Electron microscopy of Merkel cell carcinoma from formalin-fixed tissue

Merkel cell carcinomas have characteristic, but not pathognomonic, histomorphologic features. The diagnosis can be confirmed by immunohistochemistry studies and electron microscopy. However, differential diagnostic problems often occur only after all tumor material has been fixed in formalin and embedded in paraffin, which gives poor tissue preservation for electron microscopy. Therefore, in addition to histologic and immunohistochemical studies, parallel ultrastructural investigations were performed on tumor specimens fixed in glutaraldehyde and routinely processed, for electron microscopy, on formalin-fixed tissue and on formalin-fixed paraffin blocks. Formalin fixation led to an almost complete loss of neurosecretory granules and cell membranes; however, the characteristic paranuclear whorls of intermediate filaments were retained in all tumors. Merkel cell carcinomas are immunoreactive for neuron-specific enolase (NSE), but NSE-antisera have only recently become commercially available. Cytokeratin is demonstrable as a paranuclear clump, and this feature was found in four out of six tumors. Thus histologic, immunohistochemical, and electron microscopy studies of formalin-fixed tissue are able to confirm the diagnosis of neuroendocrine Merkel cell carcinoma.     

Real-time,in vivo confocal reflectance microscopy of basal cell carcinoma

BACKGROUND: Real-time, near-infrared confocal laser scanning microscopy may provide a way to diagnose basal cell carcinoma in vivo and might potentially eliminate the need for invasive diagnostic biopsies in the future. OBJECTIVE: The purpose of this study is to define the in vivo histologic features of basal cell carcinoma by using a high-resolution imaging technique. METHODS: Five fair-skinned white patients with 8 basal cell carcinoma lesions were recruited for this study. Near-infrared reflectance confocal microscopy imaging was used to characterize the histologic features of these lesions in vivo. Subsequently, the confocal histologic features were correlated with the corresponding routine hematoxylin-and-eosin-stained sections obtained from invasive biopsies. RESULTS: A uniform population of basal cell carcinoma cells with characteristic elongated nuclei oriented along the same axis was always present. Abundant blood vessels demonstrating prominent tortuosity were seen, as well as prominent, predominantly mononuclear inflammatory infiltrate admixed or in close apposition with basal cell carcinoma cells. Trafficking of leukocytes was visualized in real time. CONCLUSION: Our results demonstrate that near-infrared confocal microscopy may facilitate diagnosis of basal cell carcinoma with the use of in vivo high-resolution confocal features. Accuracy studies to evaluate these in vivo histologic criteria are warranted.     

Canine epidermotropic cutaneous lymphoma

The histologic features of an epidermotropic cutaneous lymphoma in a dog are presented. The neoplasm, which was intensely epidermotropic, thoroughly invaded the follicular and apocrine gland epithelium. The intense epidermotropism was retained in the tumor stage. By comparison to human mycosis fungoides, the cell nucleus was less convoluted and the infiltrate was less polymorphic. The lymphoid cell appeared to undergo neoplastic transformation into a cell with a large pale nucleus, often with a prominent nucleolus and variable cytoplasm. In situ marker studies are needed to clarify the cell type in this neoplasm. These studies could have relevance for the pathogenesis of human epidermotropic lymphoma.     

The dysplastic nevus: from historical perspective to management in the modern era: part II. Molecular aspects and clinical management

The dysplastic nevus is a discreet histologic entity that exhibits some clinical and histologic features overlapping with common nevi and melanoma. These overlapping features present a therapeutic challenge, and with a lack of accepted guidelines, the management of dysplastic nevi remains a controversial subject. Although some differences between dysplastic and common nevi can be detected at the molecular level, there are currently no established markers to predict biologic behavior. In part II of this continuing medical education article, we will review the molecular aspects of dysplastic nevi and their therapeutic implications. Our goal is to provide the clinician with an up-to-date understanding of this entity to facilitate clinical management of patients with nevi that have histologic dysplasia.     

Neutrophilic spongiosis in pemphigus herpetiformis

Pemphigus herpetiformis is a rare pemphigus variant with light microscopic features that have historically been described as either "acantholytic dermatitis herpetiformis" or as "eosinophilic spongiosis in pemphigus". The clinical features of this form of pemphigus are reminiscent of dermatitis herpetiformis; however, the direct immunofluorescence finding of epidermal intercellular IgG deposition is that of the pemphigus group. We report two patients with clinical presentations suggestive of dermatitis herpetiformis in whom the histopathologic features were those of a neutrophilic intraepidermal blistering disorder. Biopsies showed marked epidermal spongiosis with midepidermal acantholytic vesicles containing predominantly neutrophils and a few eosinophils. Direct immunofluorescence was positive for epidermal intercellular IgG; IgA deposition was not present. Neutrophilic spongiosis, in the absence of a prominent eosinophilic infiltrate, should be recognized as an early finding in some cases of pemphigus, and immunofluorescence studies are justified when this histologic feature is encountered in a skin biopsy.     

Patrones de microscopia confocal para el cáncer cutáneo no melanoma y aplicaciones clínicas

Reflectance confocal microscopy is currently the most promising noninvasive diagnostic tool for studying cutaneous structures between the stratum corneum and the superficial reticular dermis. This tool gives real-time images parallel to the skin surface; the microscopic resolution is similar to that of conventional histology. Numerous studies have identified the main confocal features of various inflammatory skin diseases and tumors, demonstrating the good correlation of these features with certain dermatoscopic patterns and histologic findings. Confocal patterns and diagnostic algorithms have been shown to have high sensitivity and specificity in melanoma and nonmelanoma skin cancer. Possible present and future applications of this noninvasive technology are wide ranging and reach beyond its use in noninvasive diagnosis. This tool can also be used, for example, to evaluate dynamic skin processes that occur after UV exposure or to assess tumor response to noninvasive treatments such as photodynamic therapy. We explain the characteristic confocal features found in the main nonmelanoma skin tumors and discuss possible applications for this novel diagnostic technique in routine dermatology practice.     

A primary cutaneous vascular neoplasm with histologic features of anastomosing hemangioma

Anastomosing hemangioma (AH) is a relatively novel variant of benign vascular tumors originally described in the genitourinary tract. Although AH was subsequently documented in various anatomic locations, a primary AH of the skin has not been reported in the literature. The current case report documents a vascular lesion with histologic features reminiscent of an AH. A 41‐year‐old female patient underwent an excision of a painful nodule on the leg. Histologic examination showed a well‐circumscribed vascular lesion composed of anastomosing sinusoidal capillary‐sized vessels, several intravascular fibrin thrombi, rare intraluminal nucleated red blood cells, and focal intracytoplasmic hyaline globules. As AH was hitherto only documented in extracutaneous sites, most dermatopathologists are probably not familiar with this variant of hemangioma. The current case report details the morphologic features of a potential example of a primary cutaneous AH to increase the awareness of this distinctive hemangioma variant among dermatopathologists. Larger studies of vascular lesions with similar histologic features and immunohistochemical profiles are warranted to investigate the potential existence of primary AH in the skin.     

Primary cutaneous malignant melanoma

The prognosis of localized malignant melanoma is related to several histologic features of the primary lesion. Growth pattern, level of invasion, and tumor thickness are currently most widely used in clinical practice, but other features, including ulceration, mitotic rate, density of the inflammatory response, evidence of partial regression, angioinvasion, cell type, cross-sectional profile, and amelanosis have been accorded prognostic significance in single factor analyses. Although stringently controlled prospective studies have yet to demonstrate the validity of these factors for the determination of optimal surgical treatment in individual cases, newer statistical methods of multivariate analysis have made possible assessment of the relative importance of each of these histologic characteristics. The most important and reproducible factor for predicting survival is maximum tumor thickness. Consensus also supports ulceration as another important, independent prognostic indicator, whereas growth pattern and level of invasion derive most of their prognostic value from a secondary correlation with tumor thickness. Mitotic rate may influence survival in the subgroup of patients with high-risk, thick melanomas.     

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.     

Quantification of histologic features of dysplastic nevi

We quantified the histologic features of 100 consecutive dysplastic nevi. Although there is heterogeneity in the microscopic attributes of dysplastic nevi, certain features that are seen repeatedly should enable the histologic identification of these melanocytic neoplasms. These features include a central dermal nevocytic component with a peripheral extension of a junctional component, elongated epidermal rete ridges, bridging of nests of melanocytes at the dermo-epidermal junction, nests of melanocytes at the sides of rete ridges as well as at their bases, and concentric eosinophilic fibrosis. Cytologic features of melanocytes were not as valuable as architectural features of individual nevi in classifying these lesions. We also provide an atlas of selected histologic features that depicts some aspects of this heterogeneity.     

Neuroendocrine differentiation of a metastatic basal cell carcinoma in a patient with basal cell nevus syndrome

A 48 year-old white male with basal cell nevus syndrome presented with a metastatic basal cell carcinoma with neuroendocrine features. The tumor manifested aggressive behavior, having deep local invasion and metastases to para-aortic lymph nodes and bone. Neuroendocrine differentiation has rarely been associated with basal cell carcinoma. The histologic, immunohistochemical, and electron microscopic studies of this rare tumor are described.     

Cutaneous lymphadenoma

Cutaneous lymphadenoma is a rare tumor with distinctive histologic features. This entity was originally described as lymphoepithelial tumor by Santa Cruz and Barr in 1987. It was renamed cutaneous lymphadenoma in 1991. To date, at least 31 cases of this entity have been reported. The literature did not contain a clinical photograph of this lesion. A case of this rare tumor is described that includes clinical and histologic features. The literature regarding the unclear histogenesis of this distinctive tumor is reviewed. This report is one of a only few clinical illustrations of cutaneous lymphadenoma. Consistent with previous reports, the histologic findings in this case include basaloid proliferation and intraepithelial lymphocytes. The usual initial clinical diagnosis is basal cell carcinoma localized mainly to the head and neck area. The incidence is approximately equal in male and female patients. Excision of this benign neoplasm is curative. Controversy exists regarding the histogenesis of this tumor.     

Assessment of histologic criteria in the diagnosis of mycosis fungoides

BACKGROUND: The histologic diagnosis of early mycosis fungoides (MF) can be difficult to establish in many instances because the subtle changes observed in patches of MF are also present in many inflammatory dermatoses. METHODS: To assess the frequency and significance of many of these histologic parameters, we retrospectively reviewed 50 slides from patients with documented MF in patch, plaque, and tumor stages. The diagnosis of MF was unequivocally established either by the progression of patients to advanced stages of the disease or by indubitable histologic findings. In the second phase of the study, we compared the histologic parameters observed in 24 patch stage MF patients with those in 24 non-MF patients. The non-MF group were patients whose pathologic pattern was suspicious for MF, but who definitely did not have MF on clinical grounds. The two groups were matched by histologic pattern. Two different observers evaluated the slides and the intensities of 32 histologic parameters were graded on a four-point scale to minimize the subjective variability in the histologic reports. RESULTS: On univariate analysis, the following parameters achieved significance in distinguishing MF from non-MF: Pautrier's microabscesses, haloed lymphocytes, disproportionate epidermotropism, epidermal lymphocytes larger than dermal lymphocytes, hyperconvoluted lymphocytes in the epidermis and dermis, absence of dyskeratosis, and papillary dermal fibrosis. None of these features proved to have additional discriminating power on multivariate analysis. CONCLUSIONS: The efficacy of single histologic features in the diagnosis of early MF is generally poor and, to discriminate MF from its inflammatory simulators, a combination of cytologic and architectural features must be used.     

Subepidermal Bullous Disease

The histologic features of 51 cases of subepidermal bullous disease were evaluated and correlated with the clinical features including the course of the disease and the response to therapy. There was a good clinico-pathologic correlation, 46 out of 51 cases showing concordant clinical and histologic diagnoses. We conclude that although immuno-fluorescence is a confirmatory procedure histologic diagnosis is still of great value, particularly in the early stages of the disease when the clinical features may not yet have evolved sufficiently to allow for a confident diagnosis.     

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.     

Papular umbilicated granuloma annulare. A report of four pediatric cases.

BACKGROUND--Granuloma annulare is a common skin condition usually presenting as annular plaques composed of intradermal papules. Variants such as disseminated, subcutaneous, and perforating have been described. In this article, the clinical and histologic features of a distinct papular umbilicated form of granuloma annulare are described. OBSERVATIONS--Four boys aged 5 to 9 years presented with papular, umbilicated, flesh-colored papules limited to the dorsa of the hands and fingers. Histologically there were unusually distributed but typical features of granuloma annulare, including well-demarcated areas of necrobiosis of collagen, localized beneath areas of epidermal thinning and parakeratosis. There was no perforation. CONCLUSIONS--Papular umbilicated granuloma annulare appears to be a distinct variant that may be difficult to diagnose because of its unique clinical and histologic features.     

Ataxia-telangiectasia Associated with Sarcoidosis

Ataxia-telangiectasia and sarcoidosis are diseases characterized by abnormalities of the immune system. We examined a 13-year-old female with ataxia-telangiectasia who developed atrophic, violaceous plaques of the skin and a destructive, polyarticular arthritis. The histologic features of both skin and synovium were most consistent with a diagnosis of sarcoidosis. Interaction of these two immunologic disorders may have resulted in the unusual features of this patient's disease.     

Eccrine Angiomatous Hamartoma: Report of Three Patients

Abstract: Eccrine angiomatous hamartoma is a rare, benign entity. The histologic features include proliferation of eccrine sweat glands and angiomatous capillary channels. We report three children who each had a single lesion on a limb. These lesions were clinically angiomatous, and we obtained the diagnosis by histologic and immunohistochemical studies.     

Is melanocyte density our last hope? Comparison of histologic features of photodamaged skin and melanoma in situ after staged surgical excision with concurrent scouting biopsies

Differentiating melanocytic hyperplasia (MH) on photodamaged skin from junctional lentiginous melanocytic proliferations (JLMP), early evolving melanoma in situ (MIS), or the periphery of a lesion of MIS on staged excision can be challenging. Although previous cross‐sectional studies have elucidated important criteria for distinguishing MH on photodamaged skin from more concerning lesions, this study highlights a technique to treat JLMP and MIS with staged mapped excision and baseline scouting biopsies of adjacent nonlesional photodamaged skin to assist in determination of surgical margin clearance. Additionally, we compare the lesional and photodamaged control biopsies from the same patient to evaluate relevant histologic criteria that may be used to distinguish MH in photodamaged skin from JLMP/MIS, while minimizing confounding factors. There was a statistically significant difference (P ≤ 0.05) found for melanocyte density, irregular melanocyte distribution, melanocyte clustering, follicular infundibulum involvement, and nesting. However, criteria such as nesting, epithelioid cells and melanocyte clustering were seen in both photodamaged skin and MIS. These findings underscore the fact that histologic features of photodamaged skin can overlap with the histopathological features of MIS. Of all of the criteria evaluated, melanocytic density was the most objective histologic criterion and did not show overlap between the sun‐damaged and JLMP/MIS groups.     

Palmoplantar Eccrine Hidradenitis: Three New Cases and Review

Abstract: Palmoplantar eccrine hidradenitis (PEH) is characterized by painful erythematous papules and nodules of abrupt onset on the soles of young individuals. The histologic hallmark is a predominant neutrophilic infiltrate surrounding the eccrine gland apparatus. A total of 28 cases have been published since 1988, with a broad variation in the age of patients, symptomatology, associated diseases, clinical course, and histologic features. These different histologic pictures have resulted in several names for this entity, including idiopathic plantar hidradenitis, neutrophilic eccrine hidradenitis, recurrent palmoplantar hidradenitis in children, and idiopathic palmoplantar hidradenitis. We present three cases of this disorder and review the literature on the varying symptomatology, clinical course, and histology that have led to the myriad of names for this disease.