Clinical Neurology and Neurosurgery 125 (2014) 125–130
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Review
Ipilimumab treatment associated pituitary hypophysitis: Clinical presentation and imaging diagnosis Yosef Chodakiewitz a , Sanford Brown b , Jerrold L. Boxerman b , Jeffrey M. Brody b , Jeffrey M. Rogg b,∗ a b
Alpert Medical School, Brown University, 222 Richmond St, Providence 02903, USA Department of Diagnostic Imaging, Rhode Island Hospital, Alpert Medical School of Brown University, 593 Eddy Street, Providence 02903, USA
a r t i c l e
i n f o
Article history: Received 19 March 2014 Received in revised form 5 June 2014 Accepted 8 June 2014 Available online 29 July 2014 Keywords: Melanoma Ipilimumab Autoimmune lymphocytic hypophysitis MRI Pituitary
a b s t r a c t Ipilimumab is an immunomodulating drug for use in treatment of unresectable or metastatic melanoma with autoimmune lymphocytic hypophysitis as a reported complication. We describe three recent cases of ipilimumab associated autoimmune hypophysitis (IAH) at our institution, and provide a selected literature review showing its variable clinical presentation, imaging appearance and treatment in order to expedite early and appropriate IAH management. Patients had variable clinical presentation of hypophysitis, including headache, fatigue, visual changes, endocrinopathy, and/or hyponatremia. Contrast enhanced MRI showed symmetric pituitary gland and stalk enlargement in all of our cases and received a presumptive diagnosis of IAH. Following cessation of therapy and treatment there was normalization of pituitary morphology at follow-up MRI and return to clinical baseline. Varying clinical presentation can complicate the diagnosis of lymphocytic hypophysitis. One must be cognizant of its overall clinical and radiologic picture in patients receiving ipilimumab, now commonly used for the treatment of metastatic melanoma. © 2014 Elsevier B.V. All rights reserved.
Contents 1. 2.
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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Case reports . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Case 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Case 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Case 3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction In 2011, the Food and Drug Administration (FDA) first approved ipilimumab for clinical use in the treatment of unresectable or metastatic melanoma [1]. Additionally, ipilimumab is currently undergoing clinical trials for use in lung cancers and metastatic hormone-refractory prostate cancer [2,3].
∗ Corresponding author. Tel.: +1 11 401 444 5184. E-mail address: [email protected] (J.M. Rogg). http://dx.doi.org/10.1016/j.clineuro.2014.06.011 0303-8467/© 2014 Elsevier B.V. All rights reserved.
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Ipilimumab, also known as Yervoy, is a fully human monoclonal antibody that binds to and blocks CTLA-4. CTLA-4 is a protein receptor on the surface of activated cytotoxic T-lymphocytes (CTLs) that delivers inhibitory signals to the CTLs in response to binding B7 proteins from antigen presenting cells [4]. In this fashion, CTLA-4 normally functions in a negative feedback loop to modulate the immune response and prevent damage to normal host tissue [5]. Ipilimumab is therefore designed to potentiate antitumor T-cell responses in cancer therapy by inhibiting the down-regulation of activated CTLs. The most common complications observed with ipilimumab treatment are immune-related adverse events (irAEs), which have
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been reported to occur in 64% of patients enrolled in clinical trials and typically affect the GI tract and skin, while hepatic, endocrine, and neurologic events occur less frequently [1]. Regarding irAEs affecting the endocrine system, ipilimumab autoimmune hypophysitis (IAH) is one of the most frequent dose-limiting complications, with a reported incidence of up to 17% in clinical trials [6]. This side-effect poses significant management difficulties, particularly due to the fact that endocrinopathies often masquerade as nonspecific conditions ascribed to other causes [7]. Brain MRI with close attention to the pituitary gland may aid in the diagnosis of IAH and thereby help guide appropriate clinical management. In general, lymphocytic hypophyitis had always been considered a rare autoimmune disease, with an estimated incidence of one in 9 million [8]. However, following the use of immunomodulating medications, such as ipilimumab, the frequency appears to be increasing [9]. At our institution within the last year we have confirmed by MRI three cases of IAH secondary to Ipilimumab treatment. We discuss the variable presentation and clinical course of these cases. 2. Case reports 2.1. Case 1 A 45 year-old female, previously diagnosed in February 2006 with melanoma in situ and treated with Mohs surgery, represented despite negative biannual skin exams with a lung nodule detected on a routine screening chest radiograph and confirmed by chest CT in July 2011. This was found to be metastatic melanoma with negative margins by bronchoscopy and right-sided videoassisted thoracoscopic surgery with wedge resection. A PET scan for completion of staging showed no other evidence of metastatic disease and the patient was treated with ipilimumab (3 mg/kg IV q3Week for a total of 4 doses). The patient had no prior history of autoimmune disease. Prior to initiating ipilimumab treatment, a brain MRI was performed as part of her metastatic workup that revealed no brain pathology (Fig. 1A). In the interval between her second and third ipilimumab doses, the patient complained of headaches. Laboratory evaluation was significant for low free T3 levels (130 pg/dl, normal 230–420). A brain MRI was performed 5 weeks after the pre-treatment MRI and showed interval enlargement of the pituitary gland, increased from 5 mm to 12 mm in craniocaudal dimension, with thickening of the pituitary infundibulum and intense homogenous enhancement of these structures (Fig. 1B). Metastatic disease to the pituitary was considered, but given the short time interval since the normal pre-treatment MRI and the diffuse uniform enhancement of the pituitary gland and infundibulum, IAH was considered to be the most likely diagnosis. Daily steroid therapy to reduce inflammation (1 mg per kg for a total dose of 80 mg daily) and levothyroxine to treat thyroid deficiency (50 mcg daily) were initiated. Further ipilimumab administration was postponed for four weeks, pending successful steroid taper without return of the patient’s headaches. The patient was then able to complete cycles three and four of ipilimumab therapy without return of symptoms. Brain MRI performed 8 months following completion of ipilimumab showed normalization of pituitary size and enhancement pattern (Fig. 1C). This finding confirmed the prior preliminary diagnosis of hypophysitis secondary to ipilimumab treatment. 2.2. Case 2 A 65 year-old female with metastatic BRAF mutant melanoma presented in February 2013 with symptoms of headaches and
blurry vision, and was found to have a single right occipital brain metastatic lesion. She was subsequently found to also have metastatic disease to the lung and mediastinum. The patient underwent occipital craniotomy and gamma knife radiosurgery for treatment of the brain metastasis. Three weeks following her craniotomy, four-cycle ipilimumab therapy was initiated for treatment of residual systemic metastatic disease. Two weeks following initiation of the third cycle of ipilimumab, the patient experienced severe fatigue and reduced visual acuity, and was found to be hyponatremic and hypotensive. She was treated with intravenous normal saline and dexamethasone, with improvement in plasma sodium level and blood pressure. Additional work-up revealed panhypopituitarism with low levels of TSH (0.122 IU/ml, normal 0.350–5.50), free T4 (0.52 ng/dl, normal 0.80–1.80), total T3 (67 ng/dl, normal 80–180) and morning cortisol (1.5 g/dl, normal 5.5–20.0). In comparison to a pre-ipilimumab brain MRI from February 2013 (Fig. 2A), brain MRI demonstrated enlargement of the pituitary gland with upwardly convex superior margin and heterogenous contrast enhancement (Fig. 2B). Differential diagnosis included hypohysistis related to ipilimumab treatment versus metastatic disease to the pituitary. Again, course of change favored IAH. The patient was placed on hydrocortisone and on levothyroxine to treat her panhypopituitarism. Her final dose of ipilimumab was deferred pending the follow-up imaging study, which occurred 20 days later (Fig. 2C). The pituitary gland was then shown to be trending toward normal size and morphology, confirming the diagnosis of IAH.
2.3. Case 3 A 63-year-old female presented in September 2011 with a palpable left supraclavicular lymph node. An excisional biopsy revealed BRAF positive malignant melanoma. An extensive workup was performed including a staging PET/CT, MR of the brain, and skin, without evidence of a primary lesion. Bilateral modified radical neck dissections were performed and did not identify additional sites of nodal disease. Findings were consistent with stage IIIa disease without a known primary and the patient was observed. She re-presented the following year with a new non-pigmented nodule on her left upper back consistent with biopsy-proven metastatic melanoma. Following a wide local excision, staging PET/CT demonstrated additional sites of subcarinal nodal disease that was resected. Seven months after this resection, a screening PET/CT demonstrated recurrent subcarinal and right supraclavicular nodal disease, right clavicular and T6 osseous disease. A four cycle treatment with ipilimumab was initiated in March 2012 with an unremarkable clinical course during the first 3 cycles of treatment. After the 4th cycle, the patient developed progressive fatigue and serum endocrinology work-up revealed panhypopituitarism with low levels of TSH (0.211 uIU/ml, normal 0.350–5.50), free T4 (0.48 ng/dl, normal 0.80–1.80), total T3 (60 ng/dl, normal 80–180) and morning cortisol (1.7 g/dl, normal 5.5–20.0). Contrast enhanced brain MRI demonstrated thickening with homogeneous enhancement of the pituitary infundibulum and gland (Fig. 3B) which was new in comparison to the preipilimumab brain MRI from March 2013 (Fig. 3A). The differential diagnosis included IAH, pituitary adenoma, or metastatic disease. She was treated with systemic glucocorticoids and pituitary hormone replacement including hydrocortisone and levothyroxine. The patient’s fatigue resolved and a follow-up MRI of the brain in August 2013 demonstrated a normal appearance of the pituitary infundibulum and gland (Fig. 3C). Both clinical course and radiographic findings were consistent with IAH.
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Fig. 1. MRI at three different time points (left column, pre-contrast sagittal T1-weighted; middle column, post-contrast sagittal T1-weighted; right column, post-contrast coronal T1-weighted) showing transient pituitary hypophysitis in a 45 year old woman treated with ipilimumab for metastatic melanoma. (A) Pre-ipilimumab MRI showing baseline pituitary measuring 5 mm craniocaudal dimension. (B) MRI for assessment of new onset headache after second cycle of ipilimumab showing interval homogenous enhancement and enlargement of pituitary to 12 mm craniocaudal dimension. These findings are indicative of lymphocytic hypophysitis. (C) MRI 8 months following completion of ipilimumab treatment showing interval normalization of pituitary enhancement pattern and size to 3 mm craniocaudal dimension.
3. Discussion Hypophysitis can be a complication arising from the use of Ipilimumab treatment in cancer patients. The clinical presentation of hypophysitis can vary. Symptoms will often include those related to mass effect from pituitary enlargement, hypopituitarism, or hyperprolactinemia [10,11]. The symptoms associated with pituitary enlargement (i.e. headache, visual change) typically precede endocrinopathy caused by pituitary inflammation. A working diagnosis of IAH can be made based on typical clinical presentation (Table 1) in combination with characteristic MRI findings, although a definitive diagnosis of hypophysitis requires histological examination of pituitary tissue [10].
Table 1 Clinical association of ipilimumab induced hyphophysitis. Mass effect from pituitary enlargement Deficient anterior pituitary hormones Cortisol deficiency (ACTH) Thyroid-stimulating hormone Gonadotropins (FSH, LH)
Deficient posterior pituitary hormones Diabetes insipidus (ADH)
The characteristic findings of hypophysitis on MRI include a symmetrically enlarged pituitary gland and stalk that enhance homogenously following gadolinium-based contrast administration. On pre-contrast images, the typical “posterior pituitary bright spot”, related to the presence of vasopressin, is typically absent. Often the inflammatory process results in the presence of a “dural tail” on contrast enhanced images adjacent to the pituitary gland. By contrast, pituitary macroadenomas are typically associated with an asymmetrically enlarged and heterogeneously enhancing intrapituitary mass, without “dural tail” or stalk thickening (Table 2) [11]. These MRI findings have been described specifically in the setting of ipilimumab-induced IAH [12]. Also, as demonstrated in our patients, normalization of the pituitary gland enhancement and
Table 2 MR features of lymphocytic hypophysitis versus pituitary adenoma.
Headache, visual loss, diplopia Pituitary shape Fatigue, anorexia, weight loss, hypoglycemia, hypotension Fatigue, cold intolerance, anorexia, constipation, dry skin, bradycardia Women → infertility, dysmenorrhea, amenorrhea Men → infertility, fatigue, decrease libido Polyuria, polydipsia
Enhancement
Neurohypophysis (T1bright posterior pit) Sella tursica Gland normalization following cessation of therapy
Hypophysitis
Adenoma
Symmetrically enlarged gland and stalk Intense homogeneous may have dural tail Absent
Asymmetrically or focally enlarged gland with normal stalk Mild to moderate, heterogeneous without dural tail Preserved
Normal Present
May be expanded Absent
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Fig. 2. MRI at three different time points (left column, pre-contrast sagittal T1-weighted; middle column, post-contrast sagittal T1-weighted; right column, post-contrast coronal T1-weighted) showing transient pituitary hypophysitis in a 65 year old woman treated with ipilimumab for metastatic melanoma. (A) Pre-ipilimumab MRI showing baseline pituitary measuring 6 mm craniocaudal dimension with concave-down shape of superior margin of pituitary gland. (B) After the third cycle of ipilimumab, the patient presented with fatigue, hypotension, hyponatremia, hypocortisolemia, and central hypothyroidism. MRI demonstrates a convex-upward superior margin of the pituitary gland with heterogenous enhancement and 12 mm craniocaudal dimension. (C) MRI 20 days after diagnosis of ipilimumab-induced hypophysitis and consequent withholding of ipilimumab treatment. There is normalization of the pituitary gland morphology, now measuring 8 mm craniocaudal dimension with concave-down superior margin.
morphology rapidly follows cessation of drug therapy and steroid initiation. Case 1and Case 3 described above exemplify the more typical diagnosis of early hypophysitis with a presenting symptom of headache and/or fatigue, respectively, followed by discovery of subclinical endocrinopathy. MRI demonstrated symmetric enlargement and homogenous enhancement of pituitary gland and stalk in these cases. Case 2, on the other hand, had less typical features of hypophysitis. Hypophysitis usually clinically affects the function of the adenohypophesis, and involvement of the posterior pituitary is less common [13]. In the unusual case where the posterior pituitary function is involved, diabetes insipidus, rather than hyponatremia, has typically been reported [13]. However, there has been one other reported case of hyponatremia associated with hypophysitis secondary to ipilimumab treatment [14]. Because cortisol has a negative feedback effect in the regulation of ADH secretion from the posterior pituitary, the loss of cortisol can lead to SIADH and hyponatremia. Thus, in our Case 2, hyponatremia may be due to SIADH secondary to the anterior pituitary lesion causing cortisol deficiency. Hypopituitarism is an often overlooked cause of hyponatremia [15]. Additionally, the MRI findings in Case 2 were atypical since during the active hypophysitis stage, a heterogeneous enhancement pattern of the pituitary, rather than a more characteristic homogenous enhancement, was seen. This less typical MRI pattern has
been previously reported in a minority of cases of lymphocytic hypophysitis [13]. The variable clinical presentations and radiologic findings complicate the diagnosis of lymphocytic hypophysitis. For instance, many of the associated typical imaging findings overlap with those of the much more-common condition of nonsecreting pituitary adenoma (NSPA) [16]. It is important to distinguish hypophysitis from NSPA, as surgery may be indicated for NSPA but typically not for hypophysitis. Though lymphocytic hypophysitis is presumed to involve autoimmune-antibodies, there is no reliable serologic test based on autoantibodies yet available. Consequently, the presurgical diagnosis of hypophysitis is currently best made based on clinical suspicion and consistent MRI. No single radiologic sign can be relied upon to completely distinguish hypophysitis from NSPA, resulting in approximately 40% of patients with autoimmune hypophysitis unnecessarily undergoing surgical resection for presumed NSPA [16]. A recent case-control study described a radiologic scoring system for distinguishing automimmune hypohysitis from NSPA, which significantly improves the rate of accurate classification of hypophysitis patients to >95%, increased from the more typical moderate rate of 60% [16]. In this system, the individual significance of various MRI associated findings was defined. Comparing NSPA to hypophysitis, features most typical of hypophysitis are symmetric pituitary enlargement, homogenous appearance both on pre- and post-contrast images, and intense pituitary enhancement. In contrast, the individual features
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Fig. 3. MRI at three different time points (left column, pre-contrast sagittal T1-weighted; middle column, post-contrast sagittal T1-weighted; right column, post-contrast coronal T1-weighted) showing transient pituitary hypophysitis in a 63 year old woman treated with ipilimumab for metastatic melanoma. (A) Pre-ipilimumab MRI showing baseline appearance of the sella tursica with a partially empty sella. (B) After the fourth cycle of ipilimumab, the patient presented with progressive fatigue and serum endocrinology work-up revealed panhypopituitarism. MRI demonstrates a convex-upward superior margin of an enlarged pituitary gland with homogeneous enhancement. (C) MRI 3 months following the diagnosis of ipilimumab-induced hypophysitis demonstrates normalization of the pituitary gland with initial sellar morphology.
of NSPAs were asymmetric pituitary enlargement, heterogenous contrast uptake, and less intense enhancement. In that study, thickened pituitary stalk and/or loss of pituitary bright spot strongly favored hypophysitis over NSPA. The “dural tail sign” was nonspecific, being seen commonly in both conditions. Lymphocytic hypophysitis is the most common histopathological subtype of hypophysitis. Other subtypes have been recognized, such as xanthomatous hypophysitis, granulomatous hypophysitis, IgG4-related hypophysitis, and mixed forms, though they are rare [17]. Hypophysitis may occur as a primary lesion, or may result secondarily to some other primary cause. The condition may be secondary to inflammation from adjacent lesions, such as a Rathke’s cleft cyst, menigioma, or germinoma [8]. It may result as a consequence of underlying systemic conditions, such as Wegener’s granulomatosis, sarcoidosis, tuberculosis, syphilis, or Langerhan’s cell histiocytosis [8,18,19]. In fact, it most commonly arises as a rare complication of pregnancy in the late pregnancy or early postpartum period [8,17]. Or, as described in the present report, hypophysitis may result as an adverse effect of immunomodulatory drugs, such as with ipilimumab. At present, the treatment for IAH is directed primarily to symptom relief. Medical treatment is preferred to surgical or radiosurgical interventions except in refractory symptomatic cases [8,16]. Replacement of deficient hormones is common, though opinions diverge on whether the aim should be solely to adopt supportive therapy with hormonal replacement or whether treatment should rather primarily aim to reduce the inflammatory process [17]. Glucorticoids are often an initial treatment of choice, as they can be effective both as anti-inflammatory agent to reduce
enlarged pituitary mass and as replacement of defective adrenal function [8,17]. When steroid treatment fails or cannot be tolerated by patients, other treatment with agents directed at immune modulation, including azathioprine (AZA), methotrexate, and cyclosporin A have been described [20–22]. However, these steroid alternatives do not have as much proven efficacy in treating hypophysitis in comparison to steroid treatment [17]. The need for long term hormone-replacement in hypophysitis is unpredictable, therefore long term follow-up is required as hormonal deficits may be permanent [17]. As the use of ipilimumab for treatment of melanoma becomes more common, clinicians must be aware of the risk for developing the complication of IAH. Early MRI is recommended in the setting of appropriate clinical symptoms for early diagnosis and management of this potential therapeutic complication in patients with melanoma.
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[6] Dillard T, Yedinak CG, Alumkal J, Fleseriu M. Anti-CTLA-4 antibody therapy associated autoimmune hypophysitis: serious immune related adverse events across a spectrum of cancer subtypes. Pituitary 2010;13:29–38. [7] Weber JS, Dummer R, de Pril V, Lebbe C, Hodi FS. Patterns of onset and resolution of immune-related adverse events of special interest with ipilimumab: detailed safety analysis from a phase 3 trial in patients with advanced melanoma. Cancer 2013;119:1675–82. [8] Caturegli P, Newschaffer C, Olivi A, Pomper MG, Burger PC, Rose NR. Autoimmune hypophysitis. Endocr Rev 2005;26:599–614. [9] Juszczak A, Gupta A, Karavitaki N, Middleton MR, Grossman AB. Ipilimumab: a novel immunomodulating therapy causing autoimmune hypophysitis: a case report and review. Eur J Endocrinol Eur Feder Endocr Soc 2012;167:1–5. [10] Glezer A, Bronstein MD. Pituitary autoimmune disease: nuances in clinical presentation. Endocrine 2012;42:74–9. [11] Bellastella A, Bizzarro A, Coronella C, Bellastella G, Sinisi AA, De Bellis A. Lymphocytic hypophysitis: a rare or underestimated disease? Eur J Endocrinol Eur Feder Endocr Soc 2003;149:363–76. [12] Carpenter KJ, Murtagh RD, Lilienfeld H, Weber J, Murtagh FR. Ipilimumabinduced hypophysitis: MR imaging findings. AJNR Am J Neuroradiol 2009;30:1751–3. [13] Hindocha A, Chaudhary BR, Kearney T, Pal P, Gnanalingham K. Lymphocytic hypophysitis in males. Jo Clin Neurosci 2013;20:743–5. [14] Barnard ZR, Walcott BP, Kahle KT, Nahed BV, Coumans JV. Hyponatremia associated with Ipilimumab-induced hypophysitis. Med Oncol 2012;29:374–7.
[15] Diederich S, Franzen NF, Bahr V, Oelkers W. Severe hyponatremia due to hypopituitarism with adrenal insufficiency: report on 28 cases. Eur J Endocrinol 2003;148:609–17. [16] Gutenberg A, Larsen J, Lupi I, Rohde V, Caturegli P. A radiologic score to distinguish autoimmune hypophysitis from nonsecreting pituitary adenoma preoperatively. Am J Neuroradiol 2009;30:1766–72. [17] Carmichael JD. Update on the diagnosis and management of hypophysitis. Curr Opin Endocrinol Diabetes Obes 2012;19:314–21. [18] Sautner D, Saeger W, Lüdecke DK, Jansen V, Puchner MJA. Hypophysitis in surgical and autoptical specimens. Acta Neuropathol (Berl) 1995;90: 637–44. [19] Goyal M, Kucharczyk W, Keystone E. Granulomatous hypophysitis due to Wegener’s granulomatosis. Am J Neuroradiol 2000;21:1466–9. [20] Lecube A, Francisco G, Rodriguez D, Ortega A, Codina A, Hernandez C, et al. Lymphocytic hypophysitis successfully treated with azathioprine: first case report. J Neurol Neurosurg Psychiatry 2003;74:1581–3. [21] Tubridy N, Saunders D, Thom M, Asa SL, Powell M, Plant GT, et al. Infundibulohypophysitis in a man presenting with diabetes insipidus and cavernous sinus involvement. J Neurol Neurosurg Psychiatry 2001;71:798–801. [22] Ward L, Paquette J, Seidman E, Huot C, Alvarez F, Crock P, et al. Severe autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy in an adolescent girl with a novel AIRE mutation: response to immunosuppressive therapy. J Clin Endocrinol Metab 1999;84:844–52.
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Review
Ipilimumab treatment associated pituitary hypophysitis: Clinical presentation and imaging diagnosis Yosef Chodakiewitz a , Sanford Brown b , Jerrold L. Boxerman b , Jeffrey M. Brody b , Jeffrey M. Rogg b,∗ a b
Alpert Medical School, Brown University, 222 Richmond St, Providence 02903, USA Department of Diagnostic Imaging, Rhode Island Hospital, Alpert Medical School of Brown University, 593 Eddy Street, Providence 02903, USA
a r t i c l e
i n f o
Article history: Received 19 March 2014 Received in revised form 5 June 2014 Accepted 8 June 2014 Available online 29 July 2014 Keywords: Melanoma Ipilimumab Autoimmune lymphocytic hypophysitis MRI Pituitary
a b s t r a c t Ipilimumab is an immunomodulating drug for use in treatment of unresectable or metastatic melanoma with autoimmune lymphocytic hypophysitis as a reported complication. We describe three recent cases of ipilimumab associated autoimmune hypophysitis (IAH) at our institution, and provide a selected literature review showing its variable clinical presentation, imaging appearance and treatment in order to expedite early and appropriate IAH management. Patients had variable clinical presentation of hypophysitis, including headache, fatigue, visual changes, endocrinopathy, and/or hyponatremia. Contrast enhanced MRI showed symmetric pituitary gland and stalk enlargement in all of our cases and received a presumptive diagnosis of IAH. Following cessation of therapy and treatment there was normalization of pituitary morphology at follow-up MRI and return to clinical baseline. Varying clinical presentation can complicate the diagnosis of lymphocytic hypophysitis. One must be cognizant of its overall clinical and radiologic picture in patients receiving ipilimumab, now commonly used for the treatment of metastatic melanoma. © 2014 Elsevier B.V. All rights reserved.
Contents 1. 2.
3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Case reports . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Case 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Case 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Case 3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction In 2011, the Food and Drug Administration (FDA) first approved ipilimumab for clinical use in the treatment of unresectable or metastatic melanoma [1]. Additionally, ipilimumab is currently undergoing clinical trials for use in lung cancers and metastatic hormone-refractory prostate cancer [2,3].
∗ Corresponding author. Tel.: +1 11 401 444 5184. E-mail address: [email protected] (J.M. Rogg). http://dx.doi.org/10.1016/j.clineuro.2014.06.011 0303-8467/© 2014 Elsevier B.V. All rights reserved.
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Ipilimumab, also known as Yervoy, is a fully human monoclonal antibody that binds to and blocks CTLA-4. CTLA-4 is a protein receptor on the surface of activated cytotoxic T-lymphocytes (CTLs) that delivers inhibitory signals to the CTLs in response to binding B7 proteins from antigen presenting cells [4]. In this fashion, CTLA-4 normally functions in a negative feedback loop to modulate the immune response and prevent damage to normal host tissue [5]. Ipilimumab is therefore designed to potentiate antitumor T-cell responses in cancer therapy by inhibiting the down-regulation of activated CTLs. The most common complications observed with ipilimumab treatment are immune-related adverse events (irAEs), which have
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been reported to occur in 64% of patients enrolled in clinical trials and typically affect the GI tract and skin, while hepatic, endocrine, and neurologic events occur less frequently [1]. Regarding irAEs affecting the endocrine system, ipilimumab autoimmune hypophysitis (IAH) is one of the most frequent dose-limiting complications, with a reported incidence of up to 17% in clinical trials [6]. This side-effect poses significant management difficulties, particularly due to the fact that endocrinopathies often masquerade as nonspecific conditions ascribed to other causes [7]. Brain MRI with close attention to the pituitary gland may aid in the diagnosis of IAH and thereby help guide appropriate clinical management. In general, lymphocytic hypophyitis had always been considered a rare autoimmune disease, with an estimated incidence of one in 9 million [8]. However, following the use of immunomodulating medications, such as ipilimumab, the frequency appears to be increasing [9]. At our institution within the last year we have confirmed by MRI three cases of IAH secondary to Ipilimumab treatment. We discuss the variable presentation and clinical course of these cases. 2. Case reports 2.1. Case 1 A 45 year-old female, previously diagnosed in February 2006 with melanoma in situ and treated with Mohs surgery, represented despite negative biannual skin exams with a lung nodule detected on a routine screening chest radiograph and confirmed by chest CT in July 2011. This was found to be metastatic melanoma with negative margins by bronchoscopy and right-sided videoassisted thoracoscopic surgery with wedge resection. A PET scan for completion of staging showed no other evidence of metastatic disease and the patient was treated with ipilimumab (3 mg/kg IV q3Week for a total of 4 doses). The patient had no prior history of autoimmune disease. Prior to initiating ipilimumab treatment, a brain MRI was performed as part of her metastatic workup that revealed no brain pathology (Fig. 1A). In the interval between her second and third ipilimumab doses, the patient complained of headaches. Laboratory evaluation was significant for low free T3 levels (130 pg/dl, normal 230–420). A brain MRI was performed 5 weeks after the pre-treatment MRI and showed interval enlargement of the pituitary gland, increased from 5 mm to 12 mm in craniocaudal dimension, with thickening of the pituitary infundibulum and intense homogenous enhancement of these structures (Fig. 1B). Metastatic disease to the pituitary was considered, but given the short time interval since the normal pre-treatment MRI and the diffuse uniform enhancement of the pituitary gland and infundibulum, IAH was considered to be the most likely diagnosis. Daily steroid therapy to reduce inflammation (1 mg per kg for a total dose of 80 mg daily) and levothyroxine to treat thyroid deficiency (50 mcg daily) were initiated. Further ipilimumab administration was postponed for four weeks, pending successful steroid taper without return of the patient’s headaches. The patient was then able to complete cycles three and four of ipilimumab therapy without return of symptoms. Brain MRI performed 8 months following completion of ipilimumab showed normalization of pituitary size and enhancement pattern (Fig. 1C). This finding confirmed the prior preliminary diagnosis of hypophysitis secondary to ipilimumab treatment. 2.2. Case 2 A 65 year-old female with metastatic BRAF mutant melanoma presented in February 2013 with symptoms of headaches and
blurry vision, and was found to have a single right occipital brain metastatic lesion. She was subsequently found to also have metastatic disease to the lung and mediastinum. The patient underwent occipital craniotomy and gamma knife radiosurgery for treatment of the brain metastasis. Three weeks following her craniotomy, four-cycle ipilimumab therapy was initiated for treatment of residual systemic metastatic disease. Two weeks following initiation of the third cycle of ipilimumab, the patient experienced severe fatigue and reduced visual acuity, and was found to be hyponatremic and hypotensive. She was treated with intravenous normal saline and dexamethasone, with improvement in plasma sodium level and blood pressure. Additional work-up revealed panhypopituitarism with low levels of TSH (0.122 IU/ml, normal 0.350–5.50), free T4 (0.52 ng/dl, normal 0.80–1.80), total T3 (67 ng/dl, normal 80–180) and morning cortisol (1.5 g/dl, normal 5.5–20.0). In comparison to a pre-ipilimumab brain MRI from February 2013 (Fig. 2A), brain MRI demonstrated enlargement of the pituitary gland with upwardly convex superior margin and heterogenous contrast enhancement (Fig. 2B). Differential diagnosis included hypohysistis related to ipilimumab treatment versus metastatic disease to the pituitary. Again, course of change favored IAH. The patient was placed on hydrocortisone and on levothyroxine to treat her panhypopituitarism. Her final dose of ipilimumab was deferred pending the follow-up imaging study, which occurred 20 days later (Fig. 2C). The pituitary gland was then shown to be trending toward normal size and morphology, confirming the diagnosis of IAH.
2.3. Case 3 A 63-year-old female presented in September 2011 with a palpable left supraclavicular lymph node. An excisional biopsy revealed BRAF positive malignant melanoma. An extensive workup was performed including a staging PET/CT, MR of the brain, and skin, without evidence of a primary lesion. Bilateral modified radical neck dissections were performed and did not identify additional sites of nodal disease. Findings were consistent with stage IIIa disease without a known primary and the patient was observed. She re-presented the following year with a new non-pigmented nodule on her left upper back consistent with biopsy-proven metastatic melanoma. Following a wide local excision, staging PET/CT demonstrated additional sites of subcarinal nodal disease that was resected. Seven months after this resection, a screening PET/CT demonstrated recurrent subcarinal and right supraclavicular nodal disease, right clavicular and T6 osseous disease. A four cycle treatment with ipilimumab was initiated in March 2012 with an unremarkable clinical course during the first 3 cycles of treatment. After the 4th cycle, the patient developed progressive fatigue and serum endocrinology work-up revealed panhypopituitarism with low levels of TSH (0.211 uIU/ml, normal 0.350–5.50), free T4 (0.48 ng/dl, normal 0.80–1.80), total T3 (60 ng/dl, normal 80–180) and morning cortisol (1.7 g/dl, normal 5.5–20.0). Contrast enhanced brain MRI demonstrated thickening with homogeneous enhancement of the pituitary infundibulum and gland (Fig. 3B) which was new in comparison to the preipilimumab brain MRI from March 2013 (Fig. 3A). The differential diagnosis included IAH, pituitary adenoma, or metastatic disease. She was treated with systemic glucocorticoids and pituitary hormone replacement including hydrocortisone and levothyroxine. The patient’s fatigue resolved and a follow-up MRI of the brain in August 2013 demonstrated a normal appearance of the pituitary infundibulum and gland (Fig. 3C). Both clinical course and radiographic findings were consistent with IAH.
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Fig. 1. MRI at three different time points (left column, pre-contrast sagittal T1-weighted; middle column, post-contrast sagittal T1-weighted; right column, post-contrast coronal T1-weighted) showing transient pituitary hypophysitis in a 45 year old woman treated with ipilimumab for metastatic melanoma. (A) Pre-ipilimumab MRI showing baseline pituitary measuring 5 mm craniocaudal dimension. (B) MRI for assessment of new onset headache after second cycle of ipilimumab showing interval homogenous enhancement and enlargement of pituitary to 12 mm craniocaudal dimension. These findings are indicative of lymphocytic hypophysitis. (C) MRI 8 months following completion of ipilimumab treatment showing interval normalization of pituitary enhancement pattern and size to 3 mm craniocaudal dimension.
3. Discussion Hypophysitis can be a complication arising from the use of Ipilimumab treatment in cancer patients. The clinical presentation of hypophysitis can vary. Symptoms will often include those related to mass effect from pituitary enlargement, hypopituitarism, or hyperprolactinemia [10,11]. The symptoms associated with pituitary enlargement (i.e. headache, visual change) typically precede endocrinopathy caused by pituitary inflammation. A working diagnosis of IAH can be made based on typical clinical presentation (Table 1) in combination with characteristic MRI findings, although a definitive diagnosis of hypophysitis requires histological examination of pituitary tissue [10].
Table 1 Clinical association of ipilimumab induced hyphophysitis. Mass effect from pituitary enlargement Deficient anterior pituitary hormones Cortisol deficiency (ACTH) Thyroid-stimulating hormone Gonadotropins (FSH, LH)
Deficient posterior pituitary hormones Diabetes insipidus (ADH)
The characteristic findings of hypophysitis on MRI include a symmetrically enlarged pituitary gland and stalk that enhance homogenously following gadolinium-based contrast administration. On pre-contrast images, the typical “posterior pituitary bright spot”, related to the presence of vasopressin, is typically absent. Often the inflammatory process results in the presence of a “dural tail” on contrast enhanced images adjacent to the pituitary gland. By contrast, pituitary macroadenomas are typically associated with an asymmetrically enlarged and heterogeneously enhancing intrapituitary mass, without “dural tail” or stalk thickening (Table 2) [11]. These MRI findings have been described specifically in the setting of ipilimumab-induced IAH [12]. Also, as demonstrated in our patients, normalization of the pituitary gland enhancement and
Table 2 MR features of lymphocytic hypophysitis versus pituitary adenoma.
Headache, visual loss, diplopia Pituitary shape Fatigue, anorexia, weight loss, hypoglycemia, hypotension Fatigue, cold intolerance, anorexia, constipation, dry skin, bradycardia Women → infertility, dysmenorrhea, amenorrhea Men → infertility, fatigue, decrease libido Polyuria, polydipsia
Enhancement
Neurohypophysis (T1bright posterior pit) Sella tursica Gland normalization following cessation of therapy
Hypophysitis
Adenoma
Symmetrically enlarged gland and stalk Intense homogeneous may have dural tail Absent
Asymmetrically or focally enlarged gland with normal stalk Mild to moderate, heterogeneous without dural tail Preserved
Normal Present
May be expanded Absent
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Fig. 2. MRI at three different time points (left column, pre-contrast sagittal T1-weighted; middle column, post-contrast sagittal T1-weighted; right column, post-contrast coronal T1-weighted) showing transient pituitary hypophysitis in a 65 year old woman treated with ipilimumab for metastatic melanoma. (A) Pre-ipilimumab MRI showing baseline pituitary measuring 6 mm craniocaudal dimension with concave-down shape of superior margin of pituitary gland. (B) After the third cycle of ipilimumab, the patient presented with fatigue, hypotension, hyponatremia, hypocortisolemia, and central hypothyroidism. MRI demonstrates a convex-upward superior margin of the pituitary gland with heterogenous enhancement and 12 mm craniocaudal dimension. (C) MRI 20 days after diagnosis of ipilimumab-induced hypophysitis and consequent withholding of ipilimumab treatment. There is normalization of the pituitary gland morphology, now measuring 8 mm craniocaudal dimension with concave-down superior margin.
morphology rapidly follows cessation of drug therapy and steroid initiation. Case 1and Case 3 described above exemplify the more typical diagnosis of early hypophysitis with a presenting symptom of headache and/or fatigue, respectively, followed by discovery of subclinical endocrinopathy. MRI demonstrated symmetric enlargement and homogenous enhancement of pituitary gland and stalk in these cases. Case 2, on the other hand, had less typical features of hypophysitis. Hypophysitis usually clinically affects the function of the adenohypophesis, and involvement of the posterior pituitary is less common [13]. In the unusual case where the posterior pituitary function is involved, diabetes insipidus, rather than hyponatremia, has typically been reported [13]. However, there has been one other reported case of hyponatremia associated with hypophysitis secondary to ipilimumab treatment [14]. Because cortisol has a negative feedback effect in the regulation of ADH secretion from the posterior pituitary, the loss of cortisol can lead to SIADH and hyponatremia. Thus, in our Case 2, hyponatremia may be due to SIADH secondary to the anterior pituitary lesion causing cortisol deficiency. Hypopituitarism is an often overlooked cause of hyponatremia [15]. Additionally, the MRI findings in Case 2 were atypical since during the active hypophysitis stage, a heterogeneous enhancement pattern of the pituitary, rather than a more characteristic homogenous enhancement, was seen. This less typical MRI pattern has
been previously reported in a minority of cases of lymphocytic hypophysitis [13]. The variable clinical presentations and radiologic findings complicate the diagnosis of lymphocytic hypophysitis. For instance, many of the associated typical imaging findings overlap with those of the much more-common condition of nonsecreting pituitary adenoma (NSPA) [16]. It is important to distinguish hypophysitis from NSPA, as surgery may be indicated for NSPA but typically not for hypophysitis. Though lymphocytic hypophysitis is presumed to involve autoimmune-antibodies, there is no reliable serologic test based on autoantibodies yet available. Consequently, the presurgical diagnosis of hypophysitis is currently best made based on clinical suspicion and consistent MRI. No single radiologic sign can be relied upon to completely distinguish hypophysitis from NSPA, resulting in approximately 40% of patients with autoimmune hypophysitis unnecessarily undergoing surgical resection for presumed NSPA [16]. A recent case-control study described a radiologic scoring system for distinguishing automimmune hypohysitis from NSPA, which significantly improves the rate of accurate classification of hypophysitis patients to >95%, increased from the more typical moderate rate of 60% [16]. In this system, the individual significance of various MRI associated findings was defined. Comparing NSPA to hypophysitis, features most typical of hypophysitis are symmetric pituitary enlargement, homogenous appearance both on pre- and post-contrast images, and intense pituitary enhancement. In contrast, the individual features
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Fig. 3. MRI at three different time points (left column, pre-contrast sagittal T1-weighted; middle column, post-contrast sagittal T1-weighted; right column, post-contrast coronal T1-weighted) showing transient pituitary hypophysitis in a 63 year old woman treated with ipilimumab for metastatic melanoma. (A) Pre-ipilimumab MRI showing baseline appearance of the sella tursica with a partially empty sella. (B) After the fourth cycle of ipilimumab, the patient presented with progressive fatigue and serum endocrinology work-up revealed panhypopituitarism. MRI demonstrates a convex-upward superior margin of an enlarged pituitary gland with homogeneous enhancement. (C) MRI 3 months following the diagnosis of ipilimumab-induced hypophysitis demonstrates normalization of the pituitary gland with initial sellar morphology.
of NSPAs were asymmetric pituitary enlargement, heterogenous contrast uptake, and less intense enhancement. In that study, thickened pituitary stalk and/or loss of pituitary bright spot strongly favored hypophysitis over NSPA. The “dural tail sign” was nonspecific, being seen commonly in both conditions. Lymphocytic hypophysitis is the most common histopathological subtype of hypophysitis. Other subtypes have been recognized, such as xanthomatous hypophysitis, granulomatous hypophysitis, IgG4-related hypophysitis, and mixed forms, though they are rare [17]. Hypophysitis may occur as a primary lesion, or may result secondarily to some other primary cause. The condition may be secondary to inflammation from adjacent lesions, such as a Rathke’s cleft cyst, menigioma, or germinoma [8]. It may result as a consequence of underlying systemic conditions, such as Wegener’s granulomatosis, sarcoidosis, tuberculosis, syphilis, or Langerhan’s cell histiocytosis [8,18,19]. In fact, it most commonly arises as a rare complication of pregnancy in the late pregnancy or early postpartum period [8,17]. Or, as described in the present report, hypophysitis may result as an adverse effect of immunomodulatory drugs, such as with ipilimumab. At present, the treatment for IAH is directed primarily to symptom relief. Medical treatment is preferred to surgical or radiosurgical interventions except in refractory symptomatic cases [8,16]. Replacement of deficient hormones is common, though opinions diverge on whether the aim should be solely to adopt supportive therapy with hormonal replacement or whether treatment should rather primarily aim to reduce the inflammatory process [17]. Glucorticoids are often an initial treatment of choice, as they can be effective both as anti-inflammatory agent to reduce
enlarged pituitary mass and as replacement of defective adrenal function [8,17]. When steroid treatment fails or cannot be tolerated by patients, other treatment with agents directed at immune modulation, including azathioprine (AZA), methotrexate, and cyclosporin A have been described [20–22]. However, these steroid alternatives do not have as much proven efficacy in treating hypophysitis in comparison to steroid treatment [17]. The need for long term hormone-replacement in hypophysitis is unpredictable, therefore long term follow-up is required as hormonal deficits may be permanent [17]. As the use of ipilimumab for treatment of melanoma becomes more common, clinicians must be aware of the risk for developing the complication of IAH. Early MRI is recommended in the setting of appropriate clinical symptoms for early diagnosis and management of this potential therapeutic complication in patients with melanoma.
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