Naomi Kawano

Expression of gelatinase A, tissue inhibitor of metalloproteinases-2, matrilysin, and trypsin(ogen) in lung neoplasms: An immunohistochemical study

Lung cancer is a heterogeneous tumor in terms of clinical and biological behavior, and its aggressiveness depends on its invasive and metastatic properties. Matrix metalloproteinases and serine proteinases are believed to play a crucial role in invasion and metastasis of malignant tumor cells. In the present study, the authors evaluated immunohistochemically the expression of gelatinase A; tissue inhibitor of metalloproteinases-2 (TIMP-2), an inhibitor of gelatinase A; matrilysin; and trypsin(ogen) in 67 lung tumors from a variety of histological types including 17 squamous cell carcinomas, 16 adenocarcinomas, 15 small cell carcinomas, and 12 carcinoids. Interestingly, normal bronchial, bronchiolar, and alveolar epithelial cells expressed gelatinase A, TIMP-2, matrilysin, and trypsin(ogen) at varying frequencies and intensities. Bronchial smooth muscle cells and cartilage cells expressed gelatinase A alone, whereas endothelial cells, fibroblasts, and macrophages expressed gelatinase A and TIMP-2. Gelatinase A was expressed at high levels in most lung tumors examined (47% to 80%). TIMP-2 was also expressed at high levels except in the small cell carcinomas, which showed TIMP-2 expression at a lower frequency (60%) compared with other types of lung tumors (80% to 100%). Although matrilysin was expressed by tumor cells of all the histological types at various frequencies (13% to 63%), its expression was most common in adenocarcinomas. Expression of trypsin(ogen) was observed almost exclusively in adenocarcinomas (56%); other types of lung tumors expressed trypsin(ogen) far less frequently (0% to 12%). The present results, taken together with those of previous studies, suggest that gelatinase A is associated with malignant behavior of all the types of lung tumors, whereas its activity may be controlled by the endogenous inhibitor TIMP-2. The aggressive clinical behavior of small cell carcinoma may be attributable, at least in part, to a loss of the inhibitory effect of TIMP-2, as a significant proportion of these tumors showed negative or low levels of TIMP-2 expression. Matrilysin and trypsin(ogen) expressions are unlikely to be correlated with the aggressiveness of lung tumors. The expression of trypsin (ogen) may rather reflect the differentiation of adenocarcinoma cells toward normal airway epithelial cells.

Interstitial pneumonia in Hermansky-Pudlak syndrome: significance of florid foamy swelling/degeneration (giant lamellar body degeneration) of type-2 pneumocytes

Abstract Although usual interstitial pneumonia (UIP)-like IP has been known as the most serious complication of Hermansky-Pudlak syndrome (HPS), its pathologic features and pathogenesis are poorly understood. We investigated biopsied and autopsied lung tissues from five patients who died of UIP-like IP associated with HPS (HPSIP). The salient histopathologic features of HPSIP observed were: (1) alveolar septa displaying florid proliferation of type-2 pneumocytes (2PCs) with characteristic foamy swelling/degeneration; (2) patchy fibrosis with lymphocytic and histiocytic infiltration centered around respiratory bronchioles, occasionally showing constrictive bronchiolitis; and (3) honeycomb change without predilection for the lower lobes or subpleural area. Those peculiar 2PCs were histochemically characterized by the over accumulation of phospholipid, immunohistochemically by a weak positivity for surfactant protein, and ultrastructurally by the presence of numerous giant lamellar bodies that compressed the nucleus with occasional cytoplasmic disruption, together suggesting a form of cellular degeneration with an over accumulation of surfactant (giant lamellar body degeneration). The present study strongly indicates that there is a basic defect in the formation/secretion process of surfactant by the 2PCs in HPS, which may well be the triggering factor for the HPSIP development. Other factors, such as macrophage dysfunction, may be working synergistically for further acceleration of the inflammatory process.

Aberrant Nuclear Localization and Gene Mutation of β-catenin in Low-Grade Adenocarcinoma of Fetal Lung Type: Up-Regulation of the Wnt Signaling Pathway May Be a Common Denominator for the Development of Tumors that Form Morules

The salient histopathologic features of low-grade adenocarcinoma of the fetal lung type (L-FLAC)/well-differentiated fetal adenocarcinoma (WDFA) include complex glandular structures and morules with biotin-rich optically clear nuclei. Interestingly, these characteristic features are shared by the cribriform-morular variant of papillary thyroid carcinoma, whose morphology is identical to that of familial adenomatous polyposis (FAP)-associated thyroid carcinoma. Furthermore, the single reported case of lung cancer associated with FAP was L-FLAC/WDFA. These observations lead us to hypothesize that up-regulation of the Wnt signaling pathway underlies the development of L-FLAC/WDFA. To verify this hypothesis, 11 cases of L-FLAC/WDFA, including the one FAP-associated case, eight cases of high-grade adenocarcinoma of the fetal lung type (H-FLAC), 24 cases of conventional pulmonary adenocarcinoma (CAC), and 13 fetal lungs were immunostained for β-catenin. All cases of L-FLAC/WDFA showed predominantly aberrant nuclear/cytoplasmic expression, especially in budding glands and morules, whereas six of eight cases (75%) of H-FLAC and all but one case (96%) of CAC showed predominantly membranous expression. Fetal lungs showed nuclear/cytoplasmic expression restricted to the distal branching airway epithelium. Mutational analysis of exon 3 of the β-catenin gene in five sporadic cases of L-FLAC/WDFA showed a point mutation at codon 34 and codon 37 in two cases, respectively. The present study indicates that up-regulating disturbances in the Wnt signaling pathway, including mutation of the β-catenin gene, underlie tumorigenesis of L-FLAC/WDFA. The expression pattern of β-catenin in L-FLAC/WDFA resembles that of the developing fetal lung airway. With the expression pattern of β-catenin as a marker, most cases of H-FLAC as well as CAC appear to have different oncogenic pathways from cases of L-FLAC/WDFA. The present study together with other available data also suggests that abnormal up-regulation of the Wnt signaling pathway may be a common denominator for the development of tumors with morular formation from a variety of anatomic sites.

Interdigitating Dendritic Cell Sarcoma of the Spleen: Report of a Case With a Review of the Literature

Interdigitating dendritic cell sarcoma is an extremely rare neoplasm that mainly occurs in the lymph nodes. We report a case of interdigitating dendritic cell sarcoma arising from the spleen, a previously unreported site for interdigitating dendritic cell sarcoma. An 87-year-old woman, visiting Ashigara Hospital with complaints of palpitation and dyspnea, was found to have pancytopenia and low proteinemia. Abdominal ultrasonography and CT scanning demonstrated severe splenomegaly with heterogeneous enhancement. She received a splenectomy under the clinical diagnosis of a splenic tumor. Grossly, the spleen was markedly enlarged, with confluent massive nodules. Microscopically, the normal architecture was effaced with diffuse proliferation of large pleomorphic cells arrayed in a somewhat sheet-like pattern. Erythrophagocytosis was commonly observed. Immunohistochemical studies showed that the tumor cells were positive for S-100 protein, fascin, vimentin, and CD68, but uniformly negative for CD45, B- and T-cell markers, CD1a, CD30, complement receptors, CD34, Factor VIII, HMB-45, and lysozyme. Ultrastructurally, the tumor cells possessed complex interdigitating cytoplasmic dendritic processes. Birbeck granules were absent. Based on these findings, the present case was diagnosed as interdigitating dendritic cell sarcoma. The patient died of multiple liver metastases 3 months postoperatively.

Detection of pulmonary metastasis of low-grade endometrial stromal sarcoma 25 years after hysterectomy.

Endometrial stromal sarcoma (ESS) is a rare uterine sarcoma. Low-grade ESS occasionally recurs or metastasizes after long disease-free periods, a fact that may complicate the diagnosis. Here we report a case of multiple lung metastases in a 68-year-old woman who had been disease-free for 25 years after hysterectomy for a uterine tumor. Biopsy revealed that the tumor was composed of oval cells with slight nuclear atypism but without mitotic figures, suggesting a low-grade neoplasm. Immunostaining for intermediate filaments revealed strong positivity for vimentin and weak positivity for alpha-smooth muscle actin. In addition, immunostaining for estrogen and progesterone receptors, performed under suspicion of low-grade ESS, was positive. The uterine tumor resected many years before had shown a similar morphology. Thus, it was demonstrated that the lung neoplasm was a metastatic low-grade ESS that had appeared after many disease-free years. A review of the literature revealed that this case had the longest recorded interval between the occurrence of the initial ESS and the development of distant metastases. When low-grade sarcoma appears in the lungs of female patients, it is important to consider the possibility of low-grade ESS. Detailed information on the past clinical history, together with immunostaining for estrogen and progesterone receptors, are important diagnostic keys.

Basement membrane patterns, gelatinase A and tissue inhibitor of metalloproteinase-2 expressions, and stromal fibrosis during the development of peripheral lung adenocarcinoma.

To clarify the process and mechanisms of the development and progression of peripheral lung adenocarcinoma, we investigated the relationships among the patterns of basement membrane (BM), stromal fibrosis, and the expressions of gelatinase A and tissue inhibitor of metalloproteinases-2 (TIMP-2) in 33 lesions of atypical alveolar cell hyperplasia (AAH) and 48 lesions of lung adenocarcinoma, including 24 lesions of bronchioloalveolar carcinoma (BAC). We found that the architecture of alveolar BM was intact in all 33 AAH lesions and 11 nonsclerosing BAC lesions that formed no central scar, suggesting that these lesions are early-stage intraepithelial neoplasia. The preexistent BM of the lung was disrupted, and the BM components around the neoplastic glands were disrupted or absent in the area of the central scar of some sclerosing BAC lesions with collapse fibrosis alone (2 of 4) and in those of all of the adenocarcinoma lesions associated with desmoplastic stromal fibrosis (nine sclerosing BAC and 24 non-BAC tumors). These results suggested that, in lung adenocarcinomas, destruction of the BM was correlated with the formation of a central scar, particularly with desmoplasia. It is likely that adenocarcinomas with a central scar are advanced and invasive cancers potentially having metastatic activity. The expression of gelatinase A and TIMP-2 was associated with central scar formation as well as with destruction of the BM components. Both the neoplastic and stromal cells expressed gelatinase A and TIMP-2 and probably play a role in tumor cell invasion.

Composite distal nephron-derived renal cell carcinoma with chromophobe and collecting duct carcinomatous elements.

Chromophobe renal cell carcinoma (RCC) and collecting duct carcinoma (CDC) are derived from the collecting duct epithelia, although their morphology, molecular biologic characteristics and clinical behaviors are quite different. Herein is presented a case of RCC possessing the chromophobe RCC and CDC elements occurring in a 64 year‐old Japanese woman. The patient was referred to Yokohama City University Hospital with complaints of persistent back pain and fever. Radiologic examinations revealed a left renal tumor, and radical nephrectomy was performed. The patient died with multiple metastases, 8 months after the operation. The resected tumor showed an invasive growth, and its cut surface was heterogenous with hemorrhage and necrosis. Histologically, the tumor was composed of chromophobe elements with dedifferentiation, and CDC elements. The chromophobe and CDC elements had obvious histological transition. Lectin histochemistry and immunohistochemistry confirmed that this tumor was derived from the distal nephron. c‐KIT, p53 and Ki67 antigen showed differential localization between the chromophobe and CDC elements, even in the transitional areas. Along with the previous reports, the present case seemed to be composite RCC derived from the collecting duct, which might present clues to elucidate carcinogenesis in the distal nephron.

Localization of ladsin, a homolog of laminin-5, in normal adult human tissues: immunohistochemical and immunoelectron microscopic studies.

Ladsin, a homolog of laminin-5, is a large cell-adhesive protein with potent cell-scattering activity. In the present study, we investigated, by immunohistochemistry, the distribution of ladsin in a wide range of normal adult human epithelial tissues along with that of integrin subunit α3 as a marker of integrin α3β1, which is the primary receptor of ladsin. Our results demonstrated that ladsin was localized in the basement membranes of almost all the epithelial tissues with coexisting integrin subunit α3 along the cell membranes, suggesting that their interaction is important in the maintenance of normal architecture and function of these membranes. Only cytoplasmic localization of ladsin was observed in the fundic glands, hepatocytes, renal tubuli, and acini of the mammary glands, and in these tissues, integrin subunit α3 was also localized in the cytoplasm. Both ladsin and integrin subunit α3 were absent in the acini of the pancreas, major salivary glands, and bronchial glands. These tissue- and cell type-specific localizations of ladsin and integrin subunit α3 likely reflect the differences in their role and function in each tissue.

Diagnosis of B-cell lymphoma. Utility of the polymerase chain reaction for detecting clonality from archival cytologic smears.

OBJECTIVE To apply the polymerase chain reaction (PCR) to detect clonality for potentially helping to establish a definitive diagnosis of lymphoma in cytologic material. STUDY DESIGN In this retrospective study, Papanicolaou-stained cytologic smears and formalin-fixed, paraffin-embedded tissues from 17 cases of B-cell lymphoma were examined to investigate their clonality by a PCR technique using three different approaches (FR3, FR3A and FR2) for amplification of immunoglobulin heavy chain genes. Cytologic smears from 10 cases of nonneoplastic lymphoid tissues and T-cell lymphomas served as negative controls. RESULTS Monoclonality was detected in 9 of 17 cases (53%) of B-cell lymphoma in cytologic smears as compared with 8 of 16 cases (50%) in tissue sections. Semi-nested PCRs (FR3A/FR2) were superior to the single PCR (FR3) in the detection rate (41% vs. 18%). Five of seven cases (71%) of marginal zone B-cell lymphomas showed monoclonality, whereas only 4 of 10 cases (40%) of diffuse large B-cell lymphomas did so. Monoclonality was demonstrated in none of the negative controls. CONCLUSIONS Clonality detection in B-cell lymphomas by PCR using cytologic smears is specific and equal in sensitivity to that using formalin-fixed, paraffin-embedded tissues. The detection rate is especially excellent in marginal zone B-cell lymphoma, in which the cytologic diagnosis is particularly challenging. Combined seminested PCRs for FR3A and FR2 are advocated for a reliable assessment of clonality.

Crush and imprint cytology of subependymoma: a case report.

BACKGROUND There are few descriptions of the cytologic features of subependymoma because this neoplasm is rare and most commonly encountered incidentally at autopsy. Here we report a surgical case of subependymoma occurring in the lateral ventricle and provide the first documentation of the crush cytologic features of this tumor. CASE A 34-year-old woman was found to have a tumorous lesion in the right lateral ventricle. At surgery, a 2-cm-diameter tumor was detected in the anterior horn. Histologic examination during surgery revealed that the mass was composed of loose,fibrillary networks and clusters of nuclei showing mild pleomorphism. A number of microcystic formations were evident. Histologically, the neoplasm was considered benign--specifically, a subependymoma. Papanicolaou- or Giemsa-stained crush specimens and imprint smears were also prepared. The cytologic morphology was fundamentally the same as the histologic. In the crush specimens, microcystic formations were readily visible. Moreover, details of the cellular morphology were more easily recognized in the cytologic slides than in the frozen sections. CONCLUSION Cytologic examination, particularly crush cytology, appears to be useful for the rapid diagnosis of subependymoma during surgery in combination with the examination of frozen histologic sections.