Although histologically benign, one-third of all pituitary tumors will be invasive of surrounding structures. In this study, the relationship between the proliferative activity in pituitary adenomas and their invasiveness was investigated. Invasion was defined as gross, operatively or radiologically apparent infiltration of dura or bone. Using the recently developed MIB-1 monoclonal antibody, which recognizes the Ki-67 cell cycle-specific nuclear antigen, the growth fractions of 37 noninvasive adenomas, 33 invasive adenomas, and 7 primary pituitary carcinomas were determined. All tumors were fully classified by histology, immunohistochemistry, and electron microscopy. The mean Ki-67 -derived growth fractions for noninvasive adenomas, invasive adenomas, and pituitary carcinomas were 1.37 +/- 0.15%, 4.66 +/- 0.57%, and 11.91 +/- 3.41%, respectively (mean +/- standard error of the mean). An analysis of variance and then individual pairwise comparisons confirmed significant differences in the mean Ki-67 labeling index between each of the three tumor groups (P < 0.01). The mean growth fraction of hormonally active pituitary adenomas (3.25 +/- 0.26%) was significantly higher than that for nonfunctioning adenomas (2.06 +/- 0.23%) (P = 0.03). Establishing a threshold labeling index of 3% served to distinguish invasive from noninvasive adenomas with 97% specificity and 73% sensitivity and was associated with positive and negative predictive values of 96 and 80%, respectively. Although invasive pituitary tumors exhibited significantly higher growth fractions than did noninvasive tumors, there were individual exceptions, indicating that in a subpopulation of invasive pituitary tumors, factors other than proliferative activity determine invasive potential.

This report describes the clinicopathological features of 16 patients with lymphocytic hypophysitis and compares the results with the published literature. There were 2 males and 14 females in this series. In 10 of the 14 females (71%), the presentation was associated with pregnancy. Nine patients (56%) presented with symptoms of an expanding pituitary sellar mass, 10 (63%) had anterior pituitary hypofunction, 3 had diabetes insipidus (19%). Progressive undiagnosed hypopituitarism led to the demise of 3 patients (19%). Hyperprolactinemia was encountered in 6 patients (38%), and elevated growth hormone levels (GH) resulted in IGF-1 excess in one patient. Computed tomography (CT) and magnetic resonance (MR) imaging revealed features of a pituitary mass mimicking an adenoma in 10 cases (83%). Four patients (25%) had associated autoimmune thyroiditis. Morphologic examination of the pituitary and immunohistochemistry showed a polyclonal lymphoplasmacytic infiltrate as well as occasional neutrophils, eosinophils, and macrophages; the chronic inflammatory process resulted in focal or diffuse adenohypophysial destruction of variable severity with associated fibrosis. The inflammatory infiltrate involved the neurohypophysis in 2 cases and one of these patients had diabetes insipidus; the posterior lobe of two other patients with diabetes insipidus was not examined morphologically. We conclude that lymphocytic hypophysitis should be considered in the differential diagnosis of females with pituitary enlargement presenting in the peripartum period as well as those patients in whom pituitary hormone deficiency and/or excess is noted in association with a co-existing autoimmune disorder. This clinical suspicion should probably also be extended to include patients presenting with rapidly growing pituitary masses associated with compressive symptoms with or without pituitary hormone dysfunction. Because of the transient endocrine and compressive features of this condition in many instances, conservative treatment on the basis of clinical suspicion alone may obviate the need for aggressive pituitary surgery.

Only trends toward differences were noted between Cushing's versus Nelson's adenomas and between prolactinomas of reproductive female patients versus those of menopausal female patients and male patients. Too few "atypical adenomas" were encountered to permit their comparison with premetastatic tumors, but our results suggest that most pituitary carcinomas arise by malignant transformation from adenomas.

Individuals harboring germ-line DICER1 mutations are predisposed to a rare cancer syndrome, the DICER1 Syndrome or pleuropulmonary blastoma-familial tumor and dysplasia syndrome [online Mendelian inheritance in man (OMIM) #601200]. In addition, specific somatic mutations in the DICER1 RNase III catalytic domain have been identified in several DICER1-associated tumor types. Pituitary blastoma (PitB) was identified as a distinct entity in 2008, and is a very rare, potentially lethal early childhood tumor of the pituitary gland. Since the discovery by our team of an inherited mutation in DICER1 in a child with PitB in 2011, we have identified 12 additional PitB cases. We aimed to determine the contribution of germ-line and somatic DICER1 mutations to PitB. We hypothesized that PitB is a pathognomonic feature of a germ-line DICER1 mutation and that each PitB will harbor a second somatic mutation in DICER1. Lymphocyte or saliva DNA samples ascertained from ten infants with PitB were screened and nine were found to harbor a heterozygous germ-line DICER1 mutation. We identified additional DICER1 mutations in nine of ten tested PitB tumor samples, eight of which were confirmed to be somatic in origin. Seven of these mutations occurred within the RNase IIIb catalytic domain, a domain essential to the generation of 5p miRNAs from the 5′ arm of miRNA-precursors. Germ-line DICER1 mutations are a major contributor to PitB. Second somatic DICER1 “hits” occurring within the RNase IIIb domain also appear to be critical in PitB pathogenesis.

We describe five primary tumors of the adenohypophysis featuring mitochondrion-rich spindle cells. The patient ages ranged from 53 to 71 years (mean 61.6 years); two were female. All presented with panhypopituitarism. Two also had visual field defect. On neuroimaging all tumors showed suprasellar extension and were indistinguishable from pituitary adenoma. None showed imaging or operative evidence of dural involvement. All were gross totally removed: four by transsphenoidal surgery and one by frontal craniotomy. Follow-up ranged from 2 to 68 months (mean 35.4 months). No recurrences were noted. The clinical workup was noncontributory in all but two patients: one (case no. 4) with an oncocytic thyroid adenoma and another (case no. 5) with squamous carcinoma of both the uterine cervix and of vocal cord. Histologically, the five tumors were composed mainly of fascicles of spindle cells with eosinophilic, granular cytoplasm. Mitoses were rare and necrosis was absent. Neoplastic cells were immunoreactive for vimentin, epithelial membrane antigen, S-100 protein, and galectin-3. Stains for pituitary hormones, synaptophysin, chromogranin, glial fibrillary acidic protein, cytokeratin CAM5.2, smooth muscle actin, CD34, and CD68 were negative. No thyroglobulin immunoreactivity was noted in the tumor of case no. 4. Ultrastructurally, the neoplastic cells contained numerous mitochondria with lamellar cristae. The neoplastic cells were linked by intermediate junctions and desmosomes. No secretory granules were noted. The histologic, immunohistochemical, and fine structural features of these tumors were unlike those of pituitary adenoma or any other primary sellar tumor. A derivation from adenohypophyseal folliculostellate cells is suggested.

No abstract

Tumor growth depends on several factors, including angiogenesis. Tumors cannot grow if new vessels are not formed to supply the cells with oxygen and other nutrients and to remove waste products. Increased angiogenesis can be correlated with tumor growth and metastatic potential in many tumor types, indicating that neoformation of vessels is a prognostic indicator of tumor behavior. We evaluated microvessel densities in 157 various pituitary adenoma types and seven pituitary carcinomas using immunocytochemistry for CD-34 antigen, a reliable marker of endothelial cells. The lowest percentage of microvessel density was found in growth hormone-producing adenomas, the highest level in pituitary carcinomas. In general, no major correlation was found between MIB-1 index (an indicator of cell proliferation) and microvessel density. The statistical study also demonstrated no gender-dependent changes in the microvessel density of pituitary tumors. Although the microvessel density was not significantly different in relation to invasiveness of pituitary tumors, our results demonstrate a tendency of invasive pituitary tumors to be more highly vascularized than non-invasive ones. Dopamine agonist and long-acting somatostatin analog treatment compared with untreated tumors did not significantly affect microvessel densities. Statistical differences were demonstrated in the microvessel density of macroadenomas between patients older and patients younger than 40 years. Significant differences were also apparent in the microvessel densities between microadenomas and macroadenomas diagnosed in young patients but not in the older age group. The strongly positive correlation observed between microvessel density and age is consistent with the view that age of the host may have an influence on the extent of neovascularization of pituitary adenomas.

BACKGROUND Pituitary carcinomas are rare adenohypophysial neoplasms, the definition, diagnosis, therapy, and prognosis of which are controversial. METHODS Pituitary carcinomas were defined as primary adenohypophysial neoplasms with documented craniospinal and/or systemic metastases. The authors report a clinicopathologic study of 15 examples examined by light microscopy, immunohistochemistry, and image analysis. Both proliferative activity and p53 tumor suppressor gene expression were studied. RESULTS The study group consisted of 15 patients, including 8 males and 7 females ranging in age from 34‐71 years (mean, 56 years). Of these patients, seven had adrenocorticotropic hormone (ACTH)‐producing tumors (four in the context of Nelson's syndrome), seven had prolactin‐producing tumors, and one had a nonfunctioning tumor. No evidence of diabetes insipidus was seen in any case. Fourteen tumors were initially considered macroadenomas. Of the ten cases for whom tumor extent was known, all had invasive tumors. The interval from the initial diagnosis of adenoma to that of carcinoma ranged from 0.3 to 18.0 years (mean, 6.6 years; median, 5.0 years); the longest mean interval (15.3 years) occurred for patients with Nelson's syndrome. The latency was twice as long for ACTH‐producing tumors as for prolactin (PRL) cell tumors (9.5 vs. 4.7 years). All carcinomas showed a greater tendency toward systemic metastasis than craniospinal metastasis; the rate of systemic metastasis was 71% for PRL cell tumors and 57% for ACTH‐producing tumors. Thirteen percent of tumors showed both patterns of metastasis. Fully 50% of primary tumors and the majority of metastases showed nuclear pleomorphism and/or hyperchromasia. The mean mitotic, MIB‐1, and proliferating cell nuclear antigen indices for primary tumors and metastases were as follows: 2/10 high‐power field (hpf), 2.6% and 11%, respectively; 6/10 hpf, 7.8% and 16%, respectively. Staining for p53 protein was noted in 57% of primary tumors and 88% of metastatic tumors; a relative increase in p53 expression in metastases was noted in 83%. All but one of the primary and metastatic tumors were aneuploid. The most common treatments were radiation therapy and, for PRL cell carcinomas, dopamine agonist administration. Both treatments provided only palliation. Eighty percent of the patients died of metastatic disease 7 days to 8 years after the diagnosis of carcinoma; of these, 66% died within 1 year. At last follow‐up, 20% of patients were alive with metastases 9‐18 months after diagnosis. CONCLUSIONS Nearly all pituitary carcinomas present as functioning, microscopically atypical or mitotically active, invasive macroadenomas. By definition, after an interval related to their immunotype, all metastasize. The tumors show a greater tendency toward systemic metastasis than craniospinal metastasis and are associated with poor prognosis. Radiation and dopamine agonist therapy generally provide only palliation. Proliferation indices and p53 expression tend to be higher in metastases than in ...