An Atypical Case of Lymphocytic Panhypophysitis in a Pregnant Woman

Clinical Observation An Atypical Case of Lymphocytic Panhypophysitis in a Pregnant Woman Emma C. Davies, MD, Frederick A. Jakobiec, MD, DSc, Anna M. Stagner, MD, Joseph F. Rizzo III, MD Abstract: We describe a case of lymphocytic panhypophysitis (LPH) in a 30-year-old woman presenting with throbbing headaches and vision changes during her third trimester. LPH is the rarest subclassification of lymphocytic hypophysitis; it is typically found in males and has not previously been associated with pregnancy. Anterior and posterior pituitary deficits together with headaches should raise a high degree of suspicion regarding the possibility of LPH. The atypical magnetic resonance imaging finding of a heterogeneous pituitary mass additionally raised concern about pituitary apoplexy. Tissue from a transsphenoidal biopsy permitted diagnosis of lymphocytic hypophysitis. There was infiltration of the pituitary gland by small B and T lymphocytes. Resolution of the visual symptoms occurred after the biopsy and treatment with intravenous steroids. Journal of Neuro-Ophthalmology 2016;36:313-316 doi: 10.1097/WNO.0000000000000362 © 2016 by North American Neuro-Ophthalmology Society L ymphocytic hypophysitis is a rare autoimmune inflammatory disease of the pituitary gland. It can be subclassified based on location into: lymphocytic adenohypophysitis (LAH) with anterior pituitary inflammation; lymphocytic infundibuloneurohyophysitis (LINH) with posterior pituitary inflammation; and lymphocytic panhypophysitis (LPH) with inflammation of the entire pituitary gland (1). The rarest subtype is LPH. We report LPH in a pregnant woman, a variant that has not been Department of Ophthalmology (ECD, JFR), Neuro-Ophthalmology Service, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts; Department of Ophthalmology (ECD, FAJ, AMS), David G. Cogan Laboratory of Ophthalmic Pathology, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts; and Department of Ophthalmology (ECD, FAJ, AMS, JFR), Harvard Medical School, Boston, Massachusetts. The authors report no conflicts of interest. Address correspondence to Frederick A. Jakobiec, MD, DSc, David G. Cogan Laboratory of Ophthalmic Pathology, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Suite 328, Boston, MA 02114; E-mail: [e-mail] Davies et al: J Neuro-Ophthalmol 2016; 36: 313-316 previously associated with pregnancy. It manifested the classic presenting symptoms of diffuse, throbbing headaches, visual field loss, and diabetes insipidus. CASE REPORT A 30-year-old woman at 34 weeks gestation developed a diffuse, throbbing headache and "sparkles" of colored light throughout her vision in her left eye. She had visual field testing that disclosed a temporal visual field defect in her left eye. Neuroimaging demonstrated a pituitary lesion and she was referred for further evaluation and management. Her neuro-ophthalmic examination was normal except for the following: decreased visual acuity of 20/60 in the left eye, dyschromatopsia of the left eye by Ishihara color plate testing, a left relative afferent pupillary defect, and automated (Humphrey 24-2) visual fields demonstrating a bitemporal defect (Fig. 1). Ophthalmoscopy of both eyes was normal. Laboratory workup revealed central hypothyroidism (TSH 0.1 mIU/L [normal: 0.5-5.0 nIU/L], free T4 0.7 ng/dL [normal: 0.8-1.8 ng/dL], total T4 7.8 mg/dL [normal: 8.5-12.5 mg/dL]), central adrenal insufficiency (morning cortisol 2.0 mg/dL [normal: 7-28 mg/dL]), and diabetes insipidus (serum sodium of 143 mmol/L with corresponding urine osmolality of 55 mOsm/kg water). Noncontrast brain magnetic resonance imaging (MRI) (intravenous contrast was avoided because of pregnancy) showed an 11 · 11 mm heterogenous pituitary mass that was oblate in shape, expanding the sella turcica, and exerting mass effect on the optic chiasm (Fig. 2). Given the heterogeneity of the lesion on imaging, her primary care team was concerned about the possibility of pituitary apoplexy. The patient underwent a subtotal pituitary biopsy with frozen section through a transsphenoidal approach. Histopathology of the excised specimen showed widely scattered anterior pituitary gland cells (Figs. 3A, B) varying in size and cytoplasmic eosinophilia, with dense infiltration by lymphocytes (Fig. 3C) and rare epithelioid histiocytes, 313 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Observation FIG. 1. Automated perimetry shows bitemporal hemianopic visual field loss. macrophages, and eosinophils. The surviving pituitary cells formed small clusters outlined by the reticulin silver stain (Fig. 3D). There was no posterior pituitary sampled given a subtotal biopsy. Immunohistochemical stains demonstrated the expected ratio of CD3 to CD20 cells of 7 to 3 (Fig. 3E), correlating with the normal serum ratio of T cells to B cells. CD 68 staining highlighted numerous histiocytes (Fig. 3F). Special stains for IgG and IgG4 demonstrated the presence of IgG without increased IgG4. The BrownHopps stain for bacteria and the Gomori methenamine silver stain for fungi were negative. After the biopsy and treatment with intravenous steroids (hydrocortisone 100 mg IV every 8 hours), the patient's visual acuity and dyschromatopsia in the left eye improved and her visual fields returned to normal. The central hypothyroidism, which also improved after use of intravenous steroids, was treated with levothyroxine. The diabetes insipidus was treated with desmopressin 0.2 mg orally as needed immediately after the transsphenoidal biopsy (given transient worsening of her blood chemistries), but stopped several days later because of resolution of her metabolic imbalance. She gave birth without complication and was continued on oral steroids that were slowly tapered over several months. DISCUSSION FIG. 2. Noncontrast sagittal T1 magnetic resonance imaging reveals an elongated and widened pituitary gland (arrow) with compression of the optic chiasm (arrowhead). 314 The incidence of lymphocytic hypophysitis is estimated at 1 case in 9 million persons and is found in less than 1% of pituitary surgical cases (1). The most common subtype is LAH, which predominates in females with a ratio of 6 to 1 and is strongly associated with pregnancy; 57% of all reported cases have occurred in pregnancy or the immediate postpartum period (2). It has been hypothesized that the association between LAH and pregnancy is due to an increase in pituitary antigen presentation to the immune system because of hyperplasia of the pituitary gland and its increased blood flow during gestation (3). In contrast, the much rarer (both in presentation and diagnosis) subclass LPH has been described to be more common in men with a ratio of 7 to 1 and has not previously been associated with pregnancy (4). The mean age at diagnosis of lymphocytic hypophysitis is 34.5 years for females and 44.7 years for males (2). Davies et al: J Neuro-Ophthalmol 2016; 36: 313-316 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Observation FIG. 3. Pituitary biopsy specimen. A. Surviving clusters of pituitary cells are present (hematoxylin and eosin, ·100). B. Groups of parenchymal cells are separated by fibrous septae and individual cells vary in size and cytoplasmic eosinophilia (hematoxylin and eosin, ·200). C. There is a dense accumulation of lymphocytes in the pituitary (hematoxylin and eosin, ·200). D. Reticulin silver stain demonstrates delicate fibrils enveloping clusters of anterior pituitary cells (hematoxylin and eosin, ·50). E. T cells (left panel) outnumber B cells (right panel) consistent with a polyclonal immunotype indicating an inflammatory lesion (immunoperoxidate reaction, diaminobenzidine chromogen, hematoxylin and eosin, ·200). F. CD68 positive histiocytes are present in large numbers, probably in response to damaged pituitary cells (immunoperoxidative reaction, diaminobenzidine chromagen, hematoxylin and eosin, ·200). Clinical presentation of lymphocytic hypophysitis can be variable, but the most common initial symptom is a throbbing headache, which is not commonly a feature of pituitary adenoma. Symptoms of anterior hypopituitarism include fatigue/cold intolerance from hypothyroidism, lethargy from hypocortisolism, and amenorrhea from low follicle stimulating and luteinizing hormones. Abnormality in the functioning of the posterior pituitary, either from direct invasion or compression of the pituitary stalk, results in deficient antidiuretic hormone causing diabetes insipidus. Because diabetes insipidus typically is not seen with anterior pituitary adenomas, the detection of this finding before any surgery has been performed is strong evidence of LPH when there is also anterior gland dysfunction. Usual findings of LAH on MRI are a symmetrically enlarged anterior Davies et al: J Neuro-Ophthalmol 2016; 36: 313-316 pituitary, often with suprasellar extension and enhancement, whereas typical findings of LINH on MRI are a diffusely thickened pituitary stalk, with loss of the normal T1 hyperintense spot of the pituitary stalk (4). The classic findings of LPH on MRI are a combination of the anterior and posterior pituitary abnormalities. Our patient demonstrated the characteristic diffuse, throbbing headaches, and rapidly progressive temporal visual field loss that have been documented as early findings of lymphocytic hypophysitis (5). However, there are important aspects of her presentation that are atypical and should be emphasized. LPH is more frequently encountered in male patients and previously has not been associated with pregnancy (4). Our patient's hematologic studies and neuroimaging revealed both anterior and posterior involvement. 315 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Observation Diabetes insipidus could arguably result from compression of the posterior pituitary by an anterior pituitary gland expanded by inflammation. The MRI findings of enlargement of the pituitary gland and the pituitary stalk in the current case are consistent with a diagnosis of LPH. Moreover, the pituitary enlargement on MRI demonstrated an elongated lesion that was mildly heterogeneous, which raised concern for a hemorrhage within the pituitary mass and the possibility of pituitary apoplexy. Although histologic confirmation of posterior pituitary inflammation was not possible in our patient, the diagnosis of LPH was based on neuroimaging. However, because the anterior and posterior pituitaries originate from different organs, it remains unclear what common antigen could trigger an autoimmune condition affecting both lobes of the pituitary gland (6). The etiologies of headache during pregnancy are myriad, and include, most notably, migraine but also tension and musculoskeletal pains, as well as those that occur with preeclampsia, pituitary apoplexy, and lymphocytic hypophysitis. After a pituitary mass has been confirmed on imaging, other entities must be ruled out such as pituitary adenoma with or without apoplexy, craniopharyngioma, Rathke cleft cyst, meningioma, sarcoidosis, tuberculosis, Langerhans histiocytosis, granulomatosis with polyangiitis, lymphocytic hypophysitis, IgG4 disease, and lymphoma/ leukemia (7). Although histopathologic examination serves as the basis for confirming the diagnosis of lymphocytic hypophysitis, cases with classic neuroimaging results but lacking visual field loss have successfully been treated without a biopsy and with corticosteroids alone (5). In our patient, there was improvement in visual acuity and complete recovery of the visual fields after transsphenoidal subtotal biopsy of the mass and treatment with intravenous steroids. Because cases 316 of lymphocytic hypophysitis have been documented to recur, monitoring of patients with visual field testing is recommended (8). STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: E. C. Davies, F. A. Jakobiec, A. M. Stagner, and J. F. Rizzo III; b. Acquisition of data: E. C. Davies, F. A. Jakobiec, A. M. Stagner, and J. F. Rizzo III; c. Analysis and interpretation of data: E. C. Davies, F. A. Jakobiec, A. M. Stagner, and J. F. Rizzo III. Category 2: a. Drafting the article: E. C. Davies, F. A. Jakobiec, A. M. Stagner, and J. F. Rizzo III; b. Revising it for intellectual content: E. C. Davies, F. A. Jakobiec, A. M. Stagner, and J. F. Rizzo III. Category 3: a. Final approval of the completed article: E. C. Davies, F. A. Jakobiec, A. M. Stagner, and J. F. Rizzo III. REFERENCES 1. Glezer A, Bronstein M. Pituitary autoimmune disease: nuances in clinical presentation. Endocrine. 2012;42:74-79. 2. Thodou E, Asa S, Kontogeorgos G, Kovacs K, Horvath E, Ezzat S. Clinical case seminar: lymphocytic hypophysitis: clinicopathological findings. J Clin Endocrinol Metab. 1995;80:2302-2311. 3. Laway B, Mir S. Pregnancy and pituitary disorders: challenges in diagnosis and management. Indian J Endocrinol Metab. 2013;17:996-1004. 4. Hamnvik O, Laury A, Laws E, Kaiser U. Lymphocytic hypophysitis with diabetes insipidus in a young man. Nat Rev Endocrinol. 2010;6:464-470. 5. Tubridy N, Molloy J, Saunders D, Belli A, Powell M, Plant G. Postpartum pituitary hypophysitis. J Neuroophthalmol. 2001;21:106-108. 6. Abe T. Lymphocytic infundibulo-neurohypophysitis and infundibulo-panhypophysitis regarded as lymphocytic hypophysitis variant. Brain Tumor Pathol. 2008;25:59-66. 7. Sam S, Molitch M. The pituitary mass: diagnosis and management. Rev Endocr Metab Disord. 2005;6:55-62. 8. Biswas M, Thackare H, Jones H, Jones MK, Bowen-Simpkins P. Lymphocytic hypophysitis and headache in pregnancy. BJOG. 2002;109:1184-1186. Davies et al: J Neuro-Ophthalmol 2016; 36: 313-316 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.