ACROMEGALY OCCURRING IN A PATIENT WITH A PITUITARY ADENOMA, LYMPHOCYTIC HYPOPHYSITIS, AND A RATHKE CLEFT CYST

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1 Case Report ACROMEGALY OCCURRING IN A PATIENT WITH A PITUITARY ADENOMA, LYMPHOCYTIC HYPOPHYSITIS, AND A RATHKE CLEFT CYST Anupa Sharma, DO 1 ; Eric K.Richfield, MD, PhD 2 ; Sara E. Lubitz, MD 1 ABSTRACT Objective: The concomitant presence of three histopathologically different lesions in the pituitary gland is a rare occurrence. We present a case of a woman with a large pituitary mass composed of a growth hormone producing microadenoma, lymphocytic hypophysitis, and a Rathke cleft cyst. Methods: The clinical presentation, laboratory data, imaging studies, and pathology report of the patient s hospital course are described. Results: A 35-year-old woman presented with complaints of fever, persistent headaches, and amenorrhea for 1 year. The patient noted snoring, increase in shoe size, and bilateral hand edema for 3 months. Evaluation revealed a suprasellar mass measuring cm with an upward mass effect on the optic chiasm. The physical exam revealed frontal bossing, wide-spaced teeth, prognathism, and sausage digits. Hormonal evaluation was consistent with acromegaly. She underwent a transsphenoidal resection of the lesion, and pathology revealed a growth hormone producing microadenoma, lymphocytic hypophysitis, and a Rathke cleft cyst. Submitted for publication April 28, 2016 Accepted for publication June 26, 2016 From the 1 Division of Endocrinology, Metabolism and Nutrition, Department of Medicine, and 2 Department of Pathology and Laboratory Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey. Address correspondence to Dr. Anupa Sharma, Division of Endocrinology, Metabolism and Nutrition, Department of Medicine, Rutgers Robert Wood Johnson Medical School, 1 RWJ Place-MEB 386, New Brunswick, NJ sharmaa9@rutgers.edu. DOI: /EP CR To purchase reprints of this article, please visit: Conclusion: Reports have identified the co-existence of ruptured Rathke cleft cysts with lymphocytic hypophysitis, the presence of Rathke cleft cyst with growth hormone producing pituitary adenomas, and lymphocytic hypophysitis with growth hormone producing adenomas. However, we are not aware of any reports of the presence of these three lesions in a single pituitary. (AACE Clinical Case Rep. 2017;3:e121-e125) Abbreviations: IGF-1 = insulin-like growth factor 1; MRI = magnetic resonance imaging INTRODUCTION The co-occurrence of lymphocytic hypophysitis with a Rathke cleft cyst and adenomas has been previously reported (1,2). The mechanism is not well understood and might represent the occurrence of two separate entities. The concomitant presence of three different lesions in the pituitary gland has not been reported. A mechanism that explains the co-existence of multiple pituitary lesions has not been described (2). We present a unique case of a middle-aged woman with a large pituitary mass, composed of a growth hormone producing microadenoma, lymphocytic hypophysitis, and a Rathke cleft cyst. CASE REPORT A 35-year-old woman presented to the emergency room with complaints of fever and persistent headache for 1 year. She noted amenorrhea for 1 year, with her last child born 5 years prior. She reported snoring, increase in shoe size, swelling in both hands, and rapid weight gain. Given the patient s symptoms, magnetic resonance imaging (MRI) of the brain revealed a suprasellar mass that AACE CLINICAL CASE REPORTS Vol 3 No. 2 Spring 2017 e121

2 e122 Acromegaly, LH, Rathke Cleft Cyst, AACE Clinical Case Rep. 2017;3(No. 2) measured cm (Fig. 1 and 2). There was an upward mass effect on the optic chiasm, and the pituitary stalk was not well visualized due to mass effect. Physical exam demonstrated frontal bossing, widespaced teeth, prognathism, and sausage digits. Formal visual field testing revealed no deficits. Lab testing was consistent with acromegaly, showing growth hormone of 16 ng/ml (normal, 0.01 to 3.61 ng/ml) and insulin-like growth factor 1 (IGF-1) of 683 ng/ml (normal, 73 to 244 ng/ml). Evaluation of other hormone levels revealed mildly elevated prolactin of 52 ng/ml (normal, 2 to 23 ng/ml), free thyroxine of 1.11 ng/dl (normal, 0.9 to 1.8 ng/dl), thyroid-stimulating hormone (TSH) 0.75 miu/l (normal, 0.35 to 5.5 miu/l), follicle-stimulating hormone (FSH) 2.5 miu/ml (normal, 0.3 to miu/ml), and luteinizing hormone (LH) 0.9 miu/ml (normal, 0.8 to 104 miu/ml). The patient underwent transsphenoidal surgery for the presumed diagnosis of a growth hormone secreting macroadenoma. Her postoperative course was complicated by a right thalamic stroke, subarachnoid hemorrhage, transient diabetes insipidus, and persistent cerebrospinal fluid leak requiring multiple repairs. IGF-1 normalized 3 months after the surgery to 190 ng/ml (normal, 73 to 244 ng/ml). The patient required glucocorticoid, thyroid hormone, and estrogen replacement therapy postoperatively. She continues to have hemiplegia. Pathology revealed a growth hormone secreting microadenoma, a large Rathke cleft cyst, and surrounding lymphocytic hypophysitis (Fig. 3). The microadenoma stained exclusively for growth hormone. FSH, prolactin, LH, adrenocorticotropic hormone, and minimal TSH expression were detected in the surrounding pituitary. Lymphocytic hypophysitis was noted in the surrounding pituitary with labeling for CD3, CD45, CD79a, and CD68 for macrophages and was negative for CD138. Only a small portion of a Rathke cyst remained and contained ciliated epithelium without clear mucinous secretion. Marked fibrosis was present in the specimen, indicating a longstanding disease process. A microadenoma was positive for growth hormone (Fig. 3 A) and loss of acinar structure on reticulin staining (Fig. 3 B). A Rathke cleft cyst was identified (Fig. 3 C). Lymphocytic hypophysitis was identified by the proliferation of inflammatory cells labeled with the common leukocyte antigen (Fig. 3 D), but also a significant number of cells identified with CD3, CD45, CD79a, and CD68. DISCUSSION There are many reports in the literature describing cases where Rathke cleft cysts occur with surrounding lymphocytic hypophysitis and cases of pituitary adenomas with surrounding lymphocytic hypophysitis. There are cases of concomitant growth hormone producing pituitary adenomas and Rathke cleft cysts (3). We believe that this is the first reported case of these three co-existing lesions in a single pituitary. The pathogenesis of these three co-existing entities remains unclear. One report identified a Rathke cleft cyst rupture as a potential event triggering resultant surrounding lymphocytic hypophysitis (1). It was presumed that the leakage of cystic components of the Rathke cleft cyst results in a foreign body reaction, thus promoting an inflammatory response followed by granulomatous changes (4-6). The presence of lymphocytic hypophysitis surrounding pituitary adenomas is a rare occurrence, with five cases Fig. 1. Coronal T2-weighted magnetic resonance imaging of pituitary mass.

3 Acromegaly, LH, Rathke Cleft Cyst, AACE Clinical Case Rep. 2017;3(No. 2) e123 Fig. 2. Sagittal T2-weighted magnetic resonance imaging of pituitary mass. Fig. 3. Histologic specimens of pituitary. A microadenoma was positive for growth hormone (A) and loss of acinar structure on reticulin staining (B). A Rathke cleft cyst was identified (C). Lymphocytic hypophysitis was identified by the proliferation of inflammatory cells labeled with the common leukocyte antigen (D).

4 e124 Acromegaly, LH, Rathke Cleft Cyst, AACE Clinical Case Rep. 2017;3(No. 2) reported (6,7). There is limited literature on the presence of both lymphocytic hypophysitis and a growth hormone secreting adenoma. In the setting of a pituitary adenoma, it was hypothesized that certain cytokines, such as interleukin (IL)-1, IL-2, and IL-6, cause local inflammation, which results in surrounding hypophysitis (6). In contrast, the natural history of lymphocytic hypophysitis is thought to progress from inflammation to fibrosis and subsequent atrophy (8). Atrophy of the pituitary cells may lead to alteration and dysfunction of hormonal regulatory factors, thus promoting pituitary hyperplasia and tumorigenesis (9). It is possible that lymphocytic hypophysitis may stimulate adenoma formation. The co-existence of Rathke cleft cyst and pituitary adenoma has been described in the literature but is rare. In 1987, after evaluating 464 cases, Nishio et al (10) reported the rate of co-incidence of these two co-existing etiologies was 1.7%. More recently, in 2007, Noh et al (3) identified 32 cases of concomitant pituitary adenoma and Rathke cleft cyst. Of the 32 cases, 9 were identified to produce growth hormone (3). The pathogenesis of these two co-existing etiologies remains unclear. One hypothesis is that a pituitary adenoma and Rathke cleft cyst share a common embryonic origin. Rathke cleft cysts are derived from true remnants of the embryologic Rathke pouch that has not appropriately regressed (11). Similarly, by the sixth week of embryonic life, the Rathke s pouch separates from the epithelium and gives rise to the anterior pituitary lobe, where adenomas are frequently found (2). While the presence of these entities may be fortuitous, we hypothesize it is also possible that a Rathke cleft cyst rupture promotes an inflammatory reaction and may cause pituitary cell dysfunction resulting in hyperplasia or adenoma formation. In our case of concomitant growth hormone producing pituitary adenoma, Rathke cleft cyst, and lymphocytic hypophysitis it is plausible that any of these distinct pathologies could have triggered the formation of the others. On MRI, it is difficult to distinguish between a Rathke cleft cyst, lymphocytic hypophysitis, and a pituitary adenoma. Rathke cleft cysts are of variable size and signal intensity. There is no specific pattern of pituitary displacement, and they can be indistinguishable from pituitary adenomas (12). Lymphocytic hypophysitis has been known to mimic pituitary adenomas, but features indicative of lymphocytic hypophysitis on MRI include loss of the hyperintense bright spot signal of the posterior pituitary, thickening of the pituitary stalk, and enlargement of the posterior gland (13,14). Pituitary tumors associated with acromegaly are frequently macroadenomas, as there is often a delay in diagnosis. It is possible she developed lymphocytic hypophysitis after childbirth, 5 years prior, and that her striking acromegalic features were overlooked. Unfortunately, she did not seek medical attention between childbirth and the presentation described. The pre-operative presumptive diagnosis of a single growth hormone secreting adenoma was made on the basis of the patient s signs and symptoms of acromegaly, imaging findings consistent with a pituitary macroadenoma, and presence of elevated IGF-1. The neurosurgeon resected the mass with the goal of complete suprasellar resection for a biochemical cure, as is standard of care for a growth hormone producing tumor. While we were unable to obtain the exact dimensions of the growth hormone staining adenoma, pathology revealed that it was only a small fraction of the total mass removed. Whether the patient may have had a different surgery or a better outcome if the histology of the pituitary mass was known beforehand cannot be determined. CONCLUSION The concomitant presence of pituitary adenoma with other histologically different lesions is a rare occurrence. Previous reports have identified a link between ruptured Rathke cleft cysts and lymphocytic hypophysitis, growth hormone producing adenomas, and lymphocytic hypophysitis, and the presence of a Rathke cleft cyst with growth hormone producing pituitary adenomas. This case is a valuable addition to the literature documenting the presence of three co-existing lesions in a single pituitary mass. Further research is needed into the pathogenesis of pituitary adenomas to determine which entity came first. DISCLOSURE The authors have no multiplicity of interest to disclose. REFERENCES 1. Schittenhelm, J, Beschorner R, Psaras T, et al. Rathke s cleft cyst rupture as potential initial event of a secondary perifocal lymphocytic hypophysitis: proposal of an unusual pathogenetic event and review of the literature. Neurosurg Review. 2008;31: Koutourousiou M, Kontogeorgos G, Wesseling P, Grotenhuis AJ, Seretis A. Collision sellar lesions: experience with eight cases and review of the literature. Pituitary. 2010;13: Noh S, Ahn J, Lee K, Kim SH. Pituitary adenoma and concomitant Rathke s cleft cyst. Acta Neurochir (Wien). 2007;149: Albini CH, MacGillivray MH, Fisher JE, Voorhess ML, Klein DM. 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