Primary Pituitary EBV-associated NK/T-cell Lymphoma

Background Case presentation We present a case of a 78-year-old patient with a sellar nodular mass. After onset of symptoms with productive hoarseness, swallowing disorder and recurrent her condition rapidly deteriorated. Open biopsy through a right pterional approach was performed and histopathological evaluation revealed an EBV-associated NK/ T-cell lymphoma. High-dose corticosteroid therapy was initiated. However the patient passed away 37 days after admission due to respiratory insuciency. Conclusion We describe an unusual case of EBV-associated NK-/T-cell lymphoma of the CNS manifesting as a pituitary gland tumor. This particular entity presented with a pronounced aggressive local tumor growth with lethal outcome.

patient passed away 37 days after admission due to respiratory insu ciency.

Conclusion
We describe an unusual case of EBV-associated NK-/T-cell lymphoma of the CNS manifesting as a pituitary gland tumor. This particular entity presented with a pronounced aggressive local tumor growth with lethal outcome. Background Primary central nervous system lymphoma (PCNSL) represents almost 4 % of newly diagnosed central nervous system (CNS) tumors and is usually of the B-cell-phenotype classi ed as diffuse large B-cell lymphoma. PCNSL is an aggressive and rare type of non-Hodgkin lymphoma involving brain, spinal cord and the meninges [17]. Primary pituitary lymphoma, especially of the natural killer (NK)-/T-cell phenotype is extremely rare and there is limited information about clinical features, treatment and prognosis.

Case Presentation
A 78-years-old lady presented with productive cough, hoarseness, swallowing impairment, and recurrent episodes of fever (40° C; 104° F), which started 1 month prior to hospitalization. There were no further B symptoms like night sweats or weight loss. Past medical history was unremarkable except for mild hypothyroidism and recent hospitalization for syncope two weeks prior to admission. A cranial computed tomography (CT) scan had been performed in a primary care hospital two weeks prior to admission, which retrospectively revealed a nodular mass in the middle cranial fossa restricted to the sellar region. An empiric antibiotic treatment with ceftriaxone and metronidazole was previously initiated due to elevated serum in ammation markers without signi cant improvement. Clinical examination on admission revealed left-sided glossopharyngeal and recurrence nerve palsies.
Cranial magnetic resonance imaging (MRI) revealed a contrast enhancing (CE) solid mass in the sellar region with both-sided signal alterations of the optic tract beneath the optic chiasm (Figure 1 A) as well as a CE lesion in the left jugular foramen (Figure 1 B) on T1-weighted imaging. Spinal MRI with CE did not show any further dissemination. CT of thorax, abdomen and pelvis with CE was unremarkable except for a left-sided kidney cyst. Electroencephalography (EEG) revealed a poorly modulated alpha rhythm without epileptogenic potentials.
Pituitary function tests on admission indicated a reduced cortisol serum level (0.7 µg/dl; ref: 10-25 µg/dl) and moderately elevated prolactine levels (178 ng/ml; ref: <23 ng/ml). The patient was substituted with hydrocortisone. Differential blood counts were normal. Except for an elevated lactate dehydrogenase (404 U/l) and a slightly elevated C-reactive protein (CRP) of 5,5 mg/dl, the routine laboratory results were normal. Diagnostic cerebrospinal uid (CSF) puncture showed mixed pleocytosis with increased lymphocytic cell count (170 cells/µl), but no atypical cells were found. Elevated Epstein-Barr virus (EBV) counts (2,1x10 5 Geq/ml) were detected by polymerase chain reaction (PCR) of CSF, however serologic markers did not indicate a manifest EBV infection (negative EBNA-1 IgG and VCA IgM). Herpes simplex virus (HSV) and human immunode ciency virus (HIV) serologies were also negative.
During further course of treatment, the patient developed elevated sodium levels (165 mmol/l) with high urine output and osmolality (339 mosmol/k). However, sodium serum level did not normalize until we started desmopressin medication indicating a diabetes insipidus. Antibiotic and antiviral treatment with ceftriaxone/ampicillin and ganciclovir was initiated on day 6 after admission. Due to sustained elevated in ammation markers antibiotic treatment was escalated with piperacillin/tazobactam on day 12. An episode with respiratory insu ciency due to glossopharyngeal nerve palsy occurred on day 13 and the patient was intubated and transferred to the intensive care unit. Once again antibiotic treatment was escalated with meropenem due to suspected urosepsis caused by vancomycin resistant enterococcus faecalis. Microbiological CSF cultures were negative for bacterial or fungal infection so ceftriaxone and ganciclovir were discontinued.
On day 19 an open tumor biopsy was performed through a right-sided pterional craniotomy with optic nerve decompression. Histopathological evaluation revealed a diffuse in ltrate of medium-sized to large lymphoid cells with irregular folded nuclei, granular chromatin, small nucleoli and a narrow to moderate rim of pale to clear cytoplasm ( Figure 3A, hematoxylin/eosin, 400x). Mitotic gures were readily found.
There was some geographic necrosis and angiocentric growth. By immunohistochemistry, the lymphoid cells stained positive for the T-cell markers CD2 and CD3 ( Figure 3B), the NK-cell marker CD56 ( Figure 3C) and the cytotoxic marker granzyme B ( Figure 3D), whereas CD20 ( Figure 3F), CD138 and Mum1 were negative. The proliferative fraction, as demonstrated by Ki-67 immunostaining was > 90 %. EBV in situ hybridisation was strongly positive in the tumor cells ( Figure 3E) and the diagnosis of an EBV-associated lymphoma of the NK/T-cell phenotype was made. Due to limited tissue, neither further immunohistochemical stainings nor molecular studies could be performed.
On day 26 a left-sided hygroma, which was detected on postoperative imaging (Figure 2A), was evacuated through a frontal burr hole in local anaesthesia. Cranial MRI +/-CE additionally indicated growing lesions in the sellar and suprasellar region with compression of the optic chiasm ( Figure 2A) and progressive lesions at the right-sided oculomotor nerve ( Figure 2C). The tumor mass in the jugular foramen also progressed over time ( Figure 2B,C). A dilative tracheotomy was performed since the patient developed ongoing aspiration due to glossopharyngeal palsy. After tapering sedation, we noticed a new right-sided oculomotor palsy. Due to a reduced state of consciousness, we were not able to examine visual acuity and visual elds throughout treatment.
Ultimately therapy with dexamethasone 40 mg daily was initiated and the patient was transferred to the oncologic department for further treatment. Despite corticosteroid medication, her status deteriorated rapidly preventing additional diagnostics and chemotherapy. The patient died due to respiratory insu ciency 37 days after admission.

Discussion
Primary pituitary lymphoma (PPL) is an extremely rare subtype of PCNSL [14].  15]. Extranodal NK/T-cell lymphoma is an aggressive lymphoma, which classically involves the nasal cavitiy and the aerodigestive tract and frequently extends locoregionally to the paranasal sinuses, orbits and lymph nodes. Sporadically it develops in non-nasal areas (skin, gastrointestinal tract, testis, soft tissue) as extranasal NK/T-cell lymphoma or as disseminated disease with a leukemic phase [4,16]. It has been suggested that most cases of extranasal NK/T-cell lymphoma actually have dissseminated occult nasal lymphoma [5,13]. Furthermore EBV appears to play an important etiologic role in the genesis as the virus has been detected in almost all cases [4,7]. Though NK/T-cell lymphoma has been related to EBV, evidence for a viral/tumor relationship is limited and the mechanisms of EBV entry into NK cells remain uncertain [7]. In fact EBV-genome is frequently positive in PCNSL cells in immunocompromised patients as an EBV infection is related to the transformation of normal lymphocytes. A chronic in ammation or a previous hypophysitis have also been suspected to induce a clonal transformation in lymphoma [9]. Moreover the coexistence of pituitary adenoma may predispose the secondary development of pituitary lymphoma, since pituitary hormones like prolactin might enhance mitosis in normal lymphoid cells and lymphatic tissue cells possess hormonal receptors [12,10]. However there was no evidence for an underlying pituitary adenoma in this case. Based on morphology, immunophenotype (expression of the T-cell markers CD2/CD3, CD56 and granzyme B) and the presence of EBV encoded RNA (EBER) by in-situ hybridisation the diagnosis of an extranodal EBVpositive NK/T-cell lymphoma was established. Interestingly radiological ndings did not reveal any tumor manifestations beyond the CNS as there were no lesions involving the nasal or paranasal sinuses, nor the aerodigestive tract. However a minor tumor manifestation outside the CNS cannot be excluded, since a F18-orodeoxyglucose (FDG) positron emission tomography (PET)-CT, which is a mandatory initial diagnostic imaging [16], was not performed. On the other hand plasma EBV DNA level, which is a reliable diagnostic and prognostic surrogate [6,16], was low indicating low lymphoma load. Even if extranodal NK/T-cell lymphoma frequently presents as limited early-stage disease it frequently disseminates with a rare CNS involvement and a median survival of 20 months across groups (7 years for early-stage I compared with only 7 months for stage IV) [11,1]. Chemotherapy and consolidation radiotherapy are usually the main treatment in extranodal NK/T-cell lymphoma, but response rates especially in advancedstage disease remain poor and overall survival is limited [11,15]. In relapsed/refractory cases, blockade of the programmed death protein 1 (PD1) has recently shown promising results with high response rates [16]. Targeted therapies based on CD30/38 tumor cell expression also demonstrated bene cial results in ongoing studies [1]. A secondary analysis of a phase III trial in PCNSL demonstrated a longer overall survival and progression free survival in patients undergoing subtotal or gross total resection compared to those undergoing biopsy only [18]. We aimed a debulking surgery in our patient since intracranial dissemination and poor general condition prevented a gross total resection. Further tumor growth impeded chemotherapy and led to an unfavourable outcome.

Conclusion
To the best of our knowledge we describe the second case of a primary pituitary EBV-associated NK-/Tcell lymphoma, which compared to other PCNSL appears to have a highly aggressive and rapid tumor growth with fatal outcome. Further investigations might bene t to nd out the speci c role of EBV infection in the activation of NK/T-cells and the particular involvement of pituitary cells as possible therapy targets.

Declarations
Ethics approval and consent to participate The research conducted has been performed in accordance with the Declaration of Helsinki. Due to the case report nature of our manuscript no ethics approval was considered neccessary.

Consent for publication
The husband of the patient gave written informed consent for publication of his wife's personal and clinical details along with any identifying images in this study. All authors read and approved the nal manuscript.

Availability of data and material
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.