Twenty-Eight Cases of Extraocular Sebaceous Carcinoma: A Correlative Clinicopathological and Immunohistochemical Analysis of Extraocular Sebaceous Carcinomas and Benign Sebaceous Gland Tumors.

ABSTRACT: Extraocular sebaceous carcinoma (ESC) is a rare appendiceal skin tumor. In contrast to ocular sebaceous carcinoma, information about the exact cellular architecture of these lesions is scarce and the histogenesis of ESC is unknown. Here, we extend our previous study and investigate 28 extraocular carcinomas in comparison to 54 benign sebaceous tumors and 8 cases of normal sebaceous glands using a broad spectrum of antibodies against p63, several keratins, adipophilin, EMA, Ki67, androgen receptor, and mismatch repair proteins. This observational study demonstrates that p63- and K5/14-positive basaloid cells are key cells in normal sebaceous gland and in all sebaceous tumors and that these basaloid cells give rise to EMA+, adipophilin+ sebocytes, and K5/14+, K7±, K10± ductal structures. Finally, about half of ESC is associated with superficial in situ neoplasia, which provides evidence that at least part of these carcinomas arises from flat superficial in situ carcinoma. In contrast to the normal sebaceous gland, about half of all sebaceous tumors lack keratin K7. MMR protein IHC-profiles role will be discussed.

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.

Spatial analysis of p63, K5 and K7 defines two groups of progenitor cells that differentially contribute to the maintenance of normal sebaceous glands, extraocular sebaceous carcinoma and benign sebaceous tumors.

The histogenesis of extraocular sebaceous carcinomas is - in contrast to ocular sebaceous carcinomas - unclear, and information about the exact cellular architecture of these lesions and even of the normal sebaceous gland is still scarce. This study attempts to elucidate the histogenesis of sebaceous tumors, using multicolor immunofluorescence stainings to analyze 21 cases of sebaceous tumors (six each of extraocular sebaceous carcinoma, sebaceous adenoma and sebaceoma, and three cases of steatocystomas) and eight cases of normal sebaceous glands for p63, several keratins, androgen receptor, adipophilin, epithelial membrane antigen (EMA) and Ki-67. The data of this observational study provide evidence for the existence of two subpopulations of progenitors in normal sebaceous glands: (i) p63+ K5+ progenitors which generate the K10+ luminal cells of sebaceous ducts; and (ii) p63+ K5+ K7+ progenitors which finally generate K7+ adipophilin+ EMA+ sebocytes. Without exception, all types of sebaceous tumors contained p63+ K5+ cells. Furthermore, these tumors showed a cellular hierarchy and differentiation to adipophilin+ and/or EMA+ mature sebocytes and to K10+ ductal cells through intermediary cells. Notably, a considerable number of sebaceous tumors lack the K7 pathway of cell maintenance in the normal sebaceous lobule. Based on our data, we propose a cellular algorithmic model of the hierarchy of normal sebaceous glands and of sebocytic tumors in which p63+ K5+ cells play a major role.

The patient benefit index: a novel approach in patient-defined outcomes measurement for skin diseases.

Evaluation of therapeutic benefits from the patient's perspective is important in medical decision-making and reimbursement. This study aimed at developing and validating an instrument on patient-defined needs and benefits in dermatology. The questionnaire was developed according to international guidelines. The benefit assessment consists of two steps: before treatment, every patient defines his treatment needs according to a standardized list. After treatment, the patient rates the degree of benefits achieved. A "patient benefit index" (PBI) is calculated by averaging the preference-weighed results of all items. The PBI questionnaire was validated in a sample of 500 patients with ten skin diseases and in a treatment study on 906 patients with acne. The patients defined a broad spectrum of needs and treatment benefits, indicating disease-specific patterns. The PBI showed good feasibility, reliability (Cronbach's alpha >0.91) and construct validity, high responsiveness, and discrimination between subgroups. The PBI permits valid evaluation of patient-relevant benefits in dermatological treatment.