Relationship between natural and infection-induced antibodies in systemic autoimmune diseases (SAD): SLE, SSc and RA.

Infection or vaccine-induced T cell-dependent immune response and the subsequent high-affinity neutralizing antibody production have been extensively studied, while the connection between natural autoantibodies (nAAbs) and disease-specific antibodies has not been thoroughly investigated. Our goal was to find the relationship between immunoglobulin (Ig)M and IgG isotype nAAbs and infection or vaccine-induced and disease-related autoantibody levels in systemic autoimmune diseases (SAD). A previously described indirect enzyme-linked immunosorbent assay (ELISA) test was used for detection of IgM/IgG nAAbs against citrate synthase (anti-CS) and F4 fragment (anti-F4) of DNA topoisomerase I in 374 SAD samples, with a special focus on systemic lupus erythematosus (SLE) (n = 92), rheumatoid arthritis (n = 73) and systemic sclerosis (n = 157) disease groups. Anti-measles IgG and anti-dsDNA IgG/IgM autoantibodies were measured using commercial and in-house indirect ELISA tests. In all SAD groups the anti-measles IgG-seropositive cases showed significantly higher anti-CS IgG titers (P = 0·011). In anti-dsDNA IgG-positive SLE patients, we detected significantly higher levels of anti-CS and anti-F4 IgG nAAbs (P = 0·001 and < 0·001, respectively). Additionally, we found increased levels of IgM isotypes of anti-CS and anti-F4 nAAbs in anti-dsDNA IgM-positive SLE patients (P = 0·002 and 0·016, respectively). The association between IgG isotypes of pathogen- or autoimmune disease-related antibodies and the IgG nAAbs may underscore the immune response-inducible nature of the diseases investigated. The relationship between protective anti-dsDNA IgM and the IgM isotype of anti-F4 and anti-CS may provide immunoserological evidence for the beneficial roles of nAAbs in SLE patients.

Aging and the human pituitary gland.

Pituitary glands obtained at autopsy from 41 men (90 to 97 years old) and 45 women (90 to 98 years old) were studied histologically and immunohistochemically to determine the age-related alterations. Pituitaries from patients 30 to 39 years old (48 cases) and 60 to 89 years old (187 cases) were also studied and served as controls. Interstitial, perivascular fibrosis was seen in 88% of the aged adenohypophyses and, although significantly more intense than that in those of the fourth decade of life (P < 0.001), was similar to that noted in those of the seventh to ninth decades. Pituitaries of men were significantly more fibrotic than were those of women (P < 0.05). In proportion to the extent of fibrosis, the number of somatotrophs decreased in the lateral wings, whereas other cell types did not change quantitatively. Small deposits of amyloid and of iron were detected in seven and three cases, respectively. Squamous metaplasia in cells of the pars tuberalis was noted in 29%. The incidence of "basophil invasion" (the presence of corticotrophs in the posterior lobe) was 30%, a figure similar to that in younger controls. Granular cell tumorlets were detected in four aged neurohypophyses (5%), a frequency similar to that in control glands. Pituitary adenomas (two null cell, two lactotroph, and one corticotroph adenomas) were found of three men and two women in the study group. This 9% incidence of adenomas did not differ from that observed in the fourth decade (8%) or seventh decade (10%).(ABSTRACT TRUNCATED AT 250 WORDS)

The pituitary gland in patients with breast carcinoma: a histologic and immunocytochemical study of 125 cases.

Pituitary glands obtained at autopsy of 125 women with disseminated breast carcinoma were studied to determine whether pituitary prolactin cell abnormalities (hyperplasia or adenoma) might be involved in the pathogenesis of breast carcinoma. In addition, we studied 85 pituitary glands obtained from unselected, consecutive autopsies in women without breast carcinoma but who died of other diseases (control group). The frequency of lactotroph hyperplasia was slightly higher in patients with breast carcinoma than in the control group, but the difference was not statistically significant, nor were differences in the frequency and size of pituitary adenomas, prolactin-producing or otherwise. No correlation was found between the presence of lactotroph hyperplasia or prolactin-producing adenomas (or both) and such factors as the patient's age, bilaterality of the carcinoma, previous treatment with tamoxifen citrate or oophorectomy, stage of disease, or survival. The frequency of breast carcinoma metastatic to the pituitary gland was higher in the study group than in the control group; however, the difference was not statistically significant. No preferential site of metastatic involvement in the pituitary gland was noted. Relative proportions of other lesions such as infarcts, cysts, lymphocytic infiltrates, and basophilic invasion were similar in the study and control groups. This study indicates that accumulation of prolactin cells, whether hyperplastic or adenomatous, cannot be considered a major risk factor for the genesis or progression of breast carcinoma.

Effects of estrogen on the human pituitary: a clinicopathologic study.

Pituitary glands obtained at autopsy of 67 men treated with diethylstilbestrol were examined for diffuse and nodular lactotrophic hyperplasia as well as prolactin cell tumorlets or adenomas. A control group consisted of 42 untreated patients with prostatic carcinoma and 209 other elderly men. Diffuse and nodular lactotrophic hyperplasia and the percentage of prolactin cells were greater in treated patients, but these differences were not statistically significant. The higher frequency of prolactin cell adenomas among treated patients (19%) than among control subjects (11%) also lacked statistical significance. An apparent low frequency of occurrence of adenoma in control patients with prostatic carcinoma remains unexplained. No correlation was noted between tumor number, size, morphologic features, or immunoreactivity and such factors as dose of estrogen therapy, associated diseases, ultimate cause of death, or patient age. A correlation was noted, however, between duration of estrogen therapy and the total number of pituitary adenomas, including those composed of prolactin cells. Relative proportions of other types of adenoma were similar within the study and control groups. We conclude that estrogen medication cannot be considered a major risk factor in the cause of prolactin-producing adenomas in older men.

Anorexia nervosa: an immunohistochemical study of the pituitary gland.

The morphologic features of the anterior pituitary gland were studied by immunohistologic methods in 12 patients who had died of complications of anorexia nervosa, 4 patients who had died while on a "crash diet", 13 patients who had died of organic disease associated with inanition, and 5 age- and sex-matched control subjects who had been involved in sudden fatal accidents. All known pituitary hormones were found to be present. Abnormalities noted in both the patients with anorexia and those with organic inanition included relative hypogranulation of adrenocorticotropic and, to a lesser extent, growth hormone cells. These changes are of unknown importance but are likely the result of starvation in that they were not observed in patients on a "crash diet" or in control patients. We conclude that no specific or etiologic abnormalities are present in the pituitary glands of subjects with anorexia nervosa and that the altered secretion of adenohypophyseal hormones often noted in patients with this disorder cannot be attributed to a primary pituitary disorder.

The pituitary gland in hyperthyroidism.

The pituitary glands of 33 patients (24 women and 9 men, 18 to 78 years old) who died in thyrotoxicosis (18 with Graves' disease and 15 with toxic multinodular goiter [Plummer's disease]) were examined by histologic and immunocytologic methods. Thirteen patients (39%) died in "thyroid storm." The avidin-biotin-peroxidase complex immunostaining method was used to demonstrate the spectrum of pituitary hormones, including growth hormone, prolactin, adrenocorticotropic hormone, thyrotropin, follicle-stimulating hormone, luteinizing hormone, and alpha-subunit. The most striking finding was a pronounced decrease or loss of immunoreactivity to thyrotropin in all thyrotoxic cases, a consistent change that allowed ready distinction of thyrotoxic from euthyroid pituitary glands. When immunoreactive thyrotrophs were identified, they were sparse and small and demonstrated only faint thyrotropin reactivity. No morphologic differences were noted between the pituitary glands of patients with Graves' disease or Plummer's disease or between sexes. Loss of thyrotropin immunoreactivity was found to be reversible in that thyrotropic cells in the pituitary glands of 16 additional concurrently studied patients, who had thyrotoxicosis but were treated and subsequently had normal thyroid function or hypothyroidism, appeared normal or even hyperplastic. Other types of adenohypophysial cells in both the thyrotoxic and the successfully treated groups exhibited no abnormalities. Pituitary adenomas were incidental findings in 6 of the 33 patients (18%). Their immunotypic spectrum included three prolactin-immunoreactive tumors, two growth hormone-containing adenomas (one of which was plurihormonal), and one tumor with follicle-stimulating hormone and luteinizing hormone; no thyrotropin-containing adenomas were noted. No examples of pituitary hyperplasia were encountered in pituitary glands of thyrotoxic patients, and no hypophysitis or fibrosis was noted.(ABSTRACT TRUNCATED AT 250 WORDS)

The pituitary gland in pregnancy: a clinicopathologic and immunohistochemical study of 69 cases.

A histologic and immunocytochemical study of 69 autopsy-obtained pituitaries from women who died during pregnancy, after abortion, or in the postpartum period revealed an accumulation of large chromophobic to slightly acidophilic and periodic acid-Schiff-negative pregnancy cells that were immunoreactive for prolactin but not for other pituitary hormones. This increase in the number of prolactin cells was confirmed by cell counts. Thus, pregnancy cells are capable of prolactin production. The finding of mitotic figures in such cells supports the view that they arise by multiplication from preexisting prolactin cells. With use of "mirror section" techniques, no mammosomatotrophs (cells immunoreactive for growth hormone and prolactin) were identified. Hyperplasia of prolactin cells was evident at 1 month of pregnancy and gradually disappeared within several months after delivery or abortion; the process of involution seemed to be retarded in the one lactating patient investigated. In some pituitaries, the accumulation of prolactin cells was so extensive that the hyperplastic foci resembled microadenomas. Another striking change in the pituitaries of pregnant women was appreciable reduction of immunostaining of gonadotropic cells, a process that was reversible as soon as 1 month after delivery. Among the 69 pituitaries studied, 8 noninvasive microadenomas (12%) were encountered (7 contained prolactin only and 1 was plurihormonal). Prolactin-producing adenomas were no more numerous or larger than were similar tumors encountered in nonpregnant women or normal men; thus, pregnancy neither initiates formation of pituitary adenomas nor accelerates their growth. In the pituitaries that harbored prolactin-producing adenomas, massive pregnancy cell hyperplasia was evident outside the tumor; thus, prolactin production by adenoma cells did not seem to suppress the proliferation of prolactin-containing pregnancy cells.

The pituitary gland in the Laurence-Moon syndrome.

The apparent hypogonadism in patients with the Laurence-Moon syndrome has been variably attributed to unresponsiveness of target organs to gonadal hormones, primary end-organ failure, hypothalamic dysfunction, or pituitary failure. We report the first immunocytologic study of the pituitary gland in this rare disorder. No morphologic abnormalities were noted. The numbers and immunoreactivities of adenohypophyseal cell types were normal. No microscopic abnormalities were evident in the hypothalamus and target organs. The results of our study are consistent with recent biochemical data that suggest that pituitary function is normal in patients with this syndrome.

Antiproliferative effect of the somatostatin analogue octreotide on growth hormone-producing pituitary tumors: results of a multicenter randomized trial.

OBJECTIVE: To determine and quantify the in vivo effects of octreotide on the cell cycle kinetics of growth hormone-producing pituitary adenomas. DESIGN: A multicenter randomized trial had been conducted to assess the clinical efficacy of octreotide, and we studied tissue specimens from pituitary macroadenomas in 32 patients with acromegaly from that trial-16 of whom had received 4 months of octreotide therapy before surgical resection and 16 of whom had undergone surgical resection only. MATERIAL AND METHODS: All tumors had been fully characterized on the basis of their immunophenotypic profile and their ultrastructural morphologic features. Included were 16 densely and 16 sparsely granulated somatotroph adenomas. In each case, immunostaining for the cell cycle-specific nuclear antigen Ki-67 was performed with use of the MIB-1 antibody. The staining reaction was manually quantified, and a tumor growth fraction was derived in each case. RESULTS: The mean growth fraction of tumors exposed to octreotide was suppressed by 83% in comparison with untreated surgical controls (0.011+/-0.004% versus 0.065+/-0.016%, respectively; P = 0.0068). The association between octreotide treatment and lower tumor growth fractions was statistically independent of tumor subtype, being evident among both sparsely and densely granulated somatotroph adenomas. CONCLUSION: Octreotide exerts a significant antineoplastic effect on somatotroph adenomas, one readily reflected at the level of the cell cycle. This antiproliferative response provides insight into several clinicopathologic issues surrounding octreotide therapy for these neoplasms.

Gonadotroph adenoma of the pituitary gland: a clinicopathologic analysis of 100 cases.

OBJECTIVE: To determine the clinical and pathologic features in a large cohort of randomly selected patients with gonadotroph pituitary adenomas. DESIGN: We retrospectively reviewed clinical, surgical, and pathologic findings in 100 patients (79 men and 21 women, 30 to 82 years old) with this tumor. RESULTS: Diagnosis of a pituitary tumor was prompted by visual loss (43%), symptoms of hypopituitarism (22%), headache (8%), or a combination of these findings (10%); 17% of the patients were asymptomatic. Visual field defects were present in 68% of the study group, and complete or partial anterior pituitary failure was present in 77%. Serum prolactin concentrations were increased (maximum, 110 ng/mL) in 33% of patients. Hypersecretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) was documented in 11 and 5 patients, respectively. The serum level of alpha-subunit was increased in 1 of 29 patients in whom it was measured. All patients had pituitary macroadenomas, only 21% of which were grossly invasive. The surgical approach was transsphenoidal in all but two patients, who underwent transfrontal craniotomy; gross total tumor resection was achieved in 90%. By definition, all tumors had at least 10% immunoreactivity for LH, FSH, or both. All tumors were chromophobic. Ultrastructurally, the tumors were characterized as gonadotroph adenomas of "male" (45%) or "female" (9%) type as well as null-cell adenomas of the oncocytic (35%) or nononcocytic (11%) type. After a median follow-up of 4.3 years, 69% of the patients who had had visual field defects noted normalization or improvement. Persistent or clinically recurrent pituitary tumor tissue was present in 42%. A second pituitary surgical procedure was required in eight patients. CONCLUSION: Most patients with clinically evident gonadotroph pituitary tumors have loss of vision and hypopituitarism. Hypersecretion of FSH or LH is unusual, and no distinct hormone-dependent clinical phenotype is present. Transsphenoidal surgical treatment generally yields normalization or improvement of visual field defects.

Prolactinomas in male and female patients: a comparative clinicopathologic study.

OBJECTIVE: To explore the basis of the gender-based differences in endocrine and surgical findings in patients with prolactinoma (prolactin cell adenoma) as well as in their clinical outcome. MATERIAL AND METHODS: In young or reproductive-age female patients, older women (beyond 40 years of age), and male patients, we systematically studied the following factors: operative and endocrine features (tumor size, invasiveness, preoperative serum prolactin level, and biochemical outcome), specific biologic variables (mitotic index, MIB-1 labeling index, and p27 immunoreactivity), and hormone receptor status (estrogen and progesterone receptor proteins as well as dopamine D2 receptor messenger RNA). RESULTS: Of the various factors assessed, the preoperative prolactin level and MIB-1 labeling index were lower in young female patients in comparison with older female and particularly male patients. Hormone levels were also positively associated with mitotic activity as well as the MIB-1 labeling index. Although invasion was infrequent in microadenomas of young female patients, no statistically significant differences in tumor size or invasiveness were noted among the three patient groups. Absence of differences in invasiveness may, in part, be explained by artifacts of case selection. CONCLUSION: The basis for the observed differences in proliferative activities in tumors of the three study groups is not readily apparent but may reflect differences in the endocrine milieu or the effect of sex steroid hormone receptors, tumoral vascularity, or specific growth factors.

Pathology of invasive pituitary tumors with special reference to functional classification.

Pituitary adenomas may remain intrasellar or infiltrate dura and bone. Invasive adenomas are not considered to be malignant; in biological behavior they are between non-infiltrative adenomas and pituitary carcinomas. The latter are defined as tumors with subarachnoid, brain, or systemic metastasis. Invasion may be defined radiologically, operatively, or histologically. On the basis of operatively assessed tumor size and gross invasion of dura and bone as well as immunocytochemical and ultrastructural analysis of 365 pituitary adenomas, the following data were obtained. There were 23 growth hormone (GH)-cell adenomas: 14% microadenomas and 86% macroadenomas; their overall frequency of invasion was 50%. There were 24 prolactin (PRL)-cell adenomas: 33% microadenomas and 67% macroadenomas, with an overall frequency of invasion of 52%. Mixed GH-cell and PRL-cell adenomas were found in 35 cases; 26% were microadenomas and 74% were macroadenomas, and the overall frequency of invasion was 31%. Sixty patients had adrenocorticotropic hormone (ACTH)-cell adenomas (Cushing's disease): 87% microadenomas and 13% macroadenomas; the overall frequency of invasion was 25% (in 8% of microadenomas and 62% of macroadenomas). Twenty patients had ACTH-cell adenomas (Nelson's syndrome): 30% microadenomas and 70% macroadenomas; the overall frequency of invasion in these cases was 50% (in 17% of microadenomas and 64% of macroadenomas). Silent ACTH-cell adenomas, 100% macroadenomas, were found in 11 patients, with an 82% frequency of invasion. There were 32 follicle-stimulating and luteinizing hormone adenomas, all macroadenomas, with a frequency of invasion of 21%. Four patients had thyroid-stimulating hormone adenomas, all macroadenomas, with a 75% frequency of invasion. Null-cell adenomas were found in 93 cases: 2% microadenomas and 98% macroadenomas, with a frequency of invasion of 42%. There were 63 plurihormonal adenomas (GH, PRL, glycoprotein): 25% microadenomas and 75% macroadenomas, with a 50% overall frequency of invasion. Based on this study, and on their usual frequency of occurrence, the estimated rate of gross invasion by pituitary adenomas of all types is approximately 35%. It is concluded that immunocytochemical and ultrastructural characteristics of pituitary adenomas reflect the tendency of these tumors to infiltrate and hence may be of prognostic significance.

Combined thyrotroph and lactotroph cell hyperplasia simulating prolactin-secreting pituitary adenoma in long-standing primary hypothyroidism.

Primary hypothyroidism accompanies more than 50% of clinically significant pituitary thyrotroph adenomas. Hypothyroidism may also produce pituitary enlargement secondary to thyrotroph hyperplasia and present with a sellar mass and hyperprolactinemia. Three hypothyroid patients who presented with presumed prolactin-producing adenomas are reported. Although laboratory and radiologic abnormalities of pituitary enlargement may resolve after corrective thyroid therapy, our patients showed no such response and underwent operation. Histologic examination revealed no adenomas, but thyrotroph and lactotroph hyperplasia were present. Thyrotroph hyperplasia probably results from lack of negative feedback of thyroid hormone upon the anterior pituitary. Whether this is due to hypothalamic release of thyrotropin-releasing hormone (TRH) or another mechanism is unclear. Lactotroph hyperplasia may result from excess TRH, which stimulates lactotrophs with resultant hyperprolactinemia, or from reduced hypothalamic dopamine, thereby facilitating prolactin secretion. This study suggest that (a) hyperprolactinemia in hypothyroidism is not necessarily due to the "stalk section effect" secondary to pituitary enlargement, and (b) patients with primary hypothyroidism and sellar mass should initially be managed medically so that potentially reversible pituitary hyperplasia is not mistaken for adenoma.

Molecular pathogenesis of pituitary adenomas: a review.

Modern theory of tumorigenesis suggests that genetic alterations may play a role in the initiation and promotion of pituitary adenomas. Gsp and MEN-1 genes play a role in the initiation event, while p53, ras, Rb and nm23 genes play some role in the progression of the tumor. Gsp gene, that may play an important role in 40% of GH-producing tumor, activation of 10% of non-functioning tumors and 6% of corticotroph adenomas, produces cAMP, which stimulates cyclin D1 and D3 which later produce cdk2 and cdk4 respectively, and stimulates cell progression from G1 to S phase. cAMP also induces ras gene, which inhibits binding of pRb with E2F that is necessary to prevent action of E2F in accelerating cell cycle. MEN-1 gene, although found in some sporadic tumors, is more likely associated with familial adenoma. p53, Ras, Rb, nm23 and c-myc genes play some role in the promotion of tumors especially toward their aggressive variant. p53 gene, which is found in up to 60% of ACTH producing adenomas, through action of p21 inhibits progression of cell cycle from G1 to S phase, by inhibiting the action of cyclin D3 on cdk4. Ras oncogene, in cooperation with c-myc gene, prevents the binding of pRb with E2F, which is necessary for preventing progression cell cycle, resulting in progression of cell cycle from G1 to S phase. Nm23 gene inhibits the action of cyclin B and arrests the cell in G2 phase. Further studies will not only be helpful in understanding the genetic pathogenesis and prognosis of pituitary tumors, but also in developing a novel treatment for patients with pituitary adenomas.

Prolactin cell carcinoma of the pituitary. Clinicopathologic, immunohistochemical, and ultrastructural study of a case with cranial and extracranial metastases.

A patient with a primary adenohypophyseal neoplasm who had a long course marked by multiple surgical resections, radiation therapy, and high-dose dopamine agonist therapy developed local invasion as well as cranial and extracranial osseous metastatic lesions. The serum prolactin levels were greatly elevated, and immunohistochemical studies demonstrated prolactin in the cytoplasm of primary and metastatic tumor cells. Ultrastructural features of lactotrophic differentiation, including misplaced granule exocytosis, were observed. This is the third reported case of prolactin cell carcinoma that metastasized despite high-dose dopamine agonist therapy. Analysis of the patient's serum prolactin showed no abnormality in the chromatographic profile of biologic activity.

Macroorchidism and testicular fibrosis associated with autoimmune thyroiditis.

A 16-year-old male with long-standing atrophic chronic lymphocytic thyroiditis was evaluated for macroorchidism. A testicular biopsy prior to treatment revealed peritubular and interstitial fibrosis, reduced spermatogenesis and sparse Leydig cells with nonprominent smooth endoplasmic reticulum. Biological/immunological LH and FSH ratios were reduced, I-LH and FSH response to GnRH was blunted, and levels of testosterone and androstenedione were low. Twenty-two months after thyroid treatment, the testicular size was unchanged, and the degree of fibrosis showed minimal regression. Spermatogenesis with normal morphology was present, Leydig cells with Reinke crystals were present, and surface area and diameter of the seminiferous tubules had increased only slightly. There was a normal I-LH and FSH response to GnRH, and normal levels of testosterone and androstenedione. This study, along with previous reports, suggests that the etiology of the hypothyroid state may influence the development of testicular fibrosis.

Pituitary carcinoma: a clinicopathologic study of 15 cases.

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 primary tumors. The current definition of pituitary carcinoma requires the demonstration of metastasis; however, high mitotic and MIB-1 labeling indices as well as p53 immunoreactivity suggest the diagnosis and appear to be of prognostic significance. A redefinition of aggressive pituitary tumors is proposed--one that facilitates the recognition of tumors prone to metastasis.