Silent Adenoma Subtype 3 of the Pituitary—Immunohistochemical and Ultrastructural Classification: A Review of 29 Cases

The silent adenoma subtype 3 (SAS-3) of undetermined cellular derivation is a seemingly nonfunctioning aggressive pituitary tumor with a high recurrence rate. At the time of diagnosis SAS-3s are macro- or giant adenomas particularly aggressive in young individuals, especially women. They are usually associated with mild hyperprolactinemia and are unremarkable by histology. Immunohistochemistry, demonstrating scattered immunoreactivity mostly for GH, PRL, TSH, and α-subunit, is not diagnostic. Presently, only TEM permits conclusive diagnosis. Ultrastructurally, the large polar adenoma cells contain abundant RER, masses of SER, extensive multipolar Golgi apparatus, and unevenly clustered mitochondria, displaced by RER and SER, which may show close spatial relationship to RER. Cell membranes often form plexiform interdigitations. Nuclear pleomorphism and nuclear inclusions are common. The 100- to 200-nm secretory granules accumulate heavily in cell processes, which is a hallmark of glycoprotein hormone cell differentiation. The endothelial cells may contain tubuloreticular inclusions. Complete surgical removal of the large often invasive tumors is difficult necessitating postoperative treatment. SAS-3 is sensitive to conventional radiation. Some tumors express somatostatin receptors and respond well to somatostatin analogues, offering long-term control in patients with residual tumor. Possible derivation of SAS-3 from rostral thyrotrophs, a cell type presently known in rodents is comtemplated.     

Immunochemical identification of endocrine cell types in the streptozotocin nicotinamide-induced rat islet adenoma

The streptozotocin nicotinamide-induced rat islet adenoma is a benign encapsulated tumor that exhibits considerable histologic and endocrine variability. Individual tumors differ in their general pattern of cellular arrangement and often contain necrotic regions, ductlike structures and large amounts of interspersed connective tissue. The majority of tumors are polyhormonal. All contain insulin by radioimmunoassay and immunohistochemistry, although the amounts vary greatly. Glucagon and/or somatostatin immunoreactive cells are present in 62% of tumors by immunohistochemistry and in 86% by radioimmunoassay. Again, the amounts vary greatly. Pancreatic polypeptide immunoreactivity was localized in a small number of scattered cells in 31% of tumors studied. Tumors demonstrated considerable hormonal intra- and intertumor heterogeneity both by immunohistochemistry and by radioimmunoassay. From these data it is indicated that the tumor can neither be considered an “insulinoma” nor “pure” in endocrine composition. This histologic and endocrine variability must be taken into account when using the tumor as a source of islet mRNA or as a source of tissue in insulin biosynthetic work.     

Somatostatin-Producing Atypical Null Cell Adenoma Manifesting as Severe Hypopituitarism and Rapid Deterioration—Case Report

Atypical adenoma has an aggressive biological character, invades the surrounding structures, and grows rapidly. Morphological malignant findings such as increasing cellularity and nuclear atypism are not involved in this entity, but some cases with overt malignant features such as significant nuclear atypism and/or necrosis are known. Null cell adenoma generally grows slowly, but hormone secretion is little understood. Atypical null cell adenoma is rare, and hormone production is unknown. A 55-year-old woman presented with severe hypopituitarism and diabetes insipidus and bilateral upper temporal quadrantanopsia. Head magnetic resonance imaging revealed a large sellar tumor compressing the optic chiasm. Transsphenoidal surgery was performed, but the tumor was partially removed because of invasion into the neuronal structures. Histological examination showed atypical null cell adenoma with significant nuclear atypism and extensive necrosis. Immunohistochemistry showed positive reaction to somatostatin. Adjuvant treatment was planned, but the tumor regrew within 3 months. Conventional irradiation resulted in slight decrease in tumor size, but she required assistance for every type of daily activity. Atypical null cell adenoma has an aggressive biological character, and immediate adjuvant treatment is essential. Somatostatin secretion was proven in this tumor type.     

The human thyrotropic adenoma: pathologic diagnosis in five cases and critical review of the literature

Five out of 400 surgically removed pituitary tumors (frequency: 1.2%) were identified as thyrotropic adenomas according to the following criteria: identification of tumoral thyrotropic cells by immunocytochemistry and ultrastructural study; elevated serum TSH levels with decrease after surgery; and elevated concentration of TSH in the tumor. Four patients presented with hyperthyroidism and one with euthyroidism. From these five cases and 11 similar observations extracted from a critical review of literature, the morphologic, immunocytochemical, and hormonal characteristics of thyrotropic adenoma are described. Thyrotropic adenomas are more often large tumors but may also be microadenomas. The diagnosis is asserted by immunoreactivity with anti-TSH antisera. The TSH positive tumor cells are numerous. In some tumors, rare cells of other types are also found (PRL, GH, FSH, or ACTH cells). Some morphologic characteristics strongly suggest the diagnosis. The cells are often large with thin processes. They show argyrophil granulations in a slightly basophil cytoplasm and signs of secretory activity. Their secretory granules are round and small without striking variations in size, shape, and electron density. Elevated concentration of TSH in the tumor confirms the diagnosis. The presence of high serum TSH levels and a molar ratio of alpha hTSH to the whole TSH molecule greater than one are other good criteria. Decrease of TSH after surgery may not be observed in invasive tumors. TSH adenoma is most often associated with hyperthyroidism but it can also be associated with hypothyroidism or euthyroidism.     

Sinonasal undifferentiated carcinoma: clinical and pathologic features and a discussion on classification, cellular differentiation, and differential diagnosis

Sinonasal undifferentiated carcinoma (SNUC) is an uncommon, highly aggressive, and clinicopathologically distinctive carcinoma of uncertain histogenesis. SNUC typically presents as a rapidly enlarging tumor mass involving multiple (sinonasal tract) sites, often with evidence of extension beyond the anatomic confines of the sinonasal tract. The light microscopic features include the presence of a hypercellular proliferation with varied growth patterns, including trabecular, sheet-like, ribbon, lobular, and organoid patterns. The tumor cells are medium to large sized and round to oval and have pleomorphic and hyperchromatic nuclei, inconspicuous to prominent nucleoli, varying amount of eosinophilic cytoplasm, high nuclear-to-cytoplasmic ratio, marked increase in mitotic activity frequently with atypical mitoses, tumor necrosis, and apoptosis. Adjunct analyses (eg, immunohistochemistry, electron microscopy, and molecular biologic studies) are often required in the diagnosis of SNUC and in differentiating it from other undifferentiated malignant neoplasms. The treatment of SNUC includes aggressive multimodality therapy, including surgical resection and adjuvant therapy (ie, radiotherapy, chemotherapy). The prognosis associated with SNUC is poor, and death due to disease often occurs within short periods following the diagnosis. We believe that the histologic definition of SNUC can be expanded to include tumors with limited differentiated foci (ie, squamous cell differentiation) predicated on the caveats that the clinical parameters (ie, rapidly enlarging and destructive sinonasal lesions) and the majority of the histologic findings (ie, undifferentiated pleomorphic cell population) match those features that have heretofore defined SNUC. The presence of squamous cell differentiation would correlate to origin in the Schneiderian epithelium, thereby conferring an ectodermal derivation to these tumors. Irrespective of its cell of origin and perhaps even in the face of differentiated foci in limited parts of the tumor, given its rather unique clinicopathologic characteristics, this tumor should be identified and classified as SNUC, thereby differentiating it from the other specific types of sinonasal carcinomas and nonepithelial malignant tumors.     

Fine structural study of postcastrational adrenocortical carcinomas in female CE-mice

Postcastrational adrenocortical carcinomas in the CE/Ki inbred strain of mice and the adrenals of noncastrated CE/Ki mice were studied using light and electron microscopic techniques. Most of the tumors appeared as large nodules of cells separated by septae comprised of collagen and blood sinusoids. The majority of tumor cells (Type 1) showed few or no lipid droplets (sudanophobic), polymorphic hyperchromatic nuclei, lack of SER, abundant RER and free ribosomes, prominent Golgi complexes, and few mitochondria with scant internal membranes. Clusters of Type 1 cells were surrounded by a basal lamina. In contrast, Type 2 cells revealed abundant and dilated tubules of SER, large number of lipid droplets and mitochondria with tubulovesicular cristae. These results suggest that Type 2 cells were probably active in steroid hormone synthesis and secretion while Type 1 cells were highly anaplastic and apparently non-steroid-secreting cells.     

Morphometric analysis, at electron microscope level, combined with hormone assay of nonfunctioning adrenocortical adenomas: comparison with aldosterone-producing adenomas

We performed electron microscopic studies of eight nonfunctioning adrenocortical adenomas (NFA) and nine aldosterone-producing adenomas (APA) obtained from surgical specimens. A comparison of these two types of adenomas was conducted by morphometric analysis of random electron micrographs. The organelles measured included mitochondria (M), smooth-surfaced endoplasmic reticulum (SER), rough-surfaced endoplasmic reticulum (RER), lipid vacuoles (LV), and lysosomes (Ly). The content of steroid hormones, including 17-alpha hydroxyprogesterone (17-OHP), aldosterone (Ald), and other steroid hormones, was measured in adenoma tissue from six NFA and eight APA. The percentages of the areas of the organelles M, SER, and RER per total cell area in the NFA were significantly lower than those in the APA. The average content of Ald in adenoma tissues in APA was markedly higher than that in the NFA, while the mean content of 17-OHP in the NFA was significantly higher than that in APA. In conclusion, NFA are morphometrically characterized by a reduction in organelles such as M, SER, and RER, compared with findings in APA. From the quantitative analysis of steroid hormones, it was suggested that NFA produce more precursor substances with less hormone activity than APA and that steroidgenesis in NFA is shifted to a glucocorticoid pathway, as indicated by the elevated 17-OHP concentration.     

Monomorphous Plurihormonal Pituitary Adenoma of Pit-1 Lineage in a Giant Adolescent with Central Hyperthyroidism

Thyrotropin (TSH)-secreting pituitary adenomas are exceedingly rare at the pediatric age and no cases of co-secretion with other pituitary hormones in these tumors have been described in this age range. We present a case of a monomorphous plurihormonal pituitary adenoma that co-secreted TSH and GH in a pediatric patient. A 13-year-old male presented with increasing height velocity (17.75 cm/year, 9.55SD), weight loss, and visual impairment. Initial biochemical evaluations revealed secondary hyperthyroidism. A giant pituitary tumor compressing the surrounding structures was detected by magnetic resonance, and a transsphenoidal surgery was initially performed. Pathological examinations revealed an atypical, monomorphous plurihormonal Pit-1 lineage tumor with mixed features of silent subtype 3 adenoma and acidophil stem cell adenoma. In the postoperative period, secondary hyperthyroidism recurred with high levels of both GH and IGF1. In addition, due to tumor re-growth, a multimodality treatment plan was undertaken including surgery, somatostatin analogs, and radiotherapy. We report the first pediatric case of a plurihormonal TSH- and GH-secreting pituitary adenoma, further expanding the clinical manifestations of pediatric pituitary tumors. Comprehensive pathological evaluation and close follow-up surveillance are crucial to the prompt delivery of the best therapeutic options in the context of this particularly aggressive pituitary tumor.     

Papillary adenoma of the lung. Histological and ultrastructural findings in two cases.

Two cases of papillary adenoma of the lung are presented along with results of histological and ultrastructural examinations. The tumors were encountered in two asymptomatic patients in a mass-survey chest X-ray examination. The chest X-ray films showed the tumors as well demarcated small lesions. Histologically, both tumors arose in the bronchioles and consisted of cuboidal cells resembling type II pneumocytes showing papillary growth with accompanying edematous connective tissue. Several tumor cells each possessed a large eosinophilic intranuclear inclusion. In case 1, ciliated cells and Clara-like cells were also present in the tumor. Ultrastructurally, most of the tumor cells had various numbers of lamellar bodies in their cytoplasm, indicative of type II pneumocytes, and some of case 1 showed features of Clara cells and ciliated cells. The intranuclear inclusions appeared as aggregates of tubular structures or had lamellar body-like features. These findings are identical to those of papillary adenoma arising from the bronchiole.     

Papillary Adenoma of the Lung

Two cases of papillary adenoma of the lung are presented along with results of histological and ultrastructural examinations. The tumors were encountered in two asymptomatic patients in a mass-survey chest X-ray examination. The chest X ray films showed the tumors as well demarcated small lesions. Histologically, both tumors arose in the bronchioles and consisted of cuboidal cells resembling type II pneumocytes showing papillary growth with accompanying edematous connective tissue. Several tumor cells each possessed a large eosinophilic intranuclear inclusion. In case 1, ciliated cells and Clara-like cells were also present in the tumor. Ultrastructurally, most of the tumor cells had various numbers of lamellar bodies in their cytoplasm, indicative of type II pneumocytes, and some of case 1 showed features of Clara cells and ciliated cells. The intranuclear inclusions appeared as aggregates of tubular structures or had lamellar body-like features. These findings are identical to those of papillary adenoma arising from the bronchiole.     

Multiple nonfunctional pancreatic islet cell tumor in multiple endocrine neoplasia type I. A case report

A case of multiple nonfunctional pancreatic islet cell tumor in multiple endocrine neoplasia type I (MEN I) is reported. The patient was a 41-year-old woman who had a past history of thyroid cancer (papillary carcinoma) and hyperparathyroidism due to parathyroid adenoma. Later, a nonfunctional pituitary tumor and five nonfunctional pancreatic tumors were found simultaneously and the patient was finally diagnosed as having MEN I. Following surgical enucleation, the pancreatic tumors were histopathologically diagnosed as benign islet cell tumors. One of them (tumor 3) exhibited a solid nodular pattern while the others showed gyriform patterns. They were divided histochemically and immunohistochemically into three types: two (tumors 1 and 2) produced a single hormone (glucagon), one (tumor 3) produced five (insulin, glucagon, somatostatin, gastrin and pancreatic polypeptide) and the remaining two (tumors 4 and 5) produced two (glucagon and pancreatic polypeptide). Electron microscopically, three types of endosecretory granules were found in the tumor cells of tumor 3 but only one type was found in tumor 4. However, in the tumor 4 extract, glucagon, pancreatic polypeptide, C-peptide, somatostatin, vasoactive intestinal peptide and growth hormone releasing factor were detected by radioimmunoassay. These findings suggest that these pancreatic tumors were both multicellular and multihormonal.     

An electron microscopic study of acute promyelocytic leukemia with chloroma

Tumor forming acute promyelocytic leukemia (APL) is rare and only three cases have been documented. However, there are no reports on either the chloromatous character or electron microscopical analysis. The present paper dealt with a light, electron microscopic and histochemical study of the tumor of APL in a 55-year-old Japanese male. The tumors found in the anterior mediastinum and right lower extremity. He died from respiratory disturbance and hydrothorax due to obstruction of the pulmonary truncus by the mediastinal tumor. In electron microscopy, the tumor cells showed dilatation, colloracious pattern and honey-comb-like structure of rough endoplasmic reticula (RER) and parallel array-arrangement of smooth endoplasmic reticula (SER). These abnormalities of ER are the same as those recently recognized in leukemic cells in APL. Furthermore, the intercellular junctions composed of opposing dense patches of the cytoplasmic plasmalemma were frequently found between the more immature tumor cell of the mediastinum.     

MULTIPLE NONFUNCTIONAL PANCREATIC ISLET CELL TUMOR IN MULTIPLE ENDOCRINE NEOPLASIA TYPE I

A case of multiple nonfunctional pancreatic islet cell tumor in multiple endocrine neoplasia type I (MEN I) is reported. The patient was a 41-year-old woman who had a past history of thyroid cancer (papillary carcinoma) and hyperparathyroidism due to parathyroid adenoma. Later, a nonfunctional pituitary tumor and Ave nonfunctional pancreatic tumors were found simultaneously and the patient was finally diagnosed as having MEN I. Following surgical enucleation, the pancreatic tumors were histopathologlcally diagnosed as benign islet cell tumors. One of them (tumor 3) exhibited a solid nodular pattern while the others showed gyriform patterns. They were divided histochemlcally and immunohistochemically into three types: two (tumors 1 and 2) produced a single hormone (glucagon), one (tumor 3) produced five (Insulin, glucagon, somatostatin, gastrin and pancreatic polypeptide) and the remaining two (tumors 4 and 5) produced two (glucagon and pancreatic polypeptide). Electron microscopically, three types of endosecretory granules were found in the tumor cells of tumor 3 but only one type was found in tumor 4. However, in the tumor 4 extract, glucagon, pancreatic polypeptide, C-peptlde, somatostatin, vasoactive intestinal peptide and growth hormone releasing factor were detected by radioimmunoassay. These findings suggest that these pancreatic tumors were both multicellular and multihormonal.     

Molecular Characterization of an Endometrial Endometrioid Adenocarcinoma Metastatic to a Thyroid Hürthle Cell Adenoma Showing Cancerization of Follicles

Tumor-to-tumor metastasis is rare. Herein, we present a unique case of endometrial endometrioid adenocarcinoma metastatic to a thyroid Hürthle cell adenoma 9 years after initial diagnosis. On histologic examination of the thyroid, the malignant endometrioid glands and single cells (donor tumor) were dispersed within the Hürthle cell adenoma (recipient tumor). In several sections of the adenoma with still preserved microfollicular architecture, malignant endometrial adenocarcinoma cells were admixed within oncocytic adenomatous epithelium (so-called “cancerization of the follicles”). This unusual phenomenon, to our knowledge, is a novel finding in the thyroid gland. Immunohistochemistry, subsequently elicited clinical history, and morphologic comparison of the tumor in the thyroid to the primary endometrial tumor confirmed the origin of the donor tumor cells. Molecular analysis of both the metastatic and primary endometrial tumors demonstrated PIK3CA and PTEN mutations in both tumors, as is characteristic of well-differentiated endometrioid tumors of the endometrium. Amplification of chromosome 1q was detected in both sites; however, only the metastatic tumor showed loss of chromosomes 2, 9, and 22. The morphologic differential diagnosis of metastatic endometrioid adenocarcinoma in the thyroid includes columnar cell variant of papillary thyroid carcinoma (CCVPTC) arising in a preexisting adenoma, endocrine glandular atypia within an adenoma, and metastasis from other anatomic sites. Histomorphologic differences among these entities may be subtle; therefore, knowledge of and morphologic comparison with prior malignancies and immunohistochemistry can be helpful in rendering the correct diagnosis.     

Ultrastructural evidence of mature Leydig cells and Leydig cell regression in the neonatal human testis

The neonatal period in male development is characterized by an acute rise in serum testosterone, which peaks at 2 to 3 months of age. The purpose of this study is to examine the neonatal human testicular interstitium at 4 months for evidence of Leydig cell maturation, as well as any morphological criteria relating to the fate of Leydig cells during this period, specifically, for signs of cell regression. Leydig cells are described with impressive development of the steroid secreting apparatus, which are consistent with the mature Leydig cells found during early fetal development and in the adult. The outstanding feature of these cells is the "organelle association" of extensive, anastamosing tubules of smooth endoplasmic reticulum (SER), pleomorphic mitochondria with a component of tubular cristae, and abundant microperoxisomes associated with the SER. Well-developed Golgi elements, regionalized RER, and diverse cell inclusions are also characteristics of these cells. Reinke crystals and paracrystalline inclusions are absent. Gap junctions are common in this system and are notable in the asymmetric nature of the adjacent cytoplasmic components. These findings provide a morphologic correlate to the reported neonatal phase of testosterone production in man. Intermediate forms of Leydig cells are described with "organelle associations" including decreased SER with increased lipid droplets, and decreased SER with prominent cytoplasmic filaments and/or dramatic mitochondrial changes supportive of mitochondrial involution. Cells consistent with immature Leydig cells are also present. The rather impressive diversity in cell morphology present during this time frame of 4 months, slightly past the peak in testosterone production, provides evidence of Leydig cell regression and a continuity of the mature neonatal Leydig cells with the immature Leydig cells of childhood (Prince, 1984). There is also some evidence of cell degeneration. Although the developmental history of Leydig cells has been described for years as biphasic, it is time to view Leydig cell development in man as a triphasic event, fetal, neonatal, and pubertal.     

Gastrointestinale gemischte adenoneuroendokrine Karzinome

Mixed adenoneuroendocrine carcinomas (MANECs) are a challenge for the diagnostics and the concept of a histogenetic tumor typing. They are classified into three malignant subgroups: high grade malignant MANECs combine an adenoma or adenocarcinoma with a small cell or large cell neuroendocrine carcinoma, intermediate grade malignant MANECs consist of a neuroendocrine tumor (NET grade 1 or 2), often a globlet cell carcinoid and a poorly differentiated adenocarcinoma or diffuse carcinoma of signet ring cell type. The prototype of a low grade malignant MANEC is the globlet cell carcinoid. Molecular analysis indicates a common clonal origin of the different components in MANECs. The prognosis is determined by the most aggressive tumor component. The pathogenesis of MANECs is apparently a sequence of increasing malignant transformation which leads either from an adenoma/adenocarcinoma to a small or large cell neuroendocrine carcinoma or from a neuroendocrine tumor (NET), often a globlet cell carcinoid to a poorly differentiated adenocarcinoma or a diffuse carcinoma of signet ring cell type.     

Malignant soft tissue neoplasms with the histologic features of renal rhabdoid tumors: An ultrastructural and immunohistochemical study

Five round cell neoplasms of the soft parts that histologically resembled malignant rhabdoid tumors of the kidney were studied. The tumors were composed mainly of poorly differentiated round or, sometimes, polygonal cells, with a minority of elongated cells; the cytoplasm of many of the cells contained filament-laden acidophilic inclusions. Ultrastructurally, the intracytoplasmic structures were seen to consist of aggregates of 10-nm intermediate filaments, and immunohistochemical staining revealed the presence of cytokeratin and vimentin. All five patients with this tumor had an aggressive clinical course; three of the patients died shortly after the initial diagnosis. As this tumor does not seem to be linked to any known entity, it is referred to as malignant rhabdoid tumor of the soft parts and could be a heterogeneous entity.     

AN ELECTRON MICROSCOPIC STUDY OF ACUTE PROMYELOCYTIC LEUKEMIA WITH CHLOROMA

Tumor forming acute promyelocytic leukemia (APL) is rare and only three cases have been documented. However, there are no reports on either the chloromatous character or electron microscopical analysis. The present paper dealt with a light, electron microscopic and histochemical study of the tumor of APL in a 55-year-old Japanese male. The tumors found in the anterior mediastinum and right lower extremity. He died from respiratory disturbance and hydrothorax due to obstruction of the pulmonary truncus by the mediastinal tumor. In electron microscopy, the tumor cells showed dilatation, eolloracious pattern and honey-comb-like structure of rough endoplasmic reticula (RER) and parallel array-arrangement of smooth endoplasmic reticula (SER). These abnormalities of ER are the same as those recently recognized in leukemic cells in APL. Furthermore, the intercellular junctions composed of opposing dense patches of the cytoplasmic plasmalemma were frequently found between the more immature tumor cell of the mediastinum.     

Malignant giant cell tumor of tendon sheath

Summary A benign, but aggressive, giant cell tumor of tendon sheath developed over a period of 20 years into a metastasizing, histologically malignant giant cell tumor. Ultrastructure of the malignant tumor showed the same five cell types as described in giant cell tumors of tendon sheath. Even the same crystals were identified in the osteoblast-like and osteoclast-like cells.It therefore appears reasonable to assume that giant cell tumors of tendon sheath indeed are neoplasms with a malignant potential and not an inflammatory reaction of synovial cells as previously suggested.Both the benign and malignant tumors seem to be of mesenchymal derivation with partial osseous differentiation. No ultrastructural similarities with fibrous histiocytoma were apparent.