[Clinicopathological features and prognosis of ALK-positive Spitz tumors].

Objective: To investigate the clinicopathologic features and prognosis of ALK-positive Spitz tumors. Methods: Thirteen patients with ALK-positive Spitz tumors diagnosed at Shanghai Cancer Center, Fudan University from October 2016 to December 2017 were collected. All cases were routinely evaluated histopathological features in HE staining and detected ALK protein expression by immunohistochemistry. The ALK fusions of 7 cases were confirmed by fluorescence in situ hybridization (FISH).Follow-up data was collected. Results: The age of patients including 2 males and 11 females ranged from 4 to 47 years (mean 25 years). 12 patients were diagnosed with atypical Spitz tumors and 1 patient was diagnosed with Spitz nevus. Clinically, most lesions presented as papules or nodules, while a few lesions presented as plaques. Histologically, most tumors were exophytic (9/13). More than half of the tumors were amelanotic and the junctional component was mainly composed of melanocytic nests. Kamino bodies were not found. The bases of the tumors were mainly wedge-shaped (5/13) and flat (7/13). Eight tumors displayed mixed cell types, while 5 tumors were composed of only spindle cells. All the tumors showed a plexiform and/or intersecting fascicular growth pattern, and perineural extension was observed in 3 tumors. ALK immunohistochemistry showed diffuse and intense cytoplasmic staining in 13 cases, and 7 of them were detected by FISH to confirm the presence of ALK fusions. All patients were followed up for 7 to 21 months (median=12), with no recurrence or lymph node dissemination. Conclusions: Spitz tumors with ALK fusions have their special histopathologic features.ALK fusions mainly occur in Spitz nevi and atypical Spitz tumors. The follow-up data of the existing literatures and our research indicates that the prognosis of ALK-positive Spitz tumors may be good.

Acral Spitz Nevi: A Clinicopathologic Study of 50 Cases With Immunohistochemical Analysis of P16 and P21 Expression.

Spitz nevi on acral sites are rare and poorly documented. The combination of Spitzoid cytomorphology and atypical architectural features of the junctional component may lead to an erroneous diagnosis of melanoma. To study the clinicopthologic and immunohistochemical features, 50 Spitz nevi localized on the distal extremities were retrieved from departmental files. Clinical data and follow-up were obtained and the histologic features were analyzed. P16 and P21 immunohistochemical staining of the dermal component was compared with that of 10 acral lentiginous melanomas and 10 acral nevi. Acral Spitz nevi affected young adults (median: 24.5 y; range: 4 to 61 y) with a female predominence and a predilection for the feet. They were pigmented measuring 1 to 15 mm (median: 4 mm). Follow-up, available for 45 patients (median: 48 mo; range: 4 to 228 mo), revealed no local recurrence, metastasis or mortality. Histologically, acral Spitz nevi were composed of large epithelioid and/or spindled melanocytes. They were well circumscribed with occasional asymmetry. The junctional component was broad with a lentiginous and nested growth and shoulder formation. Marked pagetoid spread and transepidermal elimination of junctional nests were common features. Focal active regression of the dermal component was frequently noted but there was no nuclear pleomorphism or dermal mitotic activity. Acral Spitz nevi were characterized by strong and diffuse P16 and P21 expression, which differs from acral nevi and acral lentiginous melanoma. Acral Spitz nevi are a distinctive subgroup of Spitz nevi with benign behavior. Awareness of the subtle histologic differentiating features and the distinctive P16/P21 expression pattern allows separation from melanoma.

Imaging mass spectrometry assists in the classification of diagnostically challenging atypical Spitzoid neoplasms.

BACKGROUND: Previously, using imaging mass spectrometry (IMS), we discovered proteomic differences between Spitz nevi and Spitzoid melanomas. OBJECTIVE: We sought to determine whether IMS can assist in the classification of diagnostically challenging atypical Spitzoid neoplasms (ASN), to compare and correlate the IMS and histopathological diagnoses with clinical behavior. METHODS: We conducted a retrospective collaborative study involving centers from 11 countries and 11 US institutions analyzing 102 ASNs by IMS. Patients were divided into clinical groups 1 to 4 representing best to worst clinical behavior. The association among IMS findings, histopathological diagnoses, and clinical groups was assessed. RESULTS: There was a strong association between a diagnosis of Spitzoid melanoma by IMS and lesions categorized as clinical groups 2, 3, and 4 (recurrence of disease, metastases, or death) compared with clinical group 1 (no recurrence or metastasis beyond a sentinel node) (P < .0001). Older age and greater tumor thickness were strongly associated with poorer outcome (P = .01). CONCLUSIONS: IMS diagnosis of ASN better predicted clinical outcome than histopathology. Diagnosis of Spitzoid melanoma by IMS was strongly associated with aggressive clinical behavior. IMS analysis using a proteomic signature may improve the diagnosis and prediction of outcome/risk stratification for patients with ASN.

Spitz Nevus Intermingling With a Hemangioma.

We report on a Spitz nevus intermingling with a hemangioma in the same biopsy from the right thigh of a 10-year-old boy. The hemangioma was made of dilated vessels in superficial areas but of narrow and angulated vessels in the deep and lateral zones. The Spitz nevus was typical, showing maturation, and no worrisome cytological features. The immunohistochemical study demonstrated expression by the vascular component of CD31, CD34, factor VIII-related antigen, and Wilms tumor 1, whereas the vessels did not express D2-40 human herpes virus 8 or glucose transporter-1. The melanocytic component expressed HMB-45 (weakly and mainly in the superficial zones), Melan-A and S-100 protein. A perivascular continuous layer of pericytes expressing smooth muscle actin was also evident.

Comparison of the expression of vimentin and actin in spitz nevi and spitzoid malignant melanomas.

INTRODUCTION: The differentiation between Spitz nevi (SN) and Spitzoid malignant melanomas (SMM) represents a challenge to dermatopathologists. We recently demonstrated differential expression of vimentin and Actin in SN and SMM by mass spectrometry (MS). We sought to investigate whether this differential expression could be detected using conventional immunohistochemistry or automated quantitative analysis (AQUA) of histological sections. METHODS: Cases of SN and SMM, which were previously studied by MS and have readily available blocks and enough material in the block, were selected from the Yale Spitzoid Neoplasm Repository. The cases were stained for vimentin and muscle-specific actin using standard protocols. H-scores were calculated by multiplying the percentage of cells staining and the intensity of staining. Selected cases were also studied for quantitative immunofluorescent staining using the AQUA method. RESULTS: All 21 cases of SN showed strong and diffuse staining for vimentin; 19 of 21 (91%) cases had an H-score of 300 (average, 294). Similar staining results were observed in SMM; 13 of 14 (93%) cases had an H-score of 300 (average, 297). Muscle-specific actin was weakly and focally positive in 5 of 21 (24%) SN (H-score = 3.3) and 5 of 14 (39%) SMM (H-score = 3.5). The AQUA method showed no significant difference in the staining intensity of SN and SMM for both vimentin and actin. CONCLUSIONS: There was no difference in the expression of vimentin and actin in SN and SMM shown by conventional immunohistochemistry or the AQUA method. This study shows that MS has much grater sensitivity in detecting the differential expression of these proteins.

Histopathologic clues for the diagnosis of Wiesner nevus.

The dermatologic hallmark of a recently described BAP1-associated cancer susceptibility syndrome is a dome-shaped nevus with distinct clinicopathological features, first delineated by Wiesner and colleagues. Here we describe the leading histopathological criteria of Wiesner nevus. Wiesner nevus is composed of various nevomelanocytic populations all showing different degrees of atypia ranging from hyperchromatic nevus cell-like to large atypical epithelioid cells. Immunohistochemically, Wiesner nevus is BAP1 negative and VE1 positive.

Imaging mass spectrometry--a new and promising method to differentiate Spitz nevi from Spitzoid malignant melanomas.

BACKGROUND: Differentiating Spitz nevus (SN) from Spitzoid malignant melanoma (SMM) is one the most difficult problems in dermatopathology. SPECIFIC AIM: To identify differences on proteomic level between SN and SMM. METHODS: We performed Imaging Mass Spectrometry analysis on formalin-fixed, paraffin-embedded tissue samples to identify differences on proteomic level between SN and SMM. The diagnosis of SN and SMM was based on histopathologic criteria, clinical features, and follow-up data, which confirmed that none of the lesions diagnosed as SN recurred or metastasized. The melanocytic component (tumor) and tumor microenvironment (dermis) from 114 cases of SN and SMM from the Yale Spitzoid Neoplasm Repository were analyzed. After obtaining mass spectra from each sample, classification models were built using a training set of biopsies from 26 SN and 25 SMM separately for tumor and for dermis. The classification algorithms developed on the training data set were validated on another set of 30 samples from SN and 33 from SMM. RESULTS: We found proteomic differences between the melanocytic components of SN and SMM and identified 5 peptides that were differentially expressed in the 2 groups. From these data, 29 of 30 SN and 26 of 29 SMM were recognized correctly based on tumor analysis in the validation set. This method correctly classified SN with 97% sensitivity and 90% specificity in the validation cohort. CONCLUSIONS: Imaging Mass Spectrometry analysis can reliably differentiate SN from SMM in formalin-fixed, paraffin-embedded tissue based on proteomic differences.

[Reactivity of five different antibodies with benign and malignant melanocytic lesions]. / A különbözo antitestek reaktivitása benignus és malignus melanocitás daganatokban.

At the histological examination of an increasing number of melanocytic tumors there is a need to use various immunohistochemical methods. Currently, we are supplied by several antibodies working well on formalin-fixed, paraffin-embedded samples. We have tested five antibodies (S-100, HMB-45, Melan-A, MITF, PNL-2) on 34 benign and 34 malignant melanocytic tumors. We examined the specificity and sensitivity in the junctional and dermal component separately, with special consideration to features disturbing the evaluation (regression, halo-like inflammation, etc.). We have concluded that the histological diagnosis of melanocytic tumors is based on the detailed examination of traditional HE slides and the immunohistochemical methods only confirm or weaken our opinion.

Comparison of pHH3, Ki-67, and survivin immunoreactivity in benign and malignant melanocytic lesions.

Differentiating malignant melanoma from benign melanocytic lesions can be challenging. We undertook this study to evaluate the use of the immunohistochemical mitosis marker phospho-Histone H3 (pHH3) and the proliferation markers Ki-67 and survivin in separating malignant melanoma from benign nevi. Sixty-six melanocytic lesions (18 malignant melanomas, 8 Spitz nevi, 20 dysplastic nevi, and 20 compound nevi) were stained with antibodies to pHH3, Ki-67, and survivin. No pHH3 expression was detected in the dermis of compound and dysplastic nevi. Rare mitoses were observed in the superficial dermis in 3 of 8 Spitz nevi (37%). Staining for pHH3 was higher in malignant melanomas [average 25 per 10 high-power field (HPF), range 2-75 per 10 HPF] than in Spitz nevi (average 0.5 per 10 HPF, range 0-2 per 10 HPF) and was heterogeneously distributed in the malignant melanomas compared with a superficial dermal location in Spitz nevi. There was no cytoplasmic staining for survivin in any of the 66 melanocytic lesions and no nuclear staining in any of the benign ones. Survivin nuclear staining was present in 12 of 18 cases of malignant melanoma (67%) with an average index of 7% (range 0%-15%). In benign melanocytic lesions, the Ki-67 index was less than 5% (range 0%-4%) and staining was present close to the dermo-epidermal junction compared with an average index of 27% in melanomas (range 5%-50%) and a generally heterogeneous pattern of staining throughout the dermis. pHH3 and Ki-67 can be useful adjuncts to histopathology to separate malignant melanoma from benign nevi. pHH3 is especially useful to highlight mitoses and to rapidly assess the mitotic activity in melanocytic lesions.

Multiple Spitz naevi: a report of both variants with clinical and histopathological correlation.

Spitz naevi are usually solitary lesions. Multiple Spitz naevi are extremely rare and reported as widespread (disseminated) or grouped (agminated). We report two cases of multiple Spitz naevi and review their aetiology and treatment.

Persistent (recurrent) Spitz nevi: a histopathologic, immunohistochemical, and molecular pathologic study of 22 cases.

This report describes 22 Spitz nevi that seemed to have been clinically removed but persisted and clinically recurred at the biopsy site. These were evaluated in terms of histopathology, immunohistochemistry, and molecular pathology using comparative genomic hybridization (CGH) and fluorescent in situ hybridization. One of these 22 lesions was originally reported as an atypical melanocytic proliferation with some features of a Spitz nevus and was included in the study set at an early stage but was later recognized as melanoma after metastasis to regional lymph nodes 3 years after the local recurrence. We noted four histopathologic patterns in the recurrent lesions: 1) a predominantly intraepidermal pattern resembling "pseudomelanoma" as seen in recurrent "common" melanocytic nevi, 2) a compound, mostly nested pattern above or within a scar that was nearly identical to the originally biopsied Spitz nevus, 3) a nodular growth pattern that closely simulated invasive melanoma, and 4) a desmoplastic pattern resembling an intradermal desmoplastic Spitz nevus. Although the majority of recurrent lesions exhibited asymmetry and pagetoid spread, the dermal component usually had a low mitotic rate and retained architectural and cytologic maturation, which allowed distinction from invasive melanoma. Except for the metastasizing melanoma, the immunostaining pattern with S-100 and HMB-45 was identical to that previously reported for Spitz nevi. Ki67 revealed a very low proliferation rate in all cases, including the melanoma. CGH performed in 10 cases yielded results consistent with Spitz nevi in eight cases. The remaining two cases showed CGH profiles more typical of melanoma, and one of these was the above-referenced case of melanoma, proven by metastasis. Although ancillary molecular techniques such as CGH are of great help in distinguishing these from melanoma, until such techniques become widely available we advocate complete but conservative excision of any recurrent Spitz nevus.

Spitz naevus versus Spitzoid melanoma: when and how can they be distinguished?

Spitz naevus is a benign melanocytic lesion that shares many histological features with melanoma. While Spitz naevi characteristically occur in children and young adults and melanomas in the middle-aged and elderly, either tumour can occur in patients of any age. In many cases, the histopathological diagnosis of Spitz naevus is straightforward, particularly in small lesions displaying many or all of the typical histological features and occurring in young patients. Tumours that deviate from the classic description, however, cause difficulties in diagnosis. In this review, we highlight histopathological features of Spitz naevi and those that may be useful in distinguishing Spitz naevi from melanomas. We find that the presence of good symmetry, Kamino bodies, and uniformity of cell nests or sheets from side-to-side favours a Spitz naevus. The presence of abnormal mitoses, a dermal mitotic rate of >2/mm2, and mitotic figures within 0.25 mm of the deep border of the lesion favours a melanoma. Immunohistochemical stains for HMB45 and Ki67 sometimes provide additional useful information. Despite this, in some cases it may not be possible to give an unequivocal diagnosis. Recommendations for the reporting of such cases are provided. New techniques have also demonstrated chromosomal, molecular and genetic differences between Spitz naevi and melanomas. This report highlights these new data and speculates on their possible future role in the diagnosis of borderline lesions.

Congenital giant melanocytic nevus with pigmented epithelioid cells: a variant of epithelioid blue nevus.

Epithelioid-cell blue nevus is an unusual cytologic variant of blue nevus that has been recently described mostly in patients with Carney complex, although the lesion may also appear in patients with no evidence of Carney complex. This variant of blue nevus is composed of melanin laden large polygonal epithelioid melanocytes situated within the dermis. The neoplastic cells show no maturation with progressive descent and, in contrast with the usual stromal changes in blue nevi, epithelioid-cell blue nevus exhibits no dermal fibrosis. This report describes a congenital giant melanocytic nevus with pigmented epithelioid cells located on the back of a 2-year-old male. The lesion was present at birth and the patient had no evidence of Carney complex. Histopathologically, the lesion consisted of a large and entirely intradermal melanocytic nevus composed of heavily pigmented epithelioid melanocytes involving the full-thickness of dermis, but extending also to the subcutaneous fat and underlying soft tissues. Immunohistochemically, epithelioid neoplastic melanocytes expressed immunoreactivity for S-100 protein, HMB-45, Melan-A, NK1C3, and microphthalmia transcription factor (MiTF) antibodies. MIB-1 cellular proliferation marker was expressed in the nuclei of only a few scattered epithelioid melanocytes. This report demonstrates that epithelioid-cell blue nevus is a distinctive histopathologic variant of blue nevus that may also appear as a giant congenital melanocytic nevus.

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.

What criteria reliably distinguish melanoma from benign melanocytic lesions?

The differential diagnosis of melanocytic lesions is fraught with difficulty and a common source of litigation either if a lesion misreported as 'benign' recurs locally or re-presents with nodal metastases or if an atypical naevus is called 'malignant' leading to a cosmetically unsatisfactory wider resection, unwarranted anxiety about prognosis and adverse life insurance prospects. Several authors have claimed that there are valid morphological criteria which, alone or in combination, enable reliable distinction between benign and malignant melanocytic lesions. Others question these criteria and, doubting the extent to which unequivocal diagnoses can be rendered in all cases, believe that the diagnosis is purely subjective and that most diagnostic errors are non-negligent. To address these issues, expert opinions were commissioned from three sets of authors. Okun, Edelstein & Kasznica emphasize that a significant minority of melanocytic lesions are so borderline morphologically that diagnostic uncertainty is allowable and that such uncertainty can be handled responsibly. Kirkham, in favouring the methodical use of criteria, concedes that they are 'largely opinion-based rather than evidence-based, but do go beyond mere subjective pattern analysis'. In agreement with Okun and his colleagues. Slater emphasises that no single feature is reliable by itself and that all aspects, including clinical details, should be interpreted together; he has no hesitation in reporting the diagnosis as 'uncertain' in doubtful cases. In the absence of a specific marker pathognomonic of melanocytic malignancy, the diagnosis will continue to rely on the judicious application of morphological criteria with a small proportion of elusive cases in which diagnostic uncertainty should not be concealed.

Epithelioid blue nevus: a rare variant of blue nevus not always associated with the Carney complex.

Epithelioid blue nevus is a rare variant of blue nevus that has been recently described in patients with Carney complex. Some of the patients with Carney complex have multiple epithelioid blue nevi and a familial history of similar lesions is often recorded. Epithelioid blue nevus consists of an intradermal melanocytic nevus composed of polygonal epithelioid cells laden with melanin. Neoplastic cells show no maturation at the base of the lesion and, in contrast with the usual stromal changes in blue nevi, epithelioid blue nevus exhibits no fibrosis of the dermis. We have studied three cases of epithelioid blue nevus in three patients with no evidence of Carney complex. The lesions were solitary and there was no family history of similar lesions. Therefore, epithelioid blue nevus is a distinctive variant of blue nevus that may also appear as a sporadic lesion and is not always associated with Carney complex.