Rosario Alberto Caruso

Prognostic value of intratumoral neutrophils in advanced gastric carcinoma in a high-risk area in northern Italy

Several lines of evidence indicate that neutrophils act nonspecifically against tumor cells. The correlation between tumor-infiltrating neutrophils (TINs) and clinicopathological features remains unclear and deserves to be investigated. To analyze the prognostic influence of TINs in gastric carcinoma, the authors selected 273 patients with advanced gastric carcinoma who underwent gastrectomy at Cremona Hospital (Lombardia, Italy) between 1990 and 1995 and followed them for a period of 5 years. The number of TINs was assessed in a semiquantitative manner using the mean value of 20 nonoverlapping high-power fields (magnification, 400×; 0.08 mm2). The patients were divided into two groups: patients with a moderate or extensive amount of TINs (n = 76; >10 TINs per 20 high-power fields) and patients with a minor amount of TINs (n = 197; ≤10 TINs per 20 high-power fields). The Kaplan-Meier method and Greenwood formula were used to estimate the crude survival rates in the two groups. Multivariate analyses based on the Cox proportional hazard regression model were performed to assess the effect of the prognostic factors on survival. Among the potential prognostic factors analyzed by univariate analysis, sex, age, location of neoplasia, pTNM stage, TINs, and surgical curability were significantly associated with higher survival rate. The study of the possible interaction effects of the clinical-pathological factors with TINs reveals that female patients with a moderate or extensive amount of TINs have about a 39% reduction in their risk of mortality, whereas male patients do not seem to be affected by the level of TINs. These results suggest that women appear to have a better prognosis than men in advanced gastric carcinoma. Gender differences in some host defense mechanisms and particularly in neutrophil function may be responsible for this event. Confirmation of these findings would give valuable insights about host reaction to gastric cancer growth and, ultimately, possibly would have implications regarding the identification of low-risk patients who could be spared adjuvant therapy.

Angiotensin-Converting Enzyme and Angiotensin Type 2 Receptor Gene Genotype Distributions in Italian Children with Congenital Uropathies

Angiotensin I–converting enzyme (ACE) and angiotensin type 2 receptor (AT2R) gene polymorphisms have been associated with an increased incidence of congenital anomalies of the kidney and urinary tract (CAKUT). We investigated the genotype distribution of these polymorphisms in Italian children with CAKUT. We also evaluated the association between the ACE insertion/deletion and the AT2R gene polymorphisms with the progression of renal damage in subgroups of CAKUT patients. We recruited 102 Italian children with CAKUT; 27 with vesicoureteral reflux; 12 with hypoplastic kidneys; 20 with multicystic dysplastic kidneys; 13 with ureteropelvic junctions stenosis/atresia; 18 with nonobstructed, nonrefluxing primary megaureters; and 12 with posterior urethral valves and compared them with 92 healthy control subjects. ACE and AT2R gene polymorphisms were analyzed by PCR. The identification of AT2R gene polymorphisms in intron 1 and in exon 3 was revealed by enzymatic digestion. ACE genotype distribution in children with CAKUT was no different from that of the control subjects, but the subgroup of patients with radiographic renal parenchymal abnormalities showed an increased occurrence of the D/D genotype. The frequency of the G allele of AT2R gene in children with CAKUT was increased in respect to that of the control subjects. By contrast, no significant difference in the frequency of the C and A alleles of the AT2R gene was found. Our findings indicate that the ACE gene can be a risk factor in the progression of renal parenchymal damage in CAKUT patients. Moreover, a major role of the AT2R gene in the development of CAKUT has been found, at least in Italian children.

Patterns of recurrence of bronchioloalveolar cell carcinoma after surgical resection: a radiological, histological, and immunohistochemical study.

PURPOSE Bronchioloalveolar carcinoma (BAC) is a subtype of lung adenocarcinoma whose incidence is raising. Bronchioloalveolar carcinoma has a tendency to involve diffusely the lung. No agreement exists about whether diffuse bronchioloalveolar carcinoma has a multicentric or unicentric origin. The purpose of this work is to evaluate the correlation between intrapulmonary spread of bronchioloalveolar carcinoma and its histologic and immunohistochemical characteristics. DESIGN Surgical specimens of 20 bronchioloalveolar carcinomas with radiologically proved evolution from focal to diffuse disease were retrieved and reviewed. Patterns of pulmonary spread were defined on the basis of CT and MR imaging examinations. Immunohistochemical studies were performed to investigate the expression of gelatinase A and alpha2-integrin. Correlation between immunohistochemical results and patterns of pulmonary spread was evaluated. Statistical evaluation was performed by using Fisher Exact Test. RESULTS Three histological subtypes of bronchioloalveolar carcinoma were found: mucinous (11 cases), non-mucinous (3 cases), and mixed adenocarcinoma with prominent bronchioloalveolar pattern (6 cases). Three patterns of pulmonary spread were depicted radiologically: parenchymal opacification (11 cases), multiple nodules (7 cases) and mixed pattern (2 cases). Eleven out of 12 mucin-producing versus none out of 8 non-mucin producing cancers developed parenchymal opacification. The difference was statistically significant (P<0.028). A statistically significant difference was also found between the development of parenchymal opacification and the level of alpha2-integrin: 11 out of 13 tumors with negative alpha2-integrin versus none out of 7 with positive alpha2-integrin immunoreactivity (P>0.033). CONCLUSIONS Diffuse bronchioloalveolar carcinoma may develop from a prior focal cancer. Mucinous subtype is the most prone to develop diffuse disease with parenchymal opacification, probably representing aerogenous spread. Low levels of alpha2-integrin receptors were found in bronchioloalveolar carcinoma which developed parenchymal opacification.

HER2 status in unusual histological variants of gastric adenocarcinomas

Aim To investigate HER2 status in a cohort of 109 gastric adenocarcinomas also including unusual variants, such as 14 hepatoid (HAS) and 9 mitochondrion-rich (MRC), characterised by an opposing clinical behaviour. Methods and Results Using HercepTest (DAKO) and FISH test (pharmDx DAKO), HER2 overexpression/amplification was encountered in 23 of 109 (21.10%) of all gastric adenocarcinomas. A progressive increase in HER2 overexpression was observed moving from the poorly cohesive histotype to MRC, tubular adenocarcinomas and HAS. A statistically significant difference was found between poorly cohesive carcinomas and the others; a similar significant difference was encountered between HAS and all other variants of adenocarcinoma. HER2 overexpression was significantly associated with high grade, advanced stage, high Ki-67 labelling index value and death from gastric cancer. Multivariate analysis identified HER2 overexpression as an independent unfavourable prognostic variable for adenocarcinomas as a whole and also for the HAS variant. Conclusions Trastuzumab has been confirmed as an additional useful therapeutic standard option for patients with HER2-positive advanced gastric cancers, and also in aggressive variants of adenocarcinomas such as HAS.

CT-pathologic correlation in nodular bronchioloalveolar carcinoma.

Objective We retrospectively reviewed CT and pathologic examinations in resected nodular bronchioloalveolar carcinomas (BACs) to correlate the histology with the appearance of the nodules on preoperative thin section CT images. Materials and Methods Thin section CT scans of 11 patients with nodular BAC were reviewed by two observers. In each case, size, tumor-lung interface, and internal characteristics of the nodule were recorded and correlated with histopathologic examinations. Results Computed tomography showed a large bronchus leading to or contained within the nodule in 36%; spiculated, lobulated, or irregular borders in 82%; pleural retraction in 36%; internal inhomogeneity in 45%; and a zone of intermediate attenuation surrounding a higher attenuation nodule and separating it from the surrounding lung parenchyma (the CT halo sign) in 18% of the 11 BACs. In two lesions internal serpentine radiolucencies could be seen. Histopathologic studies showed this correlated with the air-containing glandular spaces of the tumor. Conclusion The CT halo sign and serpentine radiolucencies should be added to the list of the CT findings of nodular BAC. However histologic examination is required to confirm the diagnosis of BAC.

Radiolucencies and cavitation in bronchioloalveolar carcinoma: CT-pathologic correlation

Abstract. Bronchioloalveolar carcinoma (BAC) is a polymorphic lung cancer the incidence of which is rising. The presence of intratumoral radiolucencies is an important feature of bronchioloalveolar carcinoma.The aim of this study was to present pictorially the spectrum of intratumoral radiolucencies visible in BAC. In 57 BACs studied with thin-slice CT, we identified six types of radiolucencies: (a) patent intratumoral bronchioles (air bronchiologram); (b) pseudocavitations; (c) cavitation; (d) serpentine radiolucencies; (e) internal alveologram; and (f) multiple cystic lesions.

Mitotic Catastrophe in Malignant Epithelial Tumors: The Pathologist’s Viewpoint

Mitotic catastrophe is a common phenomenon occurring in tumor cells with impaired p53 function exposed to various cytotoxic and genotoxic agents. The defective p53 checkpoint causes improper segregation of chromosomes, resulting in aberrant mitosis, multiple micronuclei, multinucleate giant cells, and eventual necrosis-like death and centrosome aberration. Although various descriptions explaining mitotic catastrophe exist, there is still no generally accepted definition of this phenomenon. However, the syndrome of mitotic catastrophe may be a unifying morphological concept of particular interest to cancer research, as it integrally links cell death to checkpoints of the cell cycle. Morphological findings compatible with mitotic catastrophe may be found in pleomorphic, giant cell carcinomas—neoplasms characterized by a poor prognosis. The inclusion of mitotic catastrophe as part of the microscopic evaluation of tumors will add further insight to the pathobiology of tumor progression and in novel therapeutic designs. Finally, the possibility of assimilating mitotic catastrophe into a prognostic score is discussed.

Degranulation Patterns of Eosinophils in Advanced Gastric Carcinoma: An Electron Microscopic Study

Recruitment and activation of eosinophils have been studied intensely in asthma and other allergic diseases. Less is known about the infiltration and degranulation patterns of eosinophils in the tumor stroma. Seven cases of advanced gastric carcinomas were found to be massively infiltrated by eosinophils and studied by light and electron microscopy. Gastric carcinomas, despite having similar numbers of tissue eosinophils, exhibited markedly different degranulation patterns. In 2 cases, resting nondegranulating eosinophils were found. Piecemeal degranulation was the predominant mode of secretion from eosinophils localized within the tumor stroma in 4 cases. Eosinophil exocytosis and cytolysis were rarely observed. In 1 case, crystals morphologically similar to Charcot-Leyden crystals were observed at the extracellular level as well as in phagosomes of tissue macrophages, confirming active sequestrations of eosinophil Charcot-Leyden protein by macrophages in vivo. In the same case, eosinophils showed characteristic features of early and late apoptotic changes, such as condensed chromatin, focal dilatation of nuclear envelope, and preserved plasma membrane. Morphological association between apoptotic eosinophils and deposition of granules in the tumor stroma was found. Extracellular deposition of intact granules from apoptotic eosinophils was distinct from eosinophilic (necrotic) cytolysis, and has reported previously in experimental studies in vitro. To the knowledge of the authors, this case represents the first report of late apoptotic eosinophils that release their granules within the tumor stroma in a human gastric carcinoma.

HER2 status in advanced gastric carcinoma: A retrospective multicentric analysis from Sicily.

According to the ToGA trial, HER2 has been shown to be predictive for the success of treatment with trastuzumab in advanced gastric cancer (AGC). A number of studies have analyzed HER-2/neu overexpression in gastric carcinoma and identified the rate of HER2 positivity to be markedly varied. To date, the prevalence of HER2 overexpression in Sicilian people with AGC is unknown. Therefore, in the present study, a retrospective immunohistochemical analysis of HER2 was performed in a cohort of 304 AGC samples that were obtained from the archives of 10 Sicilian anatomopathological diagnostic units in order to verify the positive rate of HER2-positive cases. Furthermore, the characteristics of histotype, grade, stage and Ki-67 expression were also analyzed. HER2 overexpression was encountered in 17.43% of all the gastric adenocarcinomas, which was consistent with the results that have been reported elsewhere in the literature. A progressive increase in HER2 overexpression was observed, from the poorly cohesive histotype to the tubular adenocarcinomas and gastric hepatoid adenocarcinomas. HER2 overexpression was significantly associated with a high grade, advanced stage and high Ki-67 labeling index. Further investigations performed jointly by pathologists and oncologists within the geographical area of the present study should confirm that the association of trastuzumab with chemotherapy results in an improvement of survival in patients with AGC.

Report of an intrapulmonary solitary fibrous tumor: fine-needle aspiration cytologic findings, clinicopathological, and immunohistochemical features.

The authors describe a rare case of intrapulmonary solitary fibrous tumor (SFT). Morphologically, the tumor showed a disorganized or “patternless” arrangement of plump to spindle cells in a collagenous stroma. Tumor cells were immunoreactive for vimentin, but not for keratin, carcinoembryonic antigen, epithelial membrane antigen, factor‐VIII related antigen, S‐100 protein, desmin, and actin. These immunohistochemical findings suggested fibroblastic differentiation, in keeping with the putative submesothelial origin of the tumor. The problems concerning the fine‐needle aspiration (FNA) preoperative diagnosis of SFT are briefly discussed. Diagn Cytopathol 1996;14:64–67.