Etienne Delgrange

Clinical and histological correlations in prolactinomas, with special reference to bromocriptine resistance.

SummaryBackground. Prolactinomas usually exhibit a benign course and can be safely and effectively managed by dopamine agonists (DA). However, some are locally invasive and may show resistance to DA therapy, and the management of such cases remains controversial. The aim of the present study was to determine whether histological features and markers of cell proliferation correlated to the clinical behaviour of prolactinomas and with DA resistance.Method. This retrospective study included 74 cases (36 men and 38 women) who had monohormonal prolactinomas removed by transsphenoidal surgery. The prolactinomas were categorized on the basis of tumour size (48 macroadenomas), invasion of the cavernous sinus (n = 31), and resistance to bromocriptine (BRC) therapy (n = 14). Group 1 consisted of non-invasive microprolactinomas (n = 24), group 2 of non-invasive macroprolactinomas (n = 19), group 3 of invasive non-BRC-resistant tumours (n = 19), and group 4 of invasive BRC-resistant tumours (n = 12). The later group included one case of carcinoma with bone and lung metastases. Seven additional parameters were studied, these being age, sex, basal prolactin (PRL) levels, the Ki-67 and PCNA labelling indices (LI), mitotic count, and cellular atypia.Findings. Age and preoperative PRL levels did not correlate to the histological parameters studied. Tumour size and invasion were related to cellular atypia and the Ki-67 LI. BRC-resistant tumours were more frequently invasive (12/14) than BRC-responsive tumours (11/30; p = 0.002) and were more frequent in men than in women (33 versus 5%; p = 0.003). BRC-resistant tumours had a higher Ki-67 LI and mitotic count (4.2±2.0% and 4±1, respectively) than other tumours (0.7±0.2% and 1±0, respectively; p<0.05). The strongest correlations with tumoural staging were seen with male sex and high mitotic activity. Six out of the 12 invasive BRC-resistant macroprolactinomas, including the PRL secreting carcinoma, exhibited histological features of aggressiveness (a mitotic count ≥3 [i.e. in the fourth quartile] and/or a high Ki-67 LI and cellular atypia).Conclusions. In this surgical retrospective series, histological signs of aggressiveness are present in 50% of invasive and BRC-resistant prolactinomas, which are more frequent in men than in women. This fits with the behaviour of BRC-resistant prolactinomas, which can continue to grow despite DA treatment. These findings justify the long-term follow up of these tumours, and the use of surgery and/or radiotherapy if there is concern about the control of tumour growth.

From pituitary adenoma to pituitary neuroendocrine tumor (PitNET): an International Pituitary Pathology Club proposal

The classification of neoplasms of adenohypophysial cells is misleading because of the simplistic distinction between adenoma and carcinoma, based solely on metastatic spread and the poor reproducibility and predictive value of the definition of atypical adenomas based on the detection of mitoses or expression of Ki-67 or p53. In addition, the current classification of neoplasms of the anterior pituitary does not accurately reflect the clinical spectrum of behavior. Invasion and regrowth of proliferative lesions and persistence of hormone hypersecretion cause significant morbidity and mortality. We propose a new terminology, pituitary neuroendocrine tumor (PitNET), which is consistent with that used for other neuroendocrine neoplasms and which recognizes the highly variable impact of these tumors on patients.

Late development of resistance to bromocriptine in a patient with macroprolactinoma.

We report the case of a man with an invasive macroprolactinoma who developed resistance to bromocriptine to which he had previously responded satisfactorily for 5 years. Subsequently, hyperprolactinemia was controlled equally well with 600 µg quinagolide daily and later with 4.5 mg cabergoline weekly. This observation suggests that a loss of dopamine receptors at the tumoral cell surface might be the mechanism underlying acquired resistance to bromocriptine. In addition, no tumor growth was observed over a 10-year follow-up, which virtually excludes a malignant transformation of the prolactinoma. This case emphasizes the need for close supervision of patients with macroprolactinoma, even after the serum prolactin concentration has been normalized by bromocriptine. It furthermore illustrates the usefulness of quinagolide and cabergoline when resistance to bromocriptine develops after a prolonged period of adequate response to this drug.

Influence of parasellar extension of macroprolactinomas defined by magnetic resonance imaging on their responsiveness to dopamine agonist therapy

Objective and Design  The resistance of macroprolactinomas to dopamine agonist (DA) therapy, whether defined as an absence of PRL normalization or the lack of significant tumour shrinkage after prolonged treatment at high doses, is usually regarded as unpredictable. The aim of this retrospective study, conducted in a teaching hospital, was to determine whether cavernous sinus (CS) invasion assessed by magnetic resonance imaging (MRI) is associated with a higher rate of resistance to DA therapy.

Expression of estrogen receptor alpha is associated with prolactin pituitary tumor prognosis and supports the sex-related difference in tumor growth

CONTEXT A sex difference in the progression of prolactin (PRL) tumors has been disputed for years. OBJECTIVE To compare tumor characteristics and postoperative clinical course between men and women, and correlate data with estrogen receptor alpha (ERα (ESR1)) expression status. DESIGN, PATIENTS, AND METHODS Eighty-nine patients (59 women and 30 men) operated on for a prolactinoma and followed for at least 5 years were selected. Tumors were classified into five grades according to their size, invasion, and proliferation characteristics. The ERα expression was detected by immunohistochemistry and a score (0-12) calculated as the product of the percentage of positive nuclei and the staining intensity. RESULTS We found a significant preponderance of high-grade tumors among men and a lower surgical cure rate in men (23%) than in women (71%). Patients resistant to medical treatment were mainly men (7/8), six of whom showed tumor progression despite postoperative medical treatment, which led to multiple therapies and eventually death in three. The median score for ERα expression was 1 in men (range, 0-8) and 8 in women (range, 0-12) (P<0.0001). The expression of ERα was inversely correlated with tumor size (r=-0.59; P<0.0001) and proliferative activity. All dopamine agonist-resistant tumors and all grade 2b (invasive and proliferative) tumors (from ten men and four women) were characterized by low ERα expression. CONCLUSIONS PRL tumors in men are characterized by lower ERα expression, which is related to higher tumor grades, resistance to treatment, and an overall worse prognosis.

MINOR ALTERATIONS IN THYROID – FUNCTION TESTS ASSOCIATED WITH DIABETES MELLITUS AND OBESITY IN OUTPATIENTS WITHOUT KNOWN THYROID ILLNESS

Abstract Thyroid function tests might be affected by diabetes and obesity. To evaluate the influence of these parameters in routine conditions, 72 diabetic and 53 non-diabetic outpatients without known thyroid diseases or severe chronic illness were recruited over a 7 – month period. For each patient, dosages of thyrotropin (TSH), total and free thyroxine (TT4 and FT4, respectively), total and free triiodothyronine (TT3 and FT3) and T3 resin uptake (T3RU) were performed by radioimmunoassays. The simultaneous influence of various parameters known to affect thyroid-function tests was evaluated by multivariate linear regression. The studied variables included gender, age, glucosteroids, estrogens, tobacco habits, iodine contacts, body mass index (BMI) and diabetes mellitus. Tobacco habits and iodine contacts did not influence any tests. As expected, estrogens induced an increase in TT4 and TT3 values (p<0.001 and 0.020, respectively) associated with a decrease in T3RU (p<0.001). Consequently, females had lower T3RU than males (p<0.0001). Corticotherapy was associated with decreased TSH values (p=0.022). TT3 and FT3 decreased with age (p<0.001), whereas T3RU and FT4 increased (p=0.020 and 0.004, respectively). In contrast to an increase in TSH (p=0.006), TT4 and FT4 decreased at higher BMI levels (p=0.018 and 0.004, respectively), which is consistent with subclinical hypothyroidism. In diabetic patients, TSH was lower than in non-diabetic subjects (p=0.039). Thus, the present study indicates that besides known parameters such as age and drugs, thyroid-function tests can also be altered by diabetes mellitus and obesity.

Diabetic muscle infarction: a difficult diagnosis suggested by magnetic resonance imaging

Panhypopituitarism, sensoneurinal defness and Noonan´s syndrome in a child of a diabetic mother. The role of maternal hypoglycaemia during pregnancy for the inducation of congenital lesions

Ingestion of antacid tablets (Rennie) and acute confusion.

The authors describe a case of milk-alkali syndrome in a man who consumed antacid tablets (Rennie) for chronic epigastric pain. Simultaneous occurrence of hypercalcemia, metabolic alkalosis, and renal insufficiency, in conjunction with the appropriate history of ingestion of calcium carbonate-containing antacids, was suggestive of the syndrome. The syndrome became uncommon with the advent of modern ulcer therapy, but currently is increasing in frequency with the calcium supplementation drugs taken to prevent osteoporosis. This syndrome may produce life-threatening hypercalcemia.

Hantavirus infections: clinical presentation in the emergency room.

We present a retrospective review of Hantavirus infection in the emergency department. Thirteen cases of Hantavirus infections with renal syndrome from July 1989 to August 1999 were analysed. The diagnosis was confirmed by detection of Hantavirus antibodies in all cases. Fever, chills and headaches were universally present. Intense back pain was associated in 77% of the patients. Thrombocytopenia, abnormal urinalysis, hypertransaminasaemia, increased lactate dehydrogenase were the principal biological patterns. All these parameters returned to their normal level, and all the patients recovered a normal renal function without sequels. The management is supportive. Only one patient in our series had to be dialysed. Hantavirus disease should be included in the differential diagnosis of acute renal failure with thrombocytopenia, particularly in patients with suspected exposure in known endemic areas. The differential diagnosis of any perplexing case of undifferentiated febrile illness with acute renal failure and thrombocytopenia should include Hantavirus infection.

Influence of age on the clinical presentation of prolactinomas in male patients.

Objective: Secreting pituitary adenomas are usually not considered a disease of older people. However, in male patients, prolactin-secreting pituitary tumours occur at a similar frequency throughout the entire life span, giving the opportunity to study in this gender the influence of age on the clinical presentation and response to treatment of these tumours. Methods: We conducted a retrospective study including 9 male patients aged ≥60 (range 60–73) years and 10 aged ≤30 (range 17–30) years presenting with a prolactinoma in order to compare clinical presentation, results of pituitary function tests, and response to dopamine agonist therapy between older and younger patients. Results: Four of the 9 elderly as well as the 10 younger patients came to medical attention for typical features of male prolactinomas including visual field defect in 5 (2 elderly), headaches in 2 (1 elderly), impotence in 3 (1 elderly), gynaecomastia and/or galactorrhoea in 2, and arrested puberty in 2. The remaining 5 older people presented for other various reasons: symptoms related to cortisol deficiency in 2, lethargy with clinical signs of hypopituitarism in 1, spontaneous multiple vertebral fractures in 1, and incidental discovery of a pituitary mass in 1. Basal prolactin levels (3,051±4,151 vs. 3,365 ± 4,949 µg/l) and mean tumour diameter (30 ± 16 vs. 25 ± 13 mm) were similar in old and young patients. Cortisol deficiency was significantly more frequent in the elderly (n = 6) than in the young (n = 1) patients (p 0.02, Fisher’s exact test). Secondary hypothyroidism was found in 2 elderly only, but not in young patients. Sixteen patients (8 elderly) received bromocriptine therapy for at least 6 months with a good tolerance. Normalization of the prolactin levels was achieved in 6 older (75%) and 4 younger patients (50%). Conclusions: The presentation of a prolactinoma in the elderly man is very heterogeneous and can be misleading. At the time of diagnosis, hypopituitarism is more frequent among older than younger patients despite a similar tumour size. We found dopamine agonists equally effective in the elderly.