Pituitary adenoma in Carney complex: an immunohistochemical,ultrastructural, and immunoelectron microscopic study

First described in 1985, Carney complex is a rare, heritable disorder featuring abnormal skin pigmentation, cardiac and cutaneous myxoma, melanotic schwannoma of psammomatous type, and endocrine abnormalities, including pituitary adenomas. Patients with the latter present with elevated growth hormone (GH) levels and acromegaly or gigantism. Prolactin (PRL) elevation may also be seen. The authors have investigated 2 resected pituitary adenomas from patients with Carney complex. One, a 19-year-old female acromegalic with elevated GH, IgF-1, and PRL levels, had a mammosomatotroph adenoma immunoreactive for GH and PRL. Ultrastructurally, GH and PRL were present in the same secretory granules. The second patient, a 27-year-old acromegalic, had a sparsely granulated GH cell adenoma that by immuno-electron microscopy revealed GH immunoreactivity only. The lack of morphologic similarity between the 2 adenomas indicates that pituitary tumors in patients with Carney complex may not exhibit the same phenotype.     

Ultrastructural and Immunoelectron Microscopic Study of Three Unusual Plurihormonal Pituitary Adenomas

Momomorphous pituitary adenomas expressing several hormones by immunocytochemistry are common, whereas adenomas displaying multiple immunoreactivities and consisting of more than one morphologic cell types are rare. Three such unusual pituitary adenomas, surgically removed from two patients with acromegaly and one patient with hyperprolactinemia, were investigated by histology, immunocytochemistry, transmission electron microscopy, as well as immunoelectron microscopy using double immunogold labeling. Immunocytochemistry revealed variable degrees of immunoreactivities for growth hormone (GH), prolactin (PRL), thyroid-stimulating hormone (beta-TSH), and alpha-subunit of glycoprotein hormones in all three tumors. The three adenomas consisted of phenotypically diverse cell populations as documented by transmission electron microscopy. In addition to monohormonal GH cells, immunoelectron microscopy demonstrated numerous cells colocalizing GH and PRL or GH and beta-TSH, and rarely PRL and beta-TSH in tumors of acromegalics. The adenoma causing hyperprolactinemia consisted chiefly of mammosomatotrophs colocalizing PRL and GH, whereas beta-TSH labeling was scant. The three tumors in the study were selected from a cluster of five plurimorphous plurihormonal adenomas received from the same locale where they accounted for an unprecedented 21% of adenomas producing GH and/or PRL. The enhanced susceptibility to develop plurimorphous adenomas of the acidophil cell line may have a genetic basis in the stable population the patients came from.     

Pituitary Corticotroph Adenoma Containing Many Apoptotic Cells: A Histologic,Immunohistochemical, Ultrastructural and Molecular Study

Apoptosis regulates cell turnover in normal tissues and occurs during the neoplastic process. Owing to difficulties in recognizing apoptotic cells by histology alone, several complementary approaches have been introduced, which disclosed the presence of cells with typical nuclear and cytoplasmic changes characteristic of apoptosis. Electron microscopy remains the most conclusive method to reveal the structural changes. Identification of caspase cleaved keratin 18 intermediate filament rearrangements can contribute to the identification of early apoptotic changes. The authors present here an unusual case of a pituitary corticotroph adenoma removed surgically from a young woman with Cushing disease. The tumor contained many apoptotic cells identified by histology. In addition, the apoptotic events were investigated using various morphologic techniques, including electron microscopy, the in situ end-labeling technique, and immunohistochemistry to confirm the caspase-cleaved keratin 18 rearrangements.     

Pituitary Carcinoma: An Ultrastructural Study of Eleven Cases

Pituitary carcinomas are very rare. Defined as adenohypophysial tumors that undergo craniospinal and/or systemic metastasis, most are PRL- or ACTH-producing. Their ultrastructural features, particularly relative to benign adenomas of similar functional type, have not been sufficiently explored. Eleven cases of immunohistochemically characterized pituitary carcinoma with documented cerebrospinal and/or systemic metastases were collected from various institutions and studied by transmission electron microscopy. The tumors were surgically removed from 7 women and 4 men ranging in age between 28 and 74 years (mean, 50 years). All were endocrinologically functioning. Six tumors secreted PRL; three were ACTH-producing; one each was GH/PRL- and TSH-producing. The patients with the ACTH-producing tumors had all presented with Cushing's disease and two of them had undergone adrenalectomy (Nelson syndrome). In most cases significant cellular atypia and mitotic activity were observed. In terms of morphologic features of functional differentiation, electron microscopy revealed that in 9 cases the tumor cells maintained at least some ultrastructural markers of their basic phenotype. A unique feature in 2 ACTH carcinomas was the variable admixture of smooth endoplasmic reticulum with intermediate (cytokeratin) filaments. In 2 cases, both PRL-producing carcinomas, the cell type comprising the tumor could not be identified on an ultrastructural basis alone. Ultrastructural investigation of pituitary carcinomas confirms their endocrine nature and, in most but not all cases, reveals their functional differentiation. Despite the diagnostic utility of electron microscopy in the assessment of theserare tumors, the distinction of pituitary carcinoma from pituitary adenoma cannot be firmly made on ultrastructural grounds alone.     

Clinicopathologic Analysis of Pituitary Adenoma: A Single Institute Experience

Pituitary adenoma (PA) is a common benign neuroendocrine tumor; however, the incidence and proportion of hormone-producing PAs in Korean patients remain unknown. Authors analyzed 506 surgically resected and pathologically proven pituitary lesions of the Seoul National University Hospital from 2006 to 2011. The lesions were categorized as: PAs (n = 422, 83.4%), Rathke''s cleft cysts (RCCs) (n = 54, 10.6%), inflammatory lesions (n = 8, 1.6%), meningiomas (n = 4), craniopharyngiomas (n = 4), granular cell tumors (n = 1), metastatic renal cell carcinomas (n = 2), germinomas (n = 1), ependymomas (n = 1), and unsatisfactory specimens (n = 9, 1.8%). PAs were slightly more prevalent in women (M: F = 1:1.17) with a mean age of 48.8 yr (9-80 yr). Immunohistochemical analysis revealed that prolactin-producing PAs (16.6%) and growth hormone-producing adenomas (9.2%) were the most common functional PAs. Plurihormonal PAs and nonfunctioning (null cell) adenomas were found in 14.9% and 42.4% of patients with PAs, respectively. The recurrence rate of PAs was 11.1%, but nearly 0% for the remaining benign lesions such as RCCs. 25.4% of patients with PAs were treated by gamma-knife after surgery due to residual tumors or regrowth of residual tumor. In conclusion, the pituitary lesions and the proportions of hormone-producing PAs in Korean patients are similar to those of previous reports except nonfunctioning (null cell) PAs, which are unusually frequent.

Graphical Abstract

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Pituitary corticotroph adenoma containing many apoptotic cells: a histologic,immunohistochemical, ultrastructural and molecular study

Apoptosis regulates cell turnover in normal tissues and occurs during the neoplastic process. Owing to difficulties in recognizing apoptotic cells by histology alone, several complementary approaches have been introduced, which disclosed the presence of cells with typical nuclear and cytoplasmic changes characteristic of apoptosis. Electron microscopy remains the most conclusive method to reveal the structural changes. Identification of caspase cleaved keratin 18 intermediate filament rearrangements can contribute to the identification of early apoptotic changes. The authors present here an unusual case of a pituitary corticotroph adenoma removed surgically from a young woman with Cushing disease. The tumor contained many apoptotic cells identified by histology. In addition, the apoptotic events were investigated using various morphologic techniques, including electron microscopy, the in situ end-labeling technique, and immunohistochemistry to confirm the caspase-cleaved keratin 18 rearrangements.     

Ultrastructural Features of Apoptosis in Human Pituitary Adenomas

Although several recent studies deal with various molecular aspects of apoptosis, or programmed cell death, very little information is available on the ultrastructural changes associated with apoptosis in the adenohypophysis and its role in the regulation of pituitary adenoma growth and progression. This paper describes the distinct ultrastructural sequences that develop during the various phases of the apoptotic process. The study is based on the ultrastructural investigation of more than 8,000 surgically removed pituitary biopsies, which were examined by histology and immunocytochemistry for diagnostic purposes. No apoptosis was found in normal adenohypophysis and it is also a rare event in pituitary adenomas. When present, adenomatous adenohypophysial cells exhibit common and characteristic apoptotic changes. The ultrastructural alterations of membraneous organelles associated with apoptosis are similar to those previously reported in other tissues. It is noteworthy that apoptosis is clearly distinguishable from the ubiquitous dark cells denoting the common way of cell death. The findings suggest that apoptosis in pituitary adenomas is not a random event. Practically every specimen containing multiple apoptotic cells represents corticotroph adenoma. Occasional examples occur in lactotroph or gonadotroph adenomas. Although electron microscopic specimens are admittedly small, the large number of investigated cases gives credence to the observations.     

Atypical Endocrine Granules in Atypical Endocrine Tumor (AET) of the Lung: An Immunoelectron Microscopic Study

Highly dense granules are a hallmark for recognizing atypical endocrine tumor (AET) of the lung. We report a case of AET with many atypical neurosecretory type granules: moderately dense granules (mean size 373.7nm) and "target" granules with a central dense core (425.1 nm), both apparently larger than the highly dense granules (223.3nm). lmmunoelectron microscopical studies demonstrated that all three types of granule were positive for gastrin releasing peptide (GRP), human chorionic gonadotropin α-subunit (hCGα), calcitonin or serotonin. Although the size profiles of positive granules were similar for calcitonin and hCGα, they were different from those of GRP or serotonin granules. The presence of atypical granules and the different size profiles of hormonal products in AET indicate that caution is required in ultra-structural evaluation of granules in lung carcinomas.     

An adolescent with large cell calcifying sertoli cell tumor of the testis and undiagnosed Carney Complex: A case report

Carney Complex (CNC) is a rare autosomal dominant condition with characteristic clinical presentation, tumor development, and unique genetic mutation. We present a unique case and literature review of CNC in which two neoplasms characteristic of this complex were initially diagnosed through cytological fine needle aspirate specimens, leading to the identification of CNC, with subsequent surgical and cytogenetic confirmation. Diagn. Cytopathol. 2017;45:634–639. © 2017 Wiley Periodicals, Inc.     

Ultrastructural Study of a Pituitary Adenoma (Prolactinoma) Within the Clivus Bone Using Immunoelectron Microscopy

In a case of a pituitary adenoma in the clivus bone in a 71-year-old man, ultrastructural investigation using conventional aldehyde-fixed, epoxy-embedded tissue revealed the tumor to be composed of cells with euchromatic nuclei, dense nucleoli, abundant rough endoplasmic reticulum, spherical secretory granules, and granule extrusion at the lateral cell surface, all of which suggest a prolactin-producing adenoma. Using a protein A-gold immunolabeling technique on snapfrozen tissue subsequently fixed in a mild fixative and embedded in a hydrophilic resin, the presence of prolactin immunoreactivity within secretory granules at the ultrastructural level was demonstrated. This case represented the first use of protein A-gold immunolabeling at the electron microscopic level for diagnostic purposes at our institution and exemplifies the value of this technique when the need for diagnostic immunoelectron microscopy is not anticipated. Because this tumor arose in an unusual location, ultrastructural study, including immunoelectron microscopy, not only confirmed the light microscopic diagnosis of pituitary adenoma, but further allowed subclassification of the tumor.     

Ultrastructural Study of a Pituitary Adenoma (Prolactinoma) Within the Clivus Bone Using Immunoelectron Microscopy

In a case of a pituitary adenoma in the clivus bone in a 71-year-old man, ultrastructural investigation using conventional aldehyde-fixed, epoxy-embedded tissue revealed the tumor to be composed of cells with euchromatic nuclei, dense nucleoli, abundant rough endoplasmic reticulum, spherical secretory granules, and granule extrusion at the lateral cell surface, all of which suggest a prolactin-producing adenoma. Using a protein A-gold immunolabeling technique on snapfrozen tissue subsequently fixed in a mild fixative and embedded in a hydrophilic resin, the presence of prolactin immunoreactivity within secretory granules at the ultrastructural level was demonstrated. This case represented the first use of protein A-gold immunolabeling at the electron microscopic level for diagnostic purposes at our institution and exemplifies the value of this technique when the need for diagnostic immunoelectron microscopy is not anticipated. Because this tumor arose in an unusual location, ultrastructural study, including immunoelectron microscopy, not only confirmed the light microscopic diagnosis of pituitary adenoma, but further allowed subclassification of the tumor.     

Pituitary Hormone mRNA in Null Cell Adenomas and Oncocytomas by In Situ Hybridization Comparison with Immunohistochemical and Clinical Data

Null cell adenomas and oncocytomas are clinically inactive adenomas of the pituitary gland. They do not show any significant hormone content detectable by immunohistochemistry. This study aimed at demonstrating mRNAs for all main pituitary hormones in 32 null cell adenomas and 31 oncocytomas by non-isotopic in situ hybridization using digoxigenin-labeled oligonucleotide probes. The results were compared with immunohistochemical and clinical data. Immunohistochemistry (ABC method) was done with monoclonal antibodies against PRL, GH, FSH, LH, TSH, ACTH, alpha-subunit, and Ki-67 (mib-1). The signals for hormone production were detected in both adenoma types in a range from 42% for GH in oncocytomas to 78% for beta-FSH in null cell adenomas. However, these signals are apparently not effective on hormone production, as was shown by almost negative immunostaining. Owing to the simultaneous detection of at least two mRNAs in 78% of null cell adenomas and in 94% of oncocytomas, we assume that both tumor types originate from pluripotential precursor cells that are capable of producing various hormones. According to our data, it is unlikely that the signals influence the clinical behavior.     

Ultrastructural features of adenoma malignum of the uterine cervix: demonstration of gastric phenotypes

Histochemical staining has shown that so-called adenoma malignum (the mucinous type of minimal deviation adenocarcinoma [mucinous MDA]) of the uterine cervix expresses gastric phenotypes. The present ultrastructural study was undertaken to explore the fine structure and phenotypic expression of this tumor, and to make comparisons with normal cervical glands and gastric pyloric mucosa. Post-embedding, double-immunogold staining for gastric gland mucous cell mucin (HIK1083-reactive mucin) and lysozyme revealed localization exclusively to the matrix and to the core of the mucin granules, respectively, both in mucinous MDA and gastric pyloric mucosa. Mucin granules of normal cervical gland cells lacked core structures and showed no immunoreactivity with HIK1083 or lysozyme. Thus, mucinous MDA was confirmed to be a tumor expressing gastric phenotypes ultrastructurally. Both markers should be useful for the identification of tumor cells.     

Glial Fibrillary Acidic Protein Expression in Pleomorphic Adenoma of Salivary Gland: An Immunoelectron Microscopic Study

Previous immunocytochemical studies of pleomorphic adenomas have demonstrated consistent labeling with glial fibrillary acidic protein (GFAP). Cross-reactivity with other intermediate filaments of similar structure and chemical composition has been suggested to account for this seemingly inappropriate pattern of immunoreactivity. To investigate further this phenomenon, we examined five pleomorphic adenomas by immunoelectron microscopy. Ultrastructural features were similar to those described by other investigators, with ductal epithelium being surrounded by myoepithelial cells and modified cells becoming detached to form the isolated stellate and spindle cells of the stroma. As part of this process, many neoplastic myoepithelial cells appeared to lose their specialized ultrastructural features, assuming a rather undifferentiated appearance. Single and double immunoelectron microscopic labeling showed vimentin filaments in all these neoplastic myoepithelial cells. In contrast, GFAP filaments were identified only in the most undifferentiated cells. Such restriction of GFAP filaments to an ultrastructurally definable subset of neoplastic cells provides strong evidence against nonspecific staining due to cross-reactivity. Given the previously described coexpression of vimentin and GFAP by neoplastic cartilage, it appears likely that this immunophenotype in neoplastic myoepithelial cells reflects early chondroid differentiation.     

Gastrointestinal Stromal Tumor of the Stomach with Rhabdoid Phenotype: Immunohistochemical,Ultrastructural, and Immunoelectron Microscopic Evaluation

A variety of neoplasms with rhabdoid differentiation have been reported in many sites. The authors describe a case of gastrointestinal stromal tumor (GIST) of the stomach that exhibited prominent rhabdoid features. Immunohistochemically, the tumor cells displayed positive staining for vimentin, c-kit, CD34, and alpha smooth muscle actin. Ultrastructural examination of the rhabdoid tumor cells revealed paranuclear whorls of intermediate filaments, which were immunoreactive for vimentin by both light microscopic immunohistochemical and protein A gold immunoelectron microscopic techniques. On H&E light microscopic examination alone, such a tumor could be mistaken for a variety of epithelial, mesenchymal, or other neoplasms that may show rhabdoid features. One report of GIST with a rhabdoid histologic phenotype has been described. This is the second known report of such a case with immunophenotypic and ultrastructural evaluation, and the first case with immunoelectron microscopic examination.     

Plasmacytoid Monocytes in Epithelioid Cell Granulomas: Ultrastructural and Immunoelectron Microscopic Study

Plasmacytoid monocytes, the so-called plasmacytoid T cells, were originally described in rare cases of lymphadenitis. Recent immunohistochemical studies have demonstrated their monocytic origin. Plasmacytoid monocytes have in common with epithelioid cells and multinucleated giant cells the expression of several antigens; they also occur in close topographic association with epithelioid and multinucleated giant cells in epithelioid cell granulomas. On the basis of these data it has been suggested that plasmacytoid monocytes may transform into epithelioid cells. The present ultrastructural and immunoelectron microscopic study of epithelioid cell granulomas provides furthei arguments in favor of this hypothesis. Moreover, the existence of a transitional cell type with characteristics of plasmacytoid monocytes and epithelioid cells is documented. Subplasmalemmal linear densities present on focal areas of the plasma membrane of the main cell components of granulomas are also discussed.     

Angiomyolipoma: Immunohistochemical and Ultrastructural Study of 14 Cases

Angiomyolipoma (AML) is a mesenchymal neoplasm of unclear histogenesis. In addition to varying amounts of smooth muscle, adipose tissue, and blood vessels, it contains a population of clear or pale eosinophilic epithelioid cells often arranged around blood vessels. Various phenotypes of AML have been described: leiomyoma-like, lipoma-like, epithelioid, and atypical. AMLs show consistent immunopositivity for HMB-45. This has been associated with the ultrastructural observation of melanosome-like structures in rare instances. In the present study, 14 AMLs from 13 patients were analyzed by electron microscopy and immunohistochemistry to determine the appearance and nature of cells composing AMLs. Overlap between cell types (spindle smooth muscle cells, epithelioid cells, and adipocytes) was found by both electron microscopy and immunohistochemistry. Melanosomes were found in 7 tumors. The cell of origin remains mysterious. Nevertheless, the study demonstrates that the AML is likely derived from a single cell that shares homology with the pericyte.     

Cushing's Syndrome from an Ectopic Pituitary Adenoma with Peliosis: A Histological,Immunohistochemical, and Ultrastructural Study and Review of the Literature

Ectopic pituitary adenoma (EPA) is rare and, to the authors’ knowledge, its association with peliosis has not yet been described. The case of a 38-yr-old woman with clinical and biochemical evidence of Cushing’s syndrome is reported. Magnetic resonance imaging (MRI) disclosed a normal pituitary and a separate mass in the sphenoid sinus. The surgically remove’s hyaline change in the corticotrophs, indicating exposure to glucocorticoid excess. By histology, the mass in the sphenoid sinus was a congested, chromophobic, partly basophilic, periodic acid-Schiff (PAS)-positive pituitary adenoma composed of pleomorphic, adrenocorticotropic hormone (ACTH)-positive, corticotrophs. There was focal immunopositivity for MIB-1 and proliferating cell nuclear antigen (PCNA). Electron microscopy confirmed the diagnosis of corticotroph adenoma. A striking finding, consistent with the diagnosis of peliosis, was the presence of multiple large blood-filled spaces lacking an endothelial lining. The capillaries were dilated, but often appeared empty and the fenestrated endothelium exhibited discontinuities. The cause of peliosis is obscure. It may be that the venous outflow was impaired in this case leading to capillary dilation, congestion, hyperpermeability, rupture, and accumulation of blood in extravascular spaces.     

Vanishing Psammoma Bodies in the Anterior Pituitary of the Human Newborn: An Immunohistochemical and Histometric Study

Adenohypophyses of human newborns contain characteristic psammoma bodies. Their numbers are maximal within 2 weeks of the neonatal period and diminish thereafter. They are very rare in infant pituitaries, seeming to disappear by shrinkage in that there is a significant direct correlation between their number and size. The bodies were found to contain a high concentration of endogenous peroxidase, thus suggesting that the enzyme may be responsible for their disappearance. A statistical majority of psammoma bodies were located within follicular lumens. By immunohistochemistry, the follicular epithelium surrounding psammoma bodies showed immunoreactivity for various pituitary hormones. Light microscopy demonstrated that adenohypophysial cells surrounding psammoma bodies contain randomly, scattered granules or globules exhibiting peroxidase activity. Extrusion of such granules into follicular lumens may play a role in the genesis of the concretions. The conspicuous lamellar nature of the calcified psammoma bodies suggests that waves of calcium deposition occur during their morphogenesis. Despite histologic similarities, the histochemical characteristics of this type of psammoma body differ from those in other organs as well as from the calcification encountered in prolactin (PRL)-producing pituitary adenomas.