018 2009 Rocque Kuo Clival prolactinoma.pdf

Case Report

SYMPTOMATIC HYPERPROLACTINEMIA FROM AN ECTOPIC PITUITARY ADENOMA LOCATED IN THE CLIVUS Brandon G. Rocque, MD1; Kelly A. G. Herold, MD2; M. Shahriar Salamat, MD, PhD3; Yoram Shenker, MD2; John S. Kuo, MD, PhD1

ABSTRACT

Objective: To report a case of an ectopic pituitary adenoma in the clivus. Methods: The clinical, laboratory, and imaging findings of the case are reviewed, and the embryogenesis of the pituitary gland, the pathophysiologic features of this condition, the diagnosis, and the treatment options are discussed. Results: A 20-year-old man presented to a local physician because of a milky nipple discharge of 2 months’ duration. He was otherwise healthy. Findings on physical examination were unremarkable except for the milky discharge from both nipples on expression. Serum prolactin, insulinlike growth factor-I, and α-fetoprotein were measured. Magnetic resonance imaging of the brain revealed a 13-mm erosive mass in the clivus. Surgical excision of the lesion was undertaken because of the propensity for aggressive lesions in this anatomic location and the high likelihood of complete resection. After the resected tissue was examined, the patient was diagnosed as having an ectopic prolactin-producing pituitary adenoma. His endocrinologic function normalized after resection, and no further therapy was needed. Conclusion: Ectopic prolactinoma in the clivus is an uncommon lesion. Surgical resection was undertaken in our patient because of the uncertainty of the diagnosis and the aggressive natural history of more common tumors of the clivus, such as chordomas. Resection provided a cure in this patient. Although it is possible that a successful trial of dopaminergic therapy would have obviated surgical intervention, this approach would be associated with additional risks if the diagnosis were incorrect. (Endocr Pract. 2009;15:143-148) Submitted for publication September 19, 2008 Accepted for publication January 5, 2009 From the 1Department of Neurological Surgery, 2Division of Endocrinology and Metabolism, Department of Medicine, and 3Department of Pathology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin. Address correspondence and reprint requests to Dr. Brandon G. Rocque, Department of Neurological Surgery, University of Wisconsin, 600 Highland Avenue, K4/822, Madison, WI 53792. © 2009 AACE.

Abbreviation: MRI = magnetic resonance imaging INTRODUCTION

The differential diagnosis for a mass in the clivus is broad, including several aggressive pathologic entities. Pituitary adenoma rarely occurs in this location. In this report, we present the first published case of an endocrinologically symptomatic ectopic prolactinoma in the clivus. CASE PRESENTATION

A 20-year-old man presented to his primary physician with a 2-month history of painless discharge from his nipples. He had noticed no other abnormalities—specifically, no changes in his appetite or stamina, polyuria, polydipsia, visual changes, diplopia, sensory or motor disturbances, or changes in bowel or bladder function. Moreover, he had no change in libido, difficulty attaining an erection, or other problem with sexual function. His medical history was remarkable only for seasonal allergies, acne, chronic knee pain, and recent removal of a benign mole from his back. Pubertal development had been normal. He took medications for seasonal allergies, daily glucosamine supplementation for knee aches, and occasional aspirin for neck pain and occipital headache. There was no history of frontal headaches or severe apoplexylike headaches. The family history was notable for hypothyroidism in both parents and diabetes in his mother. The patient was a nonsmoker, did not use alcohol, and was not sexually active. Laboratory studies performed at a local hospital revealed an elevated prolactin level (178 µg/L). Magnetic resonance imaging (MRI) of the brain, with detailed examination of the pituitary gland and adjacent anatomic areas, revealed a 13-mm erosive mass in the clivus in conjunction with a focal area of eroded bony cortex that communicated with the sella turcica (Fig. 1). The pituitary gland, infundibulum, and hypothalamus were all normal in appearance. At this point, the patient was referred to our institution. ENDOCRINE PRACTICE Vol 15 No. 2 March 2009 143

144 Ectopic Prolactinoma in the Clivus, Endocr Pract. 2009;15(No. 2)

Fig. 1. Sagittal, contrast-enhanced magnetic resonance image, showing a 13-mm erosive mass in the clivus.

Physical examination revealed a well-developed man with intact visual fields and normal findings on neurologic examination. Gynecomastia was noted, with bilateral milky white discharge. There was no lymphadenopathy or focal, tender breast lesions. He had no thyromegaly or physical signs of acromegaly. Findings on genital examination were normal. Results of laboratory studies are summarized in Table 1. The patient underwent endonasal transsphenoidal craniotomy for resection of the clival mass. A standard endonasal transsphenoidal surgical approach was performed with Stealth (Medtronic, Inc., Minneapolis, Minnesota) navigational guidance and use of the operating microscope. After removal of the sphenoid mucosa, the

fibrotic encapsulated lesion was seen eroding through the clival bone, caudal to the intact normal sella. The lesion was carefully dissected from the surrounding sclerotic clival cavity and removed en bloc for gross total resection. Inspection of the bony clival cavity revealed partial erosion into the sellar floor in the rostral direction; however, the sellar dura was intact, and no connection with the intrasellar pituitary gland was observed. Hematoxylin-eosin stained sections of the lesion revealed a fibrotic bone marrow infiltrated by a hemorrhagic neoplasm. The neoplastic cells consisted of a monomorphous population of epithelioid cells with moderate amphophilic cytoplasm and enlarged hyperchromatic nuclei. Some nuclear pleomorphism and anisonucleosis with a few mitotic figures were present. There was a relatively uniform cytoplasmic immunolabeling with chromogranin and prolactin antibodies. The tumor cells were negative for production of growth hormone and adrenocorticotropic hormone (corticotropin). The tissue also revealed various ages of hemorrhage suggested by hemosiderin deposits, hematoidin, and focal chronic inflammation (Fig. 2). The patient’s postoperative course was uneventful, and he was discharged home in good condition. Follow-up prolactin levels at 2 weeks and 3 months after resection were 47.3 and 34.0 µg/L (reference range, 0.1 to 15.0), respectively. At 3 months postoperatively, the patient continued to have a small amount of nipple discharge, although his sexual function was reportedly normal. A testosterone level was determined and confirmed to be normal, and supplemental endocrine therapy was deemed unnecessary. At 6 months after resection, the patient demonstrated no evidence of galactorrhea, decreased libido, or poor sexual function, and his prolactin level continued to decline. Dopaminergic therapy remained an option but was considered unnecessary because of the declining prolactin level and the patient’s absence of symptoms. No residual tumor was evident on MRI of the brain.

Table 1 Results of Laboratory Investigation of Study Patienta Laboratory test

Prolactin (µg/L) Insulinlike growth factor-I (µg/L) Testosterone α-Fetoprotein (µg/L) Sodium (mEq/L) Serum creatinine (mg/dL) a

NA = not available.

Preoperative results 224.7 194 NA 0 138 0.9

Postoperative results

47.3 NA Normal (level NA) NA 139 0.8

Reference range 0.1-15.0 158-497 … 0-8.5 135-145 0.6-1.3

Ectopic Prolactinoma in the Clivus, Endocr Pract. 2009;15(No. 2) 145

Fig. 2. A and B, Hematoxylin-eosin stained sections of tumor at low and high magnifications, respectively. At low magnification (A), fibrosis (arrowheads) and various ages of hemorrhage including hemosiderin deposits (arrow) are evident. At higher magnification (B), the tumor reveals a focal acinar pattern with sheets of epithelioid cells containing enlarged and pleomorphic nuclei. C and D, Prolactin antibody immunostaining of sections of tumor at low and high magnifications, respectively. At low magnification (C), most of the tumor reveals positive immunolabeling, whereas areas of fibrosis (arrowheads) are nonreactive. At higher magnification (D), strong cytoplasmic immunolabeling with prolactin is noted in the tumor cell cytoplasm.

DISCUSSION OF DIAGNOSIS

Nipple discharge can be classified into galactorrhea and nongalactorrhea discharge. The presence of fat globules in the discharge is diagnostic of galactorrhea, and the differential diagnosis is vast (1) (Table 2). In a male patient with galactorrhea, the hypothalamic-pituitary axis should be evaluated on presentation. An elevated serum prolactin level is strongly suggestive of pituitary adenoma or other less common sellar or hypothalamic lesions interrupting dopamine outflow from the hypothalamus. Thus, hyperprolactinemia should prompt evaluation with MRI. Prolactin-producing tumors larger than 10 mm in diameter, as in this case, generally are associated with serum prolactin levels that exceed 250 µg/L (2). In the case presented here, imaging showed a lesion 13 mm in greatest diameter, but the serum prolactin level was only 178 µg/L. This rendered the diagnosis somewhat uncertain. Further laboratory investigation should include dilutional analysis of the prolactin level (to correct for possible hook effect), thyroid-stimulating hormone (thyrotropin), free thyroxine, insulinlike growth factor-I, total testosterone levels, electrolyte evaluation, and morning cortisol. Clinical indications should determine the need for further work-up for a possible primary malignant tumor.

Tumors of the clivus constitute less than 1% of all intracranial neoplasms. In this rare group, there is a broad differential diagnosis, including chordoma, lymphoma, metastatic carcinoma, chondrosarcoma, meningioma, craniopharyngioma, germ cell tumor, astrocytoma, and pituitary adenoma (3). Of the last-mentioned lesions, there are about a dozen reported cases (3-13) (Table 3). Clival tumors most commonly manifest with headache, visual disturbances, or cranial nerve abnormalities or as incidental findings in the work-up of distant pathologic conditions. Other possible presentations include nasal obstruction or endocrine dysfunction. Prolactin-producing adenomas have been reported in the clivus, but no such tumors have been reported as clinically symptomatic secretory adenomas (5,7,8,10,13). The primordium of the anterior pituitary develops at approximately 4 weeks of gestational age as an outpouching of the pharyngeal stomodeum (14). During the 8th gestational week, separation occurs between the future sellar pituitary and the remnant that does not undergo migration, the pharyngeal pituitary (14). The primordium of the anterior pituitary then migrates through the craniopharyngeal canal, whereas the remnant remains within the nasopharynx. Pharyngeal pituitary tissue is present in almost all humans, as described in autopsy studies (11).

146 Ectopic Prolactinoma in the Clivus, Endocr Pract. 2009;15(No. 2)

Table 2 Differential Diagnosis of Galactorrheaa Physiologic conditions (14%)

Neoplastic processes (18%)

Pregnancy

Pituitary adenoma (prolactinoma)

Postpartum

Metastatic disease to the pituitary or hypothalamus: bronchogenic carcinoma or renal adenocarcinoma

Breast stimulation

Lymphoma

Null cell adenoma Hydatidiform mole Mixed growth hormonesecreting and prolactinsecreting tumors

Medication and herbs (20%)

Dopamine blockers: neuroleptics, metoclopramide

Inhibition of dopamine release: longterm opioid use

Inhibition of dopamine synthesis: methyldopa Depletion of dopamine stores: reserpine SSRIs: paroxetine, fluoxetine Illicit drugs: cannabis, amphetamines

Disruption of hypothalamicpituitary axis (