A case of aldosterone-producing adrenocortical adenoma associated with a probable post-operative adrenal crisis: histopathological analyses of the adrenal gland.

We describe a case of aldosterone-producing adrenocortical adenoma (APA) associated with a probable post-operative adrenal crisis possibly due to subtle autonomous cortisol secretion. The patient was a 46-year-old female who suffered from severe hypertension and hypokalemia. CT and MRI scans revealed a 2-cm diameter adrenal mass. The patient's plasma aldosterone level was increased, and her plasma renin activity was suppressed, both of which findings were consistent with APA. Cushingoid appearance was not observed. Morning and midnight serum cortisol and plasma adrenocorticotropic hormone (ACTH) levels were all within the normal range. Her serum cortisol level was suppressed to 1.9 microg/dl as measured by an overnight 1-mg dexamethasone suppression test, but was incompletely suppressed (2.7 microg/dl) by an overnight 8-mg dexamethasone suppression test. In addition, adrenocortical scintigraphy showed a strong uptake at the tumor region and a complete suppression of the contra-lateral adrenal uptake. After unilateral adrenalectomy, she had an episode of adrenal crisis, and a transient glucocorticoid replacement improved the symptoms. Histopathological studies demonstrated that the tumor was basically compatible with APA. The clear cells in the tumor were admixed with small numbers of compact cells that expressed 17alpha-hydroxylase, suggesting that the tumor was able to produce and secrete cortisol. In addition, the adjacent non-neoplastic adrenal cortex showed cortical atrophy, and dehydroepiandrosterone sulfotransferase immunoreactivity in the zonae fasciculata and reticularis was markedly diminished, suggesting that the hypothalamo-pituitary-adrenal (HPA) axis of the patient was suppressed due to neoplastic production and secretion of cortisol. Together, these findings suggested that autonomous secretion of cortisol from the tumor suppressed the HPA axis of the patient, thereby triggering the probable post-operative adrenal crisis. Post-operative adrenocortical insufficiency should be considered in clinical management of patients with relatively large APA, even when physical signs of autonomous cortisol overproduction are not apparent.     

Amino acid residues conferring the nucleotide binding properties of N-acetyl-D-glucosamine 2-epimerase (renin binding protein)

Our recent studies have demonstrated that the middle domain of N-acetyl-D-glucosamine (GlcNAc) 2-epimerase participates in the specificity for and binding of nucleotides. To identify the residue conferring nucleotide binding, amino acid substitutions were introduced in the human and rat GlcNAc 2-epimerases. The mutational analyses indicate that residue 171 of GlcNAc 2-epimerase is critical for the nucleotide binding of GlcNAc 2-epimerase.     

Increased expression levels of integrin alphavbeta5 on scleroderma fibroblasts

Integrin alphavbeta5 is a receptor for vitronectin, a plasma glycoprotein that is also distributed in extracellular matrix of various tissues. Matrix-bound vitronectin has the potential to stabilize the active form of plasminogen activator inhibitor-1, resulting in the inhibition of the plasmin-mediated pericellular proteolytic cascade. In this study, we compared the levels of alphavbeta5 and matrix-bound vitronectin between normal and scleroderma fibroblasts and investigated the association with fibrosis. We demonstrated that alphavbeta5 was up-regulated on scleroderma fibroblasts. The up-regulated alphavbeta5 contributed to the increase in vitronectin-binding ability in scleroderma fibroblasts, which led to the vitronectin-dependent activation of plasminogen activator inhibitor-1. In immunohistochemistry, the alphav and beta5 subunits were stained strongly on scleroderma fibroblasts and the amount of vitronectin was increased in the pericellular matrix of those cells. The transient overexpression of alphavbeta5 on normal fibroblasts enhanced the human alpha2(I) collagen promoter activity through Sp-1 and Smad3 as well as the vitronectin-dependent plasminogen activator inhibitor-1 activity. This effect on the promoter activity was also observed in the absence of vitronectin and completely disappeared in the presence of anti-alphavbeta5 antibody. These results indicate that the up-regulated alphavbeta5 may contribute to the phenotypical alteration of scleroderma fibroblasts, while at the same time suppressing the plasmin-mediated pericellular proteolytic cascade.     

Deoxycorticosterone-secreting adrenocortical carcinoma

A case of DOC-secreting adrenocortical carcinoma in a 66-year-old man is reported. He had hypertension, hypokalemia, suppressed PRA, and excessive serum levels of DOC. His serum aldosterone level was normal. The resected adrenal mass weighed 230 g. Histologically, the tumor was mainly composed of compact cells associated with necrosis and atypical mitoses. Invasion of venous structure, sinusoids, and capsule was also present. Immunohistochemically, P450 C21 (21 -hydroxylase) was positive in many tumor cells, and P450 C17(17 α-hydroxylase) was intensely positive in a relatively small number of tumor cells. The patient died 9 months after operation due to rupture of metastatic liver tumor.Endocr Pathol 4:165–168, 1993.     

ADENOID SQUAMOUS CELL CARCINOMA OF THE SKIN OVERLYING THE RIGHT BREAST: An Autopsy Case Clinically Manifested with Rapid Growth and Widely Spreading Metastases

An autopsy case of a 62-year-old woman with a poorly differentiated, aggressive form of adenoid squamous cell carcinoma arising in the skin overlying the right breast was studied. The tumor, 9×8cm in diameter, had rapidly enlarged since one year before admission from a verrucous lesion of 20 years duration. The histologic features of the tumor showed a well-differentiated squamous cell carcinoma mainly in the superficial areas, which transformed into, with a zone of transition in between, an alveolar or adenoid structure in the deep invading portion. The adenoid tumor cells exhibited an undifferentiated appearance with prominent nucleoli and frequent mitotic figures. These cells partly showed dyskeratotic or acantholytic features. Mucin was negative. The patient died at 8 months after the operation. Autopsy revealed widely spreading metastases in which an adenoid structure was outstanding. These unusual pathological features and an aggressive behavior of this tumor, which were hitherto rarely described for adenoid squamous cell carcinoma, seemed to be a poorly differentiated variant of the tumor. This malignant transformation might be derived from loss of cohesion of the pre-existing usual well-differentiated squamous cell carcinoma in the basal and parabasal layers, inparting marked invasiveness of these cells into the supporting connective tissue.     

Microinvasive ductal carcinoma (T1mic) of the breast. The clinicopathological profile and immunohistochemical features of 28 cases

Microinvasive ductal carcinoma of the breast, namely ductal carcinoma in situ with microinvasion (T1mic) as defined by the American Joint Committee on Cancer (AJCC) Staging Manual, is a rare disease, although it is increasing because of widespread use of mammography. The aim of the present study was to describe the clinicopathological and immunohistochemical features of this entity. Twenty-eight patients who were diagnosed as T1mic from January 1997 to August 2002 were studied by using 3-5 mm-thick serial sections with hematoxylin-eosin staining. Immunohistochemical staining for the estrogen receptor (ER), progesterone receptor (PR), p53, Ki-67, and HER-2 were performed. All 28 patients were female, with a mean age of 48.8 years. Twenty-six patients (93%) revealed mammographic abnormalities on routine examination. All foci of the invasions were measured using an ocular micrometer. Invasive foci consisted of isolated cells or cell clusters, or appeared as a tongue-like projection of tumor through the basement membrane of the duct of ductal carcinoma in situ (DCIS). The mean number of invasive foci was 3, and the mean size was 0.6 mm. We found that high nuclear grade and predominant comedo subtype of DCIS components were 57.1% and 46.4%, respectively. Twenty-four cases (86%) demonstrated necrosis of DCIS components. Microinvasion was often associated with periductal stromal reaction (71.5%) and/or a lymphocytic infiltration (78.6%). All patients, excluding two, received axillary resection (the mean number of lymph nodes examined per case was 12), and none had lymph node metastasis. The positive expression of ER and PR strongly related to low grade nuclei and non-comedo subtype; however, the positive expression of HER-2 and P53 related to high grade nuclei and comedo subtype (P<0.01). Ki-67 expression was significantly higher in the high grade nuclei group than in the low grade group (P<0.01). Our study suggested that high nuclear grade and comedo DCIS were more aggressive and more common with microinvasion, and that microinvasion is more likely to be multifocal.     

Frozen-section services by telepathology: Experience of 100 cases in the San-in District, Japan

The early experience is reported here of the use of Intra-operative frozen-section service by telepathology using the Integrated Service Digital Network (ISDN), a commercially available system that is being connected between the Department of Pathology of Tottori University and Matsue City Hospital, a distance of 30 km. The transfer rate is currently 64kbit/s. The frozen-section service was conducted for a total of 117 tissue specimens (organs) from 100 patients between August 1993 and May 1995. The average time taken for examination of each specimen of frozen section was 13min, ranging between 2 and 42min. The average number of transmitted Images was 6.2. Six cases necessitated more than 11 transmitted Images to make a diagnosis, while 13 cases could be diagnosed from two images only. Correct and permissible diagnoses were obtained in 109 (93.2%) out of 117 specimens when comparing the telepathology diagnosis with that of direct microscopy. Improper or misdiag-nosis was made for eight cases (specimens), which were misinterpreted as papillary carcinoma in Basedow's disease, adenoma and hyperplasia in two pheochromocytomas, solid-tubular carcinoma in phyilodes tumor, mastopathy in invasive carcinoma, metastatic carcinoma in astrocytoma, follicular lymphoma in reactive hyperplasia, and lymphadenitis in follicular lymphoma. in retrospect, diagnosis of these cases should have been deferred. From the results, it was concluded that the Intraoperatlve frozen-section service by telepathology may be a worthwhile substitute for hospitals with limited accessibility to local pathology service, in spite of pitfalls in some cases. Well prepared, high-quality frozen sections, sufficient verbal communication with surgeons, and a rather conservative attitude on the part of a well-trained pathologist seem to be the essential Ingredients for reaching an accurate decision when using telepathology.     

Immunolocalization of aromatase in human minor salivary glands of the lower lip with primary Sjogren's syndrome

The enzyme aromatase Is Involved In the conversion of androgens to estrogens and in the modulation of various androgenlc and estrogenlc actions. Abnormalities of estrogen metabolism have been postulated to play roles in the development and/or pathophyslology of Sjdgren's syndrome. In the present study, aromatase was immunolocal-ized In 75 cases of Inflammatory disorders of human minor salivary glands of the lower lip. These included cases of primary Sjögren's syndrome (19 cases), of chronic slaladenitis (34 cases) and of mucous extravasation cysts (22 cases), in order to clarify the possible involvement of in situ estrogen production in primary Sjögren's syndrome. Aromatase Immunoreactlvlty was detected In myoepithelial cells of acini and in interstitial cells adjacent to acini and ducts In 13/19 (68%) cases of primary Sjögren's syndrome. In contrast, aromatase expression was detected In only six of 34 (18%) cases of chronic sialadenttis and in seven of 22 (32%) cases of mucous extravasation cyst. These results suggest that Increased aromatase expression in minor salivary glands with primary Sjogren's syndrome in premenopausal women may be involved in the biological features of primary Sjogren's syndrome through the production of estrogens in situ and possibly through the aggravation of the inflammatory reaction.     

Ridge filter design for proton therapy at Hyogo Ion Beam Medical Center

At the Hyogo Ion Beam Medical Center (HIBMC) we have developed a new design method for the bar ridge filter used in proton therapy, taking into consideration the scattering and nuclear interaction effects within the filter itself, which are introduced in the design. In our beam delivery system, the bar ridge filter is employed as the range modulator. It is combined with the wobbler system, and produces a three-dimensionally uniform spread-out Bragg peak (SOBP). The design program predicts the three-dimensional dose distribution. Ridge filters of 3-12 cm SOBP in 1 cm increments were designed in the maximum radiation field for 150 MeV and 190 MeV proton beams so that a uniform physical dose area is obtained in the SOBP region three-dimensionally. Measurements were performed with the constructed ridge filters to verify the uniformity and these were compared with the predictions of the design program. The predictions and measurements were found to be in agreement except for the 12 cm SOBP. The uniformities were better than +/- 3.0% for all SOBPs produced. The ridge filters are now clinically in use.