Corticosteroids in the management of lymphocytic hypophysitis: Case series
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.227293
Source of Support: None, Conflict of Interest: None
Keywords: Corticosteroids, lymphocytic hypophysitis, outcome, surgical resection
Lymphocytic hypophysitis (LYH) is a rare inflammatory disease with an incidence of one per nine million people. It is characterized by infiltration of the pituitary gland by lymphocytes and macrophages, mimicking the presence of a pituitary adenoma on radiological images. It is often a diagnostic dilemma for the neurosurgeon with debatable approaches of management. Coexisting autoimmune etiology and pituitary antibodies have been reported in 50% and 75% biopsies, respectively.,
LYH is more often reported in women, particularly pregnant woman. Symptoms at presentation often include headache, visual disturbances, and hormonal disturbances with radiological evidence of a mass in the pituitary gland, similar to a pituitary adenoma. Presumptive diagnosis of LYH is often based on clinical, laboratory, and imaging studies using the Juan-Andres Rivera criteria; whereas, a definitive diagnosis requires histopathological assessment, i.e., the pituitary biopsy. Management of these cases of LYH is widely debated. Although surgical excision is the management of choice, medical management with steroids may result in complete resolution of the symptoms as well as radiological features., In the current case series, we report our approach to the diagnosis and treatment of LYH, evaluating the role of steroids as the first line of therapy.
A retrospective analysis of data of nine consecutive patients of LYH, who reported to a tertiary referral center in South India from 2013 August to 2015 was done after obtaining consent from the patient. Data collected included variables regarding demography, clinical features, neurological examination, laboratory results, as well as radiological, medical, surgical, and histopathological features. While five (55.5%) patients were managed with steroids, the remaining four patients underwent surgical management. All nine patients had a minimum follow-up of 4 months. The study was approved by the Institutional Ethics Committee. The work has been reported in line with the PROCESS criteria.
Among the nine patients in this series, presumptive diagnosis of LYH was made in six patients based on radiological findings reviewed earlier by Beressi et al. and Khare et al. However, because of progressive ocular palsy and headache, one patient underwent surgery, and the biopsy was reported as acute LYH. For the remaining three patients, definitive diagnosis was based on histopathology reports. The average age of the study population was 38.44 ± 19.83 years, with five (55.5%) women. [Table 1] summarizes the demographic characteristics of the study population.
The symptomatology and hormone profile has been enumerated in [Table 2]. All the patients who had been presumptively diagnosed of having an inflammatory lesion were treated with steroids (tablet prednisolone 10 mg three times per day in five patients for 6 weeks, and then supplementary dose of steroids continued for another 1 month). In one patient, tablet deflacort, 6 mg once daily for 6 weeks was given; subsequently, the dose was tapered and stopped. Among the medical intervention group, one patient (17-year-old female) developed progressive ocular symptoms with involvement of the third cranial nerve; hence, surgical intervention was carried out during the course of steroid treatment. Of the remaining five patients, four patients showed a remarkable improvement in clinical symptoms, complimented by the resolution of radiological features as well, in response to steroid treatment. One male patient who initially showed resolution of the lesion on the magnetic resonance imaging (MRI) scan and also in his symptoms during the initial days of steroid tapering period, presented with recurrence of symptoms as well the lesion visible on the MRI scan, and hence, was considered nonresponsive to steroids and referred to a rheumatologist for probable utility of chemotherapy.
In the surgical group, the diagnosis was made after the histopathological confirmation in all patients except one. On retrospective scrutiny of medical records, though all the patients were diagnosed as having a pituitary adenoma, LYH was the major differential diagnosis based on the Juan-Andres Rivera criteria.
All the patients in the surgical group presented with cortisol deficiency, and two patients had thyroid stimulating hormone (TSH) deficiency as well. Three out of four patients showed typical features of the hypophysitis in the magnetic resonance imaging (MRI) scan, i.e., homogenous enhancing pituitary with tongue-like projection along the infundibulum, absent T1 bright spot, with a normal sized sella. Only one patient had a sellar enlargement and heterogenous enhancement of the lesion. However, all the patients who had been operated upon, presented with optic nerve compression, and hence the surgical decompression of the mass was inevitable despite optimal medical management. In all these patients who underwent surgery, the tumor was very firm and not easily removable, which represented the characteristic hallmark of a pituitary granulomatous lesion. In two patients, there was arachnoidal breach, which required postoperative lumbar cerebrospinal fluid (CSF) drainage. One of the patient with CSF leak eventually required re-exploration and packing, and the other patient did not require any additional procedure.
The histopathology showed the presence of chronic granulomatous idiopathic hypophysitis in three patients, wherein the pituitary gland was replaced by a dense fibrosis with epithelioid granulomas, inflammatory giant cells, and blood vessels showing evidence of vasculitis. One patient was reported to be having acute lymphocytic hypophysitis with evidence of dense lymphocytic infiltration of the gland without any granulomas or giant cells.
All the patients who underwent surgical excision showed symptomatic improvement postoperatively, possibly due to resolution of the mass effect of the lesion; however, the symptoms related to the deficiency of pituitary hormones persisted, requiring supplementation doses of steroids [Table 3].
A 26-year old male patient presented with delayed development of secondary sexual characters with laboratory findings of decreased follicle stimulating hormone (FSH), luteinizing hormone (LH), testosterone, and thyroid stimulating hormone (TSH) levels. The patient had normal cortisol levels with elevated thyroxine (T) 3, T4, and prolactin. He was receiving testosterone replacement therapy under the supervision of an endocrinologist. He was advised to undergo MRI of the brain and then referred for surgery with the diagnosis of a prolactinoma. MRI done in December 2014 revealed a 9.5 × 7.4 × 7.5 mm size, symmetrically enlarged gland, which showed an intensive enhancement with gadolinium contrast. There was also a “tongue-like” projection into the suprasellar region with absent T1 bright spot, all features suggestive of idiopathic hypophysitis [Figure 1].
He was advised tablet deflacort (a prodrug converting into its active form, 21-desacetyldeflazacort), 6 mg once daily for 6 weeks, which was tapered and stopped subsequently. On follow-up at 6 months, a repeat MRI showed complete resolution of the lesion, and the size of the gland measured 4.5 × 3.6 × 3.5 mm [Figure 1]. The patient also improved symptomatically. However, gonadotropin deficiency did not recover, and hence, he continued to receive testosterone injections.
A 56-year old female patient presented with sudden onset of headache and vomiting, nearly 4 weeks prior to the consultation. A fortnight after the first experience of headache, she developed sudden blurring of vision in the left eye for which she was advised to undergo an MRI scan of the brain by an endocrinologist. She was diagnosed to have hypothyroidism based on her low T4 levels. The TSH levels were also low and T3 level was normal. She was prescribed tablet thyroxine 75 μg per day.
MRI revealed an intensely contrast-enhancing lesion within a normal sella with evidence of enhancement of diaphragm sella and stalk thickening, causing compression on the optic nerve [Figure 2]. A presumptive diagnosis of non-functioning pituitary adenoma was made preoperatively since other pituitary hormones were normal except for the presence of a deranged thyroid profile. She underwent trans-sphenoidal surgery and excision of the lesion was attempted. Since the tumor was firm and nonsuckable, partial excision of the lesion was done, and biopsy revealed the presence of granulomatous hypophysitis. Her vision and episodes of headache improved after the surgery.
A 20-year old male patient presented with complaints of left-side hemicranial headaches every day for 1 month lasting for half an hour without vomiting. Neurological examination revealed no focal neurological deficit. His hormone profile revealed low TSH, low cortisol, and low testosterone levels. MRI brain showed an intensely contrast-enhancing lesion within the sella with suprasellar extension and infundibular thickening, suggestive of inflammatory hypophysitis.
The patient was advised a 6-week course of tablet prednisolone, 10 mg thrice a day, along with testosterone and thyroxine supplementation. Six weeks later, the steroid dosage was tapered and an MRI repeated, which showed a decrease in the size of the lesion [Figure 3], and hence, the steroid dose was further reduced; however, thyroxine and testosterone supplementations were continued.
Two months later, the patient presented with recurrence of symptoms. A repeat assessment of the hormonal profile was normal. MRI of the brain showed an increase in the size of the gland along with infundibular thickening, suggestive of recurrence of the lesion on steroid withdrawal or a steroid nonresponsive inflammatory hypophysitis. Hence, an immunologist consult was taken to institute immunosuppression as an alternative treatment strategy, for managing the recurrence of the lesion.
In the current case series describing our experience in the management of LYH, we suggest that in these patients, medical management by the use of steroids may play an equally important role as surgical management.
Granulomatous hypophysitis and lymphocytic hypophysitis are rare autoimmune diseases, frequently seen in association with other autoimmune diseases. Although literature reports a female predominance especially in the peripartum period, our group demonstrated an equal distribution between the genders, with none of the women being in the peripartum period.
Inflammatory lesions of the sella are broadly classified as primary and secondary inflammatory lesions. Primary hypophysitis includes lymphocytic hypophysitis, granulomatous hypophysitis, and xanthomatous hypophysitis. Secondary hypophysitis occurs due to other systemic diseases, which include Takayasu's disease, Crohn's disease, Langerhans cell histiocytosis, sarcoidosis, and inflammatory pseudotumor; and, those diseases with an infective etiology including bacterial, viral, or fungal infections.
The pathophysiology behind the occurrence of primary lymphocytic/granulomatous hypophysitis is antibody formation against the pituitary gland, which leads to lymphocytic infiltration of the gland in the acute stage, and a granuloma formation and fibrosis in the chronic stage. Since these lesions often mimic a pituitary adenoma on MR imaging, surgical excision is often considered as the treatment of choice, although this intervention is not always necessary. Patients with a pituitary adenoma often present with hypogonadism and apoplexy. Radiologically, pituitary adenomas show a heterogenous enhancement, presence of T1 bright spot of the posterior pituitary gland, pituitary stalk deviation, an absence of stalk involvement, and an absence of a dural tail. In LYH, however, hypoadrenalism and diabetes insipidus are the common presentations, and apoplexy is a rare phenomenon. Radiologically, LYH presents with stalk involvement, absent T1 bright spot, the presence of a normal sella with the stalk in the midline, the presence of a dural tail, and a homogenous enhancement of the lesion after contrast administration.
The management strategy in lymphocytic/granulomatous hypophysit is debatable. Several authors have previously described the role of steroids as the first line of management in LYH.,,, However, Buxton and Robertson et al., and Honegger et al., reported in favor of surgical treatment of the lesions that present with visual symptoms with the extended benefit of obtaining a tissue diagnosis following surgery. Glucocorticoids are used as lymphocytolytic drugs in these cases. Miyamoto et al., described a 62.5% treatment rate with a pharmacological dose of prednisone equivalent to >10 mg/day, and a 44.4% treatment rate when the dose was <10 mg/day. Kristof et al., advised a high dose methylprednisolone pulse therapy, 120mg/day for 2 weeks, followed thereafter by a tapering dose of 100mg, 80mg, 60mg, 40mg and 20mg, respectively, in a week's time. The study reported a 50% rate of reduction in the size of the mass; and if the disease duration was for <6 months, 88% of the patients showed improvement in the size of the lesion. For steroid nonresponsive patients, other chemotherapeutic drugs like methotrexate (MTX), azathioprine, and cyclosporine A have been tried with a positive response. The role of radiosurgery had also been evaluated in a few cases that were not responsive to management by steroids. Importantly, the outcome of the endocrinal status plays a pivotal role in evaluating the efficacy of either surgical or medical management in LYH., A follow-up study of the hormonal/endocrine status of the patients in the current report was not feasible due to financial and logistic constraints.
In the current study, we recommend caution while diagnosing and managing a patient suffering from an autoimmune disease who presents with a sellar lesion. Steroids should be considered as the first line of management in the case of LYH. Surgery resection should be considered in the presence of optic nerve and/or chiasmal compression, and in the presence of lesions that are not responsive to medical management.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]