Bowen disease with matrical differentiation: Report of an exceptional histopathologic presentation.

Matrical differentiation is the distinctive feature of pilomatricoma and other purely matrical adnexal neoplasms; additionally, foci of matrical differentiation have been also described in hybrid cysts of Gardner syndrome, as well as in a wide variety of benign and malignant cutaneous tumors, including basal cell carcinoma. We report an exceptional case of Bowen disease exhibiting multiple foci of matrical differentiation, as confirmed by means of immunohistochemical studies. Several types of divergent, non-squamous differentiation have been exceptionally reported in cutaneous squamous cell carcinoma in situ (cSCCIS), including sebaceous, mucinous/glandular, poroid, tricholemmal, and neuroendocrine differentiation; matrical differentiation may be added to this list. Our findings further emphasize the undifferentiated nature of neoplastic cells in cSCCIS.

Mitotic rate in primary melanoma: interobserver and intraobserver reliability, analyzed using H&E sections and immunohistochemistry.

BACKGROUND: In 2009, the AJCC issued a revised melanoma staging system. In addition to tumor thickness and ulceration, the mitotic rate was introduced as the third major prognostic parameter for the classification of primary cutaneous melanoma. Given that, according to the 2009 AJCC classification, the detection of one or more dermal tumor mitoses leads to an upstaging - from stage Ia to Ib - of melanomas with a tumor thickness of ≤ 1.0 mm, we set out to investigate the reproducibility of this new parameter. METHODS: In order to assess interobserver reliability, 17 dermatopathologists und pathologists - all well versed in the diagnosis of cutaneous melanoma - analyzed the mitotic rate in 15 thin primary cutaneous melanomas (mean tumor thickness 0.91 mm) using identical slides. Mitotic rates were determined on H&E and phosphohistone H3 (Ser10)-stained samples. Without knowledge of their previous assessment, five of the aforementioned examiners reevaluated the samples after more than one year in order to ascertain intraobserver reliability. RESULTS: Interobserver reliability of the mitotic rate in thin primary melanomas is disappointing and independent of whether H&E or immunohistochemically stained samples are used (kappa value: 0.088 [H&E], 0.154 [IH], respectively). Kappa values improved to 0.345 (H&E) and 0.403 (IH) when using a cutoff of 0/1 vs. 2+ mitoses. Similarly unsatisfactory, kappa values for intraobserver reliability ranged from 0.18 and 0.348, depending on the individual examiner. DISCUSSION: Given the unsatisfactory reproducibility and large variations in assessing the mitotic rate, it remains a matter of debate whether this diagnostic parameter should play a role in therapeutic decisions.

Mitoserate beim primären Melanom: Interobserver- und Intraobserver-Reproduzierbarkeit am HE-Schnitt und in der Immunhistologie.

HINTERGRUND: Die Melanomklassifikation wurde 2009 durch die AJCC revidiert. Für die Klassifizierung primärer Melanome wurde als dritte Größe neben Tumordicke und Ulzeration die Angabe der Mitoserate neu eingeführt. Gemäß der AJCC-2009-Klassifikation des Melanoms führt der Nachweis nur einer oder mehrerer dermaler Tumormitosen bei Melanomen ≤ 1,0 mm Tumordicke zu einer Umgruppierung des Tumors von T1a nach T1b. Dies erklärt, wie wichtig die Frage nach der Reproduzierbarkeit dieses neuen Parameters ist. METHODEN: Zur Prüfung der Interobserver-Reproduzierbarkeit der Mitoserate haben 17 Dermatopathologen und Pathologen, die in der Befundung des kutanen Melanoms sehr erfahren sind, die Mitoserate in 15 dünnen Melanomen mit einer mittleren Tumordicke von 0,91 mm an demselben Tumorschnitt bestimmt. Die Mitoserate wurde am HE-Schnitt und immunhistologisch (IH) mittels des mitosespezifischen Antikörpers Phospho-Histon-H3 (Ser10) bestimmt. Fünf Befunder wiederholten die Bestimmung nach mehr als einem Jahr ohne Kenntnis ihres Vorbefundes zur Ermittlung der Intraobserver-Reproduzierbarkeit. ERGEBNISSE: Die Interobserver-Reproduzierbarkeit der Mitoserate bei dünnen Melanomen ist unbefriedigend und unabhängig davon, ob die Mitoserate am HE-Schnitt oder am immungefärbten Schnitt bestimmt wird (κ-Werte: 0,088 [HE] bzw. 0,154 [IH]). Bei einer Diskriminationsschwelle von 0/1 vs. 2+ Mitosen verbesserte sich der κ-Wert auf 0,345 (HE) bzw. 0,403 (IH). Die Intraobserver-Reproduzierbarkeit lag mit κ-Werten zwischen 0,18 und 0,348 je nach Befunder ebenfalls im unbefriedigenden Bereich. DISKUSSION: Wegen der unbefriedigenden Reproduzierbarkeit und der großen Variation der Befunde zur Mitoserate bleibt es zweifelhaft, ob dieser Befund als Grundlage für Therapieentscheidungen herangezogen werden kann.

The Malassezia genus in skin and systemic diseases.

In the last 15 years, the genus Malassezia has been a topic of intense basic research on taxonomy, physiology, biochemistry, ecology, immunology, and metabolomics. Currently, the genus encompasses 14 species. The 1996 revision of the genus resulted in seven accepted taxa: M. furfur, M. pachydermatis, M. sympodialis, M. globosa, M. obtusa, M. restricta, and M. slooffiae. In the last decade, seven new taxa isolated from healthy and lesional human and animal skin have been accepted: M. dermatis, M. japonica, M. yamatoensis, M. nana, M. caprae, M. equina, and M. cuniculi. However, forthcoming multidisciplinary research is expected to show the etiopathological relationships between these new species and skin diseases. Hitherto, basic and clinical research has established etiological links between Malassezia yeasts, pityriasis versicolor, and sepsis of neonates and immunocompromised individuals. Their role in aggravating seborrheic dermatitis, dandruff, folliculitis, and onychomycosis, though often supported by histopathological evidence and favorable antifungal therapeutic outcomes, remains under investigation. A close association between skin and Malassezia IgE binding allergens in atopic eczema has been shown, while laboratory data support a role in psoriasis exacerbations. Finally, metabolomic research resulted in the proposal of a hypothesis on the contribution of Malassezia-synthesized aryl hydrocarbon receptor (AhR) ligands to basal cell carcinoma through UV radiation-induced carcinogenesis.

Malignant dermatofibroma: clinicopathological, immunohistochemical, and molecular analysis of seven cases.

Dermatofibroma (cutaneous fibrous histiocytoma) represents a common benign mesenchymal tumor, and numerous morphological variants have been described. Some variants of dermatofibroma are characterized by an increased risk of local recurrences, and there are a few reported metastasizing cases. Unfortunately, an aggressive behavior cannot be predicted reliably by morphology at the moment, and we evaluated the value of array-comparative genomic hybridization (CGH) in this setting. Seven cases of clinically aggressive dermatofibromas were identified, and pathological and molecular features were evaluated. The neoplasms occurred in four female and in three male patients (mean age was 33 years, range 2-65 years), and arose on the shoulder, buttock, temple, lateral neck, thigh, ankle, and cheek. The size of the neoplasms ranged from 1 to 9 cm (mean: 3 cm). An infiltration of the subcutis was seen in five cases. Two neoplasms were completely excised, whereas an incomplete or marginal excision was reported in the remaining cases. Local recurrences were seen in six cases (time to the first recurrence ranged from 8 months to 9 years). Metastases were noted between 3 months and 8 years after diagnosis in six patients. Two patients died of disease, and two patients are alive with disease. Histologically, the primary tumors showed features of cellular dermatofibroma (four cases), cellular/aneurysmal dermatofibroma (one case), atypical/cellular dermatofibroma (one case), and classical dermatofibroma (one case). Mitotic figures ranged from 3 to 25 per 10 high-power fields, and focal necrosis was present in five cases. Interestingly, malignant transformation from cellular dermatofibroma to an obvious spindle cell/pleomorphic sarcoma was seen in one primary and in one recurrent neoplasm. Five neoplasms showed chromosomal aberrations by array-CGH, suggesting that these changes may represent an additional diagnostic tool in the recognition of cases of dermatofibroma with a metastatic potential.

Histological and genetic evidence for a variant of superficial spreading melanoma composed predominantly of large nests.

Cutaneous melanomas are characterized by a range of histological appearances, and several morphological variants have been described. In this study, we report a variant of superficial spreading melanoma that is characterized by large, irregular junctional melanocytic nests. The junctional nests varied in shape and size, showed focal tendency to confluence, and were often surrounded by a cuff of epidermal keratinocytes. The melanocytes comprising the nests showed variable cytological atypia. In most of the cases, scant intraepidermal or junctional single melanocytes were seen, and other well-documented diagnostic criteria for melanoma were lacking, and as a result, histological recognition of these tumors as melanoma was difficult. Some cases were associated with an invasive dermal component or showed evidence of sun damage. To provide supporting evidence for malignancy, we analyzed these tumors for genomic aberrations. Using array comparative genomic hybridization (aCGH), we identified multiple genomic aberrations in all analyzed cases. A similar pattern of genomic aberrations was seen in a control group of bona fide superficial spreading melanomas, suggesting that these 'melanomas composed exclusively or predominantly of large nests' are indeed variants of superficial spreading melanoma. Fluorescence in-situ hybridization (FISH) was positive in 40% of the cases. However, using aCGH, the FISH-negative cases showed multiple genomic aberrations in regions that are not covered by FISH. The low sensitivity of the FISH test can be explained by the fact that FISH only evaluates four genomic loci for aberrations, whereas aCGH surveys the entire genome. In summary, we present histological and molecular genetic evidence for a morphological variant of superficial spreading melanoma. Awareness of the histological features will aid in their correct diagnosis as melanoma, and in difficult cases, judicious application of ancillary tests such as aCGH (rather than FISH) will assist accurate diagnosis.

A proposal for improving multicolor FISH sensitivity in the diagnosis of malignant melanoma using new combined criteria.

Fluorescence in situ hybridization (FISH) for the diagnosis of melanoma makes use of specific fluorescent probes to detect selected chromosomal alterations on paraffin-embedded tissue samples. To date, interpretation of FISH data has been based on numerical values generated by 2 different computational algorithms that of Abbott and that of Gerami. To further evaluate the value of FISH in the diagnosis of malignant melanoma, we selected 163 clinically and histologically unequivocal cases of malignant melanoma in a cohort of 575 melanocytic tumors and analyzed FISH data using the criteria of Abbott, Gerami, and new combined criteria. Depending on the used criteria, FISH was positive in the unequivocal malignant melanoma in 69.3% (113/163) of cases using the Abbott criteria, 74.2% (121/163) of cases using the Gerami criteria, and 82.2% (134/163) of cases using the combined criteria of Abbott and Gerami. Although use of all 3 criteria was associated with 100% FISH negativity in a cohort of 30 unequivocal benign melanocytic nevi, use of the combined criteria revealed more FISH-positive cases in ambiguous benign melanocytic lesions than the criteria of Abbott or Gerami alone: Abbott, 125 of 367; Gerami, 146 of 367; combined, 161 of 367. Furthermore, we show that 66% (8/12) of FISH-negative cases of unequivocal melanoma are positive when analyzed by array comparative genomic hybridization (aCGH), demonstrating that false-negative results remain despite the usage of the combined criteria for evaluation of FISH data. In these 8 FISH-negative aCGH-positive cases, copy number alterations were often located on chromosomes 9p, a chromosomal locus that is not targeted by the FISH probes currently used. In conclusion, the existing criteria for the evaluation of multicolor melanocytic FISH are limited by a nonnegligeable rate of false negativity that can be reduced by using newly proposed combined criteria but at the cost of increased detection of FISH positivity in ambiguous benign melanocytic lesions.

Expression of apoptosis-inducing factor (AIF) in keratoacanthomas and squamous cell carcinomas of the skin.

The complex biological trait 'susceptibility to apoptosis' is a nosological feature distinguishing squamous cell carcinomas (SCC) from keratoacanthomas (KA). The purpose of this study was to compare the expression of apoptosis-inducing factor (AIF), a major effector of the caspase-independent apoptosis pathway, in formalin-fixed SCC (N = 23) and KA (N = 29) resection specimens. SCC express statistically significant more AIF than KA both as proportion of AIF+ cells by immunohistochemistry (median: 54% vs 33%; P < 0.01) and as total AIF protein content by western blot quantification (six-fold increased; P < 0.01). However, the contribution of AIF to apoptosis, measured as fraction of apoptotic nuclei with overt DNA fragmentation by the TUNEL method that co-express AIF translocated to nucleus, is significantly less prevalent among SCC (median: 19% vs 48% in KA; P < 0.01). These findings indicate to a distinctive involvement of AIF in the progression of certain epithelial skin tumors that might be exploited as a promising treatment target.

Cutaneous mixed tumor, eccrine variant: a clinicopathologic and immunohistochemical study of 50 cases, with emphasis on unusual histopathologic features.

Mixed tumor, eccrine type, is a rare cutaneous adnexal neoplasm, mostly reported as isolated case reports. A systematic analysis of its histopathologic and immunohistochemical features has not previously been performed on a large series. The purpose of our investigation was to study a large number of cutaneous eccrine mixed tumors so as to fully characterize the entire spectrum of changes in the epithelial and stromal components, with an emphasis on unusual histopathologic features that may represent a diagnostic pitfall. This article reports a light microscopic and immunohistochemical study of 50 cases of eccrine mixed tumor, complemented by a literature review. Our study identified some unusual histopathologic features, thus extending the morphologic spectrum of this neoplasm. These included prominent cribriform areas, clear cell change, pseudorosette structures, prominent osseous metaplasia, and physaliphorous-like cells. Most of these features have not been previously recorded in eccrine mixed tumors and may represent a potential diagnostic pitfall.

Histopathological diagnostics of malignant melanoma in accordance with the recent AJCC classification 2009: Review of the literature and recommendations for general practice.

BACKGROUND: TNM classifications are the basis for diagnostic and therapeutic procedures in oncology. Histopathological reports have to enable a proper indexing of tumor specific findings into recent classifications. METHODS: A systematic review of the literature was performed to identify reports dealing with the assessment of mitotic rate and the processing and evaluation of sentinel node biopsies in malignant melanoma. On the basis of this review an expert panel of dermatopathologists and general pathologists discussed and agreed recommendations for general practice. RESULTS: Following recommendations were agreed with a broad consensus (93-100 % agreement): The determination of the mitotic rate in primary melanoma is performed on HE slides. The evaluation of an area of 1 mm(2) is sufficient. Only dermal mitoses are considered. The counted number of mitoses is provided as an integer value. The mitotic rate shall be determined in primary melanomas of ≤1.00 mm vertical tumor thickness according to the hot-spot method and provided as an integer value in relation to an area of 1 mm(2) . The determination of the mitotic rate in the case of thicker primary melanomas is desirable. In general, for the evaluation of each sentinel lymph node, 4 slides should be prepared. For diagnostic purposes, immunohistochemistry (preferably with antibodies against S100ß, Melan A and HMB-45) should be performed in addition to HE staining. The pathology report should provide information about micro-metastases and their longest extension (one-tenth of a millimeter). CONCLUSIONS: These recommendations are suitable for standardizing the histopathological diagnosis of malignant melanoma and for providing a common basis for clinical decisions and scientific research.

Plasmacytoid dendritic cells: an overview of their presence and distribution in different inflammatory skin diseases, with special emphasis on Jessner's lymphocytic infiltrate of the skin and cutaneous lupus erythematosus.

BACKGROUND: Plasmacytoid dendritic cells (PDC) play a pivotal role in the induction of autoimmune diseases and other skin diseases. The present study focuses on the distribution patterns of PDC in patients with cutaneous lupus erythematosus (LE) and Jessner's lymphocytic infiltrate (LI) of the skin and compares them with other skin diseases. The goal was to scrutinize the involvement of PDC in LI, and to show that PDC present a specific pattern of distribution in various cutaneous disorders. METHODS: 353 skin biopsies of LE (various subtypes), LI, and other inflammatory skin diseases as well as two halo melanocytic nevi and 10 epithelial tumors were immunohistochemically investigated for the presence of PDC by employing antibodies against CD123 and CD2AP. RESULTS: PDC were constantly detected as distinct perivascular and periadnexal clusters in LE and LI. In other forms of dermatitis, PDC could be found as single cells or scattered throughout the infiltrate or beneath the epidermis. CONCLUSIONS: Our data suggest that the distribution of PDC in tumid LE and LI is identical, and this observation suggests that both designations signify one disease. The distinct PDC arrangement in LE represents as useful diagnostic tool in the differential diagnosis with other forms of dermatitis.

Primary cutaneous cribriform apocrine carcinoma: a clinicopathologic and immunohistochemical study of 26 cases of an under-recognized cutaneous adnexal neoplasm.

BACKGROUND: Cribriform carcinoma is the histopathologic variant of cutaneous apocrine carcinoma characterized by interconnected solid aggregations of neoplastic cells that are punctuated by small round spaces. OBJECTIVE: To describe the histopathologic and immunohistochemical characteristics of this under-recognized cutaneous adnexal neoplasm. METHODS: Twenty-six cases of primary cutaneous cribriform apocrine carcinoma were clinically, histopathologically, and immunohistochemically studied. RESULTS: Seven neoplasms arose in males and 19 in females. The median age of the patients was 47.8 years. The lower and upper limbs were the most frequent sites. Histopathologically, the neoplasms consisted of well-circumscribed dermal nodules composed of multiple, interconnected, solid aggregations of basophilic epithelial cells that were punctuated by small round spaces. Immunohistochemically, the neoplastic cells expressed immunoreactivity for MNF116, AE1/AE3, Cam 5.2, cytokeratin 7, carcinoembryonic antigen, and epithelial membrane antigen. LIMITATIONS: All specimens came from dermatopathology laboratories, and some inherent selection bias may exist. CONCLUSIONS: Primary cutaneous cribriform apocrine carcinoma is a distinctive but little-known variant of cutaneous apocrine carcinoma.

Mixed-type liposarcoma: clinicopathological, immunohistochemical, and molecular analysis of a case arising in deep soft tissues of the lower extremity.

A rare case of mixed-type liposarcoma arising in deep soft tissue of the right thigh of a 45-year-old female patient is reported. The neoplasm was completely excised and was composed of an irregular admixture of areas of atypical lipomatous tumor/well-differentiated liposarcoma of the lipoma-like subtype with areas of myxoid/round cell liposarcoma. An amplification of the MDM2 and CDK4 genes respectively in the atypical lipomatous tumor/well-differentiated liposarcoma areas was detected by fluorescence in situ hybridization (FISH) analysis, and translocations of the CHOP and FUS genes were detected by FISH analysis in the myxoid/round cell liposarcoma areas.

Apocrine mixed tumor of the skin ("mixed tumor of the folliculosebaceous-apocrine complex"). Spectrum of differentiations and metaplastic changes in the epithelial, myoepithelial, and stromal components based on a histopathologic study of 244 cases.

BACKGROUND: A systematic analysis of the entire spectrum of various forms of differentiation and metaplastic epiphenomena in cutaneous apocrine mixed tumor (AMT) has never been performed. OBJECTIVE: The purpose of our study was to study a large number of cutaneous mixed tumors so as to fully characterize the entire spectrum of differentiations and metaplastic changes that may occur in the epithelial, myoepithelial, and stromal components of AMT. METHODS: This article reports a light-microscopic study of 244 cases of cutaneous AMT, complemented by a literature review. RESULTS: All types of differentiation along the lines of the folliculosebaceous-apocrine unit can be seen in AMT. The spectrum of metaplastic changes in the epithelial components includes squamous metaplasia, mucinous metaplasia, oxyphilic metaplasia, clear cell change, columnar metaplasia, hobnail metaplasia, and cytoplasmic vacuolization. The following changes in the myoepithelial component were documented: clear cell change, hyaline cells, plasmacytoid cells, spindling, and collagenous spherulosis. Stromal alterations included chondroid metaplasia, osseous metaplasia, and adipose metaplasia. LIMITATIONS: This study utilizes tissue specimens that mainly came as consultations; therefore some inherent selection bias exists. CONCLUSIONS: AMT displays a wide range of differentiation and metaplastic changes in its epithelial, myoepithelial, and stromal components. These phenomena are not mutually exclusive. When unduly prominent, they may present diagnostic pitfalls. Our findings corroborate those of previous publications, stressing the remarkable diversity of differentiation and metaplasias that may be found in cutaneous AMT. We propose that the most appropriate name for these lesions is "mixed tumor of the folliculosebaceous-apocrine complex."

Mutations of the BRAF gene in benign and malignant melanocytic lesions.

A single-point mutation in exon 15 of the BRAF gene has recently been reported in a high percentage in cultured melanoma cells and in 6 of 9 primary melanomas examined. To evaluate the impact of the T1796A BRAF mutation, we screened primary melanomas, various types of nevi and lesions where a melanoma developed in an underlying nevus. We could detect the mutation in 28 of 97 (29%) melanomas and in 39 of 187 (21%) nevi, including blue nevi (0/20) and Spitz nevi (0/69), which did not carry the mutation. In melanomas with an underlying nevus, either the mutation was present in both the laser-microdissected nevus cells and the laser-microdissected melanoma cells (3/14) or both lesions were negative for the BRAF mutation except one case. In conclusion, mutations in exon 15 of the BRAF gene are nonspecific for progression of a nevus to a melanoma. Other so far unknown cofactors seem to be of importance.

Consumption of the epidermis: a diagnostic criterion for the differential diagnosis of melanoma and Spitz nevus.

The distinction between melanoma and its most important simulant, Spitz nevus, is usually made on microscopically. We point out "consumption of the epidermis" (COE) as an additional diagnostic criterion. We defined COE as thinning of the epidermis with attenuation of the basal and suprabasal layers and loss of rete ridges in areas of direct contact with neoplastic melanocytes. We analyzed 102 unequivocal melanomas and 125 unequivocal Spitz nevi for the presence of COE. COE had not been used in arriving at the diagnosis of these cases because we were unaware of the criterion at the time that the cases were first evaluated. COE was found in 88 of 102 (86%) of melanomas but only 12 of 125 (9.6%) of Spitz nevi (P < 0.001). We then looked for COE in an independent set of 61 ambiguous melanocytic lesions with overlapping histopathologic features that could not be classified unequivocally as Spitz nevus or melanoma. The cases were analyzed by comparative genomic hybridization (CGH) for aberration patterns suggesting a benign or a malignant process, based on previous studies. COE was found in only 6 of 42 (14%) of the ambiguous cases in which CGH suggested a benign process and 14 of 19 (74%) of the ambiguous cases in which CGH suggested melanoma (P < 0.001). Our data suggest that COE is a useful criterion in the evaluation of melanocytic neoplasms. Because COE was frequently found at the edges of ulcers in the majority of ulcerated melanomas, the thinning of the epidermis in COE may represent an early phase of ulceration. This may prove to be important in distinguishing ulceration due to an effect of the tumor from ulceration due to trauma, which would be expected not to have the same prognostic import. Future studies are required to analyze the prognostic value of COE itself.

Hemorrhagic Kaposi sarcoma. Successful treatment with IFN-alpha.

A 76-year-old woman with atypical hemorrhagic Kaposi sarcoma is presented. The patient was treated with recombinant interferon alpha-2b (3,000,000 IU) subcutaneously, three times weekly for 6 months and twice weekly as maintenance dose for 14 months with excellent response and no recurrence after a 7 years of follow-up.