TSH Adenomas Research Articles

Co-secreting TSH and GH pituitary adenoma

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Abstract #1318888: Asymptomatic Thyroid Stimulatin Hormone/Growth Hormone Cosecreting Invasive Pituitary Macroadenoma: A Rare Case Report

Thyrotropin (TSH)/growth hormone (GH) pituitary adenoma is rare and often characterized by specific signs and clinical presentations. The most common presentation of cosecreting TSH/GH pituitary adenomas is a combination of altered facial appearance (84%), goiter (91%) followed by hyperhidrosis (75%), hyperphagia (58%), trembling hands (50%), and vision impairment (50%). The patient with TSH and GH-producing pituitary adenoma had a lower surgical complete remission rate and a worse prognosis. Our case is unique in many ways in terms of the initial presentation, without having the specific signs and symptoms of TSH/GH-producing pituitary adenoma.

PSUN346 TSHoma: A Rare Cause of Pituitary Adenoma

Abstract Introduction The TSH-producing adenoma (TSHoma) prevalence in the general population is 1 to 2 cases per million, accounting for less than 2% of all pituitary adenomas. Plurihormonal tumors account for about 30% of these cases, with the most common co-secreted hormone being GH. We present the case of a patient diagnosed with TSH adenoma many years after presentation. Case Presentation A 58 year old male with a history of incidentally diagnosed pituitary microadenoma on MRI in 2007, presented in 2014 following abnormal thyroid function testing (TFT), only reported symptoms being occasional headaches. TFT was significant for elevated TSH and FT4 (TSH 4.87—Ref range: 0.27-4.2. Free T4: 1.98–Ref range 0.7-1.7). Pituitary hormone profile was remarkable for a low IGF-1 and a borderline high Alpha subunit of glycoprotein hormone. A sellar MRI confirmed a 12mm pituitary macroadenoma. He was managed conservatively on beta blockers and low dose Methimazole, owing to a stable adenoma size and poor surgical candidacy with multiple comorbidities (e. g. Atrial fibrillation). Repeat labs in 2018 showed increasing TSH (12.85), with persistent elevations of FT3, FT4 and Thyroglobulin. He had follow up TFT monitoring and surveillance MRIs until 2021 when his lesion progressed to 14 mm with mass effect on right pre chiasmatic optic nerve and adjacent internal carotid artery. The patient underwent trans sphenoidal biopsy with debulking in 2021. The biopsy showed a plurihormonal adenoma (prolactin, GH and TSH secreting). Interestingly, prolactin, GH or IGF-1 were never elevated. Following surgery, MRI showed residual 13.2×9.7 mm tumor with no mass effect. His most recent labs showed a TSH: 2.5 and FT4: 1.7. Discussion The diagnosis of a TSHoma should be considered in all centrally hyperthyroid patients, to avoid complications and undue thyroid ablation. A TSHoma must be differentiated from Resistance to Thyroid Hormone (RTH)-beta, which occurs due to mutations in the Thyroid Hormone Receptor Beta gene. Serum a-subunit concentration and Sex Hormone Binding Globulin (SHBG) concentrations are normal in RTH-beta with no TSH suppression following somatostatin analog administration. The presence of a high TSH, FT3 and FT4, in the setting of an elevated a-subunit and pituitary macroadenoma on MRI is strongly suggestive of a TSHoma. Beta blockers are recommended for symptomatic individuals however anti thyroid drug therapy is not advisable for there is risk of thyroid hormone suppression with concomitant tumor overgrowth. Definitive therapy includes trans sphenoidal tumor resection with somatostatin analog therapy to achieve euthyroidism prior to surgery. Patients should be followed up with frequent monitoring of TFT's, along with MRIs every 2-3 years. For patients with residual disease following surgery, treatment with somatostatin analogs such as Octreotide or Lanreotide is favorable as opposed to pituitary irradiation. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Thyreotroop adenoom van de hypofyse: een zeldzame oorzaak van hyperthyreoïdie

TSH-secreting pituitary adenoma: a rare cause of hyperthyroidism Central hyperthyroidism is noted in a 35-year-old man with recurrent panic attacks. Thyroid-stimulating hormone-secreting pituitary adenoma (TSH-secreting adenoma) is found to be the underlying etiology. A pituitary adenomectomy is carried out, with regression of the symptoms and hyperthyroidism. TSH-secreting adenomas are rare and cause hyperthyroidism due to autonomous TSH secretion. In addition to hyperthyroidism, dysfunction of other pituitary axes and neurological problems due to local compression may also be present. Biochemically, TSH adenoma is characterized by elevated levels of thyroid hormones without suppression of the TSH concentration. After analytical interference has been ruled out, additional biochemical and radiological investigations are necessary in the differential diagnosis and to establish diagnostic certainty. Neurosurgical resection is the cornerstone of the treatment, although radiotherapy and somatostatin analogs may also be considered.

A pituitary TSH and GH co-secreting adenoma presenting with thyrotoxicosis, but no symptoms of acromegaly: a case report

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

A Rare Case of Thyrotropin Secreting Pituitary Macroadenoma Primarily Treated With Somatostatin Analogue

Introduction/Background: Thyrotropin secreting pituitary adenomas (TSH-oma) are a rare cause of hyperthyroidism. They account for <1% of the cases of hyperthyroidism with a reported incidence of 2.8 per 1 million in Sweden. Diagnosis is suspected by the presence of elevated T4 and T3 in the setting of an unsuppressed TSH level. The presence of large pituitary adenoma is highly suggestive of the diagnosis and can be differentiated from thyroid hormone resistance by elevated alpha subunit and SHBG levels. Trans-sphenoidal surgery is the definitive treatment. Peri-operative medical treatment with somatostatin analogues is indicated to achieve euthyroidism and prevent surgical risks and thyroid storm. The use of somatostatin analogues as a primary treatment for TSH-oma is still under investigation. We hereby report a rare case of TSH-oma where somatostatin analogues successfully resulted in normalization of thyroid function and tumor size reduction. Clinical Case: A 61 years old gentleman with a history of hypothyroidism diagnosed three years before presentation to the Pituitary clinic. He was treated with Levothyroxine. On clinical examination, he had mild tremor and warm sweaty palms with no stigmata of Grave’s disease. The thyroid function test showed elevated free T4 of 3.6 ng/dl (0.9-1.7), elevated free T3 of 8.6 pg/ml (2.0-4.4), and a high TSH level of 9.10 μIU/ml (0.27-4.20). His prolactin level was mildly elevated at 24.8 ng/ml(4.0-15.2). Testosterone, IGF-1, and cortisol levels were normal. An MRI of his pituitary gland showed large pituitary macroadenoma with supra-sellar extension and mild compression of the optic nerve. He had an elevated alpha subunit of 5.6 ng/ml (<1.37) and a high SHBG level of 198 nmol/l(10-80). TSH adenoma was diagnosed and he was planned for trans-sphenoidal surgery. Pre-operative treatment with somatostatin analogue Lanerotide 90 mg monthly injection was initiated. Interestingly normal thyroid function was observed approximately 1 month after his first injection. Repeat MRI showed a considerable decrease in the size of the pituitary macroadenoma. The patient opted to hold on to surgery and to continue on medical treatment. His thyroid function remains normal 15 months after initiation of treatment and his MRI continues to show stable pituitary adenoma. Conclusion: Somatostatin analogues can be used as a primary treatment for thyrotropin secreting pituitary adenomas when the patient is unable or unwilling to undergo surgery. It is use is associated with normalization of thyroid function and in some cases with a reduction in the adenoma size.

SAT-471 Abnormal Thyroid Function Tests in Acromegaly: A Clinical Conundrum

Background: Abnormal thyroid function tests can be difficult to interpret in acromegaly. The differential includes growth hormone/IGF-1 effects on the thyroid gland, pituitary adenoma cosecretion of TSH and GH and acromegaly in the setting of resistance to thyroid hormone. Case: A 28 year old male initially presented to the Endocrine clinic following trauma workup for a fall. He was incidentally noted to have a pituitary macroadenoma (2.2 x 2.4 x 1.8 cm) with optic chiasm compression. The patient reported a history of headaches, blurry vision and joint pain with multiple physician visits for joint pain predating the trauma by 5-8 years. He mentioned changes in facial features and exam was notable for macrognathia, frontal bossing and a broad nasal bridge. He also mentioned enlarging hands and a delayed growth spurt in his early 20s. The diagnosis of acromegaly was confirmed by elevated IGF-1 (658 ng/mL, normal range 98-282) and oral glucose tolerance testing (GH 2.2 ng/mL initially and 1.2 ng/mL at 90 minutes, normal < 1). He was also noted to have elevated fT4 (2.4-2.9 ng/dL, normal range 0.70 - 1.70) and with normal TSH levels (0.77-0.98 mIU/L, normal, 0.27-4.20). He endorsed palpitations and diaphoresis but denied tremors or weight loss. Exam revealed tachycardia and diaphoresis but normal thyroid size and texture. Review of prior neck imaging (CT and MRI at time of initial trauma evaluation) described a normal appearing thyroid. Methimazole 30 mg daily and propranolol 10 mg TID were prescribed. A week later fT4 increased to 3.6 ng/dL and TSH 0.64 mIU/L. Free T4 by equilibrium dialysis (2.9-3.6 ng/dL) and T3 (207-242 ng/dL, normal range 71-180) were also elevated. Alpha subunit was 1.3 ng/mL (normal, < 0.55) and molar ratio of serum alpha subunit/TSH of 15 (normal < 0.3). TSI was < 0.10 units. Labs were suggestive of a TSH and GH co-secreting adenoma. To optimize thyroid function prior to surgery octreotide 50 mcg bid was prescribed. He underwent uncomplicated TSS resection and on POD1 revealed fT4 of 3.1 ng/dL. Immunohistochemical staining was positive for hGH and SSTR2a but negative for TSH. Conclusion: Once a diagnosis of acromegaly is made, it is important to evaluate the rest of the pituitary axis. Abnormalities in TFTs are common in this patient population and can be due to variety of etiologies including TMNG, co-secreting GH/TSH adenoma, TRH resistance and Grave’s disease. Interpreting TFTs can be challenging in these patients but understanding the physiology of GH, IGF-1 and thyroid hormones aids in diagnosis and treatment (1). Reference: (1) Gasperi, M.,Martino,E.,Manetti, L.,Arosio,M., Porretti,S.,Faglia, G., Mariotti, S. et al. 2002. “Prevalence of Thyroid Diseases in Patients with Acromegaly: Results of an Italian Multi-Center Study.” Journal of Endocrinological Investigation 25 (3): 240-45.

A literature review for 153 cases of thyrotropin-secreting pituitary adenomas in China

Objective To explore the clinical characteristics of patients with thyrotropin-secreting pituitary adenomas (TSHomas) in China. Methods All the articles related to TSHomas were retrieved from the Chinese journal databases up to July 2017. All reported cases were assessed. Results TSHomas have been diagnosed in all ages (range: 12-81 years old, average 41.9±13.8 years old) with no gender difference (male∶female=84∶69). The rate of misdiagnosis fell from 84.6%(11/13) to 50.6%(39/77) in the last 10 years. In 92 cases (60.1%), the level of TSH was elevated [median 1.57×ULN (upper limits of normal)]. The most common elevated hormones associated with TSHomas were growth hormone (GH) and prolactin (PRL; 11.1% and 9.7%, respectively). 37 cases underwent octreotide suppression test, of which the inhibitory rates ranged from 26.2% to 94.9%(median 71.79%). The detection rate of micro-adenoma was 7.7%(1/13)before year 2000, 11.4%(4/35)from 2000 to 2006, and 26.7%(28/105) after 2006. Although TSHomas usually invade surrounding tissues, they hardly cause pituitary apoplexy. Surgery or γ-knife was performed in 132 cases (86.3%). Immunohistochemistry of tumors showed that 87(52.9%) of 46 were pure TSH adenomas and 32 (36.8%) cases were mixed ones, while GH and PRL were most common (75.0% and 56.3% respectively) in the mixed adenomas. Negative immunohistochemistry for TSH was found in 9 cases (10.3%). In the follow-up, the restoring rates of thyroid hormone and TSH level were 77.0% (87/113) and 80.0%(36/45) respectively. Conclusion TSHoma is diagnosed at an earlier age in China than that reported in Europe and America, while at similar age compared with Japan. Macro-adenomas were more common in spite of the increasing detection rate of micro-adenomas. Macro-adenomas are often invasive but less likely to induce pituitary apoplexy. Immunostaining for TSH could be negative. The most common positive immunostaining in mixed adenoma is GH and/or PRL. However, a positive immunostaining for one pituitary hormone does not necessarily correlates with its hypersecretion of that hormone. (Chin J Endocrinol Metab, 2018, 34: 660-666) Key words: Thyrotropin; Pituitary adenoma; Hyperthyroidism

A case of a co-secreting TSH and growth hormone pituitary adenoma presenting with a thyroid nodule.

SummaryCo-secreting TSH and growth hormone pituitary adenomas are rare. We present a case of a 55-year-old woman who presented with symptoms of neck fullness. Ultrasound revealed multiple thyroid nodules and examination revealed several clinical features of acromegaly. She was found to have a co-secreting TSH and growth hormone pituitary macroadenoma. She underwent surgical resection followed by gamma knife radiation, which resulted in complete remission of her TSH and GH-secreting adenoma.Learning points:TSH-secreting pituitary adenomas are rare and about one-third co-secrete other hormones.Thyroid nodules are common in acromegaly and can be the presenting sign of a growth hormone-secreting pituitary adenoma.In the workup of acromegaly, assessment of other pituitary hormones is essential, even in the absence of symptoms of other pituitary hormone dysfunction.Complete remission of co-secreting GH and TSH pituitary macroadenomas is possible with surgery and radiation alone.

Endoscopic endonasal transsphenoidal surgery of 1,166 pituitary adenomas.

AimTo report the results of a series of patients undergoing pure endoscopic endonasal pituitary surgery and to evaluate the efficacy and safety of this procedure.Materials and methodsThe data of 1,166 patients that underwent endoscopic endonasal transsphenoidal adenoma removal between December 2006 and June 2013 were retrospectively reviewed. Pre- and postoperative hormonal status (3 months after surgery) were analyzed and compared with the clinical parameters originally presented by the patients. The incidences of tumor removal, hormonal control, and tumor removal complications were retrospectively analyzed.ResultOut of 577 nonfunctioning adenomas, 180 were growth hormone (GH) secreting, 308 prolactin (PRL) secreting, 26 mixed GH/PRL adenomas, 68 adrenocorticotropin secreting, and 7 thyroid-stimulating hormone-secreting adenomas. The gross total removal of pituitary adenomas was achieved in 98 % of microadenomas, 92 % of macroadenomas, and 76 % of giant adenomas. Hormonal control was achieved in 47 (69 %) cases of ACTH adenomas, 119 (66 %) GH adenomas, 262 (85 %) PRL adenomas, and 6 (86 %) TSH adenomas. Postoperative complications were observed in 168 (14.4 %) patients. The most frequent complications were diabetes insipidus (7 %), epistaxis (1.7 %), hyposmia (1.5 %), anterior lobe insufficiency (1.3 %) ,and CSF leaks (0.6 %).ConclusionThe pure endoscopic approach is a safe, efficacious, and minimally invasive technique for the removal of pituitary adenomas. A higher gross total resection rate is vital for non-functional and functional adenomas. For patients with functional adenomas, while hormonal remission is unlikely to be achieved by surgery, the use of adjuvant therapy is advocated to obtain long-term hormonal control.

Thyrotropin Pituitary Adenomas

irkman et al., by reporting on their experience at National Hospital for Neurology and Neurosurgery of London K with thyrotropin (TSH)-expressing pituitary adenomas, have contributed an important and welcomed addition to the literature about pituitary tumors. Their series is one of the largest of TSH adenomas and is the first one reporting separately on those with clinically active and clinically silent forms. TSH adenomas are rare lesions of the pituitary. According to the literature, they occur in 1% 3% of large series of pituitary adenomas and are the least common of the secretory adenomas (9, 10).

Ghrelin Immunexpression in Pituitary Adenomas

Ghrelin, an orexigenic hormone occurs mainly in stomach, and in several tumor types. We investigated ghrelin immunopositivity using the streptavidin‐biotin‐peroxidase complex method in the full spectrum of pituitary adenoma subtypes. Quantification was undertaken by analyzing both the percentage of tumor cells stained for ghrelin and the staining intensity.Cytoplasmic ghrelin immunopositivity was identified in several adenoma subtypes. Not every cell was immunopositive; the intensity of staining differed among cells within the given lesion and among the various tumors. The highest scores were noted in GH adenomas exposed to somatostatin analogues. In decreasing order, lower scores were encountered in ACTH‐producing, silent subtype 1 and 2 adenomas in Cushing disease, silent subtype 3 adenomas, untreated GH adenomas, dopamine agonist‐treated PRL adenomas, gonadotroph adenomas, and ACTH adenomas in Nelson syndrome. No immunoreactivity was found in TSH, untreated PRL‐producing, and null cell adenomas. The high immunoexpression of ghrelin in GH adenomas exposed to somatostatin analogues, may be due to increased ghrelin synthesis or to suppression of its release.

Ghrelin immunoexpression in pituitary adenomas

Ghrelin, an orexigenic hormone, is normally produced mainly in stomach. In addition, it has been demonstrated in gastric carcinoid tumors and less often in other neuroendocrine tumors. We investigated ghrelin expression by immunohistochemistry (streptavidin-biotin-peroxidase complex method) in the full spectrum of resected pituitary adenoma subtypes. Quantification of staining considered both the frequency of ghrelin-reactive tumor cells as well as their staining intensity. Cytoplasmic ghrelin immunopositivity was identified in several adenoma subtypes. Cellular staining varied considerably. In addition, the intensity of cell staining differed within the same tumor and between adenoma subtypes. The highest scores were noted in GH producing adenomas exposed to long-acting somatostatin analogs. In decreasing order, lower scores were encountered in ACTH adenomas in Cushing disease, silent subtype 3 adenomas, untreated GH adenomas, silent corticotroph adenomas of subtypes 1 and 2, dopamine agonist-treated PRL adenomas, ACTH adenomas in Nelson syndrome, and gonadotroph adenomas. No significant immunoreactivity was noted in TSH, untreated PRL, and null cell adenomas. The high immunoexpression of ghrelin in GH adenomas exposed to long-acting somatostatin analogs remains unexplained, but may be due to either increased ghrelin production or to suppression of its release. Based on our findings, it appears that ghrelin immunopositivity does not serve as a biomarker of biologic behavior, prognosis and therapeutic responsiveness in pituitary adenomas.

Localization of Carboxyl Ester Lipase in Human Pituitary Gland and Pituitary Adenomas

Carboxyl ester lipase (CEL) is an enzyme that hydrolyzes a wide variety of lipid substrates, including ceramides, which are known to show inhibitory regulation of pituitary hormone secretion in experimental models. Because no studies on CEL expression in human pituitary and pituitary adenomas have been reported in the literature, we investigated CEL expression in 10 normal pituitary glands and 86 well-characterized pituitary adenomas [12 FSH/LH cell, 17 α-subunit/null cell, 6 TSH cell, 21 ACTH cell, 11 prolactin (PRL) cell, and 19 GH cell adenomas] using IHC, immunoelectron microscopy, Western blotting, and quantitative RT-PCR. In normal adenohypophysis, CEL was localized in GH, ACTH, and TSH cells. In adenomas, it was mainly found in functioning GH, ACTH, and TSH tumors, whereas its expression was poor in the corresponding silent adenomas and was lacking in FSH/LH cell, null cell, and PRL cell adenomas. Ultrastructurally, CEL was localized in secretory granules close to their membranes. This is the first study demonstrating CEL expression in normal human pituitary glands and in functioning GH, ACTH, and TSH adenomas. Considering that CEL hydrolyzes ceramides, inactivating their inhibitory function on pituitary hormone secretion, our findings suggest a possible role of CEL in the regulation of hormone secretion in both normal and adenomatous pituitary cells.

TSH adenomas

Thyrotropin (TSH) adenomas are uncommon tumors of the anterior pituitary. Clinically, they may present with hyperthyroidism, hypothyroidism, hypopituitarism, or visual loss. Proper diagnosis requires appropriate neuroendocrine evaluation. Although transsphenoidal surgery remains the first-line treatment, adjuvant medical therapy is frequently required for these often invasive tumors. Radiotherapy or radiosurgery should be considered for those patients with persistent TSH hypersecretion following surgery and medical therapy. The clinical evaluation and treatment algorithm for patients with TSH adenomas is discussed.

Innovations and controversies in the WHO classification of pituitary adenomas

The 2004 edition of the World Heath Organization (WHO) entitled ‘‘Pathology and genetics tumors of endocrine organs,’’ presents a step forward in the classification of pituitary tumors. This classification is mainly based on immunohistochemistry, which has become the gold standard of modern diagnostic approach; electron microscopy remains an important tool in difficult cases. Immunohistochemistry can accurately identify the full spectrum of pituitary hormones produced by adenoma cells, enable more defined configuration of cell morphology and reveal several structural elements and cytoskeleton components, such as cytokeratin filaments and mitochondria. Recognition of these elements, which could previously only be identified by electron microscopy, and application to the current diagnostic approach has facilitated the classification of pituitary adenomas. Immunohistochemistry for b -a nda-subunits of glycoprotein hormones discloses the polar shape of adenoma cells and their attenuated cytoplasmic process, distinct morphological features of ‘‘glycoprotein differentiation’’ of TSH and gonadotroph adenomas [7] (Fig. 1). Antibodies against low molecular weight keratins, particularly keratin 8 reveal fibrous bodies that might be difficult to identify on hematoxylin and eosin sections alone [8]. These structures that are composed of cytokeratin filaments represent a diagnostic key feature, mostly for the sparsely granulated variant of somatotroph adenomas (Fig. 2). In contrast, keratin 8 shows diffuse cytoplasmic distribution in densely granulated somatotroph adenomas. Fibrous bodies in association with mitochondrial gigantism and misplaced exocytosis represent a diagnostic hallmark of the rare type of acidophil stem cell adenoma, whereas small fibrous bodies are also present in mammosomatotroph adeno

Thyrotropin-secreting pituitary adenoma:a clinicopathological analysis of seven cases

To study the clinicopathological features of thyrotropin-secreting pituitary adenoma (TSH adenoma). Clinical and pathological features of 7 TSH adenoma cases were studied by review of patients' medical records, light and electronic microscopy, and immunohistochemistry. All seven patients presented with clinical hyperthyroidism and high levels of plasma free T3, free T4, total T3 and total T4. The levels of TSH failed to be suppressed by thyroxin administration. MRI showed macro or giant pituitary adenomas in all seven patients with tumor diameters ranging from 2.0 to 5.0 cm. Under light microscope, there were 5 cases of chromophobe cell adenoma, 1 case of acidophil cell adenoma, and 1 case of mixed acidophil and chromophobe cell adenoma. Immunohistochemical stains showed a strong positivity of TSH in all the tumors, PRL positive cells in 1 tumor, GH positive cells in 2 tumors and scattered GH and PRL double positive cells in 3 tumors. Ki-67 proliferation index ranged from 0 approximately 0.4%. P53 immunostain was negative in all tumors. After initial surgery, 2 cases had recurrences. However, the Ki-67 proliferation index was not elevated in these two tumors. The histological features of TSH pituitary adenomas are heterogeneous with chromophobe as the most common subtype. Secretion of TSH was detected by immunohistochemistry in all cases. P53 mutation is not a feature of TSH adenoma and the proliferation marker, such as Ki-67, may not predict clinical behavior of the tumor. Recurrence is likely due to incomplete resection.

Thyrotropin-secreting pituitary adenomas. Clinical and biological heterogeneity and current treatment.

Thyrotropin (TSH)-secreting pituitary adenomas represent about 1-2% of all pituitary adenomas and cause secondary or central hyperthyroidism. TSH-secreting adenomas are part of the syndrome of 'inappropriate secretion of TSH' (SITSH). The hormonal profile is characterized by nonsuppressed TSH in the presence of high levels of free thyroid hormones (FT3 and FT4). Previous reports have described the surgical cure of TSH adenoma to be more difficult than other functional adenomas because of large and invasive features. However, with the current introduction of ultrasensitive immunometric assays, TSH-secreting adenomas are more often recognized. Early diagnosis of TSH-secreting adenomas leads to a high rate of remission of hyperthyroidism after surgery. However, some of those type of adenomas have clinical heterogeneity, and subsequently cannot be cured by surgery alone. We present our experiences and review reported cases of TSH-secreting adenomas to direct current management.

Vascular Endothelial Growth Factor (VEGF) Expression in Human Pituitary Adenomas and Carcinomas.

Vascular endothelial growth factor (VEGF) is a key mediator of endothelial cell proliferation, angiogenesis, and vascular permeability. Little is known about its expression in human pituitary adenomas. We examined 148 human pituitary adenomas for VEGF protein expression by immunohistochemistry. The strongest immunoreactivity was present in GH adenomas, corticotroph, silent corticotroph. silent subtype 3, and nononcocytic null cell adenomas. GH adenomas treated with octreotide stained less intensely than did untreated tumors. Relatively weak staining was present in PRL, gonadotroph, thyrotroph, and oncocytic null cell adenomas in the same sections showed evidence of down-regulation of VEGE protein expression in adenomas. Pituitary carcinomas usually had stronger staining than adenomas. In situ hybridization studies with oligonucleotide probes showed positive staining in all groups with stronger staining in GH, ACTH, TSH, and gonadotroph adenomas and in pituitary carcinomas. These results indicate that VEGF expression is more prominent in certain adenoma subtypes, that decreased expression occurs in adenomas as compared to nontumorous pituitary and that carcinomas show increased VEGF expression relative to adenomas suggesting up-regulation of VEGF during pituitary tumor progression.

Prevalence of lymphocytic infiltrate in 1400 pituitary adenomas.

To evaluate the prevalence of lymphocytic infiltrate in a large series of pituitary adenomas, we retrospectively studied tumor tissues from 1400 patients. Based on immunocytochemical data, tumors were classified as PRL (n=411), multihormonal (n=310), immunonegative (n=275), ACTH (n=166), GH (n=137), alpha subunit (n=44), FSH and/or LH, (n=42), and TSH (n=15) adenomas. The lymphocytic infiltrate was diagnosed on histological examination and investigated by immunostaining with anti LCA (human leucocyte common antigen), anti CD45RO (human T cell) and anti CD20 (human B cell) antibodies. Lymphocytic infiltrate was present in 40 adenomas (2.9%), 26 females and 14 males, aged 18 to 77 years (mean+/-SD, 37+/-14 years). The tumors were 19 PRL, 8 multihormonal, 4 GH, 4 alpha subunit, 3 ACTH, and 2 immunonegative adenomas. In PRL adenomas, the sex ratio (female/male) and the age were similar in patients with and without lymphocytic infiltrate (2.8 vs. 4.6 and 29+/-6 years vs. 32+/-11 years, respectively). The frequency of lymphocytic infiltrate was similar in PRL, GH, ACTH and multihormonal adenomas, but lymphocytic infiltrate was significantly more frequent in PRL adenoma than in immunonegative adenoma, and in alpha subunit adenoma than in immunonegative, ACTH and multihormonal adenomas. The lymphocytic cells were almost exclusively T cells. We conclude that lymphocytic infiltrates are rare in pituitary adenomas. Their frequency is not statistically different in major categories of secreting adenomas (PRL, GH, ACTH, multihormonal). Their pathophysiological significance remains to be established.