E-Poster Presentation 63rd Endocrine Society of Australia Annual Scientific Meeting 2020

Case:

A 27-year-old female presented with secondary amenorrhoea six months after the removal of her contraceptive progesterone implant for family planning.  Her medical history was significant for congenital developmental abnormalities including a hypoplastic right kidney, which eventually required a nephrectomy.  She also suffered from left-sided vesicoureteric reflux resulting in recurrent urosepsis and end-stage renal failure, leading to a renal transplant six years ago.  This was complicated by Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma and subsequent multifocal EBV-associated smooth muscle tumour (SMT) involving the cervical lymph nodes, lung, liver and bladder.

Several weeks earlier during an admission with urosepsis, the nephrology team had noted a TSH of 0.36 mU/L (0.38-5.30), fT4 6.0 pmol/L (8.00-16.50) and T3 2.5 pmol/L (3.80-6.90) and commenced her on thyroxine 75mcg.  A subsequent pituitary panel at the time of endocrine review showed a prolactin level of 1132 mIU/L (71-566).  She had a low morning cortisol of 59 nmol/L in the context of being on prednisolone therapy for immunosuppression of her renal transplant.  FSH was 10.9 IU/L (1.7-21.5), LH 1.7 IU/L (1.0-96.0), oestradiol 51 pmol/L (45-1461), ACTH 1.7 ng/L (7.2-63.3), IGF-1 28.22 nmol/L (12.48-39.13), growth hormone 0.27 ug/L (< 3.60) and sodium 143 mmol/L (135-145).

On clinical examination, she had a new incomplete third nerve palsy with decreased pupillary light response.  She had a mild superior temporal quadrantanopia in the left eye on formal visual field testing.  This was in addition to a pre-existing right sixth nerve palsy since childhood.  Imaging revealed a 35x 24x 22mm pituitary fossa lesion with bilateral cavernous sinus invasion, worse on the right, with left-sided optic chiasm compression (Figure 1).

Histologic examination of a trans-sphenoidal endoscopic biopsy of the suprasellar lesion showed a moderately cellular spindle cell neoplasm.  Smooth muscle actin (SMA) immunohistochemistry and EBV-encoded RNA in situ hybridisation (EBER-ISH) were positive, consistent with EBV-SMT.  She was admitted two weeks later for a planned two-stage tumour debulking.

Initially, she underwent a right-sided frontotemporal craniotomy and debulking of the cavernous tumour with peri-operative intravenous hydrocortisone.  This was changed to oral dexamethasone 4mg QID post-operatively to reduce intracranial oedema.  Fifteen hours later, she became polyuric requiring a single dose of 1 mcg intravenous desmopressin.  Histology confirmed EBV-SMT (Figure 2), associated with partially infarcted anterior pituitary tissue.

Six days later, she underwent a stage 2 stereotactic trans-sphenoidal endoscopic resection of the residual tumour.  Six hours later, she developed polyuria and required a further dose of 1mcg intravenous desmopressin.  Her serum sodium levels remained within normal limits.  Her post-operative course was otherwise uncomplicated and she continues to recover on the ward.

Discussion:

EBV-SMTs are rare neoplasms occurring almost exclusively in those who are immunosuppressed (1,2).  A single-centre retrospective study of 5006 solid organ recipients over 31 years found only 3 cases of post-transplant EBV-SMT (3).  Of those with solid organ transplants, EBV‐SMTs occur most commonly in kidney transplant patients (4) with an incidence of 1.67% (5).  They are considered a late onset complication of immunosuppression, occurring at a median of 9 years post kidney transplant (5).  Irrespective of the organ transplanted, EBV‐SMT can develop in either the graft or any other organ.  Risk factors include EBV seronegativity followed by primary EBV infection and persistently high EBV viral loads (3).

The only reported pituitary EBV-SMTs are from a retrospective case series of 21 EBV-SMTs associated with HIV infection where 2 were in the pituitary (2).  The clinical presentations of these cases were not characterised.  A systematic review of 53 EBV-SMTs in the central nervous system found that the most common presenting symptom was a headache (1).  However, the location within the central nervous system of these tumours was not specified and it is unknown whether any of these lesions occurred in the pituitary.

The pathogenesis of EBV-SMT is not fully understood.  EBV infects smooth muscle cells using an unclear mechanism, with hypotheses including cellular fusion with infected lymphocytes, or via surface receptor CD21 (6).  An analysis of renal transplant-associated EBV-SMTs demonstrated gene expression in keeping with a latency type III pattern, in which a range of potentially oncogenic nuclear antigens and latent membrane proteins (LMP) are expressed (7).  LMP2A activates the mTOR/Akt pathway, and is thought to be a driver of oncogenesis.  This is supported by the frequent response of these tumours to mTOR inhibitors (7).  Everolimus was trialled in this patient on initial diagnosis of EBV-SMT with no success.

Intracranial tumours are hypothesised to derive from the myogenous vascular wall (8).  EBV-SMT is frequently multifocal (1,5). Viral episomal analysis of multifocal lesions demonstrated independent viral clones, suggesting that they are the result of multiple infection events rather than metastasis (9).  Histology characteristically demonstrates intersecting fascicles of spindled cells with blunt-ended nuclei, with positive immunohistochemistry for SMA and caldesmon (9) with diffuse EBER-ISH positivity.  Cytologically malignant features including primitive areas, higher cellularity, necrosis, and mitotic activity can be observed; however, prognosis is independent of histology, relating primarily to patient immunity status.

The optimal management of EBV-SMT remains unclear.  Surgical resection is the most common therapy (1,5,8).  Other strategies have included involved field radiation therapy, stereotactic radiosurgery, systemic chemotherapy, mTOR inhibitors, modification of post-transplant immunosuppression therapy or a combination of these (1,4,5).  However, there is no evidence supporting superiority of one modality over another.  Previous studies have demonstrated comparable survival in those treated with resection versus reduced immunosuppression (4), sirolimus versus reduced immunosuppression (5), chemotherapy versus no chemotherapy (4) and complete versus partial resection (8).

Compared with those who develop EBV-SMT in the context of HIV, EBV-SMT arising in the setting of a solid organ transplant had poorer tumour outcomes, with only 20% of patients having no recurrence or stable disease on long term follow up (1).  However, these tumours do not often cause mortality, and a retrospective study of 16 patients with EBV-SMT post kidney transplant found a survival rate of 75% over a mean follow up period of 5 years (5).

In a large case series of 29 tumours from 19 patients, mortality was recorded in only 3 patients, of whom only 1 died of tumour-related complications (9).  This patient had widespread disease involving the spinal cord, gallbladder, lung, and liver.  Another 5 patients from the same study with widespread disease were alive at the time of most recent follow-up.  In another large series, death occurred in 17 of 25 patients, but was mainly the result of comorbid diseases (10).

Those with early-onset tumours and intracranial tumours have poorer survival (4,8).  However, multiple tumours, tumour size or histological features of the tumour were not predictive of survival (8).

In conclusion, we have presented the rare case of an EBV-SMT occurring in the pituitary in a young woman with a renal transplant 6 years ago.  This is the first report to our knowledge that characterises the clinical presentation of an EBV-SMT in the pituitary in a solid organ transplant recipient.  EBV‐SMTs are rare tumours and the optimal management of this condition remains unclear.

Learning points:

• EBV-SMTs are rare neoplasms occurring almost exclusively in immunosuppressed patients
• In such patients presenting with a pituitary mass, the differentials should be kept broad and EBV-SMT should be considered
• Due to the rarity of this condition, the optimal management remains unclear, but surgery is commonly performed