Giovanni Falconieri

Cervical cytopathology: An evaluation of its accuracy based on cytohistologic comparison

Background. Although Papanicolaou cytology represents the most effective technique to prevent and detect precancerous conditions of the uterine cervix, its false‐negative yield is still a reason of concern among pathologists and gynecologists.

Glioma-Associated Stem Cells: A Novel Class of Tumor-Supporting Cells Able to Predict Prognosis of Human Low-Grade Gliomas

Background: Translational medicine aims at transferring advances in basic science research into new approaches for diagnosis and treatment of diseases. Low‐grade gliomas (LGG) have a heterogeneous clinical behavior that can be only partially predicted employing current state‐of‐the‐art markers, hindering the decision‐making process. To deepen our comprehension on tumor heterogeneity, we dissected the mechanism of interaction between tumor cells and relevant components of the neoplastic environment, isolating, from LGG and high‐grade gliomas (HGG), proliferating stem cell lines from both the glioma stroma and, where possible, the neoplasm. Methods and Findings: We isolated glioma‐associated stem cells (GASC) from LGG (n=40) and HGG (n=73). GASC showed stem cell features, anchorage‐independent growth, and supported the malignant properties of both A172 cells and human glioma‐stem cells, mainly through the release of exosomes. Finally, starting from GASC obtained from HGG (n=13) and LGG (n=12) we defined a score, based on the expression of 9 GASC surface markers, whose prognostic value was assayed on 40 subsequent LGG‐patients. At the multivariate Cox analysis, the GASC‐based score was the only independent predictor of overall survival and malignant progression free‐survival. Conclusions: The microenvironment of both LGG and HGG hosts non‐tumorigenic multipotent stem cells that can increase in vitro the biological aggressiveness of glioma‐initiating cells through the release of exosomes. The clinical importance of this finding is supported by the strong prognostic value associated with the characteristics of GASC. This patient‐based approach can provide a groundbreaking method to predict prognosis and to exploit novel strategies that target the tumor stroma. Stem Cells 2014;32:1239–1253

Intrapulmonary solitary fibrous tumors: clinicopathologic and immunohistochemical study of 24 cases.

Solitary fibrous tumor (SFT) is a ubiquitous neoplasm that arises most commonly from the pleura. SFT arising within lung parenchyma (intrapulmonary SFT) has been rarely reported and is therefore not well recognized. We present a clinicopathologic and immunohistochemical study of 24 cases of primary intrapulmonary SFT. Patients’ ages ranged from 44 to 83 years (mean, 58 y). None of the patients had evidence or history of a similar tumor elsewhere. Tumor size ranged from 2.3 to 22 cm (mean, 8.5 cm). On the basis of the degree of cytologic atypia, cellularity, mitotic activity, and areas of necrosis, the lesions were divided into low-grade, intermediate-grade, and high-grade histology. Twenty-one tumors showed the conventional features of SFT of low-grade histology (<5 mitoses per 10 high-power fields), with alternating bands of rope-like collagen flanked by a bland-appearing spindle cell proliferation. Hemangiopericytic, angiofibromatous, and a neural-like plexiform growth pattern were also observed. Five of 21 cases showed an “adenofibromatous” appearance imparted by entrapped normal airspaces at the advancing edges of the lesion. One intermediate-grade tumor showed overall increased cellularity with plump, pleomorphic nuclei, 5 to 10 mitoses per 10 high-power fields, and focal areas of classic SFT. Two cases showed high-grade features at initial presentation, with areas resembling a pleomorphic high-grade sarcoma admixed with foci of conventional, low-grade SFT. Immunohistochemical staining analyses performed in 13 cases showed positivity of the tumor cells for CD34, bcl-2, and CD99 in the majority of cases tested. Clinical follow-up was available in 18 patients, with long-term follow-up (>5 y) in 6. Fourteen (14/18) patients were alive and well without evidence of disease 1 month to 14 years after initial diagnosis. Three patients died of their tumors after 4, 5, and 7 years; in 2 of them the initial tumor was of low-grade histology, but the recurrence/metastases showed a high-grade histology; the third fatal case showed a tumor with high-grade histology at initial diagnosis. One patient with intermediate-grade histology also had chest wall metastases at 5 years but was subsequently lost to follow-up. The results of our study indicate that although tumors with overtly malignant histologic features can be expected to behave as high-grade sarcomas, tumors with bland-appearing morphologic features at presentation may also follow an aggressive behavior. Adequate excision with close clinical follow-up, thus, appears to be the most prudent course of action for the management of primary intrapulmonary fibrous tumors.

Pseudoangiomatous Hyperplasia of the Mammary Stroma: True Entity or Phenotype?

We report the clinical and pathologic features seen in 14 cases of pseudoangiomatous hyperplasia of the mammary stroma. The lesion manifested as a discrete palpable lump in twelve women and two men. The excisional biopsy specimens showed firm, circumscribed grey-tan lesions measuring from 3 to 5.5 cm in largest dimension. Histologic study revealed diffuse, anastomosing, enlongated slits with open lumina, covered by spindle cells with bland nuclei and no mitotic activity. Strong reactivity for vimentin and CD34 was noted. Smooth muscle actin was focally noted in most cases. Immunostains for other markers, including CD31 and factor VIII related antigen was negative. Spindle cells from two cases expressed both estrogen and progesterone receptors. In all the cases, there was some degree of glandular hyperplasia accompanying the stromal changes. Fibroadenoma or fibrocystic disease were also common features. Our study confirms that pseudoangiomatous hyperplasia of mammary stroma represents a proliferation of local myofibroblasts, likely related to a hormonal stimulus. The wide range of associated changes of breast parenchyma further indicates that this lesion may represent a local, non specific change rather than a true clinico-pathologic entity.

Small Cell Carcinoma of Lung Simulating Pleural Mesothelioma : Report of 4 Cases with Autopsy Confirmation

Four cases of small cell carcinoma characterized by a striking involvement of the pleural sheets were investigated. The patients, four adult males with a long history of cigarette smoking, presented with symptoms common to pleural tumors, including cough and chest pain. Malignant cells were identified in pleural effusions of all cases and in the bronchial aspirate of one patient. Antitumoral treatments included chemo- and/or radiotherapy. Survival ranged from three to 17 months. At autopsy, the serosal sheets resulted to be extensively involved by thick tumor rinds, associated with massive hilar metastases. Histologically, the tumors were composed of small epithelial cells, expressing carcinoembryonic antigen and keratins and occasionally neuroendocrine markers. Our findings indicate that small cell carcinoma should be added to the group of pseudomesotheliomatous lung carcinomas and, above all, that it deserves distinction from ordinary mesothelioma, especially the small cell variant, because of its medico-legal implications and possible antitumoral treatment.

Expression of the Polycomb-Group protein BMI1 and correlation with p16 in astrocytomas an immunohistochemical study on 80 cases.

A number of studies on the putative relation between Polycomb-Group (PcG) proteins overexpression and carcinogenesis have been published recently. BMI1, the prototype PcG gene, is critically involved in cell cycle control and differentiation, and despite the regulatory role demonstrated in central nervous system (CNS) development, its implication in brain tumorigenesis is scarcely known. Moreover, to the best of our knowledge, large studies on human brain tumors tissue are lacking. To gain a new insight, we tested 80 primary brain astrocytomas for BMI1 expression using immunohistochemistry and established a correlation with the expression of p16, a negatively regulated target of BMI1 function. Fifty-four cases (72.5%) were BMI1 + /p16-, and 22 cases (27.5%) were BMI1 + /p16+. Slight non-significant differences were noted in the expression profile between grades II, III, and IV astrocytomas. However, when the 22 BMI1 + /p16+ tumors were examined cytologically, a substantial proportion contained a significant gemistocytic component, which is thought to be an adverse prognostic factor or to display a high degree of anaplasia, suggesting a common molecular mechanism of BMI1/p16 pathway disruption, which may have prognostic implications.

Aggressive “Breast-like” Adenocarcinoma of Vulva

A case of vulvar adenocarcinoma seen in a 42-year-old woman is reported. The tumor involved the right labium majus and diffusely spread into the surrounding soft tissues as well as the inguinal lymph nodes and was histologically composed of nests, cords, and tubular formations recalling an aggressive duct carcinoma of breast. Likewise, tumor cells exhibited positivity for common breast tumor markers, such as epithelial membrane antigen, carcinoembryonic antigen, and glandular keratins. The possible origin of the neoplasm from mammary ectopic tissue in vulva or from vulvar skin adnexa is briefly discussed.

Hodgkin's disease occurring in a Warthin's tumor: first case report

The case of a Warthins tumor whose lymphoid component was totally replaced by a malignant lymphoma, Hodgkins type, is reported. The disease was characterized by a rapid downhill course, with repeated medullary relapses and subsequent episodes of bone marrow failure. Death occurred 13 months after the initial diagnosis and was due to severe visceral involvement by Hodgkins lymphoma, as confirmed at post mortem examination.

Eosinophil-rich squamous carcinoma of the oral cavity: a study of 13 cases and delineation of a possible new microscopic entity

We report 13 cases of squamous cell carcinoma (SCC) of the oral cavity characterized by a prominent eosinophilic infiltration of the stroma. All patients were adults, 10 men and 3 women (aged 54 to 92 years; median, 71 years). They presented with tumors of the gingiva (5 cases), tongue (3 cases), palatine tonsil (2 cases), palate (2 cases), and mucosal aspect of lip (1 case). Metastatic involvement of regional lymph nodes was seen in 5 cases. The metastatic foci were associated with heavy eosinophilia as well. No patient had an abnormal eosinophil count in blood. Microscopically, the clusters of eosinophils were characteristically noticed in intimate admixture with the advancing edge of squamous carcinoma, either as nests or small tumor cords. The pattern of eosinophilic infiltration was comparable, regardless of tumor site or grade. Data from our series indicate that SCC with a reactive inflammatory infiltrate rich in eosinophils is consistently associated with stromal invasion. This observation may be useful in dealing with small tissue fragments where subepithelial stromal invasion cannot be easily assessed by conventional criteria. In addition, our data seem to confirm that eosinophil-rich SCC, although associated with metastatic involvement of cervical lymph node, seems to pursue a less aggressive course if compared with ordinary SCC.

Polypoid osteosarcoma of the left atrium: Report of a new case with autopsy confirmation and review of the literature

We describe a new case of heart osteosarcoma manifesting as a large polypoid mass of the left atrium. Clinically, the lesion presented with dyspnea, syncopal attacks, and fever. Ultrasound scans of the heart were suggestive of a cardiac myxoma, although some imaging features could retrospectively indicate a malignant neoplasm. In particular, the lesion was relatively immobile, did not show the characteristic myxoma motion during the heart cycle, and extended into the left pulmonary veins. Exploratory thoracotomy showed a nonresectable polypoid mass of the left atrium widely infiltrating the myocardium and the epicardium, histological features of a polymorphic sarcoma. The patient died 5 months after presentation with diffuse metastases. At autopsy, a 5-cm polypoid tumor was seen protruding into the left atrium. Neoplastic infiltration of the atrial myocardium, pericardium, and pulmonary veins was evident. Extensive metastatic deposits were observed in numerous sites, including the skin, lung, liver, and brain. Microscopically, a spindle cell sarcoma forming malignant osteoid was seen, admixed with areas indistinguishable from myxoid and pleomorphic malignant fibrous histiocytoma. This case provides further evidence that although rare, osteosarcoma of the heart usually presents as a polypoid mass of the left atrium and is histologically characterized by conspicuous polymorphism. It is associated with a poor prognosis and rapid appearance of distant metastases. Although at echocardiography it may mimic a myxoma, subtle features such as tumor extension into pulmonary veins and main origin from nonseptal atrial walls suggest the presence of a nonmyxomatous tumor and a preoperatory diagnosis of aggressive malignant disease.