Novel Classification of Acromegaly in Accordance with Immunohistochemical Subtypes: Is There Really a Clinical Relevance?

According to the recent studies, immunohistochemical subtypes of growth hormone (GH) secreting adenomas have been considered as a predictive factor in determining the clinical outcomes including biochemical, radiologic, and endocrine remission. In a 20 year-of time period, acromegaly patients who were treated and followed at the Endocrinology Department of our University Hospital were screened for the study. Of total 98 patients, 65 patients who had been operated by transsphenoidal surgery and having postoperative specimens were included. Postoperative specimens of the surgery of the patients were classified into 3 groups based on the histochemical characteristics (densely, sparsely, and mixed). Parasellar extensions of pituitary tumors were classified into the five grades according to Knosp classification. The patients were investigated and evaluated for postoperative clinical progress, remission rates, comorbidities regarding with the histopathological patterns. Of total 65 patients, 31 were classified as densely granulated (group 1), 32 were classified as sparsely granulated (group 2), and 2 patients were assessed as mixed granulated (group 3). There was no difference between groups for age and gender. Pre-treatment of adenoma size in all groups was correlated with each other and the frequency of macroadenoma (1 vs. 2, 77.4 vs. 84.3%) was higher in two groups. Although mean initial GH levels in group 1 was higher than the other groups (p=0.03), IGF1 levels (age and gender matched) were similar in each group. Adenomas in all groups demonstrated noninvasive radiological characteristics (Knosp grade 0-1-2). Ki-67 proliferation index of both groups (64.5 vs. 50%) was predominantly 1%. With a similar follow-up period, the endocrine remission rates (GH<1 µg/l) in groups were 64 vs. 69%, respectively. In conclusion, classification according to immunohistochemical subtypes of growth hormone secreting adenomas may not be a qualified parameter to evaluate patients with patterns of aggressiveness, clinical outcomes, or treatment response.

Digital analysis of hormonal immunostaining in pituitary adenomas classified according to WHO 2017 criteria and correlation with preoperative laboratory findings.

OBJECTIVE: The authors sought to evaluate clinical and laboratory data from pituitary adenoma (PA) patients with functioning PA (associated with acromegaly [n = 10] or Cushing disease [n = 10]) or nonfunctioning PA (NFPA; n = 10) that were classified according to 2017 WHO criteria (based on the expression of the transcription factors pituitary-specific positive transcription factor 1 [Pit-1], a transcription factor member of the T-box family [Tpit], and steroidogenic factor 1 [SF-1]) and to assess the immunostaining results for growth hormone (GH) and adrenocorticotropic hormone (ACTH) in the corresponding tumors. METHODS: Clinical and laboratory data were collected retrospectively. The percentage of tumoral cells positive for Pit-1, Tpit, or SF-1 was assessed and ImageJ software was used to evaluate immunopositivity in PAs with 2 different antibodies against GH (primary antibody 1 [AbGH-1] and primary antibody 2 [AbGH-2]) and 2 different antibodies against ACTH (primary antibody 1 [AbACTH-1] and primary antibody 2 [AbACTH-2]). RESULTS: Cells with positive Pit-1 staining were more frequently observed in lesions from patients with acromegaly (acromegaly group) than in lesions from patients with Cushing disease (Cushing group; p < 0.001) and those from patients with NFPA (NFPA group; p < 0.001). The percentage of Tpit-positive cells was higher in the Cushing group than in the acromegaly (p < 0.001) and NFPA (p < 0.001) groups. No difference was detected regarding SF-1 frequency among all groups (p = 0.855). In acromegalic individuals, GH immunostaining levels varied depending on the antibody employed, and only one of the antibodies (AbGH-2) yielded higher values in comparison with the values for NFPA patients (p < 0.001). For all of the antibodies employed, no significant correlations were detected between GH tissue expression and the laboratory data (serum GH vs AbGH-1, p = 0.933; serum GH vs AbGH-2, p = 0.853; serum insulin-like growth factor-1 [IGF-1] vs AbGH-1, p = 0.407; serum IGF-1 vs AbGH-2, p = 0.881). In the Cushing group data, both antibodies showed similar ACTH tissue expression, which was higher than that obtained in the NFPA group (p < 0.001). There were no significant associations between ACTH immunohistochemical findings and ACTH serum levels (serum ACTH vs AbACTH-1, p = 0.651; serum ACTH vs AbACTH-2, p = 0.987). However, ACTH immunostaining evaluated with AbACTH-1 showed a significant correlation with 24-hour urinary cortisol (24-hour cortisol vs AbACTH-1, p = 0.047; 24-hour cortisol vs AbACTH-2, p = 0.071). CONCLUSIONS: Immunostaining for Pit-1 and Tpit accurately identified lesions associated with acromegaly and Cushing disease, respectively. Conversely, SF-1 did not differentiate NFPA from lesions of the other two groups. Regarding hormonal tissue detection, results of the current investigation indicate that different antibodies may lead not only to divergent immunohistochemical results but also to lack of correlation with laboratory findings. Finally, PA classification based on transcription factor expression (Pit-1, Tpit, and SF-1), as proposed by the 2017 WHO classification of pituitary tumors, may avoid the limitations of PA classification based solely on digital immunohistochemical detection of hormones.

Surgical treatment of acromegaly according to the 2010 remission criteria: systematic review and meta-analysis.

BACKGROUND: In 2010, the Acromegaly Consensus Group revised the criteria for cure of acromegaly and thus rates of surgical remission need to be revised in light of these new thresholds. Two subgroups consisted of patients with discordant GH and IGF-1 levels and patients in remission according to the 2000 criteria, but not to the 2010 criteria, have been reported after adenomectomy and for these subgroups the precise incidence and management has not been established. The objective of the study was to update rates of surgical remission and complications and to evaluate the incidence, management, and long-term outcome of the two previously described subgroups of patients. METHODS: Systematic review and meta-analysis of surgical series that defined remission according to the 2010 biochemical criteria. RESULTS: We included 13 studies (1105 patients). The pooled rate of overall surgical remission was 54.8 % (95 % CI 44.4-65.2 %), and 72.2 % with previous criteria. Remission was achieved in 77.9 % (95 % CI 68.1-87.6 %) of microadenomas; 52.7 % (95 % CI 41-64.4 %) of macroadenomas; 29 % (95 % CI 20.1-37.8 %) of invasive and 68.8 % (95 % CI 60-77.6 %) of non-invasive adenomas. Complication rates were 1.2 % (95 % CI 0.6-1.9 %) for CSF leak, 1.3 % (95 % CI 0.6-2.1 %) for permanent diabetes insipidus, 8.7 % (95 % CI 4.8-12.5 %) for new anterior pituitary dysfunction and 0.6 % (95 % CI 0.1-1.1 %) for severe intraoperative hemorrhage. We identified an intermediate group of patients, defined as: (1) Remission according to one, but not the other biochemical criteria (GH or IGF-1) or 2010 criteria (14.3 % and 47.1 % cases), (2) Remission according to 2000, but not 2010 criteria (13.2-58.8 % cases). Two studies reported a remission rate of 56.5 % and 100 %, in the two subgroups respectively, in a long-term outcome without adjuvant therapy. CONCLUSIONS: Overall remission with transsphenoidal surgery is achieved in ∼55 % of patients. For the intermediate group of patients, future prospective studies with long-term follow-up are required to determine the long-term biochemical remission rates and clinical implications.

Growth hormone tumor histological subtypes predict response to surgical and medical therapy.

Growth hormone (GH) pituitary tumors are associated with significant morbidity and mortality. Current treatments, including surgery and medical therapy with somatostatin analogs (SSA), dopamine agonists and/or a GH receptor antagonist, result in disease remission in approximately half of patients. Predictors of GH tumor response to different therapies have been incompletely defined based on histologic subtype, particularly densely (DG) versus sparsely (SG) granulated adenomas. The aim of this study was to examine our own institutional experience with GH adenomas and correlate how subtype related to clinical parameters as well as response to surgery and medical therapies. A retrospective chart review of 101 acromegalic patients operated by a single neurosurgeon was performed. Clinical data were correlated with histologic subtype and disease control, as defined by IGF-1 levels, and random growth hormone levels in response to surgery and/or medical therapies. SG tumors, compared to DG, occurred in younger patients (p = 0.0010), were 3-fold larger (p = 0.0030) but showed no differences in tumor-invasion characteristics (p = 0.12). DG tumors had a higher rate of remission in response to surgery compared to SG, 65.7 vs. 14.3 % (p < 0.0001), as well as to medical therapy with SSAs (68.8 % for DG vs. 28.6 % for SG tumors; p = 0.028). SG tumors not controlled with SSAs consistently responded to a switch to, or addition of, a GH receptor antagonist. Histological GH tumor subtyping implicates a different clinical phenotype and biologic behavior, and provides prognostic significance for surgical success and response to medical therapies.

A structural and functional acromegaly classification.

CONTEXT: GH-secreting pituitary adenomas exhibit heterogeneous natural history ranging from small tumors to large aggressive adenomas. OBJECTIVE: To rigorously classify an acromegaly patient cohort defined by clinical, radiological, histopathological, and outcome characteristics. DESIGN: Cross-sectional study. SETTING: Tertiary referral pituitary center. PATIENTS: Subjects were selected from a pituitary tumor research registry that includes 1178 patients with pituitary disease. Cluster analysis was performed on 338 acromegaly patients. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Biochemically active disease with elevated IGF-1 levels at follow-up. RESULTS: Cluster analysis of all patients yielded 292 who were rigorously classified to three acromegaly types. Type 1 (50%) comprised older patients with the longest follow-up and most favorable outcomes, characterized by densely granulated, nonaggressive microadenomas and macroadenomas. Type 1 tumors extend to the sphenoid sinus more frequently than suprasellar extension (concave tumor image) and express abundant immunoreactive p21 and somatostatin receptor 2. Type 2 (19%) comprised noninvasive, densely or sparsely granulated macroadenomas, without significant extension (flat tumor image), with intermediate biochemical outcome. Type 3 (31%) was characterized by sparsely granulated aggressive macroadenomas and comprised patients with adverse therapeutic outcomes, despite receiving more treatments. These tumors extend to both the sphenoid sinus and suprasellar regions with commonly encountered optic chiasm compression ("peanut" magnetic resonance image), with low tumor p21 and somatostatin receptor 2 expression. CONCLUSIONS: After validation, this classification may be useful to accurately identify acromegaly patients with distinctive patterns of disease aggressiveness and outcome, as well as to provide an accurate tool for selection criteria in clinical studies.

Long-term echocardiographic follow-up of acromegalic heart disease.

Heart muscle disease in acromegaly manifests usually as cardiac hypertrophy. Based on a retrospective analysis, it was suggested that cardiac hypertrophy is slowly reversible after normalization of plasma growth hormone levels. The reversibility of acromegalic heart muscle disease during and after treatment of acromegaly was studied prospectively. A cohort of 78 patients was examined echocardiographically in 1981, and 38 survivors of this group were reexamined 10 years later. Patients were classified according to original hormonal activity in 1981, and change in hormonal activity during follow-up into the following 4 groups: group I--hormonally inactive for entire follow-up (n = 10); group II--hormonally active for entire follow-up (n = 11); group III--initially hormonally inactive with later resurgence (n = 6); and group IV--initially hormonally active with later normalization of growth hormone levels (n = 11). No significant echocardiographic changes occurred during follow-up in group I. Left ventricular posterior wall and septal diastolic thickness, and left ventricular mass increased significantly (all p < 0.05) in group II. Left ventricular posterior wall thickness, mass and diastolic volume increased significantly (p < 0.05, < 0.01 and < 0.001, respectively) in group III. On the contrary, there were significant decreases in left ventricular mass, and both diastolic and systolic left ventricular volumes (p < 0.01, < 0.05 and < 0.05, respectively) in group IV. It is concluded that both hypertrophy and dilatation of the left ventricle in acromegaly are slowly reversible after successful treatment. On the contrary, continuing or relapsed hyperproduction of growth hormone causes further deterioration of acromegalic heart disease.

The spectrum of GH responses to GHRH and somatostatin in patients with acromegaly.

Plasma GH responses to GHRH and somatostatin were examined in 43 patients with active acromegaly. Thirty-two of these patients showed GH increases 50% above the basal values in response to at least 1 of 3 stimuli (TRH, LHRH, arginine) (categorized as group I). The remaining 11 patients showed no response to any of the stimuli (categorized as group II). Following somatostatin infusion, group I (n = 31) showed significantly greater GH suppression than group II (n = 11) from 30 to 90 min (p less than 0.05-0.01). In addition, plasma GH responses to GHRH at 15 and 30 min was also greater in group I (n = 12) than in group II (n = 5) (p less than 0.05 & 0.01). There was a positive correlation between the log value of the peak GH after GHRH and the maximal % decrement after somatostatin (r = 0.64, p less than 0.02). However there were no differences in the responses of normal thyrotrophs (TSH) to TRH between the two groups. These results indicate that there are two types of acromegaly, i.e., one is more responsive and another is less responsive to either non-specific (TRH & LHRH) or specific GH stimulations (GHRH & somatostatin).

Functional treatment of acromegaly by transsphenoidal microsurgery.

The authors have analyzed the results from 41 acromegalic patients who underwent transsphenoidal surgery. In 31 patients, postoperative growth hormone (GH) levels fell and remained below 10 ng/ml. This represents an endocrinological "cure" of 78%. In the remaining 10 cases, postoperative GH values have not stabilized below 10 ng/ml, although seven show some clinical improvement. The results were particularly good in those cases of localized adenomas, which allowed a selective removal while maintaining pituitary function within normal limits in 65.5% of cases. The postoperative GH level in this group fell and remained below 10 ng/ml in more than 90% of cases. Four patients required reoperation to normalize the GH levels which had not been sufficiently modified after the first operation; only one of them remained with plasma GH levels above normal limits. There were no deaths in this series. Rhinorrhea occurred as a postsurgical complication in four cases. In three this disappeared with bed rest and lumbar drainage; in the other, surgical repair was necessary. The occurrence of surgical complications has decreased as our experience has increased, and the need for reoperation has been unusual after the first year of our study.

Differences in autonomity of growth hormone secretion in patients with acromegaly.

Thirteen patients with acromegaly were subjected to the examination of autonomity in growth hormone (GH) secretion. TRH (500 mug iv), arginine (0.5 g/kg of body weight iv infusion), LH-RH (100 mug iv) and L-dopa (500 mg orally) were administered, and plasma GH was measured. Among them, 11 patients showed some response in plasma GH to at least one agent, but the other 2 cases showed no response to any of the above 4 agents. In the former 11 cases, the patients were regarded as belonging to the less autonomous type and in the latter 2, to the more autonomous type in GH secretion. Six cases (4 cases of the less autonomous and 2 cases of the more autonomous type) received an administration of 500 mug of synthetic somatostatin parenterally. Following administration of somatostatin, the patients of both types showed significant GH decrease, although GH decrease in the more autonomous type was smaller than that of the less autonomous type. These results would suggest that there might be no acromegalics secreting GH FROM THE PITUITARY WITH COMPLETE AUTONOMITY, AND THE DIFFERENCE OF AUTONOMITY IN ACROMEGALIC PATIENTS MIGHT DEPEND EITHER ON THE DIFFERENCE IN SENSITIVITY AND/OR THE NUMBER OF RECEPTORS IN THE PITUITARY RATHER THAN THOSE IN HYPOTHALAMUS TO EXOGENOUS STIMULI.

Lepra e acromegalia

O autor relata um caso de lepra nervosa e acromegalia. Julga ser o primeiro caso observado, pois revsndo cuidadosamente a literatura, somente encontrou referencia a 2 casos, ambos de lepra cutanea e acromegalia. Diz que a acromegalia é indiscutivel, não podendo entretando, afirmar si é posterior ou anterior á lepra e evidenciar a sua causa. O autor chama ainda a atenção neste caso e em 11 ginecomestias por ele observados, não ter notado lesões evidentes da hipofise pelos processos semiologicos atuaes, não obstante haver sinais clinicos declarados.