Usefulness of Wieneke criteria in assessing morphologic characteristics of adrenocortical tumors in children.

PURPOSE: Adrenocortical tumors (ACT) occur rarely in pediatric age group. Pediatric ACTs behave differently from their histologically similar adult counterparts and standard adult criteria often cannot accurately predict their clinical behavior. The aim of the present study was to document the clinicopathologic spectrum of pediatric ACTs and to assess the utility of Wieneke scoring system in predicting clinical behavior of these tumors. METHODS: This multi-institutional study comprised of 13 cases of pediatric ACTs from January 2005 to May 2014. Clinical features and gross pathologic characteristics were obtained from records. Comprehensive analyses of microscopic features were performed. Each tumor was assessed according to criteria proposed by Wieneke et al. and was assigned to benign, intermediate for malignancy or malignant group. The standard adult Weiss criteria were also applied for comparison. RESULTS: There were total 6 cases of adrenocortical adenomas and 7 cases of adrenocortical carcinomas. Most of the children (76.9%) presented with endocrine dysfunction. Lower age of presentation was significantly associated with better prognosis. Applying Wieneke criteria, there were 6 benign and 6 malignant cases and one case was assigned to intermediate for malignancy group. The clinical behavior of all the cases was consistent with Wieneke criteria categorization. Applying Weiss criteria, 3 cases with benign clinical behavior were assigned to malignant group. CONCLUSION: Our study validates the reliability of Wieneke scoring system in predicting malignancy in pediatric ACTs. It is simple and easy to use and therefore useful in day-to-day practice.

Interference of amino-terminal desmin fragments with desmin filament formation.

Short polypeptides from intermediate filament (IF) proteins containing one of the two IF-consensus motifs interfere severely with filament assembly in vitro. We now have systematically investigated a series of larger fragments of the muscle-specific IF protein desmin representing entire functional domains such as coil1 or coil 2. "Half molecules" comprising the amino-terminal portion of desmin, such as DesDeltaC240 and the "tagged" derivative Des(ESA)DeltaC244, assembled into large, roundish aggregates already at low ionic strength, DesDeltaC250 formed extended, relatively uniform filaments, whereas DesDeltaC265 and DesDeltaC300 were soluble under these conditions. Surprisingly, all mutant desmin fragments assembled very rapidly into long thick filaments or spacious aggregates when the ionic strength was raised to standard assembly conditions. In contrast, when these desmin mutants were assembled in the presence of wild-type (WT) desmin, their assembly properties were completely changed: The elongation of the two shorter desmin fragments was completely inhibited by WT desmin, whereas DesDeltaC250, DesDeltaC265 and DesDeltaC300 coassembled with desmin into filaments, but these mixed filaments were distinctly disturbed and exhibited a very different phenotype for each mutant. After transfection into fibroblasts and cardiomyocytes, the truncated mutant Des (ESA)DeltaC244 localized largely to the cytoplasm, as revealed by a tag-specific monoclonal antibody, and also partially colocalized there with the collapsed endogenous vimentin and desmin systems indicating its interference with IF-organizing processes. In contrast, in cells without an authentic cytoplasmic IF system such as line SW13, Des(ESA)DeltaC242 entered the nucleus and was deposited in small dot-like structures in chromatin-free spaces without any noticeable effect on nuclear morphology.

[Analysis of adrenocortical tumors morphology as regards their structure and potential malignancy]. / Analiza morfologii guzów kory nadnerczy pod wzgledem ich struktury i potencjalnej zlosliwosci.

INTRODUCTION: A consequence of diagnosis of adrenocortical carcinoma (ACC) is introduction of pharmacological therapy, precise monitoring of the patients and in some cases re-operation. The aim of the study is to analyse morphology of adrenocortical tumours as regards their malignancy by use of criteria proposed by Weiss. MATERIAL AND METHODS: 110 adrenocortical tumours in 107 patients were analysed (M 27.1%, F 72.9%; age 32 to 77 years, mean 55.2 +/- 9.7). Conn syndrome was diagnosed in 16 patients (14.9%), Cushing syndrome in 12 (11.2%), and virilisation in 3 (2.8%). In 76 patients (71.0%) biochemical tests did not reveal hormonal hyperactivity of the tumour. RESULTS: In routine histopatological examination ACC was diagnosed in 6 tumours (5.4%), adrenocortical adenoma (ACA) in 92 (83.6%) and adrenocortical hyperplasia in 12 (10.9%). Nuclear grade III or IV was observed in 8 tumours (7.3%), mitotic rate > 5/50 high power fields in 6 (5.4%), atypical mitoses in 5 (4.5%), clear cells constituting < 25% of the tumour in 10 (9.1%), diffuse architecture in 8 (7.3%), necrosis in 16 (14.5%), veins infiltration in 4 (3.6%), sinusoids infiltration in 7 (6.3%), and tumour capsule infiltration in 5 (4.5%). Among ACC tumours 4-9 features of malignancy were present, among ACA--0-3 features. Statistical analysis revealed correlation between number of criteria proposed by Weiss and maximal tumour size (p < 0.05). CONCLUSION: The structure and cell arrangement in adrenocortical adenoma are heterogeneous. Application of criteria proposed by Weiss in histopathological examination of adrenocortical tumours can be useful in differentiating adrenocortical adenoma from carcinoma.

Myxoid variant of adrenocortical carcinoma: report of a unique case.

Myxoid variant of adrenocortical carcinomas (ACC) are rare, there being only 11 cases in the literature to date. Reported herein are the findings of a case, which in contrast to all previously reported myxoid ACC, was devoid of typical non-myxoid areas. The patient was a 61-year-old man in whom a left adrenal mass was detected during investigation of Cushing's syndrome. The adrenal was replaced by malignant cells and expanses of myxoid material. The cells were positive for melan-A, synaptophysin, vimentin and alpha-inhibin. The ultrastructural features of the cells were typical of adrenal cortical differentiation. The differential diagnosis of myxoid ACC includes extraskeletal myxoid chondrosarcoma, chordoma, myxoid adenocarcinoma, myxoma, lipomatous tumors, nerve sheath tumors, smooth muscle tumors, gastrointestinal stromal tumor and other sarcomas. The presence of myxoid material in a retroperitoneal lesion raises a broad differential diagnosis in which myxoid adrenocortical neoplasms should be included. Clinicoradiological correlation may be helpful, but special stains, immunohistochemistry and ultrastructural examination may be necessary to establish the diagnosis.

Neuropeptides B and W enhance the growth of human adrenocortical carcinoma-derived NCI-H295 cells by exerting MAPK p42/p44-mediated proliferogenic and antiapoptotic effects.

Neuropeptides B and W (NPB and NPW) are endogenous ligands of two G protein-coupled receptors, named GPR7 and GPR8. GPR7 and GPR8 are expressed in the adrenal cortex, and there is evidence that NPB and NPW stimulate glucocorticoid secretion from human adrenocortical cells by activating protein kinase (PK) A and PKC signaling. To gain insight into the role of NPB and NPW in human adrenal functional regulation, we have investigated their effects on the secretion and growth of the human adrenocortical carcinoma-derived NCI-H295 cell line. NCI-H295 cells were found to express both GPR7 and GPR8 mRNAs, but neither NPB nor NPW (up to 10(-6) M) affected their secretory activity. In contrast, both peptides (from 10(-10) to 10(-6) M) enhanced the growth of NCI-H295 cells, by raising their proliferative activity and lowering their apoptotic deletion rate. NPB and NPW (10(-6) M) stimulated tyrosine kinase (TK) and mitogen-activated PK (MAPK) p42/p44 activities in NCI-H295 cells. Both these effects were blocked by the TK inhibitor tyrphostin-23, while the MAPK p42/p44 inhibitor PD-98059 annulled only MAPK p42/p44 activation. The growth-stimulating effect of 10(-6) M NPB and NPW were not affected by either the PKA and PKC inhibitors H-89 and calphostin-C or the MAPK p38 antagonist SB-293580, but were abolished by both tyrphostin-23 and PD-98059. Taken together, our findings allow us to conclude that GPR7 and GPR8 expressed in NCI-H295 cells: i) are, at variance with those present in normal human adrenocortical cells, uncoupled to PKA- and PKC-dependent cascades, thereby explaining the absence of any secretory response to NPB and NPW; and ii) are coupled to the TK-dependent MAPK p42/p44 signaling, whose activation mediates the proliferogenic and antiapoptotic effect of NPB and NPW.

Pediatric adrenal cortical carcinoma: brain metastases and relationship to NF-1, case reports and review of the literature.

Adrenal cortical carcinoma (ACC) is a rare childhood neoplasm that seldom manifests brain metastases; hence few papers in the literature focus on neurological manifestations associated with ACC. Although ACC is known to be a signature tumor type in several inherited cancer predisposition syndromes, particularly Li Fraumeni, ACC has not been previously associated with neurofibromatosis, type 1 (NF-1), an inherited disorder with frequent CNS lesions that might prompt concern for metastatic disease by neuroimaging studies. We present two pediatric patients with ACC and unusual CNS findings. The first child developed metastasis to the brain 4 years after resection of his adrenal primary and 2 and 1 years, respectively, after metastases to the liver and lungs. Soon after our experience with this patient, a girl with known NF-1 presented with virilization; adrenalectomy disclosed an ACC and systemic metastases were found within months. Disseminated disease prompted concern that her complex intracranial lesions identified by neuroimaging studies might represent brain metastases, but this proved to be NF1-related hamartomatous lesions. We review the literature on ACCs in pediatric patients regarding brain metastases and previous associations with NF-1.

[Ultrastructural criteria of clinical prognosis in hormonally non-active adrenocortical tumors]. / Ul'trastrukturnye kriterii klinicheskogo prognoza pri gormonal'no-neaktivnykh adrenokortikal'nykh opukholiakh nadpochechnikov.

The investigation was concerned with histological and ultrastructural features of adrenocortical tumors of the adrenals, which have a differential-diagnostic and clinico-prognostic relevance. Histological and electron-microscopical examination of 60 tumors (adrenocortical adenoma--12; adrenocortical cancer--48) was carried out and the findings were compared with clinical data. No significant correlation between histological pattern of adrenocortical tumors and survival was established. Ultrastructural evidence showed electron-microscopical examination to be a reliable procedure for making prognosis of adrenocortical cancers. There was a direct correlation between the level of differentiated cells and degree of their differentiation, on the one hand, and the quality of prognosis and survival, on the other. The significant predominance of differentiated cells was characteristic of adrenocortical adenomas.

Oncocytic adrenocortical carcinoma: a morphologic, immunohistochemical and ultrastructural study of four cases.

We present the clinical, histologic, immunohistochemical, and ultrastructural findings of four cases of non-functioning oncocytic adrenocortical carcinomas. The patients' ages ranged from 39 to 71 years. There was no sex predilection. Large yellow-tan tumors (8.5 to 17.0 cm), well demarcated from the adjacent kidney, were seen with a thin rim of normal adrenal gland along one edge. One tumor invaded the inferior vena cava and extended up to the level of the right atrium, and another metastasized to bone. The other two tumors had similar morphologic features and therefore were considered carcinomas. Histologic sections of all four cases showed a diffuse proliferation of polygonal neoplastic cells with large nuclei containing prominent nucleoli and abundant granular and eosinophilic cytoplasm. Occasional mononuclear and binucleated giant cells were noted in one case. There were rare mitotic figures (less than one per 10 high power fields). All tumors were immunoreactive for cytokeratins (AE1/AE3 and CAM5.2). Inhibin was focally expressed by one tumor and its bone metastasis. Ultrastructurally, the cytoplasm of the neoplastic cells was packed with innumerable mitochondria. Cytologic atypia or mitotic rate cannot reliably predict the biologic behavior of oncocytic adrenocortical neoplasms. Large tumor size (4/4), extracapsular extension (3/4), blood vessel invasion (2/4), necrosis (4/4), and metastasis (1/4) are features of malignancy for oncocytic adrenocortical carcinomas. The treatment of these tumors is complete surgical excision.

[Adrenocortical tumors with neuroendocrine differentiation]. / Adrenokortikal'nye opukholi s neiroéndokrinnoi differentsirovkoi.

18 adrenocortical tumours and 5 pheochromocytomas were studied immunohistochemically. Expression of synaptophysin and chromogranin A was found in cells of cortical adenomas, "frontier" neoplasms and in 20-75% of carcinoma cells, this ultramicroscopically was confirmed by observation of typical neuroendocrine granules. Some groups of cells of cortico-medullary tumours also expressed proteins of neural differentiation (protein S-100).

Use of electron microscopic evaluation for the diagnosis of adrenal cortical carcinoma in fine needle aspiration cytology: a case report and review of the literature.

Bilateral adrenal tumors were detected in a 72-year-old man who had a history of hepatic inflammatory pseudotumor. Computet tomography (CT)-guided fine needle aspiration cytology (FNAC) of the adrenal glands was performed. The cytologic findings were similar to the previous diagnosis of "inflammatory pseudotumor" in the liver. However, the origin of some aggregated large atypical cells observed in the adrenal FNAC specimens was not known. Immunocytochemically, these large atypical cells were positive for vimentin and negative for cytokeratin and chromogranin A. An electron-microscopic study showed that these large atypical cells contained mitochondria with tubulovesicular cristae and smooth endoplasmic reticulum arranged in whorled and laminated patterns, and these findings confirmed diagnosis of primary adrenal cortical carcinoma. The histopathological diagnosis of the resected bilateral adrenal tumor was adrenal cortical carcinoma. The patient died 7 months after surgery, with recurrence of the bilateral adrenal cortical carcinoma and extensive metastases. A diagnosis of primary adrenal cortical carcinoma with extensive metastases was finally demonstrated by autopsy. Retrospectively, the previous liver tumor was determined to be a metastatic lesion.

Paclitaxel is an effective antiproliferative agent on the human NCI-H295 adrenocortical carcinoma cell line.

In view of a potential clinical use, we assessed the antiproliferative effect of paclitaxel on the human steroid-secreting NCI-H295 adrenocarcinoma cell line. By MTT, paclitaxel induced a dose-dependent inhibition of cell proliferation, with IC50 lower than blood levels of the drug achieved in patients treated for other malignancies. Cell exposure to paclitaxel for 24 h at the different IC50S produced a dose-responsive increase in DNA fragmentation, morphologically confirmed by electron microscopy. A time-dependent decrease in aldosterone, cortisol and testosterone was observed. Paclitaxel is an effective antiproliferative agent in this human adrenocortical carcinoma cell line. Apoptosis induced by the drug in involved in neoplastic cell death. A potential role of the drug in the treatment of patients with adrenocortical cancer could be considered.

[Ultrastructural and immunohistochemical localization of endothelin-1 in nonneoplastic, hyperplastic and neoplastic adrenal gland].

OBJECTIVE: To determine the ET-1 immunoreactivity in human nonneoplastic, hyperplastic and neoplastic adrenal gland ultrastructurally and histologically. METHODS: Sensitive immunohistochemical technique was used. RESULTS: The ET-1 immunoreactivity was found in non-neoplastic (100%), adrenal cortical adenoma (100%) and cortical carcinoma (3/10). ET-1 immunoreactivity was regularly seen in the cortex, especially in zona fasciculata and to a varying extent also in the other two zones, but not in the medulla. The immunoreactive material in the cytoplasm was mostly in vacuolar or grain-like structures. Focally, cell membrane also showed immunoreactive staining. Most cortical adenomas displayed numerous immunoreactive cells. The immunoreactivity in the tumor tissue was in the same forms as in normal cortex, but the reactive products were generally few. No obvious differences in immunostaining were seen between the aldosterone- and cortisol-producing adenomas or the non-functioning ones. Three of the ten carcinomas contained immunoreactive cells, but they were few and appeared focally. The ET-1 immunoreactive structures were seen as "dust-like" material. Electronmicroscopical investigation revealed ET-1 immunoreactive products adjacent to the outer surface of the membrane of lipid bodies, in mitochondria, rough endoplasmic reticulum and focally on the cell membrane, but no immunolabelling was seen in the medulla. CONCLUSIONS: The localization of ET-1 in the endoplasmic reticulum indicates that this peptide is synthesized in the cortical cells. The localization in the membrane of the lipid bodies and in the mitochondria indicates that it may take part in steroid synthesis. The focally immunolabelled cell membranes may depend on ET-1 bond to ET receptors. The difference in immunoreactivity between the benign and the malignant cortical neoplasms may be of diagnostic value.