REDUCTION IN THYMOMA SIZE AFTER PITUITARY SURGERY FOR GROWTH HORMONE SECRETING TUMOR. Hema Padmanabhan, M.D, FACP, FACE

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1 AACE Clinical Case Reports Rapid Electronic Articles in Press Rapid Electronic Articles in Press are preprinted manuscripts that have been reviewed and accepted for publication, but have yet to be edited, typeset and finalized. This version of the manuscript will be replaced with the final, published version after it has been published in the print edition of the journal. The final, published version may differ from this proof. Case Report ACCR REDUCTION IN THYMOMA SIZE AFTER PITUITARY SURGERY FOR GROWTH HORMONE SECRETING TUMOR Hema Padmanabhan, M.D, FACP, FACE From: Medical Center Navicent Health Running title: Thymoma,a trophic effect of growth hormone in acromegaly Corresponding address: Dr. Hema Padmanabhan Endocrinologist (locum) Medical Center Navicent Health 777 Hemlock St Macon, GA

2 ABSTRACT Objective: A thymoma is a rare tumor of anterior mediastinum and may be under the control of prolactin and growth hormone (GH), as well as GH IGF1 mediated paracrine and autocrine pathways. Methods: Case Report Results: The following case report highlights the unexpected outcome in a mediastinal thymoma after pituitary surgery for a growth hormone producing macroadenoma. A 58 year-old Caucasian man with history of acromegaly caused by a pituitary macroadenoma was also known to have a mediastinal thymoma (proven by biopsy). The thymoma was being monitored by annual imaging studies, as patient was asymptomatic and had declined surgery. The octreotide scan was negative and tests ruled out a growth hormome releasing hormone (GH RH) producing tumor. He underwent transphenoidal surgery for removal of pituitary tumor. After surgery, his insulin growth factor1 (IGF) levels normalized and there was adequate suppression of GH by oral glucose tolerance test (OGTT). Follow up imaging after 6 weeks and 10 months of surgery showed absence of pituitary tumor and marked reduction in size of the mediastinal thymoma. Conclusion: In a patient with acromegaly and thymoma, the surgical treatment of the GH producing tumor might be expected to cause reduction in thymoma size. Therefore, such tumors in patients with acromegaly may simply be monitored clinically. Abbreviations: GH = Growth Hormone; GHRH = Growth Hormone Releasing Hormone; OGTT = Oral Glucose Tolerance Test; IGF1 = Insulin Growth Factor 1; CT = Computed Tomography; MRI = Magnetic Resonance Imaging; CTS = Carpel Tunnel Syndrome; TEC = Thymocyte Epithelial Cell.

3 INTRODUCTION Acromegaly is characterized by excessive secretion of growth hormone (GH) and is usually caused by a GH-secreting pituitary adenoma [1]. Rarely, carcinoid and pancreatic islet cell tumors produce growth hormone- releasing hormone (GH-RH) and may cause excessive GH secretion [2, 3, and 4]. Acromegaly is frequently diagnosed after many years of active GH hypersecretion and causes significant morbidity and mortality due to cardiac, pulmonary and musculoskeletal changes[5].measurement of elevated plasma insulin like growth factor 1 (IGF1) is the single best screening test to make the diagnosis. Treatment is directed at preventing local complications of the tumor mass as well as normalizing GH secretion. Although complete surgical resection of these tumors provides lasting remission, incompletely removed tumors may be adequately treated using long acting somatostatin analogs [6]. Thymomas are rare tumors which usually develop in the chest. Although confirmatory diagnosis relies on guided-biopsy, computerized tomography (CT) alone or in combination with magnetic resonance imaging (MRI) provides important information regarding the extent of the tumor, its boundaries with adjacent organs, the choice of the appropriate therapeutic option and the assessment of response to treatment. More recently radiopharmaceuticals and nuclear imaging procedures have been used increasingly employed in the functional characterization of benign and malignant thymic disorders [7]. The following case illustrates a marked reduction in size of a mediastinal thymoma after surgical removal of growth hormone producing pituitary tumor. CASE REPORT A 60 year old Caucasian man with history of obstructive sleep apnea (OSAP), renal calculi, generalized osteoarthritis and colon cancer (status post surgery and chemotherapy in 2000) was referred for evaluation of secondary hypogonadism. His phenotypic features, typical of acromegaly (frontal bossing, broad nose, large tongue, increased spacing of teeth, prognathism, large spade like hands and large feet), prompted a work-up for the disease. He had noted increase in shoe size from 9 to 12 between 1969 to 2004, had carpel tunnel syndrome (CTS) surgery of left hand in 1985, and active CTS involving the right hand. He had noted sinus congestion and

4 headaches 2-3 /week with a subjective intensity of 4/10. The pain was located at the center and front of his head. He had no double vision, and objective evaluation showed no deficits in peripheral vision. He had gained 70 lbs in the preceding 20 years and noted increase in tongue size over the past 10 years. He had no symptoms of diabetes insipidus or diabetes mellitus. His energy level was low but he had no symptoms of erectile dysfunction. He had a history of 3.73x3.8cm mediastinal thymoma (figure 1: A, B) which was proven by biopsy in The thymoma was being monitored by periodic imaging as patient was asymptomatic and had declined surgery. The tissue did not stain for GH. Additional staining done for immunohistochemical markers ( chromogrannin, synaptophysin, neuron specific enolase and calcitonin) were also negative.these special studies were carried out after a diagnosis of acromegaly was made, due to possibility of a GHRH or GH producing ectopic tumor (e.g. thymoma). The pathologist reiterated the diagnosis of thymoma after repeat review of slides. Family history was negative for kidney disease or pituitary tumors. He was married and had 2 children age 35 and 37. He quit smoking (after 20 yrs) in 2000, and drank 12 beers a year. He had no history of illicit drug use. Physical examination Weight lbs, Heart rate 54, BP 157/76. He had coarse facial features, macroglossia, prognathism, malocclusion, a broad nose and lips. His thyroid was enlarged on the right side. He had large hands and feet, with moist palms. He had skin tags under his arm and right chest. The remainder of the physical examination revealed normal respiratory, cardiac, abdominal and neurological systems. His initial IGF1 was 954 ng/ml (75-212) in 2007, and remained high on subsequent labs. In Feb 2009, his IGF1 was 1005 ng/ml. GH was high. An oral GTT showed non suppression of GH. The fasting and peak plasma glucose were 73mg/dl and 123mg/dl respectively. The corresponding growth hormone (GH) values were 0.26ng/ml and 0.98ng/ml respectively. The GH nadir was 0.23ng/ml.

5 His free thyroxine, and serum free and total testosterone were within normal range. He was not screened for cortisol deficiency or excess. MRI of the pituitary showed a 6.5x 8.9x 11mm pituitary macroadenoma (initial MRI done as open modality did not reveal a clear cut tumor). The GHRH level was normal thus excluding a GHRH producing ectopic tumor (e.g. carcinoid). Patient, however, declined to undergo pituitary surgery As he had declined surgery, and the IGF1 levels was progressively rising he was started on Lanreotide (Somatuline, Tercica Pharmaceuticals) in February 2009 at a dose of 90mg administered every 28 days by deep subcutaneous route. On this dose the IGF1 decreased from 1005 to 462 ng/ml in July 09, but increased to 832 ng/ml in September 09. The dose of Lanreotide was increased to 120mg which he received in September and December Patient was advised to have surgery since the IGF 1 was persistently elevated despite one year treatment with Somatuline. He consented to undergo transphenoidal surgery. Preoperative IGF 796( ng/ml), GH 2.62( ng/ml), Serum Osmolality 298 mosm/kg( ), Intact PTH 78.4( 12-65) pg/ml, prolactin 6.6( <20 ng/ml), cortisol 6.3 ug/dl, free T4 1.2 ng /dl ( ng/dl), LH 1.0 miu/ml He had transphenoidal surgery on 2/18/10. The tumor was immediately evident in the anterior portion of the gland. There was no pseudo capsule; therefore the tumor was internally debulked until a gross total resection had been accomplished. There was no evidence of invasion of either cavernous sinus and no intraoperative spinal fluid leak. Post operative period was uneventful and patient was discharged 48 hours later. Histopathology revealed a tumor composed of small cells with eosinophilic cytoplasm and occasional nucleoli. A reticulin stain confirms the loss of acinar architecture within the tumor and highlights focally entrapped normal ant pituitary gland. A panel of immunohistochemical stains revealed the tumor to be strongly positive for GH and prolactin.

6 After the surgery, the IGF 1 value normalized and OGTT showed normal suppression of GH. Follow up MRI of pituitary with gadolinium (at 6weeks) showed post operative changes without evidence of residual tumor. Chest CT scan showed marked reduction in size of the mediastinal thymoma after surgery, from 3.73x3.8cm to 3.1x2.9cm (Figure 1: C, D). The volume of tumor could not be calculated as there were only two measurements available. The finding remained stable 10 months after surgery. DISCUSSION There was significant reduction in thymoma size after removal of the pituitary tumor which might suggest trophic effects of growth hormone on thymic tissue either directly or via IGF1. There is increasing evidence that GH can influence immune functions and that it is secreted by lymphocytes. Further, GH functions as an autocrine/paracrine growth factor in the human thymus via locally synthesized IGF-1[8]. Increasing evidence has placed hormones and neuropeptides among potent immunomodulators, in both health and disease. Exogenous GH enhances thymic microenvironmental cell-derived secretory products such as cytokines and thymic hormones. Moreover, GH increases thymic epithelial cell (TEC) proliferation in vitro and exhibits a synergistic effect with anti CD3 in stimulating thymocyte proliferation, which is in keeping with the data showing that transgenic mice over expressing GH or GH releasing hormone exhibit overgrowth of the thymus [9] by IGF1 production and expression of IGF1 by TEC and thymocytes. There is an intrathymic circuitry involving not only IGF1 but also GH itself as intrathymic GH expression is seen in both TEC and thymocyte. Thymocyte derived GH could enhance thymocyte proliferation. Finally the possibility that GH improves thymic functions including thymocyte proliferation and migration, places this molecule as a potential therapeutic adjuvant in immunodefiency conditions associated with thymocyte decrease and loss of peripheral T cells. GH could directly or indirectly induce proliferation of TECs and thus might be related to formation of epithelial thymic rudiment in the fetal stage [10]. CONCLUSION

7 This case report illustrates the possible relationship between growth hormone producing pituitary tumor and thymoma. Size reduction was observed after successful pituitary tumor removal in this patient.mediastinal thymomas in patients with acromegaly (due to GH producing pituitary tumor) may be monitored if patient is asymptomatic. There is a possibility of its resolution with removal of the pituitary tumor thus preventing unnecessary thymic surgery and its attendant risks. We were not expecting any notable change in the size of the thymoma and were mainly focused on management of acromegaly. Therefore, we did not do serial imaging of the thymoma or IGF1 levels at various intervals during the phase of medical management of acromegaly. ACKNOWLEDGMENT I managed this patient while working as staff endocrinologist in VA Medical Center, Salem, VA ( ). I am grateful to Dr Michael Thorner, MBBS, DSc, Division of Endocrinology, University of Charlottesville, VA for assistance in managing the case. REFERENCES 1. Melmed S, Braunstein GD, Horvath E, Ezrin C,Kovacs K. Pathophysiology of acromegaly. Endocr Rev. 1983; 4: Frohman LA, Szabo M, Berelowitz M, Stachura ME. Partial purification and characterization of a peptide with growth hormone-releasing activity from extrapituitary tumors in patients with acromegaly. J Clin Invest.1980; 65: Thorner MO, Perryman RL, Cronin MJ, et al. Somatotroph hyperplasia: successful treatment of acromegaly by removal of a pancreatic islet tumor secreting a growth hormonereleasing factor.j Clin Invest.1982; 70: Guillemin R, Brazeau P, Bohlen P, et al. Growth hormone releasing factor from a human pancreatic tumor that caused acromegaly. Science.1982; 218:

8 5. Jaffe CA, Barkan AL. Acromegaly: Recognition and treatment. Drugs. 1994; 47: Melmed S, Ziel FH, Braunstein GD, Downs T, Frohman LA. Medical management of acromegaly due to ectopic production of GHRH by a carcinoid tumor. J Clin Endocrinol Metab.1988; 67: Lastoria S, Palmieri G, Muto P, Lombardi G. Functional imaging of thymic disorders. Ann Med. Oct: 1999; 31 Suppl 2: Sabharwal P, Varma S. Growth hormone synthesized and secreted by human thymocytes acts via insulin like growth factor 1 as an autocrine and paracrine growth factor. J Clin Endocrinol Metab.1996; 81: Savino W, Postel-Vinay MC, Smaniotto S, Dardenne.The thymus gland: a target for growth hormone. M. Scand J immunol. 2002; 55; Tsuji Y, Kinoshita Y, Hato F, Tominaga K, Yoshida K.The invitro proliferation of thymus epithelial cells stimulated with growth hormone and insulin-like growth factor -1. Cell Mol Bio.1994;l40:

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