Cushing's syndrome due to a large adrenocortical adenoma with histological features simulating ACTH-independent macronodular adrenocortical hyperplasia

A 53-year-old woman presented with Cushing's syndrome resulting from an adrenocortical adenoma, 6.5 cm in diameter and 75 g in weight, which is larger than usual. Endocrinological data of this patient showed adrenocorticotropin (ACTH)-independent hypercortisolemia. A computed tomography scan of the adrenal glands revealed a single large and well-encapsulated tumor with an irregularly shaped area of calcification and loss of parenchyma on the left adrenal. The right adrenal gland was atrophic. Laparoscopic removal of the left adrenal tumor was performed. The tumor was lobulated and clearly encapsulated, and the non-neoplastic area of the left adrenal was atrophic without any nodularity. The histological analysis confirmed the diagnosis of adrenal adenoma. In addition, this adenoma displayed histopathological features in common with ACTH-independent macronodular adrenocortical hyperplasia (AIMAH), including clear cell predominance, a pattern of small compact cell nests in clear cell areas, and very long cord-like arrangement of small compact cells. In AIMAH, adrenals are extremely enlarged and are more massive than in any other subtype of Cushing's syndrome. The fact that the present adrenocortical adenoma was larger than those typical adenomas of Cushing's syndrome may reflect an AIMAH-type cellular composition of clear cell predominance and small compact cell nests.     

Adrenocorticotropic hormone-independent bilateral adrenocortical macronodular hyperplasia as a distinct subtype of Cushing's syndrome. Enzyme histochemical and ultrastructural study of four cases with a review of the literature.

Four patients with adrenocorticotropic hormone (ACTH)-independent bilateral adrenocortical macronodular hyperplasia (AIMAH) were examined. All of them were men whose ages ranged from 37 to 52 years. Plasma cortisol levels were high, with a loss of diurnal rhythmicity, and plasma ACTH was undetectable. Adrenal cortisol secretion was not suppressed by dexamethasone, but it was ACTH responsive. Test results for corticotropin-releasing hormone (CRH) also were negative. Image analyses revealed a normal sella turcica and significantly enlarged adrenal glands, which showed enhanced uptake of isotope. Both adrenal glands in all cases were between 72 and 176 g in combined weight and were composed of, and distorted by, yellow nodules. Histologically, small cortical cells with or without lipid, occasional clear cells, and rare compact cells of the usual size were increased in number in the glandular cords. Enzyme histochemically, cortical cells showed weaker activity for 3 beta hydroxysteroid dehydrogenase and other enzymes than did usual cortisol-producing adenomas. Ultrastructurally, they had moderately to poorly developed smooth endoplasmic reticulum. Nonnodular areas of the cortex consisting of nonproliferating cells were atrophic and contained no compact cell zone. This is similar to the adrenal cortices attached to cortisol-producing adenomas. These features are unique to AIMAH and suggest the presence of a distinct subtype of Cushing's syndrome.     

Adrenocorticotropin-independent unilateral adrenocortical hyperplasia with Cushing's syndrome: Immunohistochemical studies of steroidogenic enzymes, ultrastructural examination and a review of the literature

A 60-year-old woman presented with a history of palpitations, headaches and severe hypertension, which was resistant to hypotensive agents. She had a 2-year history of obesity and a moon face. Her plasma adrenocorticotropic hormone level was below the limits of detection and did not respond to corticotropin-releasing hormone. Urinary-free cortisol was elevated and the circadian rhythm of serum cortisol level had completely disappeared. Imaging analysis demonstrated a unilaterally functioning mass in the left adrenal gland. Serum cortisol level in the left adrenal vein was elevated. The resected adrenal mass measured 4 x 3.5 x 2.5 cm, and ranged from yellow to tan in color. The adrenal cortex adjacent to the nodule did not demonstrate cortical atrophy. The mass was well circumscribed but not encapsulated, and consisted of multiple cortical nodules. These nodules were composed predominantly of clear cortical cells, and partly of compact cortical cells. Immunoreactivity of steroidogenic enzymes including cholesterol side-chain-cleavage P450, 3beta-hydroxysteroid dehydrogenase, 21-hydroxylase cytochrome P450, 11beta-hydroxylase cytochrome P450 and 17alpha-hydroxylase cytochrome P450 was marked in cortical nodules, but minimal in non-nodular cortex. Ultrastructural examination of nodular cortical cells also demonstrated well-developed mitochondria and smooth endoplasmic reticulum, consistent with elevated steroidogenesis in these cells.     

An unusual primary biphasic neuroendocrine carcinoma of lung associated with ectopic ACTH production and Cushing's syndrome

A 62-year old female presented with signs and symptoms of Cushing's syndrome. The source of the ectopic ACTH was a left lung lower lobe neuroendocrine tumour composed of two cell types: epithelioid and spindle shaped cells and; a second component of smaller, uniform round neuroendocrine cells. The tumour did not conform to any of the recognized lung neuroendocrine categories and an atypical carcinoid was the best fit based on mitotic count (6 per 10 high power field).This case highlights unusual histology for a pulmonary neuroendocrine tumour and also the nomenclatural difficulties associated with the current classification.     

Penetrance of adrenocortical tumours associated with the germline TP53 R337H mutation

Background

An inherited germline P53 mutation has been identified in cases of childhood adrenocortical carcinoma (ACT), a neoplasm with a high incidence in southern Brazil. The penetrance of ACT in carriers of the point mutation, which encodes an arginine‐to‐histidine substitution at codon 337 of TP53 (R337H), has not been determined.

Objective

To investigate the penetrance of childhood ACT in carriers of the R337H TP53 mutation.

Methods

The family histories of 30 kindreds of 41 southern Brazilian children with ACT were obtained. A PCR based assay was used to detect this P53 mutation in a large number of relatives of children with ACT. In all, 927 individuals were tested for the mutation, 232 from the non‐carrier and 695 (including the 40 probands) from the carrier parental lines.

Results

40 children with ACT carried the TP53 R337H mutation; the remaining child with ACT was not tested. There was no evidence of Li‐Fraumeni syndrome in any of the kindreds; however, seven met the criteria for Li‐Fraumeni‐like syndrome. The carrier parental line was identified in each kindred. Of the 695 individuals tested in the carrier parental line, 240 (34.5%) were positive for the mutation, while none of the 232 individuals in the other parental line carried the mutation. The penetrance of ACT was 9.9% (95% confidence interval, 8.7% to 11.1%).

Conclusions

The TP53 R337H mutation dramatically increases predisposition to childhood ACT but not to other cancers, and explains the increased frequency of ACT observed in this geographic region.     

Cushing's syndrome due to ACTH-production of an ovarian carcinoid

Summary The case of a 56-year old woman with severe Cushing's syndrome due to ovarian ACTH-production is described. Both clinical picture and biochemical pattern were consistent with the ectopic ACTH syndrome. ACTH was found by specific immunohistochemical staining in a carcinoid tumor of the patient's right ovary. In contrast, pituitary cells exhibited immunoreactive ACTH to only a minimum extent.Abbreviations ACTH adrenocorticotropic hormone - CT computerized tomography - APUDoma tumor of amine precursor utake and decarboxylation cells     

Glucose-dependent insulinotropic peptide receptor overexpression in adrenocortical hyperplasia in MEN1 syndrome without loss of heterozygosity at the 11q13 locus

BACKGROUND:

The molecular mechanisms involved in the genesis of the adrenocortical lesions seen in MEN1 syndrome (ACL-MEN1) remain poorly understood; loss of heterozygosity at 11q13 and somatic mutations of MEN1 are not usually found in these lesions. Thus, additional genes must be involved in MEN1 adrenocortical disorders. Overexpression of the glucose-dependent insulinotropic peptide receptor has been shown to promote adrenocortical tumorigenesis in a mice model and has also been associated with ACTH-independent Cushing syndrome in humans. However, to our knowledge, the status of glucose-dependent insulinotropic peptide receptor expression in adrenocortical lesions in MEN1 has not been previously investigated.

OBJECTIVE:

To evaluate glucose-dependent insulinotropic peptide receptor expression in adrenocortical hyperplasia associated with MEN1 syndrome.

MATERIALS/METHODS:

Three adrenocortical tissue samples were obtained from patients with previously known MEN1 germline mutations and in whom the presence of a second molecular event (a new MEN1 somatic mutation or an 11q13 loss of heterozygosity) had been excluded. The expression of the glucose-dependent insulinotropic peptide receptor was quantified by qPCR using the ΔΔCT method, and β-actin was used as an endogenous control.

RESULTS:

The median of glucose-dependent insulinotropic peptide receptor expression in the adrenocortical lesions associated with MEN1 syndrome was 2.6-fold (range 1.2 to 4.8) higher than the normal adrenal controls (p = 0.02).

CONCLUSION:

The current study represents the first investigation of glucose-dependent insulinotropic peptide receptor expression in adrenocortical lesions without 11q13 loss of heterozygosity in MEN1 syndrome patients. Although we studied a limited number of cases of MEN1 adrenocortical lesions retrospectively, our preliminary data suggest an involvement of glucose-dependent insulinotropic peptide receptor overexpression in the etiology of adrenocortical hyperplasia. New prospective studies will be able to clarify the exact role of the glucose-dependent insulinotropic peptide receptor in the molecular pathogenesis of MEN1 adrenocortical lesions.     

Endocrinology: Ultrasonographic appearance of polycystic ovaries is associated with exaggerated ovarian androgen and oestradiol responses to gonadotrophin-releasing hormone agonist in women undergoing assisted reproduction treatment

While no single biochemical test is diagnostic of polycysticovary syndrome (PCOS), most patients show a characteristic ovarianultrasonographic appearance. It has been proposed that a dysfunctionof cytochrome P-450c17 in PCOS leads to an increased 17-hydroxyprogesterone(17-OHP) response to a gonadotrophin-releasing hormone (GnRH)agonist-induced gonadotrophin rise. We postulated that thisabnormality of steroid metabolism might influence the ovarianresponse during assisted reproduction treatment. We investigated106 patients undergoing a short ’boost‘ stimulationregimen for assisted reproduction treatment, including in-vitrofertilization and gamete intra-Fallopian transfers. The ovarianultrasound pattern was correlated with serum testosterone, 17-OHP,androstenedione and oestradiol responses, and with the clinicaloutcome. Polycystic ovaries, defined ultrasonographically asthe presence of 10 follicles between 2 and 10 mm diameter ineither ovary, were found in 48% of the whole study population.Dexamethasone was given to suppress adrenal androgen secretion.Functional ovarian hyperandrogenism (FOH) was defined as serumtestosterone >0.5 nmol/l after dexamethasone. There was asignificantly (P < 0.001) higher prevalence of FOH in patientswith polycystic ovaries (23%) compared with normal ovaries (7%).Patients with polycystic ovaries had approximately double the17-OHP, androstenedione and oestradiol responses to a GnRH agonistas patients with non-polycystic ovaries. Exaggerated 17-OHPand oestradiol responses to GnRH agonist were found in 89% ofpatients with clinically diagnosed PCOS. The number of oocytesretrieved was positively correlated (r = 0.51, P < 0.001)with the oestradiol responses in all patients. Although therewas no difference in the total amount of follicle stimulatinghormone (FSH) used between the patients with polycystic andnormal ovaries, the median peak oestradiol concentration was1.6 times and the oocyte yield 2.3 times greater in patientswith polycystic ovaries. The overall pregnancy rate per transferwas 32% and did not differ between patients with or withoutpolycystic ovaries and FOH. No pregnancies occurred when thebaseline FSH concentration was >10 IU/l. We conclude thatthe ultrasonographic changes characteristic of polycystic ovariesshould be sought in all women undergoing assisted reproductiontreatment.     

Multifocal nodular oncocytic hyperplasia of bilateral parotid glands: A case report with a histological variant of clear cells

A case of multifocal nodular oncocytic hyperplasia (MNOH) of the bilateral parotid gland is presented. An 80-year-old woman was admitted to hospital because of painless swellings in bilateral parotid regions. Histologically, the nodular lesion had incomplete capsules and engulfed the surrounding parotid gland at the periphery. The lesions were mostly composed of clear cells, while the peripheries of the lesions had typical oncocytic cells with abundant fine granules. The histological existence of the clear cell component in the lesions led to misdiagnoses of other clear cell neoplasms. However, this case had multiple nodules in bilateral glands. No evidence of malignant histological findings was found. Moreover, the clear cells, as well as the oncocytic cells, were demonstrated to have mitochondria and glycogen in their cytoplasm using special staining. Based on these findings, the diagnosis of this case was MNOH in the parotid gland. We also discuss the differential diagnosis for clear cell lesions.     

8例原发性色素性结节状肾上腺皮质病的临床分析

目的总结原发性色素性结节状肾上腺皮质病(PPNAD)临床特点。方法回顾分析北京协和医院2001年~2009年所诊治的PPNAD患者8例,采集患者临床资料。结果PPNAD好发于青少年,62.5%伴有Carney综合征(CNC)。在临床表现中,闭经及身高增长停滞或减慢较为明显,分别占100%和62.5%。血ACTH检测不到,血F节律消失,50%的患者地塞米松抑制实验为反常性升高。75%的患者双侧肾上腺未见明显异常或仅有可疑小结节样改变。肾上腺病理可见色素沉积的结节样改变。单侧肾上腺全切术可缓解症状,但血ACTH和血F节律难以恢复,可能复发。结论对于影像学检查未见肾上腺明显病变的ACTH非依赖性库欣综合征的患者,要警惕PPNAD,同时要注意筛查及随诊有无合并CNC。     

Corticotropin-producing pulmonary gangliocytic paraganglioma associated with Cushing's syndrome

Gangliocytic paraganglioma (GP) is an unusual tumor in the wide spectrum of neuroendocrine neoplasms. The biologic behavior and histogenesis of this tumor is uncertain because, despite its benign histologic features, there have been reports of metastases to regional lymph nodes and distant metastases. Although most of these tumors have been reported in the duodenum, examples of GP arising in extra-ampullary sites have been well documented. Herein, we report the case of a lung GP corticotropin producing and presenting as Cushing's syndrome. After removal of the tumor, there was a significant drop in cortisol and corticotropin levels. To our knowledge, this is the first report of a GP causing Cushing's syndrome.     

Primary adrenocortical nodular dysplasia with Cusghing's syndrome and cardiac myxomas

Summary In a family with 4 children, 2 had slowly developing Cushing's syndrome and were adrenalectomized between the ages of 18 and 28 years. As in other cases with familial Cushing's syndrome, primary adrenocortical nodular dysplasia, the so-called adrenocortical adenomatosis, was demonstrated. The brother, now 39 years old, is in good health. The sister, however, died at the age of 36 years. Autopsy revealed a cardiac myxoma of the left atrium. A cardiac myxoma had been found incidentally at autopsy of these two patients' oldest brother, a boy who died at the age of 4 years. Both siblings with Cushing's syndrome presented additional Peutz-Jegher-like hyperpigmentation and myxomatous tumours of the skin. Identical observations of familial adrenocortical nodular dysplasia, Cushing's syndrome and cardiac myxomas have not been reported to date. However, the familial occurrence of cardiac myxomas and adrenocortical dysplasia in combination with bilateral large cell calcifying Sertoli cell tumours of the testis has been published recently.     

Adrenal black adenoma associated with preclinical Cushing's syndrome

A black adenoma of the adrenal gland was laparoscopically removed from a 60-year-old man who presented with severe hypertension. Although laboratory findings were indicative of preclinical Cushing's syndrome, there were no clinical features characteristic of Cushing's syndrome. Microscopically, the tumor showed a proliferation of polygonal cells containing numerous brown-pigmented granules. Special staining studies revealed these granules to be lipofuscin. Electron microscopy also identified lipofuscin and lysosomes in these cells. The morphological appearance of the tumor and the adjacent atrophic non-tumorous adrenal cortex supports the assumption that the black adenoma caused preclinical Cushing's syndrome.     

New epiphyseal stippling syndrome with osteoclastic hyperplasia

We present a lethal skeletal dysplasia characterized radiographically by severe stippling of the lower spine and long bones and periosteal cloaking. In contrast to the normal morphology of the epiphyses and growth plates, the marrow was filled with loose fibrous tissue containing numerous large multinucleated osteoclasts which were associated with Howship's lacunae on the endosteal surface. We suggest the term “;Pacman dysplasia”; to describe this unusual histologic change that characterizes this new bone dysplasia. © 1993 Wiley-Liss, Inc.     

Histopathology and ultrastructure of primary adrenocortical nodular dysplasia with Cushing''s syndrome

The characteristic adrenal lesions of five patients with bilateral primary adrenocortical nodular dysplasia and Cushing's syndrome developing in adolescence are presented histopathologically, and in two cases ultrastructurally. Two of the patients were siblings with additional extra-adrenal lesions such as pigmented spots on the face, myxoid cutaneous tumours and in one case familial cardiac myxoma. The adrenals were small with an uneven surface due to numerous small brown to black pigmented nodules in the inner cortex. The nodules were composed of eosinophilic giant cells filled with lipofuscin granules. The familial cases in addition revealed a pronounced disorganization of the adrenocortical architecture with capsular disruption and infiltration of periadrenal fatty tissue. The early onset of Cushing's syndrome in the second decade, the bilateral involvement of adrenal glands despite ACTH independence and the familial occurrence in combination with other peculiar rare lesions are strongly suggestive of a malformative process of the zona reticularis of the adrenal glands.     

Nodular regenerative hyperplasia of the liver in a non-treated patient with mesangiocapillary glomerulonephritis

The recognition of nodular regenerative hyperplasia of the liver in patients with renal transplant is well-known. This report, we believe, is the first well-documented case of nodular regenerative hyperplasia in a patient with chronic renal disease and who had not been transplanted.     

P-450c17mRNA在原发性醛固酮增多症肾上腺皮质腺瘤及增生组织中的表达及意义

为探讨细胞色素P-450 c17 -羟化酶(P-450 c17 )mRNA 在原发性醛固酮增多症(原醛)肾上腺皮质腺瘤（APA）及增生组织中的表达及其意义，采用 Northern Blot 法对7 例APA 组织，3 例结节样增生组织，7 例正常肾上腺组织，1 例腹壁骨骼肌组织P-450 c17 mRNA 的表达水平进行检测。结果显示P-450 c17 mRNA 在原醛APA组织与正常肾上腺组织中的表达有显著性差异P<0.05。P-450 c17 mRNA 在原醛肾上腺皮质增生组织与正常肾上腺组织中的表达、在原醛APA 组织与原醛肾上腺皮质增生组织中的表达相似。提示P-450 c17 mRNA 在APA 组织中的表达降低很可能是原醛APA 组织分泌过多醛固酮(ALD)的分子生物学原因。     

Changes of the level of cytochrome P-450 and NADPH-cytochrome P-450 reductase in rats with hereditary degeneration of the retina

In animals with hereditary degeneration of the retina the level of cytochrome P-450 in the brain microsomal fraction is found to be higher than that in healthy animals. In rats with hereditary degeneration of the retina the activity of NADPH-cytochrome P-450 reductase is unchanged in all tissues examined except for the retina, where it is markedly higher than in healthy animals on postnatal day 90. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 117, N ^o 3, pp. 259–261, March, 1994     

Multilocular thymic cyst associated with follicular hyperplasia: clinicopathologic study of 4 resected cases

We report here 4 cases of multilocular thymic cysts (MTCs) with reactive lymphoid follicular hyperplasia. They were admitted to our hospital to examine anterior mediastinal masses demonstrated on chest computed tomographic scans. Three patients presented high-grade intermittent fever, and 2 patients were associated with Sjogren syndrome with elevated serum antinuclear antibody levels. All patients were subjected to extended thymectomy. Interestingly, their fever disappeared immediately after surgery. Histologically, the lesions were characterized by several cystic spaces separated by various thick walls with dense lymphoid tissue containing large reactive germinal centers. The inner cyst walls were lined by flattened cuboidal epithelia in some portions. Columnar epithelia with focal cilia were partially observed in 2 cases. These pathological findings led to a diagnosis of MTCs that were thought to result from cystic transformation of medullary duct derivatives by acquired inflammatory processes. The pathological findings, together with clinical courses of our cases, suggest that inflammation accompanied by autoimmune diseases may play, in part, an important role in the development of MTCs.