Raymond V. Randall

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 patients serum prolactin showed no abnormality in the chromatographic profile of biologic activity.

Pituitary Adenomas Producing Growth Hormone, Prolactin, and One or More Glycoprotein Hormones: A Histologic, Immunohistochemical, and Ultrastructural Study of Four Surgically Removed Tumors

The morphologic features of four pituitary adenomas, removed from 2 men and 2 women between 31 and 62 years of age, are reported. The tumors contained growth hormone (GH), prolactin (PRL), and one or more glycoprotein hormones--usually thyrotropin (TSH). Three tumors were associated with acromegaly and one with hyperprolactinemia. Hyperthyroidism was not evident in any of the patients. In the tumors of acromegalic subjects, GH-containing cells were the most numerous, whereas PRL cells were dominant in the adenoma accompanied by hyperprolactinemia. Electron microscopy revealed plurimorphous tumors comprised of various proportions of morphologically different cell types: densely granulated GH cells, TSH-like cells, and the less common mammosomatotrophs and PRL cells. It is suggested that pituitary adenomas producing GH, PRL, and glycoprotein hormones derive from the same precursor; their immunocytochemical profile, fine structural appearance, and endocrine function may depend on the degree and direction of the cellular differentiation.

Hypothalamic neuronal hamartoma and adenohypophyseal neuronal choristoma: their association with growth hormone adenoma of the pituitary gland.

Hypothalamic neuronal hamartomas and neuronal choristomas of the anterior pituitary are rare lesions; either may be associated with endocrinopathy. We describe a case of each with associated growth hormone-producing pituitary adenomas and clinical acromegaly, both well documented and studied by immunocyto-chemistry and electron microscopy. That a functional relationship exists between the neuronal malformation and the pituitary neoplasm remains speculative. We suggest that a growth hormone-releasing factor-like substance may have been elaborated by hypothalamic-type neurons, which, by a trophic effect, may have resulted in the production of an adenohypophyseal neoplasm. Our study supports the concept that secretory neurons, either outside or within the sella, may induce adenomas.

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.

Pituitary Adenomas Associated With Hyperprolactinemia: A Clinical and Immunohistochemical Study of 97 Patients Operated on Transsphenoidally

Immunohistochemical studies were performed on the tumors of 97 of 100 patients who had undergone an operation for a presumed prolactin-secreting pituitary adenoma; no tissue was available for study in the other 3 patients. Appropriate immunohistochemical studies were done to identify the presence of growth hormone, prolactin, adrenocorticotropic hormone, luteinizing hormone, follicle-stimulating hormone, and thyroid-stimulating hormone within the adenoma cells. The presence of a prolactin-producing pituitary adenoma was confirmed in 91 patients, 3 of whom had an adenoma that consisted of cells that contained prolactin and growth hormone. One other patient, not counted among the 91 with prolactinoma, had lactotrope and thyrotrope hyperplasia. Among the five patients whose adenoma did not contain prolactin cells, four had a null cell adenoma and one had a tumor consisting of follicle-stimulating hormone and luteinizing hormone immunoreactive cells. On the basis of preoperative serum prolactin values in these patients, we concluded that moderately increased values (30 to 200 ng/ml) of serum prolactin are not a reliable guide for determining whether a prolactin-producing pituitary adenoma is present, whereas levels exceeding 200 ng/ml are usually associated with a prolactin-secreting tumor.

10 Pathology of excessive production of growth hormone

Summary Since its clinical description in the last century, much progress has been made in our understanding of acromegaly. From an initial description of pituitary enlargement as just another manifestation of generalized visceromegaly, the pituitary abnormality has come to be recognized, in most instances, as the underlying aetiological factor. Gigantism and acromegaly are manifestations of disordered pituitary physiology, but the lesion responsible may be hypothalamic, adenohypophyseal or ectopic in location. The best known pathological hypothalamic basis for acromegaly is represented by a neuronal malformation or ‘gangliocytoma’. It usually takes the form of an intrasellar gangliocytoma or, more rarely, a hypothalamic hamartoma. The neuronal elaboration of GHRH may play a role in the development of a growth hormone adenoma; the pituitary process may pass through an intermediate stage of somatotropic hyperplasia. When acromegaly has its basis in a pituitary abnormality, the lesion is almost exclusively an adenoma; the non-tumorous adenohypophysis shows no evidence of coexistent hyperplasia. Surprisingly, such tumours are more often engaged in the formation of multiple hormones rather than GH alone. They frequently produce not only GH and prolactin, the products characteristic of cells of the acidophil line, but also glycoprotein hormones, usually TSH. The spectrum of adenomas also varies in its degree of differentiation from a histogenetically primitive lesion, the acidophil stem cell adenoma, to well-differentiated tumours of varying cellular composition and hormone content. Each adenoma type has its clinicopathological, histochemical, immunocytological and ultrastructural characteristics. The isolation and characterization of GHRH has permitted the identification of neuroendocrine tumours, most of foregut origin, elaborating this releasing hormone. Such functional tumours induce hyperplasia of pituitary somatotrophs and may, on occasion, result in the formation of growth hormone adenomas. Resection of these GHRH-producing neoplasms results in reversal of endocrinological and sellar abnormalities. Future efforts should be directed toward the elucidation of the aetiology of pituitary adenomas, specifically whether they represent a proliferative a hypothalamic abnormality, or whether it has a ‘de novo’ origin in the ‘usual process of neoplastic transformation’.

Treatment of Wilson's disease (hepatolenticular degeneration) with DL‐penicillamine

SINCE IT HAS BEEN THOUGHT that the abnormal accumulation of copper in the liver, brain, and kidneys might account for the symptoms and clinical findings in Wilson’s disease, it was only logical that treatment was designed with the aim of increasing the excretion of copper from the body. McCance and Widdowson,’ in 1946, and Mandelbrote and associates,” in 1948, had demonstrated that the administration of dimercaprol (BAL) could produce an increased urinary excretion of copper. This led Cumings? to report the use of BAL in the treatment of Wilson’s disease. Denny-Brown and Porter‘ also reported their experience with the use of BAL in the treatment of this condition. Because of several disadvantages of BAL, a search has been made for other preparations that might increase the urinary excretion of copper and have the advantages of oral administration and little or no toxicity. In 1956, Walshes reported the use of p, p-dimethylcysteine ( penicillamine) in hepatolenticular degeneration, demonstrating that it appeared to be superior to BAL in promoting the urinary excretion of copper. In 1958, Fister, Boulding, and Bakers reported the results of treatment with penicillamine over a period of nine months. Seven, Kliman, and Peterson,’ in 1959, recorded their experience in the treatment of 2 patients with penicillamine for ten months. Osbom and Walshea compared the effect of penicillamine and BAL on the turnover of copper in hepatolenticular degeneration. Walshe# recently reviewed the experience of 16 medical centers involving the treatment of 22 patients with penicillamine over periods ranging from four weeks to three years. In most of these patients, penicillamine proved better than BAL in promoting the urinary excretion of copper and in producing clinical improvement. However, 3 patients showed either no improvement or actual worsening of the clinical state despite a satisfactory increase in the urinary excretion of copper. Lange and Hagerlo reported on the treatment of 3 patients, plus 1 patient in whom the condition was “preclinical,” but their patients

Long-Term Results of Transsphenoidal Surgery for the Management of Acromegaly

Although acromegaly as a medical entity was described as early as 1779, it was 100 years ago in 1886 that the French neurologist Pierre Marie (1) coined the term, acromegaly, and presented the clinical details of two cases. Considerable interest in acromegaly rapidly evolved, but the pathophysiology and etiology of the disorder was not at all clear to the initial investigators. Minkowski in 1887 and subsequently Marie and Marinesco (2) all noted that enlargement of the pituitary was a constant feature in autopsied cases of acromegaly, but this was thought by some to be merely part of a generalized process resulting in hypertrophy of various glands. By 1900 pathophysiologic correlations suggested an etiologic role for pituitary hypertrophy or neoplasia, and Dean Lewis in 1905 (3) propagated the concept among the surgical community.

Primary amenorrhea and pituitary adenomas

From 1972 to 1980, 210 patients underwent transsphenoidal operation for removal of a prolactin-secreting tumor. Eight of the patients had primary amenorrhea. All eight patients had had a normal thelarche and pubarche without menarche, and all eight had hyperprolactinemia and abnormal findings on sella turcica tomography. After operation, only one patient did not have persistent hyperprolactinemia, and this patient was the only one who began spontaneous menses. The data indicate that although prolactin hypersecretion interferes with menstrual function, it does not alter other pubertal development and that, if the source of the excessive prolactin can be removed, the removal alone may initiate spontaneous menses. In this report, however, patients with prolactin-secreting adenomas and primary amenorrhea had a high incidence of persistent hyperprolactinemia after operation (seven of eight patients).

Lupus Erythematosus and Hashimoto's Thyroiditis

The possibility of a significant association between Hashimotos thyroiditis and systemic lupus erythematosus is of considerable interest. Two cases of coexisting Hashimotos thyroiditis proved by biopsy and systemic lupus erythematosus proved by the clinical picture and positive lupus erythematosus clot tests contribute to accumulating evidence suggesting such an association.