Illuminato Carosi

Changes in CpG Islands Promoter Methylation Patterns during Ductal Breast Carcinoma Progression

Aberrant promoter methylation of several known or putative tumor suppressor genes occurs frequently during carcinogenesis, and this epigenetic change has been considered as a potential molecular marker for cancer. We examined the methylation status of nine genes (APC, CDH1, CTNNB1, TIMP3, ESR1, GSTP1, MGMT, THBS1, and TMS1), by quantitative methylation specific PCR. Synchronous preinvasive lesions (atypical ductal hyperplasia and/or ductal carcinoma in situ) and invasive ductal breast carcinoma from 52 patients, together with pure lesions from 24 patients and 12 normal tissues paired to tumor and 20 normal breast distant from tumor were analyzed. Aberrant promoter methylation was detected in both preinvasive and invasive lesions for genes APC, CDH1, CTNNB1, TIMP3, ESR1, and GSTP1. However, hierarchical mixed model and Generalized Estimating Equations model analyses showed that only APC, CDH1, and CTNNB1 promoter regions showed a higher frequency and methylation levels in pathologic samples when compared with normal breast. Whereas APC and CTNNB1 did not show differences in methylation levels or frequencies, CDH1 showed higher methylation levels in invasive tumors as compared with preinvasive lesions (P < 0.04, Mann-Whitney test with permutation correction). The analysis of APC, CDH1, and CTNNB1 methylation status was able to distinguish between normal and pathologic samples with a sensitivity of 67% (95% confidence interval, 60-71%) and a specificity of 75% (95% confidence interval, 69-81%). Our data point to the direct involvement of APC, CDH1, and CTNNB1 promoter methylation in the early stages of breast cancer progression and suggest that they may represent a useful tool for the detection of tumor cells in clinical specimens. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2694–700)

Paratesticular mesothelioma. Report of a case with comprehensive review of literature.

Paratesticular mesotheliomas are rare tumors with 223 cases described so far. The sole plausible causative factor so far ascertained in the pathogenesis of these tumors is asbestos, which however is found in only around 30% to 40% of such cases. The age range of affected individuals is wide, mostly adults and the elderly, but also includes young people and children. The most common presenting symptom is either hydrocele of unknown origin or intrascrotal mass. When hydrocele is the presenting symptom, these tumors are often clinically overlooked and the diagnosis is delayed. Most paratesticular mesotheliomas arise in the tunica vaginalis, but primary tumors of the spermatic cord and epididymis are also on record. Tumors arising from the peritoneal mesothelium of a hernia sac are excluded from this group. The correct diagnosis is almost always made after histologic examination of the operative specimen. Immunohistochemistry and electron microscopy are always helpful and sometimes necessary tools for diagnosis. So far very few cases have been identified or suspected preoperatively on cytologic examination. Three clinicopathologic types of malignant mesotheliomas of the male genital tract are recognized: diffuse tubulo-papillary mesothelioma, well-differentiated papillary mesothelioma, and multicystic mesothelioma. The histologic subtypes are almost always pure epithelial or biphasic. The differential diagnosis is mainly with serous papillary tumors arising from Mullerian vestiges, but several diverse primary or secondary tumors also need to be considered. A clinicopathologic evaluation of a case of tunical diffuse mesothelioma in a 74-year-old male from the AMR Series is the starting point for this general review.

Primary Embryonal Rhabdomyosarcoma of the Prostate in Adults Report of a Case and Review of the Literature

This study reports on a case of an adult patient with embryonal rhadomyosarcoma of the prostate and comprehensively reviews the world literature on this subject. The patient was a 49-year-old man with advanced stage disease, who initially underwent transurethral tumor resection and after diagnosis was given courses of chemotherapy prior to undergoing radical cystoprostatevesiculectomy. The tumor underwent histological examination supplemented by immunohistochemical analysis. After surgery, the patient experienced a huge pelvic recurrence and eventually died of disease 1 year after the original diagnosis. The world literature was reviewed based both on a PubMed/Medline search and the reference lists of all the available publications on this subject and only 24 cases of primary embryonal prostatic rhabdomyosarcoma have been found in the world literature in adult males (≥18 years). Embryonal rhadomyosarcoma of the prostate in adults is a very rare and aggressive disease. The long-term disease-specific survival rate is poor. Stage influences the outcome. Early diagnosis and complete surgical resection offer patients the best chance of improved survival.

Cystic lymphangioma-like adenomatoid tumor of the adrenal gland: Case presentation and review of the literature.

Adenomatoid tumors (AT) are usually found in the genital tract of both sexes. They are very rarely located in extragenital sites, and are exceedingly rare in the adrenal. AT of the adrenal gland (AT-AG) are nonfunctioning, usually discovered incidentally and confused on imaging with other more common adrenal neoplasms. The overwhelming majority occur in males. Thirty-four cases have been reported so far, more often presenting grossly as solid tumors, rarely as solid with cystic areas, and 5 cases were almost entirely cystic. At histology they can be either circumscribed or locally infiltrative, and may pose diagnostic difficulties when the pathologist relies on morphology alone or is challenged on frozen section. On light microscopy the diagnosis may be very difficult if the tumor is rich in vacuolated cells, mimicking metastatic signet ring-cell adenocarcinoma. Immunophenotyping and/or electron microscopy are paramount in helping to ascertain their mesothelial lineage. Lymphangioma is the main histologic mimic of solid-cystic and cystic AT-AG, but lymphangioma is immunopositive for endothelial markers and negative for cytokeratins and mesothelial markers. Ultrastructural analysis has been performed in 10 published cases of AT-AG, in all of which the classical microvilli of coelomic type were always observed. In brief we report herein the sixth case of cystic lymphangioma-like AT, which was incidentally discovered during clinical follow-up in a 39-year-old man undergoing cancer staging and surveillance after surgery. The adrenal tumor was 5.5 cm in size and was fully investigated immunohistochemically and ultrastructurally. A complete review of the literature is also presented.

Tuberous Sclerosis Complex With Polycystic Kidney Disease of the Adult Type: the TSC2/ADPKD1 Contiguous Gene Syndrome

Although different diseases, tuberous sclerosis complex and autosomal dominant polycystic kidney disease have been seen in association, the molecular basis of this being the proximity of tuberous sclerosis complex 2 and polycystic kidney disease 1 genes on the same chromosome (16p13.3). Therefore, the classic autosomal dominant polycystic kidney disease renal phenotype may occur in the context of tuberous sclerosis complex disease as a result of large deletions involving both the polycystic kidney disease 1 and tuberous sclerosis complex 2 genes. This is known as the tuberous sclerosis complex 2/autosomal dominant polycystic kidney disease 1 contiguous gene syndrome. The criteria for this condition are fulfilled when renal lesions typical for classic autosomal dominant polycystic kidney disease phenotype are associated with tuberous sclerosis complex phenotype. We present a new case of the sporadic form of this genetic disorder. The diagnosis of tuberous sclerosis complex in this patient was established on the presence of major and minor features, and the diagnosis of ADPKD was based on the presence of numerous large roundish renal cysts lined by a nondescript tubular epithelium. Sporadic cases of autosomal dominant polycystic kidney disease and tuberous sclerosis complex do occur. Molecular analysis was not performed because the patients parents refused permission.

LATERAL VENTRICLE TUMORS

OBJECTIVE Optimal surgical management in lateral ventricle tumors remains controversial. We conducted a retrospective study of patients with these lesions treated with a surgical strategy on the basis of tumor origin: primary or secondary ventricular and associated transependymal development. METHODS A total of 72 patients underwent surgery for lateral ventricle tumors. The mean patient age was 39 years (range, 6 mo to 78 yr). Raised intracranial pressure occurred in 53% of patients, followed by mental disturbances or psychiatric symptoms (32%) and motor deficits (21%). The transcortical approach was used in 44 patients, and an interhemispheric approach was used in 28 patients; a transcallosal approach was used in 16 patients, and a parasplenial approach was used in 12 patients. Neuropsychological tests were performed in selected patients. RESULTS Total resection was performed in 82% of patients. Sixty-five percent of tumors were benign and low-grade tumors. There was no surgical mortality, and the morbidity rate was 11%. Postoperative epilepsy (5.9%) was significantly increased in the transcortical group. The mean follow-up period was 55 months; 59% of patients achieved good recovery and moderate disability. In postoperative neuropsychological testing sessions, deficits in verbal memory were observed in six patients (8%). Final morbidity correlated well with preoperative clinical condition and pathological diagnosis. CONCLUSION Lateral ventricle tumors can be treated best by careful selection of the approach according to tumor origin and development. Overall, the transcallosal approach is preferred, but in patients with transependymal growth or large primary or secondary ventricular tumors, the transcortical is a better option.

Lipofuscin-like granules of the juxtaglomerular apparatus of the kidney. The diagnostic significance of a quasi-normal subcellular structure incidentally encountered in the course of routine ultrastructural evaluation of renal biopsies.

Lipofuscin-like granules, first described by Biava and West in 1965, are a subcellular, quasi-physiologic finding mainly seen in the smooth muscle cells of renal arterioles, but also in juxtaglomerular cells and the lacis cells of human kidneys. They increase in number in subjects affected by arterial hypertension and diabetes. They do not correlate with a specific primary renal disease. Lipofuscin-like granules are not related to renin granules. The world literature on this subject is almost non-existent, and the awareness of this finding or its clinical significance among either pathologists or nephrologists is very poor. We incidentally observed these lipofuscin-like granules in 8 cases during the routine electron microscope examination of 440 renal biopsies, and report herein on their ultrastructural features. Six of these 8 patients were affected by arterial hypertension, one of whom was also concomitantly affected by diabetes mellitus. These lipofuscin-like granules appear as dense bodies with a lipid component, a coarsely granular matrix, and a crystalloid component which may appear in a band or dot pattern, according to the plane of sectioning. The pathologist has to be aware of these lipofuscin-like granules in order not to confuse them with the semicircularly organized (fingerprint) linear immune deposits associated with some specific glomerulopathies.

Spontaneous cutaneous cholesterol crystal embolism with focal clinical symptomatology: report of a case in an unusual location with secondary histological changes reminiscent of atypical decubital fibroplasia.

Cholesterol crystal embolization (CCE) is one of the many complications of atherosclerosis. CCE is usually an iatrogenic event occurring either after vascular surgery, usually aortic surgery, or invasive angiographic investigations or in the course of anticoagulant or thrombolytic therapy. More rarely, it occurs after trauma or even in the absence of any inciting cause. CCE may manifest with single or multiorgan involvement. Skin involvement is usually seen in the context of a systemic disease, especially affecting the lower extremities and lower trunk. We report on a rare case of isolated spontaneous focal cutaneous involvement of the upper limb, with peculiar mesenchymal and reactive histological changes. A 65-year-old man with a clinical history of atherosclerosis was admitted complaining of a nonhealing painful skin ulceration on his left elbow for 5-month duration. A skin biopsy was taken, and histopathological examination documented an intrarteriolar cholesterol embolus in the dermis along with a peculiar adjacent bizarre fibroblastic reaction, of the type usually seen in atypical decubital fibroplasia of debilitated patients. The ulceration was surgically excised, and the wound was sutured and repaired. At 18-month follow-up, the patient has no evidence of local disease.