Chie Inomoto

A case of IgG4-related hypophysitis without pituitary insufficiency.

CONTEXT IgG4-related hypophysitis is a novel clinical disease entity, which is typically complicated by hypopituitarism. OBJECTIVE The objective of the study was to describe a novel case of IgG4-related hypophysitis without pituitary insufficiency and summarize the current relevant literature. PATIENT AND METHODS A 55-year-old Japanese man presented with an enlarged pituitary gland and bitemporal hemianopsia. Endocrine studies revealed normal pituitary function, although his serum IgG4 level was high. The patient underwent a transsphenoidal biopsy of the pituitary gland, and the pathological tissues were consistent with IgG4-related hypophysitis. Oral prednisolone therapy was started, and after 6 months, his serum IgG4 level decreased and visual field improved. CONCLUSION We described the first case of IgG4-related hypophysitis without pituitary insufficiency. However, further case collection is needed to characterize the pathophysiology of IgG4-related hypophysitis.

Mucoepidermoid carcinoma of the palate composed exclusively of clear cells (clear cell variant).

To the Editor, Mucoepidermoid carcinoma (MC) of the salivary glands is a malignant epithelial tumor that is composed of varying proportions of mucus, epidermoid, intermediate, columnar, and clear cells [2]. It is classified into low-, intermediate-, and high-grade types on the basis of morphologic and cytologic features [2, 6]. Although mucous, intermediate, and epidermoid cells are predominant in most MCs, it is well known that clear cells very infrequently predominate over other cell types [1, 2, 3, 4, 5]. Such cases are called clear cell variant of MC [1, 2, 3, 4, 5]. The authors here report a rare case of MC of the palate composed exclusively of clear cells. A 42-year-old Japanese man presented a palate mass measuring approximately 2 cm in diameter. The mass in the palate was whitish pink and relatively hard in consistency. The overlying mucosa showed mild hyperemia. A needle biopsy was performed, and it showed clear cells that were arranged in a medullary, solid pattern (Fig. 1). The clear cells had small hyperchromatic nuclei and abundant clear cytoplasm. A low-grade malignant tumor was suspected pathologically, and the tumor was excised with wide margins. Scrutiny of visceral organs including kidneys showed no remarkable changes. The patient is now free of disease 11 months after the operation. Grossly, the resected tumor measured 20 20 12 mm and was whitish tan in color and relatively hard in consistency. The mucosal surface showed mild erosion. Histologically, the tumor was composed exclusively of clear tumor cells (Fig. 2A). They were arranged in a medullary, sheet-like, and solid pattern separated by thin fibrous septae (Fig. 2B). Invasions into the surrounding mucosa and minor salivary glands were recognized. Clusters of non-clear cells having small hyperchromatic nuclei and small acidophilic cytoplasm were noted in a very few areas (Fig. 2C). They were regarded as intermediate cells. These cells appeared to merge with the clear cells (Fig. 2C). Relatively large cells with mucus in the cytoplasm were scattered in a very small number (Fig. 2D). These cells were considered as mucous cells. The proportions of clear cells, intermediate cells, and mucous cells were approximately 95%, 4%, and less than 1%, respectively. The surgical margins were negative for tumor cells. Cytologically, the clear cells showed small hyperchromatic nuclei that were centrally located in the cytoplasm (Fig. 2B). The cytoplasm was clear, and cell membranes were clearly recognized. Neither keratinization nor intercellular bridges were recognized. The intermediate cells showed small hyperchromatic nuclei and small acidophilic cytoplasm (Fig. 2C). The mucous cells show acidophilic mucin-like materials in the cytoplasm

Granulogenesis in Non-neuroendocrine COS-7 Cells Induced by EGFP-tagged Chromogranin A Gene Transfection: Identical and Distinct Distribution of CgA and EGFP

We examined whether an enhanced green fluorescent protein (EGFP)-tagged chromogranin A (CgA) gene construct could serve as a marker protein to follow the synthesis of CgA and the process of granulogenesis in non-neuroendocrine (NE) cells. We transfected a CgA-EGFP expression vector into non-NE COS-7 cells and investigated the localization of a chimeric CgA-EGFP protein using confocal laser scanning microscopy (CLSM). The fluorescent signal of CgA-EGFP was distributed granularly in the cytoplasm. An immunocytochemical study using anti-CgA antibody with a quantum dot (Qd)525 shows colocalization of fluorescent signal of chimeric CgA-EGFP and CgA-Qd525 signals in granular structures, particularly at the periphery of the cytoplasm. We interpreted granules that were immunoreactive to CgA in electron micrographs as secretory. Spectral analysis of EGFP fluorescence revealed distinct EGFP signals without CgA colocalization. This is the first report to show that a granular structure can be induced by transfecting the EGFP-tagged human CgA gene into non-NE cells. The EGFP-tagged CgA gene could be a useful tool to investigate processes of the regulatory pathway. A more precise analysis of the fluorescence signal of EGFP by combination with the Qd system or by spectral analysis with CLSM can provide insight into biological phenomena.

A method for estimating spatial resolution of real image in the Fourier domain

Spatial resolution is a fundamental parameter in structural sciences. In crystallography, the resolution is determined from the detection limit of high‐angle diffraction in reciprocal space. In electron microscopy, correlation in the Fourier domain is used for estimating the resolution. In this paper, we report a method for estimating the spatial resolution of real images from a logarithmic intensity plot in the Fourier domain. The logarithmic intensity plots of test images indicated that the full width at half maximum of a Gaussian point spread function can be estimated from the images. The spatial resolution of imaging X‐ray microtomography using Fresnel zone‐plate optics was also estimated with this method. A cross section of a test object visualized with the imaging microtomography indicated that square‐wave patterns up to 120‐nm pitch were resolved. The logarithmic intensity plot was calculated from a tomographic cross section of brain tissue. The full width at half maximum of the point spread function estimated from the plot coincided with the resolution determined from the test object. These results indicated that the logarithmic intensity plot in the Fourier domain provides an alternative measure of the spatial resolution without explicitly defining a noise criterion.

Diffusion magnetic resonance imaging with gadofosveset trisodium as a negative contrast agent for lymph node metastases assessment.

PurposeThe aim of this study was to assess the feasibility of using intravenously administered gadofosveset trisodium as a negative contrast agent for lymph node (LN) assessment with diffusion-weighted imaging (DWI) using a VX2 tumor model in rabbits.Materials and methodsVX2 cells were injected in the right hind limb of five Japanese white rabbits to induce ipsilateral popliteal LN metastasis. DWI was performed before and every 7.5 min (until 1 h) after intravenous gadofosveset trisodium administration, at 1.5 T. Signal intensities (SIs) of right (metastatic) and left (nonmetastatic) popliteal LNs at each time point were measured and compared to each other using two-sided unpaired t-tests.ResultsThe SIs of metastatic lymph nodes were significantly higher (P < 0.05) than those of nonmetastatic LNs at each time point after intravenous gadofosveset trisodium administration. Although the SI of metastatic LNs was significantly higher (P = 0.0237) than that of nonmetastatic LNs before contrast injection, this difference became even more significant (P ≤ 0.0105) after gadofosveset trisodium administration.ConclusionThe SI of metastatic LNs at DWI is less suppressed than that of nonmetastatic LNs after the intravenous administration of gadofosveset trisodium. Therefore, intravenously administered gadofosveset trisodium shows promise for use as a negative contrast agent for discriminating metastatic from nonmetastatic LNs at DWI.

Pathology, Pathogenesis and Therapy of Growth Hormone (GH)-producing Pituitary Adenomas: Technical Advances in Histochemistry and Their Contribution

Growth hormone (GH)-producing adenomas (GHomas) are one of the most frequently-occurring pituitary adenomas. Differentiation of hormone-producing cells in the pituitary gland is regulated by transcription factors and co-factors. The transcription factors include Pit-1, Prop-1, NeuroD1, Tpit, GATA-2, SF-1. Aberrant expression of transcription factors such as Pit-1 results in translineage expression of GH in adrenocorticotropic hormone-producing adenomas (ACTHomas). This situation has been substantiated by GFP-Pit-1 transfection expression in the AtT20 cell line. Experimentally, GHomas have been induced in GH-releasing hormone (GHRH) or Prop-1 transgenic animals. Immunohistochemical detection of somatostatin receptor (SSTR2a) has recently emphasized their role in the response of GHomas to somatostatin analogue therapy. In this review, the advances in technology and their contribution to cell biology and medical practice are discussed.

Renal cell carcinoma arising in a long pre-existing angiomyolipoma

Angiomyolipoma (AML) is a mixed mesenchymal tumor belonging to the family of perivascular epithelioid cell tumors. Concurrent development of AML and adult renal cell carcinoma (RCC) is very rare. Herein is presented a unique case in which RCC arose within a previously detected AML tumor mass. A 40‐year‐old woman had been diagnosed with AML of the right kidney. Fifteen years later, during a regular radiographic examination, a new lesion was detected at the lower pole of the right kidney adjacent to the previously described AML. Because RCC was clinically suspected, the patient underwent right nephrectomy. Macroscopically, the tumor had a yellowish, transparent, fatty area and an opaque yellowish area with cystic features. Microscopically, the former tumor, consisting of an admixture of mature adipose tissue with smooth muscle and vascular tissue, was diagnosed as AML. The latter tumor was diagnosed as RCC (clear cell type). RCC was not completely enclosed within the AML, but overlapped it. No fibrous capsule was found between these tumors. Although this situation is very rare, from a clinical and pathological point of view it is important to consider the possibility that RCC might arise within AML. The relationship between the two lesions is discussed with a review of the literature.

Intratumoral heterogeneity of HER2 protein and amplification of HER2 gene in salivary duct carcinoma

Salivary duct carcinoma (SDC) is an aggressive adenocarcinoma of the salivary glands, and accounts for 1–3% of all malignant salivary gland tumors, resembling morphologically invasive ductal carcinoma (IDC) of the breast. In contrast to IDC of the breast and gastric carcinoma (GC), the study of human epidermal growth factor receptor 2 (HER2) in SDC has not progressed. Therefore, we investigated the relationship between HER2 protein expression and amplification of the HER2 gene, and compared them in terms of intratumoral heterogeneity (ITH) in 13 cases of SDC using immunohistochemistry and dual color in situ hybridization. We found seven cases with protein overexpression (53.8%) and five cases with gene amplification (38.5%) in accordance with ASCO/CAP guidelines. ITH of HER2 protein expression was seen in seven cases (53.8%). Interestingly, the ratio of the HER2 gene showed homogenous distribution with or without the presence of ITH of HER2 protein expression. SDC tends to have more ITH of HER2 protein similarly to GC, in contrast to IDC of the breast. ITH of HER2 protein in SDC has no heterogeneity of the HER2 gene amplification. The mechanism of HER2 protein expression in SDC might proceed through a more complex pathway relative to that of IDC of the breast.

Hepatic adrenal rest tumor: Diagnostic pitfall and proposed algorithms to prevent misdiagnosis as lipid-rich hepatocellular carcinoma.

We present a case of adrenal rest tumor of the liver in which differential diagnosis from lipid rich‐hepatocellular carcinoma (HCC) was challenging. The patient was a 50‐year‐old woman in whom a 3‐cm tumorous mass was discovered in segment 7 of the liver during computed tomography evaluation of a uterine leiomyoma. The preoperative diagnosis was HCC, and subsegmental liver resection was performed. The tumor appeared as a well‐demarcated golden yellow nodule consisting of clear or partially eosinophilic cells arranged in a trabecular pattern. The initial impression of this lesion was that of clear cell type or lipid‐rich type HCC because it stained positive for Hep Par1, but negative for arginase‐1 and positive for CD56 which is one of the neuroendocrine markers. The lesion also stained positive for SF‐1 and 3β‐HSD, both of which are markers of adrenocortical tissue. The final diagnosis was hepatic adrenal rest tumor. Hepatic adrenal rest tumor should be considered in the differential diagnosis of segment 7 tumor. A diagnostic algorithm that includes immunohistochemical staining for CD56 and arginase‐1 is to rule out the possibility of lipid‐rich HCC.

Mutations in the Mitochondrial ND1 Gene Are Associated with Postoperative Prognosis of Localized Renal Cell Carcinoma.

We analyzed mutations in the mitochondrial ND1 gene to determine their association with clinicopathological parameters and postoperative recurrence of renal cell carcinoma (RCC) in Japanese patients. Among 62 RCC cases for which tumor pathology was confirmed by histopathology, ND1 sequencing revealed the presence of 30 mutation sites in 19 cases. Most mutations were heteroplasmic, with 16 of 19 cases harboring one or more heteroplasmic sites. Additionally, 12 sites had amino acid mutations, which were frequent in 10 of the cases. The 5-year recurrence-free survival (RFS) rate was significantly worse in patients with tumors >40 mm in diameter (p = 0.0091), pathological T (pT) stage ≥3 (p = 0.0122), Fuhrman nuclear atypia grade ≥III (p = 0.0070), and ND1 mutations (p = 0.0006). Multivariate analysis using these factors revealed that mutations in ND1 were significantly associated with the 5-year RFS rate (p = 0.0044). These results suggest a strong correlation between the presence of ND1 mutations in cancer tissue and postoperative recurrence of localized RCC in Japanese patients.