Rahel Sahli

Glucagon-like peptide-1 receptor imaging for localization of insulinomas.

CONTEXT The surgical removal of insulinomas is hampered by difficulties to localize it using conventional radiological procedures. Recently these tumors were shown to exhibit a very high density of glucagon-like peptide-1 receptors (GLP-1R) in vitro that may be used as specific targets for in vivo receptor radiolabeling. OBJECTIVE The objective of the study was to test the 111In-labeled GLP-1R agonist 111In-DOTA-exendin-4 in localizing insulinomas using single photon emission computed tomography in combination with computed tomography images. DESIGN This was a prospective open-label investigation. SETTING The study was conducted at three tertiary referral centers in Switzerland. PATIENTS Patients included six consecutive patients with proven clinical and biochemical endogenous hyperinsulinemic hypoglycemia. INTERVENTION (111)In-DOTA-exendin-4 was administered iv at a dose of about 90 MBq (30 microg peptide) over 5 min. Whole-body planar images of the abdomen were performed at 20 min, 4 h, 23 h, 96 h, and up to 168 h after injection. After surgical removal of the insulinomas, GLP-1R expression was assessed in the tumor tissue in vitro by GLP-1R autoradiography. MAIN OUTCOME MEASURE The detection rate of insulinomas was measured. RESULTS In all six cases, the GLP-1R scans successfully detected the insulinomas identified using conventional methods in four cases. By using a gamma-probe intraoperatively, GLP-1R detection permitted a successful surgical removal of the tumors in all patients, diagnosed histopathologically as five pancreatic and one extrapancreatic insulinomas. In vitro GLP-1R autoradiography showed a high density of GLP-1R in all tested insulinomas. CONCLUSION In vivo GLP-1R imaging is an innovative, noninvasive diagnostic approach that successfully localizes small insulinomas pre- and intraoperatively and that may in the future affect the strategy of insulinoma localization.

Hyponatremia associated coma due to pituitary apoplexy in early pregnancy: a case report

Pituitary apoplexy in pregnancy is rare. Its clinical features may range from unspecific complaints to panhypopituitarism resulting even in coma and death. Therefore, alertness to signs and symptoms of acute loss of pituitary function in pregnancy is mandatory. We report a woman in her 7th week of her first gestation presenting with sudden coma due to severe hyponatremia. Secondary adrenal insufficiency could be identified as the underlying cause. Panhypopituitarism including central diabetes insipidus and spontaneous abortion developed during the follow-up. Magnetic resonance imaging showed pituitary apoplexy without a pre-existing pituitary mass. The clinical course was notable for severe complications, including neurological deficits through cerebral ischemia, but eventual recovery could be achieved. We discuss the diagnostic difficulties in the evaluation of pituitary disease in pregnancy.

Manifestation of a sellar hemangioblastoma due to pituitary apoplexy: a case report

IntroductionHemangioblastomas are rare, benign tumors occurring in any part of the nervous system. Most are found as sporadic tumors in the cerebellum or spinal cord. However, these neoplasms are also associated with von Hippel-Lindau disease. We report a rare case of a sporadic sellar hemangioblastoma that became symptomatic due to pituitary apoplexy.Case presentationAn 80-year-old, otherwise healthy Caucasian woman presented to our facility with severe headache attacks, hypocortisolism and blurred vision. A magnetic resonance imaging scan showed an acute hemorrhage of a known, stable and asymptomatic sellar mass lesion with chiasmatic compression accounting for our patients acute visual impairment. The tumor was resected by a transnasal, transsphenoidal approach and histological examination revealed a capillary hemangioblastoma (World Health Organization grade I). Our patient recovered well and substitutional therapy was started for panhypopituitarism. A follow-up magnetic resonance imaging scan performed 16 months postoperatively showed good chiasmatic decompression with no tumor recurrence.ConclusionsA review of the literature confirmed supratentorial locations of hemangioblastomas to be very unusual, especially within the sellar region. However, intrasellar hemangioblastoma must be considered in the differential diagnosis of pituitary apoplexy.

Sellar collision tumor involving pituitary gonadotroph adenoma and chondroma: a potential clinical diagnosis

We report on a 74-year-old male patient who presented with progressive neuroophthalmologic symptoms soon after the administration of a long-acting gonadotropin-releasing hormone agonist for treatment of a prostate cancer. Imaging revealed a destructively growing and extensively calcified sellar mass inconsistent with a pituitary adenoma. A transseptal transsphenoidal tumor mass reduction yielded a histological diagnosis of a collision tumor comprised of a gonadotroph adenoma intermingled with osteochondroma. We discuss a potential causal relationship between the administration of the long-acting gonadotropin-releasing hormone agonist and the sudden appearance of the previously unsuspected sellar lesion. Although the association of these two tumors is very likely coincidental, the possibility of causal relationship is addressed.

Pituitary prolactinoma with T cell rich inflammatory infiltrate: a possible example of antitumoral immune response to be differentiated from lymphocytic hypophysitis

InXammatory disorders of the pituitary comprise a nosologically heterogenous group of lesions, the wide spectrum of which actually belies the perceived rarity of individual entities. These range from “bystander” involvement by inXammation of adjacent skull base or meninges (secondary hypophysitis), to self-perpetuating reparative lesions (sellar xanthogranuloma), to mononuclear inWltrates that can involve the pituitary either primarily or as part of systemic autoimmune disease [7, 9, 10]. Among the latter, lymphocytic hypophysitis (LYH) stands out as the single most important lesion, both because of its relative frequency and complex diVerential diagnosis [3, 7]. LYH tends to come to attention by virtue of its local tissue destruction or space-occupying character. While virtually every combination of sitespeciWc clinical symptoms may result, hyperprolactinemia—especially one referable to “stalk section eVect”— may occasionally occur as well [7]. In the context of ongoing or recently completed pregnancy, and more generally female gender and reproductive age, LYH has been notorious for often being nearly indistinguishable—if thought of at all—from prolactinoma, on clinical grounds. Histological conWrmation of either diagnosis has been regarded as one excluding its alternative counterpart, for there is no reference in the literature to any case of pituitary harboring both prolactinoma and lymphocytic inXammation. We recently had the privilege of studying an adenomectomy specimen with concurrent prolactinoma and conspicuous intratumoral inWltration by reactive lymphocytes. The patient, a 31-year-old nulliparous woman, underwent transsphenoidal microsurgery for oligo-amenorrhea with laboratory evidence of moderate hyperprolactinemia (140 g/l). No preoperative dopaminergic therapy was attempted. The referring physician negated any clinical evidence of coexistent systemic inXammatory or autoimmune disease. Magnetic resonance imaging (MRI) showed a macroadenoma of 12 mm in diameter with intact sellar contours (Fig. 1a, b). A fairly generous surgical specimen of 1.2 £ 1 £ 0.3 cm was available for processing, complete with some wellpreserved residues of nontumorous adenohypophysis as well as small fragments of posterior lobe. The neoplastic moiety consisted of a slightly basophilic prolactin cell adenoma (WHO grade I) with monotypic expression of prolactin (PRL) in a Golgi-bound pattern, as well as robust CAM 5.2 (for cytokeratin 8 and cytokeratin 18) positivity (Fig. 1d, e). In addition, multiple angiocentric inWltrates of mononuclear cells were seen along intratumoral vascular septa (Fig. 1c). These comprised mostly CD3+ T lymphocytes, among which CD4+ helper cells predominated over those of CD8+ suppressor phenotype (Fig. 1f, h). Cytotoxic T cells featuring Granzyme-B or TIA-1 positive granules occurred very rarely (not shown). There were lesser amounts of interspersed CD79a+ B cells and only scarce CD68+ monocytes (Fig. 1i). Only seldom did the latter assume macrophage morphology; neither epithelioid cells nor granulomas were present. Morphological evidence of cell destruction, especially apoptotic Wgures or necrosis were absent, as was Wbrosis. However, occasional CD68+ cells were seen intimately engaged with minute clusters of MHC II (HLA-DR) expressing adenoma cells via dendritic processes (Fig. 1j). The inWltrate was felt to be conWned within intratumoral boundaries, while the adjacent residual parenchyma remained remarkably free of any inXammatory cells (Fig. 1k, l). Our review of the literature yielded a mere two speciWc references to simultaneous neoplastic and inXammatory pathologies of the pituitary. The case reported by Holck and Laursen [4] involved a prolactinoma coexisting with I. Vajtai (&) · A. Kappeler Institute of Pathology, University of Bern, Murtenstrasse 31, Postfach 62, 3010 Bern, Switzerland E-mail: istvanvajtai@yahoo.com Tel.: +41-31-6323210 Fax: +-41-31-6329938

Pregnancy in active acromegaly

Anamnese und klinische Befunde: Es wird der Fall einer 29-jahrigen Patientin beschrieben, die nach einer langen Vorgeschichte von Oligomenorrhoe schwanger wurde, kurz nach Diagnosestellung einer noch unbehandelten Akromegalie. Untersuchungen: Der klinische Akromegalieverdacht wurde bei fehlender Suppression des Wachstumshormons im oralen Glukosetoleranztest und erhohtem insulinahnlichen Wachstumsfaktor (IGF-1) bestatigt. Kernspintomographisch zeigte sich ein Makroadenom der Hypophyse mit suprasellarem Tumorwachstum und Kompression des Chiasma opticum mit inkompletter Hemianopsie. Therapie und Verlauf: Aufgrund der Chiasmakompression wurde eine transsphenoidale Operation mit Normalisierung des Gesichtsfeldes im 2. Trimenon durchgefuhrt. Wahrend der Schwangerschaft gelang eine problemlose Kontrolle der Akromegalie, die postpartal erst durch eine multimodale Therapie erreicht werden konnte. Die Tochter wies ein normales Geburtsgewicht auf und zeigt bis heute eine absolut unauffallige Entwicklung. Folgerungen: Hypophysenadenome fuhren haufig zu Oligoamenorrhoe und eingeschrankter Fruchtbarkeit. In den wenigen dokumentierten Schwangerschaften in aktiver Akromegalie ist einerseits das Risiko von Adenomwachstum, andererseits von metabolischen und kardiovaskularen Komplikationen erhoht, andererseits kann die Schwangerschaft die Akromegalieaktivitat beeinflussen und wie im aktuellen Fall sogar verbessern. Es bestehen bislang keine Hinweise fur einen transplazentaren Ubertritt von Wachstumshormon oder IGF-1. History and clinical findings: A 29-year-old woman with a long-lasting history of oligoamenorrhea, fell pregnant shortly after being diagnosed with acromegaly. Laboratory tests and imaging: A high IGF-1 concentration and an oral glucose tolerance test confirmed the diagnosis. Cranial magnetic resonance imaging demonstrated a macroadenoma of the pituitary with suprasellar extension and compression of the optic chiasm leading to incomplete hemianopsia. Treatment and course: Transsphenoidal surgery was performed during the second trimester, impaired visual fields became normal and subsequent biochemical tests suggested remission. She delivered a healthy full-term infant via cesarean section after an uncomplicated pregnancy. The infants development was unremarkable. Postpartum assessment showed persistent acromegaly activity and the patient was judged to require secondary multimodal therapy. Conclusions: Pituitary adenomas often cause oligoamenorrhea and may interfere with fertility. Although pregnancy rarely occurs during the course of active acromegaly, the maternal morbidity, including hypertension and gestational diabetes, is increased. While pregnancy may cause an increase in tumor size, biochemical improvement in acromegaly is - as illustrated by the present case - also possible. A maternal-to-fetal transfer of growth hormone or IGF-1 has not been proved.HISTORY AND CLINICAL FINDINGS A 29-year-old woman with a long-lasting history of oligoamenorrhea, fell pregnant shortly after being diagnosed with acromegaly. LABORATORY TESTS AND IMAGING: A high IGF-1 concentration and an oral glucose tolerance test confirmed the diagnosis. Cranial magnetic resonance imaging demonstrated a macroadenoma of the pituitary with suprasellar extension and compression of the optic chiasm leading to incomplete hemianopsia. TREATMENT AND COURSE Transsphenoidal surgery was performed during the second trimester, impaired visual fields became normal and subsequent biochemical tests suggested remission. She delivered a healthy full-term infant via cesarean section after an uncomplicated pregnancy. The infants development was unremarkable. Postpartum assessment showed persistent acromegaly activity and the patient was judged to require secondary multimodal therapy. CONCLUSIONS Pituitary adenomas often cause oligoamenorrhea and may interfere with fertility. Although pregnancy rarely occurs during the course of active acromegaly, the maternal morbidity, including hypertension and gestational diabetes, is increased. While pregnancy may cause an increase in tumor size, biochemical improvement in acromegaly is--as illustrated by the present case--also possible. A maternal-to-fetal transfer of growth hormone or IGF-1 has not been proved.

Diabetes mellitus und Alter

Diabetes mellitus Typ 2 ist im Alter haufig. Dennoch gibt es wenig Daten uber die adaquate blutzuckersenkende Therapie. Bei alteren Patienten ( > 70 Jahre) oder kurzer Lebenserwartung (< 10 Jahre) ist HbA1c um 7 % (bis max 8.0 %) erstrebenswert. Bei schwerer Komorbiditat ist das Ziel Symptomkontrolle und Stabilisierung des Gewichtes, insbesondere der Muskelmasse. Insulin ist bei symptomatischen Patienten aufgrund seiner Effizienz und anabolen Wirkung das bevorzugte Therapeutikum. Alle Behandlungskonzepte sollten Hypoglykamien moglichst vermeiden. Regelmasige Ernahrung vereinfacht die Therapie und tragt zur Lebensqualitat bei. Die Bedeutung der Therapie assoziierter kardiovaskularer Risikofaktoren wird ebenfalls von den Komorbiditaten mitbestimmt.Type 2 Diabetes is frequent among elderly people. The appropriate target for HbA1c in elderly patients ( > 70 years or life expectancy < 10 years) should be around 7.0% (maximally 8%). In patients with multiple co-morbidities, the goal must be an improvement of symptoms and preservation of weight, especially muscle mass. In the setting of an uncontrolled symptomatic diabetes with concomitant catabolism, insulin is the most effective therapy and, therefore, the treatment of choice. The prevention of hypoglycemia must be a major aim. A balanced and regular food intake facilitates therapy and improves quality of life. The priorities of the management of cardiovascular risk factors should be based upon the individuals overall health condition.

Acute Onset of Polyarthralgia and High Anti-Cyclic Citrullinated Peptide Antibodies in a Case of Idiopathic Granulomatous Hypophysitis

Idiopathic granulomatous hypophysitis (IGH) is a very rare autoimmune disease of the pituitary gland that leads to a spectrum of pituitary hormone deficiencies of varying severity. We describe an unusual case of a 45-yearold man presenting with acute onset of peripheral arthralgia and diffuse myofascial pain with high anti-cyclic citrullinated peptide (CCP) antibodies and negative laboratory values for antinuclear antibodies (ANA), rheumatoid factor (RF), and antineutrophil cytoplasmic antibodies (ANCA), followed by panhypopituitarism caused by IGH. The anti-CCP antibodies, measured by a third-generation anti-CCP antibodies assay (INOVA), were highly elevated (411 units/ml, < 20 negative). Anti-CCP positivity and its diagnostic value is best known in patients with rheumatoid arthritis (RA). Anti-CCP antibodies have a positive predictive value of 87.9% for RA. The sensitivity of anti-CCP antibodies for the diagnosis of RA is 77% and the specificity for RA is 86.1%1. A relatively high frequency of anti-CCP antibodies has also been reported in patients with non-RA connective tissue disorders such as systemic lupus erythematosus (SLE; 15%), Sjögren’s syndrome (SS; 14%), polymyositis/dermatomyositis (23%), and scleroderma (16%). The median level of anti-CCP antibodies, however, was lower in these non-RA patients (7–35 units per ml) compared to patients with RA (100 units per ml or more)2. The acute onset of polyarthralgia and elevated anti-CCP antibodies will be discussed in relation to the case. In our patient the diffuse myofascial pain and arthralgia may, in part, be associated with hypothyroidism. Our review of the literature has not yielded a similar clinical presentation of IGH. The defining pathological feature and treatment of IGH are reviewed. A 45-year-old man was admitted to hospital for evaluation of diffuse myofascial pain and peripheral arthralgia. The diffuse myofascial pain and peripheral arthralgia started overnight 4 weeks prior to admission, increased during physical exercise, and resulted in decreased muscular strength and inability to work. He denied any symptoms of morning stiffness or of a previous infection, fever, or any skin lesions. However, mild anorexia with substantial weight loss of 7 kg over 4 weeks was reported. Clinical examination showed a patient in good general condition but with painful metacarpophalangeal joints, metatarsophalangeal joints, and wrists on both sides. Subsequently, both ankle joints became swollen. Laboratory investigation showed slightly elevated monocytes (11.7%) and highly elevated anti-CCP antibodies (411 units). ANA, RF, and ANCA were negative. Liver and kidney function, C-reactive protein, and erythrocyte sedimentation rate were all within normal range. Plain radiography of both hands, shoulders, and the spine showed neither erosions nor degenerative changes or calcifications. Initial thyroid evaluation (Table 1) showed very low thyroid-stimulating hormone (TSH; < 0.03 mU/l) and slightly elevated fT3 (8.1 pmol/l) together with fT4 in the low normal range (11.0 pmol/l). TSH receptor and thyroid peroxidase (TPO) antibodies were negative. He was evaluated with a thyroid ultrasound and scintigraphy within a week after the initial thyroid evaluation. The ultrasound was normal. Scintigraphy showed a tracer (99m-Tc-pertechnetate) uptake in the lower normal range (0.6%). Based on these findings a thyrotoxic phase of an antibody-negative thyroiditis seemed unlikely but could not be excluded, and it may have contributed to the weight loss. Later in the course of the disease, however, he had clear evidence of secondary hypothyroidism (Table 1). In the course of the evaluation he complained of persistent muscle and articular pain, pronounced fatigue, and decreasing body weight. He also reported polyuria and polydipsia. In summary, the laboratory values (Table 1) showed panhypopituitarism. The diagnosis of diabetes insipidus was based on clinical criteria. Visual field and acuity were normal. Magnetic resonance images revealed an intrasellar mass measuring 1.5 × 1.5 × 1.5 cm with a thickened infundibular stalk, without compression of the optic chiasm. The normally high signal intensity of the posterior pituitary on the T1-weighted images was absent (Figure 1). He received substitution with prednisone, levothyroxine, desmopressin, and testosterone undecanoate. Therapy with prednisone was started at 40 mg daily, reduced to 20 mg daily after 4 weeks, and further stepwise reduced to 7.5 mg daily. Due to rapidly progressive panhypopituitarism, exploration of the intrasellar mass was undertaken transphenoidally. There were no surgical complications. Histopathologically the diagnosis of granulomatous hypophysitis with abundant epithelioid, noncaseating granulomas and multinuclear giant cells of Langhans type was made (Figure 2). The anterior lobe parenchyma was almost entirely destroyed. The extensive search for an associated systemic granulomatous disease such as tuberculosis, syphilis, sarcoidosis, histiocytosis X and Morbus Crohn was negative. The diagnosis of IGH was therefore made. After a followup of 8 months the patient still needs hormonal substitution, but the presenting symptoms of diffuse myofascial pain and peripheral arthralgia have disappeared. He first presented with acute onset of polyarthralgia associated with prominent myalgia, fatigue, and weight loss followed by arthrosynovitis. Peripheral arthralgia with an increased anti-CCP antibody level is very suggestive for RA, since anti-CCP antibodies can be an early finding in RA and can even antedate the onset of disease3. Positive anti-CCP antibody level may also be detected in non-RA connective tissue disorders such as SLE, SS, polymyositis/dermatomyositis, and scleroderma2 and indicate an inflammation-associated phenomenon seen in an abnormal immune response4. A common pathological background between RA and IGH has not been described to date. An association with autoimmune diseases including RA is established for patients with autoimmune lymphocytic hypophysitis5. Since our patient rapidly developed progressive panhypopituitarism, acute glucocorticoid insufficiency could have provoked an unknown immunologically mediated condition6. In our patient diffuse myofascial pain and arthralgia may, in part, be associated with hypothyroidism7. IGH is a very rare autoimmune disorder of the pituitary gland with varying severity and spectrum of pituitary hormone deficiencies. The typical clinical picture of IGH comprises symptoms of pituitary mass lesion, most frequently headache and visual impairment8. The defining pathological feature is the formation of noncaseating granulomas, consisting of epithelioid granulocytes and multinucleated giant cells. T cell infiltrates also occur. The immune infiltrate comprises activated folliculo-stellate cells (FSC) of “true dendritic” type. The FSC are considered antigen-presenting cells, capable of processing and displaying antigens on MHC class II molecules, and initiate primary T lymphocyte responses9. The mechanism proposed in RA is very similar as the inflammatory process is understood as T cell-mediated as well. The number of T cells correlates negatively with the degree of fibrosis in IGH. An unknown autoantigen from pituitary cells is implicated in the pathogenesis of hypophysitis10. Current treatment of IGH is symptomatic and supportive. Mass reduction can be Table 1. Endocrine evaluation.

Spindle Cell Oncocytoma of the Adenohypophysis: Integrated Clinicopathologic Diagnosis by Imaging, Histology, and Immunohistochemistry

Spindle cell oncocytoma (SCO) is a nonendocrine neoplasm of uncertain histogenesis developing in and restricted to the anterior pituitary. It comprises fusiform and polygonal cells replete with mitochondria, the immunophenotype and ultrastructure of which preclude direct histogenetic identification with either adenohypophyseal secretory epithelial cells or pituicytes, as well as with any established tumor entity of local accessory tissues (e.g., meningioma; Schwannoma). In a broader context, no analogy of SCO is forthcoming with any known neoplastic condition in peripheral endocrine organs.