Iwao Emura

Limited Resection for Noninvasive Bronchioloalveolar Carcinoma Diagnosed by Intraoperative Pathologic Examination

BACKGROUND The establishment of limited resection procedures for non-small cell lung cancer is expected. Many groups have suggested noninvasive bronchioloalveolar carcinoma (BAC) to be a potential indication for limited resection. METHODS We designed a prospective phase II study evaluating limited resection for noninvasive BAC diagnosed by intraoperative pathologic examination. From 1999 to 2007, limited resection was the procedure in 46 patients (16 men and 30 women; median age, 69 years; range, 49 to 83) who were diagnosed intraoperatively as having noninvasive BAC. The first end point was the predictive value of the intraoperative pathologic examination for noninvasive BAC diagnosis. The second end point was overall survival, disease-free survival, and cancer-specific survival, calculated using the Kaplan-Meier method. RESULTS We performed wedge resections for 44 patients and segmentectomy for 2 patients. Permanent pathologic examination revealed 3 patients had primary lung adenocarcinomas other than noninvasive BAC. The predictive value of intraoperative pathologic examination for noninvasive BAC diagnosis was 94%. During a median 51-month follow-up, there were only 2 cancer unrelated deaths. The 5-year overall survival rate and the disease-free survival rate were 93%, and the 5-year cancer-specific survival rate was 100%. CONCLUSIONS The results of our prospective phase II study indicate that limited resection, mainly by wedge resection, is a potentially curative surgical procedure and may be an acceptable alternative to lobectomy for patients with noninvasive BAC. Furthermore, an intraoperative pathologic diagnosis of noninvasive BAC is strongly predictive and allows for an intraoperative decision to perform a limited resection in these patients.

Do the level of nodal disease according to the TNM classification and the number of involved cervical nodes reflect prognosis in patients with differentiated carcinoma of the thyroid gland

The importance of nodal involvement as a prognostic factor in differentiated carcinoma of the thyroid gland remains controversial. We therefore attempted to confirm the prognostic factors in differentiated thyroid carcinoma, with special reference to nodal status.

Tubulointerstitial nephritis associated with IgG4-related systemic disease

We report three patients with tubulointerstitial nephritis (TIN) with high serum IgG4 concentrations. None of the patients had notable pancreatic lesions when the TIN developed, although one had a history of autoimmune pancreatitis (AIP). Nevertheless, the clinicopathological findings were quite similar to those of AIP. They were all middle-aged to elderly men. Sialadenitis and lymphadenopathy were often evident. Serum total IgG and IgG4 concentrations were elevated and hypocomplementemia was observed. Although antinuclear antibodies were positive, anti-Ro and anti-La antibodies were negative. Renal biopsy showed dense lymphoplasmacytic infiltration with fibrosis in the renal interstitium, and the infiltrated plasma cells had strong immunoreactivity for IgG4. Furthermore, lymphoplasmacytic infiltration and abundant IgG4-positive plasma cells were observed in the salivary glands of a patient. Steroid therapy was effective for TIN in all three patients. The present findings support the recently proposed concept of IgG4-related systemic disease, and suggest that IgG4 is associated not only with AIP but also with other systemic lymphoplasmacytic diseases, including TIN. The conditions responsible for the pathogenesis of TIN need to be considered, irrespective of the presence of AIP.

Recurrent malignant variant of phosphaturic mesenchymal tumor with oncogenic osteomalacia.

Abstract Phosphaturic mesenchymal tumor is a rare neoplasm which causes osteomalacia or rickets. The tumor typically follows a benign clinical course. Even in the rare malignant cases, local recurrence and distant metastasis are uncommon. We report on an example of a malignant phosphaturic mesenchymal tumor which recurred several times over 16 years concurrently causing hypophosphatemia, bone pain, and osteomalacia. Following each surgery, symptoms and hypophosphatemia improved. The patient died of disease 17 years after the first surgery. Histologically, the initial tumor was composed of small spindle cells with clusters of giant cells, prominent blood vessels, poorly formed cartilaginous areas, and crystalline material. Cytological atypia was minimal. Following multiple recurrences, the tumor demonstrated areas of high-grade sarcoma exhibiting marked pleomorphism, numerous mitotic figures, and p53 overexpression. This case illustrates the potential lethality of incompletely removed phosphaturic mesenchymal tumors.

Plasma Cells and the Chronic Nonsuppurative Destructive Cholangitis of Primary Biliary Cirrhosis

There has been increased interest in the role of B cells in the pathogenesis of primary biliary cirrhosis (PBC). Although the vast majority of patients with this disease have anti‐mitochondrial antibodies, there is no correlation of anti‐mitochondrial antibody titer and/or presence with disease severity. Furthermore, in murine models of PBC, it has been suggested that depletion of B cells may exacerbate biliary pathology. To address this issue, we focused on a detailed phenotypic characterization of mononuclear cell infiltrates surrounding the intrahepatic bile ducts of patients with PBC, primary sclerosing cholangitis, autoimmune hepatitis, chronic hepatitis C, and graft‐versus‐host disease, including CD3, CD4, CD8, CD20, CD38, and immunoglobulin classes, as well as double immunohistochemical staining for CD38 and IgM. Interestingly, CD20 B lymphocytes, which are a precursor of plasma cells, were found in scattered locations or occasionally forming follicle‐like aggregations but were not noted at the proximal location of chronic nonsuppurative destructive cholangitis. In contrast, there was a unique and distinct coronal arrangement of CD38 cells around the intrahepatic ducts in PBC but not controls; the majority of such cells were considered plasma cells based on their expression of intracellular immunoglobulins, including IgM and IgG, but not IgA. Patients with PBC who manifest this unique coronal arrangement were those with significantly higher titers of anti‐mitochondrial antibodies. Conclusion: These data collectively suggest a role for plasma cells in the specific destruction of intrahepatic bile ducts in PBC and confirm the increasing interest in plasma cells and autoimmunity. (HEPATOLOGY 2012)

Pigmented renal cell carcinoma

A rare case of pigmented renal cell carcinoma is presented. The tumor was yellow, somewhat elastic, and soft with focal gray and tan areas. Microscopically, the tumor was a typical renal cell carcinoma of the clear-cell type. Tumor cells containing brown pigment in the cytoplasm were scattered throughout the tumor. Ultrastructurally, the electron-dense granules consistent with the brown pigment noted at the microscopic level showed a coarse or fine granular matrix with or without homogeneous high electron-dense areas, resembling lipofuscin. However, the nature of the pigment was different from that of lipofuscin by the Masson-Fontana method after bleaching and rather similar to neuromelanin. The current case is a rare renal cell carcinoma with pigmentation attributed to abnormally excessive accumulation of neuromelanin pigment.

HISTOCHEMICAL, IMMUNOHISTOCHEMICAL AND ULTRASTRUCTURAL INVESTIGATIONS OF GIANT CELL TUMORS OF BONE

The origin and characteristics of so‐called stromal cells (stromal cell) and the osteoclast‐like giant cell series of 19 cases of giant cell tumor (G.C.T.) of bone were studied. Immunohistochemically, two interesting cases were found. The stromal cells of one case were α‐1‐antitrypsin positive and those of the other case were α‐1‐antichymotrypsin positive. The histiocytic stromal cells of the latter case seemed to be surely neoplastic since they showed mild to moderate cell atypism. There were foci consisting of fibroblastic cells or osteoid and osteoblasts within the tumor. Those cells in the foci were apparently continuous with the surrounding stromal cells, and they were, therefore, also considered to be neoplastic. These findings strongly indicate that the stromal cells originate from the undifferentiated mesenchymal cells in the bone marrow and may differentiate to osteoblastic, fibroblastic, and histiocytic cells. All cells of these three series were not stained for a high stable form of acid phosphatase (SAPhase). SAPhase activity was demonstrated only in osteoclast‐like giant cells and some mononuclear cells, which are recently believed to be non‐neoplastic. Therefore, the cell atypia of SAPhase negative stromal cells is considered to have a prognostic value.

Primary carcinoid tumor of the testis: Immunohistochemical, ultrastructural and FISH analysis with review of the literature

Primary carcinoid tumor of the testis only accounts for 0.2% of all carcinoid tumors in Japan. The clinicopathological features, including differences between Japanese and Europe/United States (Eur/US) series’, which are known in ovarian carcinoids, have not yet been sufficiently recognized. In the present study, five testicular carcinoids from various clinicopathological viewpoints were analyzed, with a review of the literature. All 15 cases in Japan, including 10 previously reported, were insular carcinoids. Three of the 15 cases (20%) were associated with a teratoma. Serotonin production was confirmed in at least 10 cases (five cases in the present study and five cases in previous studies), but carcinoid syndrome was present in only two cases. Three of the 15 cases (20%) showed distant metastases, and the tumors that metastasized were larger than those that did not. These features were almost similar to those observed in the Eur/US series. Three pure carcinoids were also studied for the number of sex chromosomes by fluorescence in situ hybridization (FISH). They did not show a significant numerical abnormality of the X chromosome, which is common in testicular germ cell tumors. Therefore, the genetic background of pure carcinoids might be different from that of common germ cell tumors.

Regular immunohistochemical localization of endothelin-1 and endothelin-B receptor in normal, hyperplastic and neoplastic human adrenocortical cells

The locallzation of endothelin (ET)‐l/blg ET‐1, ET‐3/big ET‐3, ET‐A and ET‐B receptor was Immunohistochemlcally examined in human adrenal glands composed of 36 normal cases, nine hyperplasla, 70 adenomas and seven carcinomas of cortical cells. In normal adrenals, ET‐1/blg ET‐1 and ET‐B receptor were regularly detected In the cortical cells, especially in the zona fasciculata for ET‐1 and zone glomerulosa for ET‐B receptor but not in the medulla, while ET‐A receptor localized occasionally in endothelial cells or rarely in cortical cells and ET‐3/blg ET‐3 was very limited In the cortical cells. In hyperplasia, adenoma and carcinoma, ET‐1 /big ET‐1 and ET‐B receptor showed frequent localization, although focal distrlbutlon of the ET‐B receptor was rather predominant in these groups. ET‐A receptor and ET‐3/big ET‐3 were very Infrequently expressed. Functioning versus non‐functioning and hypertensive versus normotenshe cases revealed no significant differences in the frequency of posltive cells for ET‐l /big ET‐1, ET‐3/big ET‐3, ET‐A receptor or ET‐B receptor. Alternatively, the frequency of lmmunoreactivtty to ET‐1/big ET‐1 or ET‐B receptor significantly decreased in hyperplasia, adenoma and carcinoma, when compared wlth that of normal adrenal cortex.

Vertebral basilar system dolichoectasia with marked infiltration of IgG4-containing plasma cells: a manifestation of IgG4-related disease?

We report the histopathological features of vertebral basilar system dolichoectasia (VBD) in a 68‐year‐old man who died as a result of accompanying infarction of the medulla oblongata on day 6 of admission. During hospitalization, the patient was also found to have an elevated serum IgG level and tumors of the renal pelvis. A possible clinical diagnosis of VBD associated with IgG4‐related disease was considered postmortem. Autopsy examination, limited to the intracranial tissues, revealed marked infiltration of IgG4‐containing plasma cells in the adventitia and media of the vertebral and basilar arteries. Multiple fibrous nodules forming pseudotumors were also evident on the outer surface of the affected arteries. These histological features were very similar to those of arteriopathy, such as inflammatory aortic aneurysm, which has been described in patients with IgG4‐related disease, suggesting that autoimmune mechanisms, known to be involved in the pathogenesis of visceral lesions in the disease, also played a role in the etiology of VBD in the present patient. In conclusion, we consider that the present case may represent VBD as a manifestation of IgG4‐related disease.