Tapani Ebeling

Clinical characteristics and therapeutic responses in patients with Germ-line AIP mutations and pituitary adenomas : An international collaborative study

CONTEXTnAIP mutations (AIPmut) give rise to a pituitary adenoma predisposition that occurs in familial isolated pituitary adenomas and less often in sporadic cases. The clinical and therapeutic features of AIPmut-associated pituitary adenomas have not been studied comprehensively.nnnOBJECTIVEnThe objective of the study was to assess clinical/therapeutic characteristics of AIPmut pituitary adenomas.nnnDESIGNnThis study was an international, multicenter, retrospective case collection/database analysis.nnnSETTINGnThe study was conducted at 36 tertiary referral endocrine and clinical genetics departments.nnnPATIENTSnPatients included 96 patients with germline AIPmut and pituitary adenomas and 232 matched AIPmut-negative acromegaly controls.nnnRESULTSnThe AIPmut population was predominantly young and male (63.5%); first symptoms occurred as children/adolescents in 50%. At diagnosis, most tumors were macroadenomas (93.3%); extension and invasion was common. Somatotropinomas comprised 78.1% of the cohort; there were also prolactinomas (n = 13), nonsecreting adenomas (n = 7), and a TSH-secreting adenoma. AIPmut somatotropinomas were larger (P = 0.00026), with higher GH levels (P = 0.00068), more frequent extension (P = 0.018) and prolactin cosecretion (P = 0.00023), and occurred 2 decades before controls (P < 0.000001). Gigantism was more common in the AIPmut group (P < 0.000001). AIPmut somatotropinoma patients underwent more surgical interventions (P = 0.00069) and had lower decreases in GH (P = 0.00037) and IGF-I (P = 0.028) and less tumor shrinkage with somatostatin analogs (P < 0.00001) vs. controls. AIPmut prolactinomas occurred generally in young males and frequently required surgery or radiotherapy.nnnCONCLUSIONSnAIPmut pituitary adenomas have clinical features that may negatively impact treatment efficacy. Predisposition for aggressive disease in young patients, often in a familial setting, suggests that earlier diagnosis of AIPmut pituitary adenomas may have clinical utility.

Incidence of Pituitary Adenomas in Northern Finland in 1992-2007

CONTEXTnData on the incidence of pituitary adenomas (PAs) are scant and outdated. A population-based regional cohort with thorough case identification was used to evaluate the incidence of clinically detected PAs in the era of magnetic resonance imaging.nnnOBJECTIVEnThe objective of the study was to describe the age- and sex-specific incidence of all PA subgroups, with data on incidentally found PAs, pituitary apoplexies, and time trends.nnnDESIGN, SETTINGS, AND PATIENTSnThis was a retrospective descriptive analysis of PA patients diagnosed during 1992-2007 in Northern Finland (NFi).nnnMAIN OUTCOME MEASUREnWorld Health Organization 2000-standardized incidence rates (SIRs) of PAs per 100,000 were measured.nnnRESULTS AND CONCLUSIONnThe final cohort consisted of 355 PAs. The incidence rates of the Oulu University Hospital regional district were used as a reference to assess the applicability of our case finding over the rest of NFi. Incidence rates of all PA subgroups except microprolactinomas were statistically equal between these areas; thus, all presented SIRs are based on the NFis cohort except Oulu University Hospital regional district-based prolactinomas and PAs overall. Overall SIR of PAs was higher (4.0 per 100,000) than in previous reports. Prolactinomas had the highest SIR: 2.2 per 100,000, followed by clinically nonfunctioning PAs (1.0) and GH-secreting (0.34), ACTH-secreting (0.17), and TSH-secreting (0.03) PAs. The gender-specific SIR was 2.2 per 100,000 in males and 5.9 per 100,000 in females. Pituitary apoplexy occurred as a presenting symptom in 11% of clinically nonfunctioning PA patients. The SIR of incidentally discovered PAs increased significantly from 1992-1999 to 2000-2007 (0.59 to 1.6, respectively; P < 0.01), which accounted for the perceived increasing trend in the overall SIR of PAs (3.8 to 4.2; P > 0.05).

Clinical and genetic characterization of pituitary gigantism: an international collaborative study in 208 patients

Despite being a classical growth disorder, pituitary gigantism has not been studied previously in a standardized way. We performed a retrospective, multicenter, international study to characterize a large series of pituitary gigantism patients. We included 208 patients (163 males; 78.4%) with growth hormone excess and a current/previous abnormal growth velocity for age or final height >2 s.d. above country normal means. The median onset of rapid growth was 13 years and occurred significantly earlier in females than in males; pituitary adenomas were diagnosed earlier in females than males (15.8 vs 21.5 years respectively). Adenomas were ≥10u200amm (i.e., macroadenomas) in 84%, of which extrasellar extension occurred in 77% and invasion in 54%. GH/IGF1 control was achieved in 39% during long-term follow-up. Final height was greater in younger onset patients, with larger tumors and higher GH levels. Later disease control was associated with a greater difference from mid-parental height (r=0.23, P=0.02). AIP mutations occurred in 29%; microduplication at Xq26.3 - X-linked acrogigantism (X-LAG) - occurred in two familial isolated pituitary adenoma kindreds and in ten sporadic patients. Tumor size was not different in X-LAG, AIP mutated and genetically negative patient groups. AIP-mutated and X-LAG patients were significantly younger at onset and diagnosis, but disease control was worse in genetically negative cases. Pituitary gigantism patients are characterized by male predominance and large tumors that are difficult to control. Treatment delay increases final height and symptom burden. AIP mutations and X-LAG explain many cases, but no genetic etiology is seen in >50% of cases.

Mortality in acromegaly: a 20-year follow-up study.

OBJECTIVEnIt is unclear whether mortality still is increased in acromegaly and whether there are gender-related differences. We dynamically assessed outcome during long-term follow-up in our nationwide cohort.nnnPATIENTS AND METHODSnWe studied standardized mortality ratios (SMRs) relative to the general population and causes of death in acromegaly (n=333) compared with age- and gender-matched controls (n=4995).nnnRESULTSnDuring 20 (0-33) years follow-up, 113 (34%) patients (n=333, 52% women) and 1334 (27%) controls (n=4995) died (P=0.004). SMR (1.9, 95% CI: 1.53-2.34, P<0.001) and all-cause mortality (OR 1.6, 95% CI: 1.2-2.2, P<0.001) were increased in acromegaly. Overall distribution of causes of death (P<0.001) differed between patients and controls but not cardiovascular (34% vs 33%) or cancer deaths (27% vs 27%). In acromegaly, but not in controls, causes of deaths shifted from 44% cardiovascular and 28% cancer deaths during the first decade, to 23% cardiovascular and 35% cancer deaths during the next two decades. In acromegaly, cancer deaths were mostly attributed to pancreatic adenocarcinoma (n=5), breast (n=4), lung (n=3) and colon (n=3) carcinoma. In acromegaly, men were younger than women at diagnosis (median 44.5 vs 50 years, P<0.001) and death (67 vs 76 years, P=0.0015). Compared with controls, women (36% vs 25%, P<0.01), but not men (31% vs 28%, P=0.44), had increased mortality.nnnCONCLUSIONSnIn acromegaly, men are younger at diagnosis and death than women. Compared with controls, mortality is increased during 20 years of follow-up, especially in women. Causes of deaths shift from predominantly cardiovascular to cancer deaths.

Characteristics and Outcomes of 79 Patients with an Insulinoma: A Nationwide Retrospective Study in Finland

Objective Insulinomas are rare pancreatic tumours. Population-based data on their incidence, clinical picture, diagnosis, and treatment are almost nonexistent. The aim of this study was to clarify these aspects in a nationwide cohort of insulinoma patients diagnosed during three decades. Design and Methods Retrospective analysis on all adult patients diagnosed with insulinoma in Finland during 1980–2010. Results Seventy-nine patients were diagnosed with insulinoma over the research period. The median follow-up from diagnosis to last control visit was one (min 0, max 31) year. The incidence increased from 0.5/million/year in the 1980s to 0.9/million/year in the 2000s (p = 0.002). The median diagnostic delay was 13 months and did not change over the study period. The mean age at diagnosis was 52 (SD 16) years. The overall imaging sensitivity improved from 39% in the 1980s to 98% in the 2000s (p < 0.001). Seventy-one (90%) of the patients underwent surgery with a curative aim, two (3%) had palliative surgery, and 6 (8%) were inoperable. There were no significant differences in the types of surgical procedures between the 1980s, 1990s, and 2000s; tumour enucleations comprised 43% of the operations, distal pancreatic resections 45%, and pancreaticoduodenectomies 12%, over the whole study period. Of the patients who underwent surgery with a curative aim, 89% had a full recovery. Postoperative complications occurred in half of the patients, but postoperative mortality was rare. Conclusions The incidence of insulinomas has increased during the past three decades. Despite the improved diagnostic options, diagnostic delay has remained unchanged. To shorten the delay, clinicians should be informed and alert to consider the possibility of hypoglycemia and insulinoma, when symptomatic attacks are investigated in different sectors of the healthcare system. Developing the surgical treatment is another major target, in order to lower the overall complication rate, without compromising the high cure rate of insulinomas.