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.

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.

"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.

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.

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.

[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.

[Quality control in pathological anatomy: 10 years' experience]. / Controllo di qualità in anatomia patologica: 10 anni di esperienza.

The quality assurance scheme in use at the Section of Anatomic Pathology of the University of Bologna-Bellaria Hospital is described. Since 1992 a quality assurance (QA) scheme has been set up in this Institution. The scheme and results have been reported in this same Journal previously 1-3: here are reported the changes to the scheme that have intervened in the last four years. All data collected from January 1999 to December 2002 have been reviewed for monitoring the laboratory performance. Emphasis has been given to changes that have been introduced recently to improve QA.

Atypical cutaneous mycobacteriosis diagnosed by polymerase chain reaction.

Atypical mycobacteria are important human pathogens. Although they often cause systemic disease, mycobacterial infection may present solely as cutaneous lesions. It is not easy to detect nontuberculous mycobacteria by the traditional histochemical Ziehl-Neelsen stain, or by culture on specific media. Polymerase chain reaction (PCR) may be used to identify nontuberculous mycobacteria in skin lesions. We report a 40-year-old man and a 36-year-old woman, both of whom were immunocompetent and kept fish, who had skin lesions on the backs of their right hands. Ziehl-Neelsen staining and culture on Lowenstein-Jensen media were negative. Mycobacterial DNA was detected by amplification of 16S ribosomal DNA. In both cases, PCR-enzyme-linked immunosorbent assay showed a positive signal when probes for Mycobacterium (universal probe) and M. chelonae were used, and in one patient M. fortuitum was also discovered. Antibiotic therapy with clarithromycin 500 mg twice daily was begun. After 6 months of treatment, the skin lesions were cured.

Follicular baso-squamous melanocytic tumour of the skin.

AIMS: We describe a previously unrecognized pigmented tumour of the skin and suggest a possible relationship with the follicular bulb. METHODS AND RESULTS: A pigmented epithelial neoplasm clinically simulating a malignant melanoma of the skin was present in a 92-year-old woman, on her left leg. It was composed of three cell types: squamous cells with trichilemmal keratinization, basaloid cells and dendritic melanocytes. The presence of three cell types was confirmed by immunohistochemistry and electron microscopy. CONCLUSIONS: The tumour showed differentiation towards the hair follicular bulb and the descriptive term of follicular baso-squamous melanocytic tumour is suggested.

Gemcitabine-associated CD8+ CD30+ pseudolymphoma.

We describe a 69-year-old man with a non-small cell carcinoma of the lung, stage III B, who developed bilateral multiple erythematous lesions in the abdominal-inguinal area following treatment with gemcitabine. Histologically, the lesion was characterized by a heavy lymphocytic infiltrate with large CD30+ cells. The lesion was highly suggestive of cutaneous involvement by malignant lymphoma, but complete regression was observed after cessation of gemcitabine. Although rarely reported, gemcitabine therapy can induce skin lesions. Pathologists should be aware of this possibility in order to avoid a misdiagnosis.

[Endocrine differentiation in basocellular carcinoma]. / Differenziazione endocrina nei carcinomi basocellulari.

Three (propositus) cases of basal cell carcinoma (BCC) showing endocrine differentiation at the immunohistochemical level were studied using reverse transcriptase-polymerase chain reaction (RT-PCR) to determine the presence of mRNA of chromogranin A. Moreover, 20 (consecutive) cases of BCC were studied with immunohistochemistry alone using chromogranin A, synaptophysin, S100 protein, cytokeratin 20, and neuron-specific enolase antibodies (NSE). The three propositus cases of BCC showed positive results when RT-PCR for mRNA of chromogranin A was performed. Eleven out of 20 consecutive cases of BCC were focally positive for chromogranin A antibody. These results confirm the presence of endocrine differentiation in BCC, demonstrated both with immunohistochemistry and with RT-PCR.

[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.

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.

[Hyperkeratosis follicularis et parafollicularis in cutem penetrans (Kyrle's disease). Description of a case]. / Ipercheratosis follicularis et parafollicularis in cutem penetrans (Malattia di Kyrle). Descrizione di un caso.

A case of hyperkeratosis follicularis et parafollicularis in cutem penetrans Kyrle's disease in a 41-year-old woman is described. It was a recurrence of a lesion surgically removed and originally diagnosed as invasive squamous cell carcinoma. Kyrle's disease is a rare dermatosis and should not be confused with neoplastic conditions i.e. squamous cell carcinoma. Pathologists should be aware of such conditions in order to avoid misdiagnosis, which can imply over treatment for the patient.

Adult rhabdomyoma: report of two cases of rhabdomyoma of the lip and of the eyelid.

We describe two cases of adult rhabdomyoma. One was located in the lip of a 66-year-old woman and was removed because it was clinically suspicious for infiltrating carcinoma. The other arose in the eyelid of a 60-year-old woman with a glass eye and was initially interpreted as a reactive process due to the prosthesis. Both lesions were composed of cells with oval nuclei and deeply eosinophilic cytoplasms with occasional cross striations. Immunoreactivity for desmin and myoglobin excluded the diagnosis of other tumors with similar morphology. The unusual association of the eyelid tumor with the prosthesis suggests a role for chronic irritation in the pathogenesis of rhabdomyoma.

Actin-rich desmoplastic malignant melanoma: report of three cases.

We report three cases of desmoplastic malignant melanoma (DMM) rich in smooth muscle actin. They occurred in two men (Cases 1 and 3) and in one woman (Case 2). Cases 1 and 2 were recurrent lesions from common melanomas excised, respectively, 3 and 1 years previously. In Case 3, DMM was associated with lentigo maligna at the time of presentation. Morphologically, DMMs were composed of spindle neoplastic cells organized in haphazardly orientated long fascicles separated by collagen bundles. Perineural invasion was present and mitotic activity was prominent in all cases. The neoplastic spindle cells were intensely positive with S100 protein and smooth muscle actin antisera and negative with HMB45 and Melan-A (Mart-1) antibodies. Double staining for smooth muscle actin and S100 protein revealed no definite coexpression of the two antigens. Follow-up was available for patients 1 and 2 who had local recurrences and are still alive. It is possible that actin rich elements differentiate toward mesenchymal elements, paralleling the phenotypic changes seen in sarcomatoid carcinomas. Therefore, multidirectional differentiation may explain the mesenchymal (sarcomatoid) differentiation of neoplastic melanocytes and may be responsible for the different biologic behavior of DMMs, which is closer to mesenchymal tumors than to conventional melanomas.

[Quality control of the "M. Malpighi" Anatomy, Histology, and Pathologic Cytology Section, Oncology Department, University of Bologna, Bellaria Hospital]. / Controllo di qualità della Sezione di Anatomia, Istologia e Citologia Patologica "M. Malpighi", Dipartimento di Oncologia, Università di Bologna, Ospedale Bellaria.

The quality control scheme in use at the Department of Anatomic Pathology of the University of Bologna-Bellaria Hospital Since 1993 a quality assurance (QA) scheme has been set up in our Department, modified from the protocol in use at the Department of Pathology of Yale University and published by J. Rosai in his textbook. A QA committee has been appointed and each member is responsible for a specific branch of the total workload; the areas involved are: 1. review of frozen section diagnoses with the final diagnoses 2. randomized review of biopsies (1:25) 3. quality control of cytological cases 4. quality control of specimen adequacy 5. quality control of immunohistochemistry and in situ Hybridization 6. quality control of the cytogenetics laboratory 7. quality control of autopsies All data collected from january 1996 to february 1999 have been reviewed and analyzed in order to provide references for other laboratories and for the purpose of monitoring our laboratory' performance.