Atypical Spitz nevi/tumors: lack of consensus for diagnosis, discrimination from melanoma, and prediction of outcome.

The biological nature of Spitz nevi/tumors and their diagnostic distinction from, or relationship to, melanoma remain unresolved issues. In this report, a series of 30 melanocytic lesions removed from 28 patients, including atypical Spitz nevi/tumors and metastasizing Spitzoid tumors/melanomas, were evaluated by a panel of dermatopathologists to evaluate interobserver diagnostic concordance and to assess the prognostic power of histological criteria. For inclusion in the study, each lesion had to display some criteria for the Spitz nevus, and in addition one of the following was required: (1) definitive clinical outcome such as metastasis or death of disease, or (2) long-term follow-up if the patient remained disease free. Each lesion was reviewed independently and blinded as to the clinical data by 10 pathologists, who categorized them as (1) typical Spitz nevus/tumor, (2) atypical Spitz nevus/tumor, (3) melanoma, (4) tumor with unknown biological potential, or (5) other melanocytic lesion. There was limited discussion of criteria before the review. Evaluation of 17 Spitzoid lesions yielded no clear consensus as to diagnosis; in only one case did six or more pathologists agree on a single category, regardless of clinical outcome. Notably, however, some lesions that proved fatal were categorized by most observers as either Spitz nevi or atypical Spitz tumors. Conversely, seven or more pathologists scored 13 lesions as melanoma. These results illustrate (1) substantial diagnostic difficulties posed by many Spitz tumors, especially those with atypical features, even among experts, and (2) the lack of objective criteria for their distinction from melanoma and for gauging their malignant potential. Nevertheless, our observations do suggest that a biological relationship exists between the Spitz nevus/tumor and melanoma.

Cutaneous parachordoma. A light microscopic and immunohistochemical report of two cases and review of the literature.

Parachordomas are rare cutaneous tumors that show virtually identical histologic findings to chordomas. Therefore, the major differential diagnosis in a case of parchordoma is metastatic chordoma. Parachordomas are benign neoplasms and most often develop on the extremities adjacent to tendons, synovium or osseous structures, as opposed to chordomas, which are malignant tumors located along the craniospinal axis. While recurrences may occur in cases of parachordoma, metastases have not been reported. In this report, two cases of parachordomas are reported and the literature reviewed. By light microscopy, parachordomas show eosinophilic bands of fibrous tissue separating lobules of cells with variably vacuolated cytoplasm (physaliphorous cells) admixed with more epithelioid cells in a myxoid stroma. Parachordomas and chordomas share immunohistochemical and ultrastructural features. Both stain with S-100 protein and vimentin, and ultrastructurally both demonstrate cytoplasmic vacuoles, intermediate filaments, pinocytotic vesicles, celljunctions, and cytoplasmic membranes with microvillous processes. Chordomas more frequently express cytokeratin (98% vs. 66% in parachordomas) and epithelial membrane antigen (90% vs. 20% in parachordomas) and chordomas have a larger number of rough endoplasmic reticulum-mitochondrial complexes. Thus, positive staining with epithelial membrane antigen and the identification of a large number of rough endoplasmic reticulum-mitochondrial complexes are suggestive of metastatic chordoma. However, the definitive distinction remains a clinical one after appropriate radiologic studies of the skull and spinal chord.

A new application of BCG antibody for rapid screening of various tissue microorganisms.

BACKGROUND: In routine dermatopathology there is growing demand for a simple, fast, cost-effective, and highly sensitive screening tool for the detection of microorganisms. OBJECTIVE: Our purpose was to determine whether immunostaining with polyclonal anti-Mycobacterium bovis (BCG), which is known for its interspecies cross-reactivity, is a suitable screening method for many common microorganisms in dermatopathologic specimens. METHODS: A total of 254 formalin-fixed, paraffin-embedded skin specimens of viral, protozoal, fungal, and bacterial infections were stained with appropriate histochemical stains and with anti-BCG. RESULTS: Anti-BCG labeled bacteria and fungi with high sensitivity and minimal background staining, but did not react with spirochetes, viruses, or protozoa (Leishmania). The quality and sensitivity of anti-BCG staining were superior to conventional histochemical stains. CONCLUSION: Because of its cross-reactivity with many bacteria and fungi as well as its high sensitivity and minimal background staining, the anti-BCG immunostain is a promising screening tool for the detection of the most common bacterial and fungal microorganisms in paraffin-embedded skin specimens.

Dermoscopy (epiluminescence microscopy) of pigmented skin lesions. Current status and evolving trends.

Dermoscopy (epiluminescence microscopy) is a noninvasive technique that is designed for in vivo microscopic examination of pigmented skin lesions, particularly for the early recognition of malignant melanoma. Since its introduction, dermoscopy technique has undergone extensive improvements; the instruments have become more readily available; and the diagnostic indications, benefits, and limitations have been better delineated. This article offers a concise review of the technique of dermoscopy, assesses the current status, and makes some predictions for future applications.

CD44 expression in benign and malignant nevomelanocytic lesions.

CD44 is an integral membrane glycoprotein that is a principal receptor for hyaluronan and plays a role in cell-extracellular matrix interactions. Recent studies of melanomas in mouse models have suggested that increased CD44 expression by these tumors may relate to metastatic potential. Immunohistochemical expression of CD44 (standard [s] and variant [v6]) in benign and malignant nevomelanocytic lesions was assessed in formalin-fixed, paraffin-embedded tissue and was correlated with histological parameters and prognostic factors. Cases included benign nevi (three junctional, four compound, five intradermal, five blue, six Spitz, one deep penetrating), architecturally disordered (dysplastic) nevi (three, and primary (22) and metastatic melanomas (eight). All of the benign lesions showed diffuse and essentially uniform membrane staining of CD44s in nevomelanocytic cells, regardless of lesion size, depth, or extent of dermal involvement. In contrast, semiquantitative analysis (0 to 3+) of the primary melanomas showed heterogeneous and decreased staining of CD44s, which inversely correlated with lesion size (-0.569) and depth of invasion (-0.622 and -0.617 for Breslow's depth and Clark's level, respectively). These results were significant at P < .05. CD44s expression in metastases paralleled that of their respective primaries. None of the benign nevomelanocytic lesions showed CD44v6 staining. In contrast, all of the malignant nevomelanocytic lesions showed cytoplasmic staining of the tumor cells. Pretreatment with chondroitinase did not alter CD44s staining. CD44s expression by immunohistochemical determination is uniform in benign nevomelanocytic lesions. Malignant melanomas show decreased, heterogeneous staining that inversely correlates with increasing size, depth, and level of invasion. CD44 expression may be a prognostic indicator in malignant melanomas. Tumor staining with anti-chondroitin sulfate monoclonal antibodies suggests that CD44s may be expressed as a chondroitin sulfate proteoglycan in primary melanomas.

Expression of nerve growth factor and epidermal growth factor receptors in neural nevi with nevic corpuscles.

The histogenesis of "nevic corpuscles" (NCs) in neural nevi is still controversial. Recent studies have revealed that nerve growth factors (NGFs) and other growth factors [that is, epidermal growth factor (EGF)] could have various paracrine and autocrine functions on Schwann cells and melanocytes. We examined the immunohistochemical expression of NGF and EGF receptors (r) in 15 cases of neural nevi containing NCs along with 37 cases of other benign and malignant melanocytic lesions without neural differentiation (total, 52). Section were prepared from formalin-fixed and paraffin-embedded tissues. Monoclonal antibodies to NGFr and EGFr were used with the Avidin-biotin-complex (ABC) technique. We found strong reactivity for NGFr in 14 of 15 neural nevi with a predilection for NCs, but only eight of 37 were positive in the other group of melanocytic lesions without neural differentiation (four Spitz nevi, two melanomas, and two compound nevi). EGFr expression was limited mainly to NCs in four cases of neural nevi. We conclude that neural differentiation and NC formation are associated with NGFr overexpression, whereas EGFr expression is only limited. The relative paucity of NGFr expression in other type of benign and malignant melanocytic lesions supports the view that neural "differentiation" is a distinct process in certain long-standing melanocytic nevi. We postulate that NGFr overexpression may be the result of the reactivation of oncofetal genes that could become manifest in either abnormal schwannian differentiation (as seen in neural nevi), in a neoplastic context (as seen in neural and melanocytic tumors).

Cutaneous neural heterotopias and related tumors relevant for the dermatopathologist.

Heterotopic neural tumors are rare in the skin; however, when encountered, they often pose a diagnostic problem. While the clinicopathologic features of most neuroaxis abnormalities are well-documented in the neuropathologic literature, their significance in cutaneous pathology as well as the associated nonneural dermatopathologic findings have not received enough attention. This report offers a comprehensive review of the most common cutaneous neural heterotopic abnormalities and their related tumors. The clinicopathologic features of the following entities along with their histogenetic considerations are discussed: classical and rudimentary meningocele, primary cutaneous meningioma, heterotopic brain tissue (nasal glioma), peripheral primitive neuroectodermal tumor, metastatic neuroblastoma, and ganglioneuroma. Familiarity with the associated dermatopathologic changes and with the differential diagnosis should assist in arriving at the correct diagnosis even without special training in dermatopathology or neuropathology.

Trisomy 7 in keratoacanthoma and squamous cell carcinoma detected by fluorescence in-situ hybridization.

Keratoacanthoma (KA) is generally considered to be a clinically and histologically distinct entity, but it often remains difficult to separate from well-differentiated squamous cell carcinoma (WDSCC). Recently, trisomy 7 has been identified in squamous cell carcinoma of the skin. In this study, we examined classical KA (n = 6), WDSCC (n = 7) and squamous cell carcinoma with KA-like features (SCC-KA) (n = 8) for trisomy 7 by fluorescence in-situ hybridization (FISH) to determine if this chromosomal abnormality is unique to squamous lesions diagnosed as WDSCC, or shared by both KA and SCC. In addition, the pertinent clinical-histopathologic findings were summarized. Trisomy 7 was identified in one KA, one SCC-KA and two WDSCC. This study demonstrates that there is a chromosomal abnormality shared by KA and SCC, providing further evidence that KA is most likely a form of SCC. Further studies are required to determine if trisomy 7 in these lesions is of prognostic significance.

Keratoacanthoma versus squamous cell carcinoma. An immunohistochemical reappraisal of p53 protein and proliferating cell nuclear antigen expression in keratoacanthoma-like tumors.

The controversy of distinguishing keratoacanthomas (KAs) from well-differentiated squamous cell carcinomas (WDSCCs) is well established. A number of recent studies have attempted to separate these processes with the use of immunohistochemical stains. In corroboration, we have retrospectively reviewed three groups of patients with tissue biopsies with features of classical KA (n = 7), WDSCC (n = 8), and squamous cell carcinoma with KA-like features (SCC-KA) (n = 9). We compared their clinical and histological differences as well as their immunohistochemical differences using antibodies to proliferating cell nuclear antigen (PCNA), and wild- and mutant-type p53 protein. Classical KA showed a PCNA staining pattern located predominantly around the basal cell layers, in contrast to a relatively diffuse staining pattern seen in WDSCC. SCC-KA showed considerable overlap with these two types of staining patterns. The p53 staining showed basal, patchy, or diffuse patterns. These patterns were present in all three groups. Although both PCNA and p53 expression was more often present in SCC-KA, there were no statistical differences among the groups. In conclusion, the overlapping expression patterns of PCNA and p53 in keratocanthoma-like tumors support the hypothesis that these tumors represent a possible biologic spectrum. Because of the absence of significant statistical differences in the expression of these antigens, PCNA and p53 have not proved to be helpful in differentiating KA from KA-like squamous cell carcinoma.

CD31 immunoreactivity in mesenchymal neoplasms of the skin and subcutis: report of 145 cases and review of putative immunohistologic markers of endothelial differentiation.

CD31 has recently been reported as a specific marker of endothelial differentiation among non-hematopoietic human neoplasms. In order to address this contention in particular regard to tumors of the skin and subcutis, the authors undertook a comparative study that surveyed 145 mesenchymal lesions. The antibodies used were directed against CD31 (clone JC/70A) and CD34 (clone My10), and these were compared with binding of Ulex europaeus I agglutinin (UEA). Proliferations that were included in the category of vascular tumors included cavernous and capillary hemangiomas (17 cases); lymphangiomas (8); epithelioid ("histiocytoid") hemangiomas (3), papillary endovascular hemangioendothelioma (1), angiosarcoma (7), and Kaposi's sarcoma of the mixed angiomatoid and spindle-cell type (17). CD31-immunoreactivity was observed in 35 of 53 vascular lesions; the neoplastic cells in a single angiosarcoma and the spindle cells in each case of Kaposi's sarcoma (KS) were not labeled. In all of the latter tumors, however, staining for CD31 was identified in the endothelia of angiomatoid areas and non-neoplastic blood vessels. These results compared favorably with those seen with anti-CD34, which decorated 36 of 53 vascular tumors--including 8 of 17 KS cases--and UEA, which bound to the neoplastic cells of 36 lesions. In contrast, all of 92 non-endothelial tumors included in this study (34 nerve sheath tumors [30 benign; 4 malignant]; 39 fibrohistiocytic neoplasms [11 benign; 28 malignant]; 9 smooth muscle tumors [6 benign; 3 malignant]; 7 glomus tumors; and 3 giant cell fibroblastomas) were negative for CD31. UEA labeled 3 non-vascular neoplasms, whereas 38 lesions of that type were CD34-positive.(ABSTRACT TRUNCATED AT 250 WORDS)

Ultrastructural spectrum of cutaneous nerve sheath myxoma/cellular neurothekeoma.

The histogenesis of cutaneous nerve sheath myxoma (NSM)/cellular neurothekeoma (CNT) is still controversial. In this study, we examined the ultrastructural features of 16 NSM (3 classical, 11 CNT, and 2 mixed NSM/CNT). We classified the cells into 4 groups ultrastructurally. Type I cells were undifferentiated polygonal cells with ovoid nuclei, cytoplasmic microfilaments, and occassionally with microfilament-associated dense bodies. In most cells, the cytoplasmic membrane showed focal membranous densities and occasional basal-lamina-like material. This cell type comprised approximately 90% of CNT. Type II cells were more differentiated, had ovoid or spindled shapes, were rich in intracytoplasmic filaments, and were surrounded by continuous basal lamina. These cells were consistent with Schwann cells and were present in the classical and mixed forms of NSM, and in a single case of CNT. Type III cells had features of perineurial cells and were relatively rare in classical NSM. Type IV cells resembled fibroblasts and were encountered in all variants of NSM. These results support the view that 1) the classical NSM has neural (mainly Schwann cell) differentiation, 2) CNT is predominantly composed of undifferentiated cells with partial features of Schwann cells, smooth muscle cells, myofibroblasts and fibroblasts, suggesting a divergent differentiation, and 3) CNT and NSM represent a histologic spectrum, but in CNT, the neural features are not fully expressed.

Histiocytosis X of the vulva with a confusing clinical and pathologic presentation. A case report.

Histiocytosis X (HX) is a rare disorder of Langerhans cells and most commonly occurs in children. We report a case of HX of the vulva in a 76-year-old woman that clinically simulated a yeast infection of the vulva but histologically resembled an amelanotic melanoma. We briefly report the clinical and pathologic features of this case, which responded to vincristine followed by vinblastine and was in complete remission after nine months.

Primary cutaneous meningioma associated with von Recklinghausen's disease.

Cutaneous meningeal tumors are rare and can pose a diagnostic problem. We present a case of a 12-year-old girl with a family history of von Recklinghausen's disease. The patient was asymptomatic until the age of 11, when she developed two lesions on the head, both diagnosed as plexiform neurofibroma. Subsequently, she presented with a subcutaneous nodule on the left posterior occipital scalp which was excised. On histology, the tumor was composed of spindle-shaped cells with diffuse and nested patterns. A whorled configuration of the cells, with occasional giant cells and psammoma bodies, was present. There was no evidence of connection between the tumor and the underlying tissues. Immunohistochemical studies were positive for epithelial membrane antigen, vimentin, and weakly for neuron-specific enolase. Cytokeratin, S-100 protein, and muscle markers were negative. Based on these features, the diagnosis of cutaneous meningioma was made. An MRI examination failed to detect any communication between the tumor site and the meninges; however, asymptomatic bilateral acoustic neuromas were identified. This case, besides being of interest as a primary cutaneous meningioma, also documents a unique combination of findings, i.e., plexiform neurofibroma, meningioma, and cerebellopontine acoustic neuromas, which should alert the clinician to a forme fruste presentation of von Recklinghausen's disease.

S-100 protein-negative malignant melanoma: fact or fiction? A light-microscopic and immunohistochemical study.

S-100 protein is considered a characteristic immunohistochemical marker for all nevomelanocytic lesions, in which it is expected to be present consistently. We reviewed 17 cases of malignant melanomas that previously tested negative for S-100 protein. They were reevaluated by light microscopy, a broad panel of immunohistochemical reagents including monoclonal and polyclonal antibodies to S-100 protein, and electron microscopy. On reexamination, five of the 17 cases were reclassified as non-melanoma tumors, and eight of the 17 cases were found to be positive for S-100 protein (six with monoclonal and eight with polyclonal antibodies) and HMB-45 antigen, consistent with melanoma. The remaining four cases repeatedly tested negative for S-100 protein despite various antigen enhancement methods, but they were positive for HMB-45 antigen and contained premelanosomes or melanosome-like structures by electron microscopy. Two of these repeatedly S-100 negative melanomas were acrally located; although the numbers are small, a possible relationship to a specific anatomic location cannot be excluded. These findings suggest that in a small subset of melanomas S-100 protein is either not fully expressed or is below the level that can be detected by routine immunohistochemistry. We also conclude that in the majority of the initially S-100-negative cases of melanomas, the misdiagnosis may occur due to the use of an incomplete immunohistochemical panel, technical reasons, or the inherent variability of tissue expression of S-100 protein.

Large-cell acanthoma of the skin. A study by image analysis cytometry and immunohistochemistry.

Although large-cell acanthoma is a well-known clinicopathological entity, its biologic spectrum and nature are still subject to debate. We studied seven cases of large-cell acanthoma by image analysis cytometry for DNA content and by immunohistochemistry, using antibodies to proliferating cell nuclear antigen (PCNA)/cyclin. The data were compared with individual cases of seborrheic keratosis (SK), actinic keratosis (AK), and Bowen's disease (BD). The DNA distribution of large-cell acanthoma was variable. There were varying peaks at the DNA index values of 1 and 2 (diploid and tetraploid values), but all cases contained a significant aneuploid population between DNA index of 1 and 2. The mean DNA index was 1.44 (1.27-1.77); 1-20% of the cells exceeded 2, and 0-2% exceeded 3. The DNA index for lesions in the other differential diagnostic groups studied was as follows: SK, 1.0; AK, 1.4; BD, 1.8. The percentage of cells with positive nuclear staining for PCNA/cyclin was < 20% in all cases of large-cell acanthoma. The discrepancy between the high number of aneuploid and tetraploid cells observed on the DNA distribution curve and the lack of evidence for significant proliferation based on immunohistochemical stains suggest that these cells are resting cells with abnormal DNA clone. Although these results provide additional information about the biologic nature of large-cell acanthoma, they do not resolve the controversial nosologic status of lesions in this histologic group.

Hamartoma of the tongue in an infant with a primary diagnosis of ectrodactyly-ectodermal dysplasia-cleft lip and palate syndrome.

We describe a case of an unusual tongue hamartoma associated with ectrodactyly-ectodermal dysplasia-clefting syndrome in a 3-month-old white female infant. The lesion was composed of a mixture of salivary glands, adipose tissue, smooth muscle and skeletal muscle in a haphazard fashion. Lingual hamartomas are rare and can present a clinical differential diagnostic problem. We review the literature on this unique combination of malformations.

The preparation of frozen sections for micrographic surgery. A review of current methodology.

BACKGROUND: Various methods are currently in use for preparing histological slides for micrographic surgery. OBJECTIVE: Because many variables contribute to the quality preparation of frozen sections, a review of techniques available is useful to the Mohs surgeon. TECHNICAL METHODS AND RESULTS: Our techniques as well as the published work of others regarding mounting, embedding, freezing, slides, fixation, staining, and clearing are reviewed in detail. By the use of the options selected we were able to produce, in a short turn-around time, frozen sections with excellent quality and minimal artifact. CONCLUSION: Presently all preparation techniques may introduce some degree of artifact. However, we feel the process described herein is adaptable to all Mohs surgery laboratories and will result in high quality specimens with minimal artifact.

Immunohistochemical study of Spitz nevi and malignant melanoma with use of antibody to proliferating cell nuclear antigen.

Spitz nevi and malignant melanoma may be difficult to differentiate histologically. We applied an antibody to proliferating cell nuclear antigen (PCNA) to cases of Spitz nevi and malignant melanoma to determine if there were differences in reactivity. Cases were selected from the material of the Department of Pathology, University of Iowa Hospital. Formalin-fixed, paraffin-embedded cases were immunohistochemically stained with anti-PCNA (PC 10) with use of avidin-biotin complex technique. The cases were evaluated for the presence or absence of reactivity, staining intensity, and semiquantitative percentage of positive cells. Positive staining was observed in six of the 10 cases of Spitz nevi. The intensity of staining was weak and the number of positive cells varied from 10% to 40%. Positive staining was observed in all 10 cases of malignant melanoma. In eight of these 10 cases the intensity of staining was strong and the number of positive cells was greater than 40%. In the remaining two cases of melanoma, the intensity of staining was weak and the percentage of positive cells was 20-30%. These results indicate that PCNA staining may be observed in both Spitz nevi and malignant melanoma. Presence or absence of reactivity cannot be used in distinguishing these processes. However, a pattern of strong, diffuse reactivity may be used as an adjunct for supporting a diagnosis of melanoma.

Nerve sheath myxoma (neurothekeoma) of the skin: light microscopic and immunohistochemical reappraisal of the cellular variant.

Nerve sheath myxoma (NSM) is a rare cutaneous neoplasm, the histogenesis of which is controversial. Fifteen cases of NSM were studied by routine light microscopy and with a broad panel of immunohistochemical stains. NSM were classified into three groups based on cellularity, mucin content and growth pattern. 1) The hypocellular (myxoid) type (5/15 cases) showed frequent encapsulation or sharp circumscription. Immunohistochemically this type was strongly positive for S-100 protein and collagen type IV and variably positive for epithelial membrane antigen. 2) The cellular type (4/15 cases) had scant mucin and ill-defined nodular or infiltrating growth. Immunostaining showed positive reaction for neuron specific enolase (2/4), Leu-7 (1/4) and smooth muscle specific actin (2/4), and was negative with the other antibodies. 3) The "mixed type" (6/15 cases) had variable cellularity and mucin content with poor demarcation and variable immunolabeling. We conclude that: 1) there are major light microscopic and immunohistochemical differences between the classical hypocellular (myxoid) and the cellular forms of NSM (neurothekeoma); 2) while the immunohistochemical results support the presence of nerve sheath differentiation in the classical forms of NSM, and to some extent in the mixed forms, there is an absence of convincing evidence of neural differentiation in the cellular variant by either light microscopy or immunohistochemistry; 3) the variable immunophenotypes suggest that differentiation other than neural may take place in CNT.

Degenerative ("ancient") changes in benign cutaneous schwannoma. A light microscopic, histochemical and immunohistochemical study.

We studied the degenerative "ancient" changes in 19 cases of benign cutaneous schwannoma (BCS). Using conventional and immunohistochemical stains, we found (a) degenerative changes in 15 of 19 BCS; (b) prominent vascular abnormalities in 11 of 15 BCS; and (c) cytologic atypia in 15 of 19 BCS, without mitotic figures. We concluded that (1) degenerative, i.e., "ancient" changes are common in BCS and are qualitatively similar to those described in cellular schwannoma; (2) vascular abnormalities may be related to these degenerative changes; (3) cytologic atypia is commonly associated with "ancient" changes in BCS, but BCS is less cellular and has few if any mitotic figures as opposed to cellular schwannomas; and (4) the changes in "ancient" schwannoma do not indicate a "cellular" schwannoma.