellular blue nevus. No hemosiderin was identified on Perls' stain, whereas Fontana-Masson stain was variably positive. Usually there was fibrous stroma. In most cases, the histologic differential diagnosis was dermatofibroma. Other histologic differential diagnoses included amelanotic and/or spindle cell melanoma, dermal Spitz nevus, neurofibroma, and scar. There was no pleomorphism or increased mitotic activity. Evidence of epidermal melanocytic hyperplasia was seen in two cases. Furthermore, the lesions had been present for many years without evidence of recent change. Immunohistochemistry showed all cases to be strongly positive with anti Mel-5 antibody, but only weakly positive or negative with anti S-100 and HMB-45 antibodies. We would like dermatologists and pathologists to be aware of this unusual and uncommon entity.