Male secretory breast cancer: case in a 6-year-old boy with a peculiar gene duplication and review of the literature.

PURPOSE: Secretory breast cancer (SBC) is one of the rarest breast cancer (BC), representing the majority of BC in childhood. Nevertheless, it elicits a lot of interest both for the peculiar morphology and the characteristic genetic features. Currently, there is no consensus on optimal treatment strategy. Therefore, it is useful to report every case in order to establish treatment algorithms. METHODS: We describe the case of a 6-year-old boy diagnosed with a SBC, with peculiar genomic and immunohistochemical features. Moreover, we carried out a review of the literature in order to analyze the present state of knowledge about this rare entity. RESULTS: To the best of our knowledge, there are only 120 cases published in literature, only 32 in males and only 2 younger than 6 years. Furthermore, this one had peculiar genomic and immunohistochemical features. Indeed, even if SBC expresses basal-cell markers, our patient had a triple-negative tumor expressing both basal and luminal cell markers. Furthermore, the boy's genomic profile revealed not only positivity for the typical SBC's translocation t(12;15), but also for a 3q28 duplication, found in his father (healthy) and paternal grandfather (with a previous BC). None were positive for BRCA mutation. This locus includes only one gene encoding for a growth factor recently linked to Early Infantile Epileptic Encephalopathy-47 and Idiopathic ventricular tachycardia. Even if the literature does not provide evidence of a pathogenic role it is not possible to exclude a cancer-predisposing activity. CONCLUSIONS: SBC is a rare type of BC, characterized by triple-negative features with an unexpectedly good prognosis. More data are needed to fully understand the behavior of this cancer and genomic profiling could be helpful in improving its diagnosis and management.

Expression of microRNAs miR21, miR146a, and miR155 in tuberous sclerosis complex cortical tubers and their regulation in human astrocytes and SEGA-derived cell cultures.

Tuberous sclerosis complex (TSC) is a genetic disease presenting with multiple neurological symptoms including epilepsy, mental retardation, and autism. Abnormal activation of various inflammatory pathways has been observed in astrocytes in brain lesions associated with TSC. Increasing evidence supports the involvement of microRNAs in the regulation of astrocyte-mediated inflammatory response. To study the role of inflammation-related microRNAs in TSC, we employed real-time PCR and in situ hybridization to characterize the expression of miR21, miR146a, and miR155 in TSC lesions (cortical tubers and subependymal giant cell astrocytomas, SEGAs). We observed an increased expression of miR21, miR146a, and miR155 in TSC tubers compared with control and perituberal brain tissue. Expression was localized in dysmorphic neurons, giant cells, and reactive astrocytes and positively correlated with IL-1ß expression. In addition, cultured human astrocytes and SEGA-derived cell cultures were used to study the regulation of the expression of these miRNAs in response to the proinflammatory cytokine IL-1ß and to evaluate the effects of overexpression or knockdown of miR21, miR146a, and miR155 on inflammatory signaling. IL-1ß stimulation of cultured glial cells strongly induced intracellular miR21, miR146a, and miR155 expression, as well as miR146a extracellular release. IL-1ß signaling was differentially modulated by overexpression of miR155 or miR146a, which resulted in pro- or anti-inflammatory effects, respectively. This study provides supportive evidence that inflammation-related microRNAs play a role in TSC. In particular, miR146a and miR155 appear to be key players in the regulation of astrocyte-mediated inflammatory response, with miR146a as most interesting anti-inflammatory therapeutic candidate.

Focal dysplasia of the cerebral cortex and infantile spasms associated with somatic 1q21.1-q44 duplication including the AKT3 gene.

Somatic and germline duplications or activating mutations of AKT3 have been reported in patients with hemimegalencephaly and megalencephaly. We performed array comparative genomic hybridization on brain tissue and blood in 16 consecutive patients with symptomatic epilepsy due to focal or multilobar malformations of cortical development who underwent surgical treatment of epilepsy. One patient with infantile spasms and a dysplastic left frontal lobe harboured a somatic trisomy of the 1q21.1-q44 chromosomal region, encompassing the AKT3 gene, in the dysplastic brain tissue but not in blood and saliva. Histopathology revealed severe cortical dyslamination, a thin cortex in the premotor area with microgyri and microsulci, immature neurons with disoriented dendrites and areas of cortical heterotopia in the sub-cortical white matter. These cytoarchitectural changes are close to those defining type Ib focal cortical dysplasia. Immunohistochemistry in brain specimens showed hyperactivation of the PI3K/AKT/mTOR pathway. These findings indicate that AKT3 upregulation may cause focal malformations of cortical development. There appears to be an etiologic continuum between hemimegalencephaly and focal cortical dysplastic lesions. The extent of brain malformations due to AKT3 upregulation may be related to the embryonic stage when the post-zygotic gene alteration occurs.

Myxoid glioneuronal tumor: Histopathologic, neuroradiologic, and molecular features in a single center series.

BACKGROUND: Myxoid glioneuronal tumor (MGT) is a benign glioneuronal neoplasm recently introduced in the World Health Organization (WHO) classification of the central nervous system (CNS) tumors. MGTs are typically located in the septum pellucidum, foramen of Monro or periventricular white matter of the lateral ventricle. They were previously diagnosed as dysembryoplastic neuroepithelial tumors (DNT), showing histological features almost indistinguishable from classical cortical DNT. Despite that, MGTs have been associated with a specific dinucleotide substitution at codon 385 in the platelet-derived growth factor receptor alpha (PDGFRA) gene, replacing a lysine residue with either leucine or isoleucine (p. LysK385Leu/Iso). This genetic variation has never been described in any other CNS tumor. MATERIALS AND METHODS: Thirty-one consecutive tumors, previously diagnosed as DNTs at the Meyer Children's Hospital IRCCS between January 2010 and June 2021 were collected for a comprehensive study of their clinical, imaging, pathological features, and molecular profile. RESULTS: In six out of the thirty-one tumors we had previously diagnosed as DNTs, we identified the recurrent dinucleotide mutation in the PDGFRA. All six tumors were typically located within the periventricular white matter of the lateral ventricle and in the septum pellucidum. We then renamed these lesions as MGT, according to the latest WHO CNS classification. In all patients we observed an indolent clinical course, without recurrence. CONCLUSION: MGT represent a rare but distinct group of neoplasm with a typical molecular profiling, a characteristic localization, and a relative indolent clinical course.

[Tamoxifen, endometrial cancer risk and liquid based cytology. A paradigmatic case]. / Tamoxifene, rischio oncologico endometriale e citologia in fase liquida. Un caso clinico paradigmatico.

Long-term users of tamoxifen (TMX) are at increased risk for developing endometrial cancer. Early diagnosis is mainly based on transvaginal scan (TVS) and hysteroscopy with endometrial biopsy. Nevertheless, TVS does not provide a definitive diagnosis in most cases, particularly due to its high false-positive rate. In addition TMX related changes, such as "pseudocistic" pattern, affect endoscopic evaluation of the endometrium and biopsy sampling (in particular blind procedures) frequently yields insufficient tissue for diagnosis. The cause of the high inadequacy rate of endometrial biopsies in women on TMX might be related to the increase in endometrial fibrous component. The present case emphasizes the main difficulties in surveillance and early diagnosis of endometrial pathologies in TMX users. Liquid-based endometrial cytology played a determinant role in the diagnostic pathway of this patient. We believe it could be used solely or in association with TVS leading to many advantages in the surveillance of women receiving TMX.

Clinical utility of liquid-based cytology for the characterization and management of endometrial polyps in postmenopausal age.

The proper management of endometrial polyps still represents a clinical ongoing challenge, especially when they are asymptomatic and occasionally discovered. The aim of this study was to evaluate liquid-based endometrial cytology to manage endometrial polyps in postmenopausal age by its ability to exclude hidden premalignant and malignant changes within polyps. Three hundred fifty-nine consecutive postmenopausal patients who underwent hysteroscopic diagnosis of endometrial polyp over a 3-year period and who were scheduled for surgical removal within the three subsequent months were retrospectively evaluated. Histologic results after resection during operative hysteroscopy or during hysterectomy were compared with liquid-based cytology and endometrial biopsy obtained at the time of diagnostic hysteroscopy. Eight of 359 patients (2.2%) had malignant or premalignant polyps interpreted as benign finding at hysteroscopy. Unsatisfactory samples were higher for endometrial biopsy compared to liquid-based cytology in the whole series and in the subgroup of low-risk asymptomatic patients (P < 0.001). Endometrial biopsy and liquid-based cytology revealed a sensitivity of 62% and 87.5%, respectively and a 100% specificity. Considering the subgroup of low-risk asymptomatic patients, liquid-based cytology disclosed all the five pathologic lesions with a 100% sensitivity and specificity. In conclusion, liquid-based cytology proved to be a useful tool to establish the nature of endometrial polyps in postmenopausal patients. Complete removal of the lesion should be offered to all symptomatic patients and those with established risk factors for endometrial cancer. Conversely, a wait and see attitude should be considered in case of asymptomatic low-risk polyps with typical appearance on hysteroscopy and negative liquid-based cytology.

Occipital pilomyxoid astrocytoma in a 14-year-old girl--case report.

Pilomyxoid astrocytoma is a recently described tumor. Its most typical morphological characteristics are an angiocentric astrocytic proliferation embedded in a myxoid background. The behavior seems to be unfavorable due to the reported high rate of local recurrence. The earlier studies indicated that pilomyxoid astrocytoma typically affects young children and arises in the hypothalamic/chiasmatic region. We report a case of a 14-year-old patient with a 6-year history of absence seizure. Magnetic resonance imaging showed a right occipital lesion of approximately 3 cm in diameter. The patient underwent the surgical procedure with gross total excision. Histologically, the tumor was mainly composed of a monomorphous population of bipolar elongated piloid cells radially arranged around thin-walled blood vessels in a prominent myxoid background. There were focal hemorrhagic foci but no bona fide evidence of tumor necrosis or mitoses. Rosenthal fibers and eosinophilic granular bodies were not observed. The postoperative course was uneventful. No adjuvant therapy was administered. The patient is alive and well at 18-month follow-up. The case presented provides evidence that pilomyxoid astrocytoma can occur at a later age and can arise in regions different from hypothalamic/chiasmatic.

Intracranial meningioma containing metastatic colon carcinoma.

Tumour-to-tumour metastasis is a rare pathological entity. Meningioma is the most common intracranial tumour to host metastases, the majority of which arise from breast and lung cancers. We present the first report of a colonic cancer metastasis within an intracranial meningioma.A 76-year-old woman presented with a one month history of partial seizures. Her medical history included resection of an adenocarcinoma of the descending colon followed by adjuvant chemotherapy 1 year before our evaluation. Magnetic resonance imaging revealed a homogeneously enhancing lesion in the right frontal convexity.A well capsulated tumour attached to the frontal dura was surgically removed. The pathological examination demonstrated a mixture of fibrous meningioma and colloid adenocarcinoma. Possible explanations for the development of a cohesive chimeric mass of composite pathology are investigated.

Inducible cyclooxygenase (COX-2) in glioblastoma--clinical and immunohistochemical (COX-2-VEGF) correlations.

Cyclooxygenase-2 (COX-2) is the inducible form of the enzyme responsible for the first step in the prostaglandin synthesis. COX-2 upregulation is demonstrated in different tumors. COX-2 products may modulate tumoral growth, apoptosis, metastasis, multidrug resistance and angiogenesis. Moreover, the antitumoral effect of the COX inhibitors has been documented. We studied the immunohistochemical expression and the prognostic value of COX-2 on 43 surgical specimens of glioblastoma-affected patients. Furthermore, we evaluated the correlation between the immunohistochemical expression of COX-2 and vascular endothelial growth factor (VEGF). Of the glioblastomas, 63% resulted as COX-2-positive. Median survival of the patients with COX-2-positive lesions was 10 months; median survival of the patients with COX-2 negative glioblastoma was 21 months (NS). All 4 patients who survived longer than 24 months had COX-2 negative lesions (p = 0.017). Concordance between COX-2 and VEGF was documented in 60% of the cases. Our findings show that glioblastoma can immunohistochemically express COX-2 and that its expression is unrelated with VEGF and significantly less frequent in the long survivors. Nevertheless, the absence of statistical correlation with survival time advises further studies on larger series to ascertain the concrete prognostic value of COX-2 in glioblastoma.

Oligodendrogliomas lacking O6-methylguanine-DNA-methyltransferase expression.

O6-Methylguanine-DNA-Methyltransferase (MGMT) is a DNA repair protein considered to be a chemosensitivity predictor. We evaluated the immunohistochemical MGMT expression in 28 consecutive oligodendroglial tumors (21 oligodendrogliomas, 5 mixed oligoastrocytomas, and 2 glioblastomas with prominent oligodendroglial features; 13 treated with CCNU) and compared it with that of 13 glioblastomas. Twenty-six (93%) oligodendroglial tumors were MGMT-negative, 2 (7%) were MGMT-positive. Twelve (92%) patients treated with CCNU had MGMT-negative lesions and their median survival was 73 months; 1 patient had an MGMT-positive oligodendroglioma and is alive at 28 months. Three (23%) glioblastomas were MGMT-negative and 10 (77%) MGMT-positive. The lower MGMT expression in oligodendroglial tumors compared to glioblastomas (P < 0.05), which have different chemosensitivity, suggests a possible role of MGMT in the determination of chemoresistance. Nevertheless, the heterogeneous outcome of our MGMT-negative oligodendroglial tumors treated with CCNU, indicates that MGMT expression alone is insufficient to predict the response to alkylating drugs, presumably because of the numerous mechanisms involved.

Inhibitory effect of luteinising hormone-releasing hormone analogues on human endometrial cancer in vitro.

We studied the effects of luteinising hormone-releasing hormone (LHRH) agonist leuproreline (1 microM for 96 h) and LHRH antagonist cetrorelix on the cell growth of primary cultures from nine human endometrial cancers using the sulphorhodamine colorimetric test. Histological examinations and reverse transcription and polymerase chain reaction amplification (RT-PCR) for LHRH receptors were also performed. The endometrial cancers examined had a medium to high degree of proliferative activity and a low degree of apoptotic power; furthermore, they expressed the LHRH receptor RNA variably, detectable in 71% of cases. The addition of leuproreline or cetrorelix to cell cultures inhibited growth in a statistically significant way compared to untreated control cells; nevertheless, the percentage of cell growth inhibition obtained was very variable. These data suggest that LHRH analogues can exert differential inhibitory effects on the growth of endometrial cancer, which seems to be independent of the expression of specific LHRH receptors.

Oligodendroglioma: HMB-45 positivity using catalyzed signal amplification method: an immunohistochemical (HMB-45, CD31, p53, Mib-1) and ultrastructural study.

Although melanin synthesis and the presence of melanosomes are exceptionally reported in nervous system tumors, there is no record of melanotic oligodendrogliomas in the literature. The purpose of the current study was to evaluate whether melanosomes are immunohistochemically and ultrastructurally detectable in nonmelanotic oligodendrogliomas and to verify whether these data are related to prognosis. Thirty surgical specimens (19 primary lesions and 11 recurrences) from 19 patients were examined. Median survival was 80 months. Immunohistochemical studies were performed using the monoclonal antibodies HMB-45, CD31. Mib-1, and p53. Using catalyzed signal amplification (CSA), HMB-45 positivity was noticed in 3 (10%) of the oligodendrogliomas being studied. No correlation with survival was found. Ultrastructural examination displayed the presence of melanosomelike structures. Tumor vascularization, estimated by means of CD31 antibody, was increased in 6 of 19 primary lesions but there was no significant correlation with survival. Nine of the19 primary lesions were p53 negative. In these cases, survival was longer than in p53-positive tumors (P = 0.0213). Proliferation rate, evaluated with Mib-1, was unrelated to survival, but proved greater in recurrences (10 of 11 cases) than in primary tumors (7 of 19 lesions; P = 0.007).

Oligodendroglioma: CD44 as a possible prognostic opportunity.

CD44, in its standard form as well in its isoforms, is a cell surface adhesion glycoprotein which occurs in a wide variety of non-neoplastic and neoplastic cells. CD44 has been considered to be implicated in tumoral growth and in metastatic potential. We studied the immunohistochemical expression of CD44 standard in 30 oligodendrogliomas (19 primary lesions and 11 recurrences) in order to verify its possible prognostic role. Twelve primary oligodendrogliomas (63%) and 8 recurrences (73%) were CD44-positive. Three of 9 (33%) primary oligodendrogliomas with a Smith grade A-B and 9 of 10 (90%) primary oligodendrogliomas with a Smith grade C-D were found to be in CD44H-positive (p = 0.020). Three of 9 (33%) primary oligodendrogliomas that had not relapsed and 9 of 10 (90%) successively relapsed primary lesions were found to be CD44H-positive (p = 0.020). Median survival of the patients with a CD44H-positive lesion was 84 months; median survival of the patients with a CD44H-negative lesion was 91 months. We conclude that CD44H could have prognostic value regarding the occurrence of relapses.

Interstitial radiosurgery with the photon radiosurgery system in the minimally-invasive treatment of selected deep-seated brain tumors.

The purpose of this study was to evaluate the results of interstitial radiosurgery (IR) with Photon Radiosurgery System (PRS) in 18 patients (P) with deep-seated brain primary or secondary tumors. Follow-up varied from 2 to 53 months (mean, 13.6 mo). Seven P with glioblastomas died due to tumor progression. Five P with metastases died for systemic disease while local control was achieved in all. Six P with low-grade astrocytomas were well and imaging showed tumor control. We conclude that PRS IR is effective in the treatment of metastases while it provides lower benefit in malignant gliomas. It could play a major role in low-grade astrocytomas.

Amniotic band syndrome: a case report.

Amniotic band syndrome is an uncommon congenital pathological condition that may lead to malformations and foetal-infant death. We report an autoptic case. The patient was a male preterm infant. At 14 weeks of gestation, a routine ultrasonography showed severe craniofacial anomalies and a close contiguity of the foetal head with the amnios. The neonate survived three days, after which an autopsy was carried out. The infant had a frontoparietal meningoencephalocele; a fibrous band was attached to the skin, close to the meningoencephalocele base. Cleft lip and palate, nose deformation and agenesis of the right eye were also present. At the opening of the cranial cavity, occipital hyperostosis was observed. The herniated brain showed anatomical abnormalities that made identification of normal structures difficult. Microscopically, the nervous parenchyma had architectural disorganization and immaturity, and the fibrous band consisted of amniotic membranes. As evident from this case report, amniotic band syndrome may cause severe malformations and foetal-infant death.

Liquid-based endometrial cytology: the Florence and Bari experience.

Several diagnostic procedures are available to investigate the endometrium, i.e. sonography, hysteroscopy, biopsy, endometrial curettage and cytology. Among these, endometrial cytology is less commonly utilized. Although the use of cytology in the diagnosis of endometrial adenocarcinoma has already been proposed due to its low cost and simple execution, a general consensus has not been reached. The improvement of the diagnostic capacity of endometrial cytology following the introduction of a liquid-based method suggests that this test should be routinely used in endometrial diagnosis. The main advantages of this method are the reduction in confounding factors, the distribution of cells on a thin layer and the possibility to obtain more slides from the same sample. The aim of this article is to focus on the methodological procedures and diagnostic criteria in liquid-based endometrial cytology based on the experience in two Italian centres: Department of Pathology, University of Bari and Department of Human Pathology and Oncology, University of Florence. The sampling method used by the Bari authors consists in the collection of liquid for uterine distension during hysteroscopy, while the Florence group used an endometrial brush. The sensitivity and specificity at Bari were 75% and 83%, respectively, and were 94-100% and 95-100% at Florence, respectively. Endometrial cytology provided sufficient diagnostic material significantly more often than biopsy. We thus propose that endometrial cytology can be used in routine diagnosis either alone or in association with other diagnostic procedures in order to improve diagnostic accuracy.

Gestational diabetes insipidus: a morphological study of the placenta.

Gestational diabetes insipidus (GDI) refers to the state of excessive water intake and hypotonic polyuria. Those cases manifesting in pregnancy and referred to as GDI may persist thereafter or may be a transient latent form that resolves after delivery. Microscopic examination of affected subjects has not been previously reported. In the literature, there are various case reports and case series on diabetes insipidus in pregnancy. In this study, we present a case that had transient diabetes insipidus during pregnancy in which the placenta was examined.