aPKCzeta cortical loading is associated with Lgl cytoplasmic release and tumor growth in Drosophila and human epithelia.

Atypical protein kinase C (aPKC) and Lethal giant larvae (Lgl) regulate apical-basal polarity in Drosophila and mammalian epithelia. At the apical domain, aPKC phosphorylates and displaces Lgl that, in turn, maintains aPKC inactive at the basolateral region. The mutual exclusion of these two proteins seems to be crucial for the correct epithelial structure and function. Here we show that a cortical aPKC loading induces Lgl cytoplasmic release and massive overgrowth in Drosophila imaginal epithelia, whereas a cytoplasmic expression does not alter proliferation and epithelial overall structure. As two aPKC isoforms (iota and zeta) exist in humans and we previously showed that Drosophila Lgl is the functional homologue of the Human giant larvae-1 (Hugl-1) protein, we argued if the same mechanism of mutual exclusion could be impaired in human epithelial disorders and investigated aPKCiota, aPKCzeta and Hugl-1 localization in cancers deriving from ovarian surface epithelium. Both in mucinous and serous histotypes, aPKCzeta showed an apical-to-cortical redistribution and Hugl-1 showed a membrane-to-cytoplasm release, perfectly recapitulating the Drosophila model. Although several recent works support a causative role for aPKCiota overexpression in human carcinomas, our results suggest a key role for aPKCzeta in apical-basal polarity loosening, a mechanism that seems to be driven by changes in protein localization rather than in protein abundance.

Expression of MHC class I and class II antigens in primary breast carcinomas and synchronous nodal metastases.

Expression of the major histocompatibility (MHC) class I and class II antigens was studied by immunohistochemistry in a series of 70 primary breast carcinomas and in nodal metastases. In particular, the expression of class I (HLA A-B-C) and class II (DP, DQ and DR) molecules was compared in: a) primary breast cancers devoid of nodal metastases (n = 36) and tumors exhibiting metastatic deposits (n = 34) at the time of surgery, and b) primary breast carcinomas and their corresponding synchronous axillary nodal metastases. Reduced or absent HLA A-B-C antigen expression was seen in approximately 54.3% of primary breast carcinomas, whereas a partial or complete induction of class II products was observed in 18.5% (DQ), 30% (DP) or 48.5% (DR) of the same cases. An almost complete overlap of antigen expression was observed in breast tumors in which no metastases were found by histological examination of axillary nodes and in neoplasms showing histologically-diagnosed synchronous metastases. The reactivity for class I and class II antigens in nodal metastases roughly paralleled that exhibited by corresponding primary tumors. A discordant expression was seen in 11 cases (32%) stained for HLA A-B-C and in 8 (24%), 7 (21%) and 6 (18%) cases assayed for DP, DQ and DR products, respectively. When a discordant expression was detected, either decreased or increased staining patterns were observed in metastases. The finding of overlapping MHC antigenic profiles in the majority of primary breast tumors and nodal metastases casts doubts on the hypothesis that loss of MHC antigens can play an important role in the seeding and growth of metastatic breast carcinoma cells.

Histoplasma capsulatum var. capsulatum occurring in an HIV-positive Ghanaian immigrant to Italy. Identification of H. capsulatum DNA by PCR from paraffin sample.

Histoplasmosis, which is highly endemic in the United States, is rare in Europe, usually imported but sometimes autochthonous. In Africa, histoplasmosis capsulati coexists with "African histoplasmosis", a characteristic skin infection caused by H. capsulatum var. duboisii. Histoplamosis due to H. capsulatum is one of the 12 secondary infections listed in the surveillance definitions of AIDS. We report the case of a 36-year-old black man with acquired immunodeficiency syndrome (AIDS) who was living in Italy but originally came from Ghana. Histoplasmosis was disseminated with fever and cutaneous manifestations. The diagnosis was demonstrated morphologically based on the presence of yeast, observed by light microscopy, in skin lesions and by identification of H. capsulatum var. capsulatum DNA by nested PCR from a paraffin sample. No clinical reports of histoplamosis capsulati in Ghana have been published until now. The present case stresses the role of immigration of subjects from outside Europe who have been infected in their native country.

Merkel cell differentiation in trichoblastoma.

Four cases of trichoblastoma rich in Merkel cells (MCs) are reported. They occurred in two men and two women, with ages ranging from 58 to 76 years (mean 67.5 years). MCs were detected immunohistochemically with antibodies to keratin 20, chromogranin A and neuron-specific enolase (NSE). In an attempt at better definition of the nature and role of MCs in trichoblastoma, the distribution of MCs in normal adult and fetal skins obtained at autopsy was studied. In addition, ten cases of sebaceous naevus of Jadassohn (NSJ) were evaluated along similar lines. MCs made up 2-20% of the tumour cells in trichoblastomas; they were present in normal fetal skin and were rare in normal adult skin. All but one of the cases of NSJ showed numerous positive cells in the epidermal component of the lesion with all three antibodies. Six basal cell carcinomas and one syringocystadenoma papilliferum associated with NSJ were negative with keratin 20, chromogranin A and NSE antibodies, whereas a minute trichoblastoma arising against the same background was positive for these markers. Hair follicle cell tumours may recapitulate the skin embryogenesis, as numerous MCs are present in fetal follicles, but only occasional such cells are seen in adult skin.

Epithelioid angiosarcoma of the thyroid. Clinicopathological analysis of seven cases from non-Alpine areas.

Epithelioid angiosarcomas of the thyroid usually develop in people living in Alpine regions, and only rare cases arising in subjects living in nonmountainous areas have been reported. We describe the clinicopathological features of a series of seven cases collected from non-Alpine areas. All patients were adults. The tumours appeared as haemorrhagic, unencapsulated, sometimes cystic nodules. In two cases multinodularity was present. They were composed of large, epithelioid cells, which lined vascular-like spaces or were arranged in solid sheets. Intracytoplasmic lumina containing red blood cells were identified. Neoplastic cells were diffusely positive for factor VIII-related antigen, Ulex europaeus agglutinin, CD31 and keratin peptides. Ultrastructural studies were performed in four cases and showed features of endothelial differentiation. An average follow-up of 3.8 years disclosed that four patients died of disease after a median survival time of 5 months, whereas 3 patients are still alive with no evidence or residual disease 27, 32 and 66 months after thyroidectomy. The good prognosis in these patients appears to be related mainly to the absence of extraglandular tumour spread at the time of surgery.

Pleomorphic adenoma with lymph-node metastases report of two cases.

Two cases of pleomorphic adenoma showing morphologically benign metastases to lymph nodes are reported. In the first case, a 26-year old woman, the lymph node metastases appeared nine years after the primary tumor. In the second case, an 8-year old boy, six years elapsed between the primary and metastatic lesion. A review of the literature of similar cases has been performed.

Sampling in diagnostic morphometry: the influence of variation sources.

The variation sources relevant to a diagnostic morphometric study were analysed. The influence of each source was estimated in two experiments, performed in systems applying computer assisted interactive morphometry. In the first experiment one observer measured the areas of a large number of nuclei in a section from a grade II transitional cell carcinoma of the bladder. In the second experiment two groups of researchers, from Ancona and Kuopio, measured one field from five different samples of transitional cell tumours (including the case of grade II carcinoma). It turned out that pure interobserver variation was responsible for about a half of the total variation present in the diagnostic system. When the variation characteristics of the diagnostic system had been determined, the number of nuclei that had to be measured to reach a defined level of accuracy could be estimated. Such an estimate was also dependent on the predefined expectancy probability of reaching a correct estimate. The study showed that group morphometry (statistical, investigative morphometry) and diagnostic morphometry must be understood as two different approaches in histopathology. By applying group morphometry, good research results can be gathered with cruder measurements than in diagnostic morphometry. Because investigations in group morphometry are more standardized than in diagnostic morphometry, a larger number of structures has to be measured in diagnostic histopathology for the same level of accuracy.

Medullary carcinoma of the thyroid gland with sustentacular cell-like cells in a patient with multiple endocrine neoplasia, type IIA. Report of a case with ultrastructural and immunohistochemical studies.

We report a case of a medullary carcinoma of the left lobe of the thyroid gland that occurred in a 57-year-old woman. The patient had undergone surgery for treatment of a bilateral-functioning pheochromocytoma when she was 39 years old. A medullary carcinoma of the thyroid gland and/or a pheochromocytoma had also been diagnosed in other family members. The tumor was composed of cells arranged in nests and large sheets separated by fibrous stroma that contained amyloid deposits. Elongated cells with thin, branched cytoplasmic projections that were strongly reminiscent of sustentacular cells usually found in paragangliomas were seen among the neoplastic cells. Immunohistochemical study showed a diffuse positive reaction for calcitonin and low-weight keratins (CAM 5.2) in neoplastic cells, whereas the sustentacular cell-like cells were positive for S100 protein. The reaction for thyroglobulin was negative. Electron microscopy disclosed large numbers of typical neurosecretory granules in the cytoplasm of tumor cells. The sustentacular cell-like cells showed elongated cytoplasmic processes and lacked neurosecretory granules. We concluded that the finding of sustentacular cell-like cells in a medullary carcinoma of the thyroid gland made its differential diagnosis from paraganglioma more problematic.

Carcinoma in situ in sclerosing adenosis of the breast: an immunocytochemical study.

In this report, seven cases of sclerosing adenosis of the breast are reported in which a lobular (5) or ductal (2) in situ carcinoma was also present. In two cases, mastectomy was performed because invasive carcinoma was diagnosed on frozen section. In the other cases, the referring pathologists initially considered the diagnosis of invasive carcinoma. A well-defined PAS-positive basal lamina (BL) was always present around the proliferating glandular structures. In addition, residual myoepithelial cells lying on the BL were immunologically demonstrated, a feature usually seen in in situ carcinomas. Therefore, it appears that the study of BL and myoepithelial cells should be added to pattern recognition in the diagnosis of these lesions.

Inflammatory pseudotumor of the liver: report of two cases.

Inflammatory pseudotumor of the liver is a rare benign lesion which clinically and grossly is often interpreted as a neoplastic condition. It usually arises in children or young adults. Only 11 cases have been described in the literature, and its etiology is still uncertain. Two new cases of inflammatory pseudotumor in adult male patients are reported here. Morphologically, these cases summarize all the features seen in the other cases described previously. They showed fibrous bands delimiting microabscesses made up of granulocytes, mononuclear elements and foamy macrophages. These lesions have in common the symptomatology which is amenable to infectious disease. The purpose of this paper is to draw attention to the existence of a lesion that clinically simulates a neoplastic condition of the liver. This lesion should be histologically recognized to avoid excessive surgical treatment.

Epithelial-myoepithelial carcinoma of the parotid gland: a clinico-pathologic and immunohistochemical study of seven cases.

Seven cases of epithelial-myoepithelial carcinoma of the parotid gland are reported. Immunohistochemical evidence for the dual (glandular secretory and myoepithelial) differentiation of the cells composing these lesions is presented. Three of the cases recurred locally and two gave rise to metastases. The biologic behavior does not appear to be correlated with the histologic features that constitute the morphologic spectrum of epithelial-myoepithelial carcinoma.

[Congenital fetal neuroblastoma]. / Neuroblastome congénital foetal.

Neuroblastoma are pediatric tumors of neural crest origin, most often localized in adrenal glands and infrequently congenital. We report two fetal cases found at autopsy, performed at 24 and 28 weeks of gestation, respectively. The 24 week old fetus did not show any malformation; systematic histological analysis found neuroblastoma cells in both the adrenal glands and the retroperitoneal fat tissue. The 28 week old fetus was hydropic and exhibited a nodule (3 cm) in the posterior mediastinum, next to the thoracic spinal cord. This tumor responded to a neuroblastoma associated with small metastatic foci in the adrenal glands, the liver and the frontal brain cortex. The placenta was abnormally heavy and showed hemorrhagic and necrotic areas. Microscopically plugged clumps of neuroblastoma cells were found inside fetal vessels. Immunohistochemistry was employed in both cases and the cells showed immunoreactivity for NSE, NB 84, chromogranin, synaptophysin and neurofilaments, while desmin, MIC 2, and protein S-100 were negative. Congenital neuroblastomas are rare and, to our knowledge this is the thirteenth report of congenital neuroblastoma associated with placental metastasis.

Prognostic significance of MGMT gene promoter methylation in differently treated metastatic melanomas.

AIMS: The methylation status of the MGMT gene promoter, considered of prognostic significance by enhancing chemosensitivity to alkylating drugs in gliomas and melanomas, was evaluated in a series of primary melanomas and metastases of patients treated with different therapies, to identify any correlation with the patients' outcome or response to different therapeutic regimens. METHODS: Twenty-nine primary melanomas and 74 metastases, collected from 52 patients, were assessed for MGMT gene promoter methylation using a standard methylation specific PCR-based method. All materials were formalin fixed and paraffin embedded. RESULTS: One of 29 primary melanomas (3.4%) and 22 of 74 metastases (29.7%) showed MGMT gene promoter methylation. MGMT methylation was more frequent in visceral (17/40, 42.5%) than in cutaneous/lymph node metastases (5/34, 14.7%) (p = 0.019). Both disease free (DFS) and overall survival (OS) were significantly longer in patients with methylated metastases (p = 0.009 and p = 0.007, respectively). No correlations were found among methylation, therapeutic regimens and DFS or OS. CONCLUSIONS: MGMT methylation appears to be a late event in the biological history of melanoma and is more frequently seen in visceral metastases. The MGMT gene promoter methylation in metastatic disease is associated with longer survival, irrespective of therapy. Thus it could be considered a prognostic factor in metastatic melanoma.

"Combined" desmoplastic melanoma of the vulva with poor clinical outcome.

Desmoplastic melanomas in an unusual variant of melanoma that usually occurs in sun-damaged skin of elderly people. Desmoplasia may be the prominent features of the lesion or represent a portion of an otherwise non-desmoplastic melanoma; these latter are called "combined" desmoplastic melanoma. Desmoplastic melanomas of the vulva are rare. Herein, we report a case of "combined" DM of the labia minor consisting of a superficial spitzoid component and a deeper spindle desmoplastic component. Protein S-100 expression was ubiquitous, while MART-1 and HMB-45 were limited to the superficial spitzoid component and were negative in desmoplastic areas. Notably, the nodal metastasis retained the same biphasic pattern seen in the primary tumour. The patient died of widespread metastatic disease 3 years after diagnosis.

Ductal carcinoma of the prostate metastatic to the skin.

A case of skin metastases of prostatic ductal adenocarcinoma in a 78-year-old patient is reported. This case is characterized by two rare features: uncommon type of prostate carcinoma that metastatized to the skin.

Recurrence of nevoid melanoma originally diagnosed as benign nevus.

We report the case of a 27 year-old woman who had a pigmented lesion in her left leg in 2004. The lesion, which was diagnosed as a congenital compound nevus, recurred four years later as an obvious melanoma.

[The utility of aspiration cytology for the distinction of aggressive and non-aggressive papillary carcinoma of the thyroid]. / L'utilità della distinzione di varianti aggressive e non aggressive del carcinoma papillare della tiroide in citologia agoaspirativa.

Preoperative identification of the aggressive variants of papillary thyroid carcinoma (PTC) by fine needle aspiration (FNAC) has been suggested and different systems for distinguishing them from classical variant of PTC have been employed, including a point-based cytology grading system as suggested by Damiani et al., that we currently use in our Institution. The aim of this paper is to verify if distinction of PTC in aggressive or nonaggressive variants impacts on surgical treatment. In 7 years, from 1998 to 2005, 13586 cases of FNAC of thyroid have been performed; among them 156 PTC. The cytological material of thirty complete thyroidectomies with histology proven papillary thyroid carcinoma were reviewed. 11/30 cases were correctly stratified into the appropriate low or high-grade category. The cytological grading system was discordant with the final histopathological diagnosis in 9/30 cases while in 10 cases the grade was not assessed. Eight cases were downgraded and therefore the low grade papillary carcinoma diagnosed at cytological level turned to be high grade at histology. When those cases were reviewed, the histology of seven cases diagnosed as tall cell variant of PTC failed to show a percentage of tumour cells higher than 50% and therefore it would be better to diagnose them as classical variant of PTC. One case was under-graded at FNAC. The case that was cytologically upgraded was a follicular variant of PTC in Hashimoto thyroiditis with a focus of tall cells. All patients underwent thyroidectomy or thyroidectomy plus lymphadenectomy and from our results the pre-operative diagnosis did not effect the surgical treatment. No patient died of the disease.

[Mature cystic teratoma of the ovary with a small ganglioneuroma]. / Teratoma cistico maturo ovarico con un piccolo ganglioneuroma.

A case of ganglioneuroma arising within a cystic mature teratoma of the ovary in a 34-year-old woman is reported. Patient underwent right adnexectomy. The ovary was completely replaced by a bilocular cystic lesion, measuring 8 cm in diameter and filled with adipose tissue and pilosebaceous material. Microscopically the cyst was composed by a mature cystic teratoma containing skin with dermal appendages, fatty tissue and bronchial epithelium. Furthermore a nodule (0.5 cm in size) composed of mature ganglion cells, axons and Schwann cells, was identified. Ganglion cells were positive for NSE and synaptophysin, while Schwann cells stained positively with S100 protein and GFAP. To the best of our knowledgment this is the first reported cases of ganglioneuroma arisen within a cystic mature teratoma of the ovary.