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An 18-year old male is reported who presented with a history of a growtn spurt over the year preceding his admission. His height was above the 97th percentile, and he had incompletely developed secondary sexual characters. Pituitary evaluation demonstrated a moderately elevated level of growth hormone (hGH) not suppressible by a glucose load and not stimulable by TRH or by L-DOPA. Serum prolactin (PRL) concentration was also increased while gonadotrophin, thyroid and adrenal function were all subnormal. There was clear radiological evidence of a large pituitary tumour with suprasellar extension and transsphenoidal total hypophysectomy was performed. A mixed chromophobe and acidophilic adenoma was found and both growth hormone and prolactin were demonstrable in different cells of the tumour by the immunoperoxidase technique. Post-operatively the patient has hypopituitarism and levels of growth hormone and prolactin have remained low or undetectable after 6 months. Thus early diagnosis and surgical treatment of gigantism of this mixed hGH-PRL secreting pituitary tumour was associated with a cure, which contrasts with the unfavourable outcome of many of the patients previously reported.
85 surgically removed pituitary adenomas were studied by light and electron microscopical and in part immunohistochemical methods. The tumors were histogically classified and reexamined by the ultrastructure. Histochemically the adenomas could be differentiated in acidophil adenomas (1. group, 41%), mucoid cell adenomas (2. group, 6%), and chromophobe adenomas (3. group, 37%) whereas oncocytic adenomas (4. group, 16%) could be identified only in plastic-embedded sections. About half of the acidophil adenomas were highly differentiated and showed structures which correspond to those of normal STH cells (subgroup 1.1). 1 adenoma consisted of cells of prolactin type (subgroup 1.2). The other acidophil adenomas were differentiated to a lower degree and showed no resemblance to the structures of normal acidophil cells. The 5 mucoid cell adenomas were proved to be with all methods highly differentiated adenomas of ACTH-cell type (subgroup 2.1). TSH-cell adenomas (subgroup 2.2) and lower differentiated mucoid cell adenomas (subgroup 2.0) were lacking in our collection. More than one third of the chromophobe adenomas showed well developed endoplasmic reticulum and Golgi complexes. The other had little and small organellas that resemblances to immature stem cells were evident. The oncocytic adenomas were identified in plastic-embedded sections by their fine-granular structures which were based ultrastructurally not on small secretory granules but on closely arranged mitochondrias.
INTRODUCTION: Chromophobe adenomas have been defined by the absence of secretory granules in them. But this definition has become doubtful since a granulation could be electron microscopically demonstrated. Hence we studied a collection of more than 100 surgically removed pituitary adenomas in order to find precise morphological criteria for the differential diagnosis of chromophobe adenomas, specially from the sparsely granulated chromophilic tumors. Furthermore we tried to find relations between the amount and type of granulation of the tumor cells and the clinical endocrine hyperfunction. MATERIAL AND METHODS: 108 unselected pituitary tumors were studied by light and electron microscopic methods. For histology the tissue was fixed in Helly's fluid or in buffered formalin. The paraffin wax sections were stained with haematoxylin-eosin, PAS, gallocyanin-chrome alum, carmoisine L-orange G-wool green, Herlant's tetrachrome method, and performic acid-alcian blue-PAS-orange G. For electron microscopy small pieces of the tumor were fixed in buffered glutaraldehyde, postfixed in osmium tetroxide, and embedded in epon 812. Sections were stained with toluidine blue for light microscopy. Thin sections were stained with uranyl acetate and lead citrate. Electron microscopical pictures with a primary magnification of 4000 were semi-quantitatively judged for the content and the extent of rough endoplasmic reticulum, Golgi complexes, secretory granules, lysosomes, and mitochondria by a grading with 6 degrees. Results. With special stains and the electron microscope 46 adenomas could be identified which consisted only of slightly granulated or agranular cells but not of densely granulated cells. These were defined as chromophobe adenomas. Oncocytic adenomas were regarded as another tumor type and were not included. One half of the chromophobe adenomas showed ultrastructurally well developed protein-synthesizing organellas. The diameter of the secretory granules amounts up to 500 mum. One quarter had many autolysosomes or lipid droplets. On the other hand, 18 adenomas of our collection exhibited moderate acidophilic granulation with only a few denser or fully granulated cells. These were designated as sparsely granulated acidophilic adenomas. They were rich in organelles. 89% of them showed a well developed rough endoplasmic reticulum and large Golgi complexes as signs of high endocrine activity. The secretory granules had diameters between 200 and 600 upsilonm. The autolysosomes were for the most part small and rare. The 20 fully granulated acidophilic adenomas could be easily recognized and are not discussed in this paper. The sparsely granulated mucoid cell-adenomas were easily identified by a positive PAS-reaction. DISCUSSION: From our studies we conclude that chromophobe adenomas exhibit only sparse granulation and no denser or fully granulated tumor cell...
Ultrastructural examination of 28 human pituitary adenomas was performed. Findings were correlated to the clinical history and light microscopic observations. As revealed by light and electron microscopy 15 adenomas were of the chromophobe type causing no endocrine dysfunction. In 8 cases acidophilic adenomas were associated with endocrine symptoms. In this group two adenomas were of the densely granulated type, whereas 6 of the sparsely granulated type. The latter showed marked ultrastructural signs of enhanced secretory activity. Five cases corresponding electronmicroscopically to sparsely granulated acidophilic adenomas but causing no endocrine symptoms constituted a separate group. They suggest the possibility of the production of abnormal proteins by this type of adenoma cells. Oncocyte cell-groups were seen in chromophobe adenomas. Morphometric data on granule size and distribution proved to be useful in the differentiation of chromophobe and acidophilic adenomas. Hypertrophic cell organelles, filamentous and tubular structures are interpreted as ultrastructural signs of cellular adaptation.
In a collection of 108 surgically removed, light and electron microscopically studied pituitary tumors, 19 adenomas (17.6%) could be found of which oncocytic tumor cells constituted more than 50%. These showed histologically, in conformity with the criteria of oncocytes, a fairly broad cytoplasm with finely granular or, in part, finely vacuolar structures and distinct cell membranes. The nuclei were predominantly round and moderately rich in chromatin but also in part, pyknotic. In paraffin-embedded sections the tumors could not be distinguished with certainty from chromophobe or moderately granulated acidophil adenomas. In plastic-embedded sections they could be identified by the typical filmy and finely granular feature of the cytoplasm which was distinctly different from conglomerations of secretory granules. Ultrastructurally they were characterized by many densely packed mitochondria. These were, in part, hydropically swollen. Furthermore, 5 tumors exhibited increased hormone-synthesizing organelles, 2 of which induced an acromegaly. Probably the oncocytic pituitary adenomas are secondarily transformed chromophobe or moderately chromophil tumors which must be regarded as independent, for the most part endocrinologically inactive pituitary tumors. In addition to these purely or almost purely oncocytic tumors further 12 adenomas (11.1%) with oncocytic parts constituting between 10 and 50% of the tissue were in our collection. Of these, 5 were moderately or distinctly acidophil adenomas with clinical symptoms of acromegaly; 2 were, for the most part, mucoid cell adenomas with Nelson's syndrome.
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A unique example of a clinically unsuspected large parasellar meningioma is described in a 36-yr-old pituitary giant who had been treated initially with conventional irradiation, subsequently by surgical excision of an acidophil adenoma, and ultimately with medroxyprogesterone acetate (MPA) prior to his demise. The patient died of increased intracranial pressure resulting from a combined mass effect of the meningioma and recurrent tumor. The relationship between radiation and the development of the meningioma is discussed, as well as the fine ultrastructure of a highly functioning acidophil adenoma.
Unusually large, oval and pleomorphic secretory granules were noted by electron microscopy in an acidophilic adenoma of the pituitary. The tumor, which was removed by surgery from a 42-year-old woman with elevated blood growth hormone levels and the clinical features of acromegaly, was found to contain growth hormone by the immunoperoxidase technique. This ultrastructural abnormality of secretory granules was not reported so far and was not seen among the 58 cases of growth hormone-producing adenomas investigated in our laboratory. The present case clearly shows that the cytogenesis and cellular composition of pituitary adenomas cannot be determined by solely examining the size and shape of secretory granules.
34 pituitary adenomas were examined by light and electron microscopical methods. Slices of tumor tissue fixed in formaldehyde or Bouin's solution, respectively, and embeded in paraffin were stained by hematoxylin-eosin, Goldner's method (including Orang G), periodic acid Schiff (PAS) reaction, and in some cases by Herlant's tetrachrom. The ultrastructure was studied using tumor tissue fixed in glutaraldehyde within 1 hour after removal. The adenomas were classified by their light microscopical characteristics as chromophilic or chromophobe tumors. Employing the PAS reaction and Goldner's staining method, 27 adenomas were found to give intense or weak staining reactions. By electron microscopical investigation , all the adenomas studied were seen to contain secretory granules more or less densely packed within the cytoplasm. The number of these granules was strongly correlated with the intensity of the tinctorial properties of the tumor tissue. Out of 11 acidophilic adenomas, 10 were observed consisting of typical STH cells. 4 acromegalic patients were found to possess heavily or poorly granulated STH cell adenomas (two patients in each of these groups). One patient with a clinical history of liver cirrhosis and gynecomastia was observed bearing an acidophilic (and erythrosinophilic) adenomatous hyperplasia of prolactin cells, 13 tumors consisted of cells exhibiting almost weak amphophilic staining properties and secretory granules of 100-250nm diameter, thus resembling cells which have been reported to produced ACTH. One of the patients suffering from these adenomas, showed the clinical signs of M. Cushing. By ultrastructural criterions, 3 adenomas with PAS-positive tumor cells were considered to be composed of gonadotropic cells. Only 7 adenomas were observed which did not give any chromophilic reaction. These tumors consisted of extreme poorly granulated cells which could not be significantly associated with one of the pituitary hormones by their morphological properties. In respect of the abundance of mitochondria, 4 out of the adenomas were designated as oncocytic tumors.
Among 87 pituitary adenomas, four neoplasms had a superficial resemblance to undifferentiated cell adenomas and some fine structural features of both sparsely granulated adenomatous growth hormone and prolactin cells. Misplaced exocytosis, fibrous bodies, and multiple centrioles were sometimes revealed within the same cell and usually were accompanied by oncocytic transformation, mitochondrial alterations, and abnormal centriologenesis. The patients had normal or low blood growth hormone levels and elevated or normal prolactin values. All the tumors that were tested contained immunoreactive growth hormone and prolactin, irrespective of the blood hormone levels. The four tumors could represent a hitherto unclassified adenoma type and derive from the common, committed precursor of the two acidophils. The term acidophil stem cell adenoma is proposed to designate this entity.
Two surgically resected pituitary adenomas that appeared to be chromophobe or poorly granulated acidophil adenomas by light microscopy were correctly identified as oncocytomas by electron microscopy. The tumor cells ahd markedly hyperplastic, moderately pleomorphic mitochondria in the cytoplasm of virtually all cells. Scattered secretory granules were displaced to the periphery of the cytoplasm but the secretion type of pituitary cell remained obscure. Histochemical and immunocytochemical methods imperfectly characterized these unusual tumors. Even though these neoplasms have been considered rare, they are now being recognized more often after ultrastructural study. Eventually their pathobiologic features may be better understood. One of our patients was 24 years old and is the youngest patient, to our knowledge, in whom a pituitary oncocytoma has been documented.
A new pituitary classification has been developed, based on the histologic, histochemical, immunocytologic and electron microscopic investigation of 207 pituitary adenomas removed surgically from male and female patients of various ages and different clinical symptomatology. Based principally on cytogenesis, the classification attempts to correlate the morphologic features of the tumor cells with their secretory activities, the clinical history, symptomatology, and biochemical findings. The classification consists of the following eight entities: 1) growth hormone cell adenoma; 2) prolactin cell adenoma; 3) mixed growth hormone cell-prolactin cell adenoma; 4) acidophil stem cell adenoma; 5) corticotroph cell adenoma; 6) thyrotroph cell adenoma; 7) gonadotroph cell adenoma; 8) undifferentiated cell adenoma, including oncocytoma. Prolactin adenomas were found to be the most frequently occurring pituitary adenoma type.
The structural features of 26 spontaneous pituitary tumors in aging female Long-Evans rats have been investigated by different morphologic techniques including immunoperoxidase staining and electron microscopy. By light microscopy, the tumors corresponded to chromophobic-sparsely granulated acidophilic adenomas, containing numerous pigment granules and showing congestion as well as focal hemorrhages. Positive cytoplasmic staining was obtained with Herlant's erythrosin as well as with Brookes' carmoisine methods, used to detect secretory granules of prolactin cells. Immunoperoxidase technique revealed the presence of immunoreactive prolactin in the cytoplasm of many adenoma cells. Growth hormone and TSH immuno-stainings were negative. By electron microscopy, the tumors were found to consist of prolactin cells exhibiting marked variability in subcellular morphology and differing considerably from non-tumorous resting prolactin cells. A decrease in size and number of secretory granules, proliferation of rough-surfaced endoplasmic reticulum, formation of "Nebenkerne", accumulation of free ribosomes, prominence of Golgi complex and the presence of misplaced exocytosis were characteristic features of the adenoma cells and were interpreted as indicating enhanced secretory activity. Crinophagy and transformation of secretory granules into pigment deposits were striking findings in many adenomas. Since all the adenomas seemed to derive from prolactin cells and belong to the same tumor class, it is assumed that prolactin cells in female Long-Evans rats are more susceptible to oncogenic stimuli than other hypophysial cell types.
During the first two years with the 160 X 160 matrix EMI scanner at Rigshospitalet, Copenhagen 108 consecutive patients referred with the suspicion of intra- or juxtasellar tumor were subjected to 166 computed tomography (CT) examinations. The X-ray attenuation and contrast enhancement patterns of the various lesions were analyzed. In general, it was difficult to correlate these parameters with the histopathological features. Arachnoid cysts, however, had typical low preinjection attenuation and no contrast enhancement. Chromophobe and eosinophilic pituitary adenomas rarely contained calcium and only in minute amounts, hardly visible on the polaroid pictures. Craniopharyngiomas and low grade suprasellar gliomas frequently contained large calcifications. Grade I gliomas, when located in the optic nerves or hypothalamus, showed significantly higher contrast enhancement than elsewhere in the brain. Three purely intrasellar adenomas were demonstrated with CT only. The diagnostic accuracy of CT was compared to that of carotid angiography, PEG and plain skull films in the lesions verified by initial operation (n = 32). CT gave the highest accuracy of the four methods, but the accuracy of CT differed statistically only from that of carotid angiography.
Tubular inclusions were present in 13 out of 43 pituitary adenomas of acromegalic patients and in a single chromophobe pituitary adenoma. There were none in 76 other pituitary adenomas with differing endocrinological symptomatology. The arrays were usually located in the perinuclear cistern of capillary endothelial cells. The tubule diameter in osmium fixed material measured 19-26 nm and the light core averaged 6-11 nm. A longitudinal period of about 4.5 nm could be demonstrated with PTA block staining. Fixation with glutaraldehyde and block staining with ethidium bromide as well as permanganate fixation followed by RNAse treatment showed only the core of the tubules consisting of globular subunits. Several histochemical reactions (perchloric acid extraction, methenamine-silver staining, trypsin and DNAse digestion of frozen sections) suggested that the particles consist of a core of DNA coated with protein. No virus multiplication could be detected in cell cultures or in mice innoculated with fresh tumor material. No significant antibody titers against several virus antigens could be demonstrated.
LH-RH tests of hypothalamo-pituitary gonadotropinfunction were performed in 26 patients with pituitary adenomata before and after prolactin suppression and/or surgical treatment. Various degrees of galactorrhea together with menstrual disorders were the key symptoms in all patients. There was a significant association of elevated prolactin levels with impaired LH-responses. Seven patients have undergone transspenoidal dissection of the pituitary adenoma and in five of them the pituitary LH-response reverted to normal (R2) after surgery. Nine of 15 amenorrhoic patients had a recurrence of menstrual cyclicity, partly biphasic within 3 months and a normalized LH-response after Bromocriptin therapy. 19 of our patients were desirous of pregnancy. Five pregnancies were confirmed within 4 months of treatment.