Journal of Neuro-Ophthalmology:
Sellar and Parasellar Intravascular Lymphoma Mimicking Pituitary Apoplexy
Rizek, Philippe MSc, MD; Seitelbach, Maayan MD; Alturkustani, Murad MD; Leung, Andrew MD; Fraser, J. Alexander MD
Departments of Clinical Neurological Sciences (PR, JAF), Medicine (MS), Pathology (MA), Radiology (AL), and Ophthalmology (JAF), Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.
Address correspondence to J. Alexander Fraser, MD, Department of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, University of Western Ontario, Room B7 104, 339 Windermere Road, London, Ontario, Canada N6A 5A5; E-mail: email@example.com
The authors report no conflicts of interest.
Background: Intravascular lymphoma (IVL) is a rare subtype of large-cell non-Hodgkin lymphoma, characterized by proliferation of lymphoma cells within the lumina of small vessels. There are no previously reported cases of IVL involving the pituitary gland presenting with neuro-ophthalmic findings.
Methods: A 68-year-old female presented with headache, right third nerve palsy, and Horner syndrome. MRI showed a 1.4-cm sellar mass consistent with a pituitary macroadenoma. Two weeks later, despite treatment with dexamethasone, the patient developed complete bilateral ophthalmoplegia and ptosis. Repeat MRI showed invasion of the clivus and cavernous sinuses, and a transsphenoidal pituitary biopsy was undertaken.
Results: The preliminary histopathology was consistent with bland pituitary apoplexy, but subsequent examination of an incidentally biopsied nasal polyp revealed endovascular malignant lymphoid cells that, on further scrutiny, were also present in the pituitary tissue. The diagnosis of IVL was confirmed, and the patient had an excellent clinical and radiological response to cyclophosphamide, doxorubicin, vincristine, prednisolone, and rituximab (CHOP-R) chemotherapy.
Conclusion: IVL may involve the pituitary gland, causing sellar mass effect, cavernous sinus infiltration, and pituitary ischemia, mimicking pituitary apoplexy with neuro-ophthalmic features. It can be effectively treated with CHOP-R chemotherapy.
Intravascular lymphoma (IVL) is a rare subtype of large-cell non-Hodgkin lymphoma, characterized by proliferation of lymphoma cells within the lumina of small vessels. The true incidence is unknown. There is no gender predominance, and the median age of patients diagnosed with IVL is 70 years (range, 34–90 years) (1–3). Immunophenotypes of reported cases are 91% B cell and 9% T cell. Only 2 cases of natural killer cell type IVL have been described (4,5).
IVL is more common in Asian populations and has been termed the “Asian variant” (6). In the Asian variant, central nervous system (CNS) and cutaneous involvement are less common than in Western countries (7), and patients frequently present with involvement of the bone marrow (75%), spleen (67%), and liver (55%) (2,8,9). By contrast, the “Western variant” presents most commonly with CNS (39%) and skin involvement (39%), although other organ systems may be affected as well (10). Fever, skin rash, and rapidly progressive neurological signs (e.g., dementia, stroke, peripheral neuropathy) may occur (1,11). Due to this heterogeneous presentation, IVL is underrecognized and often only diagnosed postmortem.
Systemic IVL can spread to the pituitary vasculature without mass formation and cause pituitary dysfunction (12–14). We present a rare case of IVL within the pituitary gland, with mass effect, cavernous sinus infiltration, and associated neuro-ophthalmic findings. The clinical course simulated pituitary apoplexy.
A 68-year-old left-handed female was admitted to the hospital from the emergency room with right ptosis and diplopia. Over the previous month, she developed left cheek pain and severe frontal and retro-orbital headaches. Diagnosed with a sinus infection, the patient failed to improve with decongestants and antibiotics. One week prior to admission, she developed horizontal binocular diplopia associated with nausea and presyncope. The onset of complete right ptosis prompted her visit to the emergency room.
Medical history was significant for type 2 diabetes mellitus, hypercholesterolemia, and a hysterectomy for endometrial carcinoma 20 years ago. She was an ex-smoker and rarely used alcohol.
On physical examination, the patient was afebrile with stable vital signs. Systemic examination was unremarkable. Visual acuity was 20/25 bilaterally, color vision was intact, and kinetic visual fields were normal. She had a miotic right pupil, most apparent in dim light without a relative afferent pupillary defect. In primary position, the patient had a 30–prism diopter exotropia. Ocular motility was normal with the exception of diminished adduction of the right eye. There was no slowing of adducting saccades and no nystagmus of the abducting eye to suggest internuclear ophthalmoplegia. Anterior segment and funduscopic examinations were unremarkable. The remainder of the neurological examination, including facial sensation, was normal. Testing with 4% cocaine eyedrops confirmed a right Horner syndrome.
Neuroimaging revealed a sellar mass extending into the right cavernous sinus (Fig. 1A). The patient was placed on dexamethasone to treat edema related to a presumed pituitary macroadenoma and possible apoplexy. Blood work showed deficiency of anterior pituitary hormones: luteinizing hormone and follicle-stimulating hormone were 2.0 IU/L (normal, 16.0–54.0 IU/L) and 3.0 IU/L (normal, 23.0–116.0 IU/L), respectively; TSH was 0.11 mIU/L (normal, 0.27–4.2 mIU/L); and free T3 and T4 were 2.4 pmol/L (normal, 3.0–6.5 pmol/L) and 15 pmol/L (normal, 10–24 pmol/L), respectively. Cortisol was 31 nmol/L (normal, 119.0–618.0 nmol/L); however, this was measured after the patient had received corticosteroids. Her prolactin was normal at 25 μg/L (normal, 2.0–20.0 μg/L).
There was a significant improvement in the patient's headache and cranial nerve findings with steroids. The neurosurgery service felt there was no urgency for surgical intervention, given the rapid clinical improvement on dexamethasone. She was discharged home with close outpatient follow-up 4 days after admission.
The patient was readmitted 2 days later with worsening headache. Brain CT revealed no pituitary hemorrhage. Over the next several days, she developed complete bilateral ophthalmoplegia, with bilateral ptosis and nonreactive pupils. Brain MRI performed 17 days after the first study revealed increased size of the sellar mass with bilateral cavernous sinus involvement (Fig. 1B). Dural thickening and enhancement and signal change within the marrow of the dorsum sella and clivus were now detected raising the suspicion for an infiltrative or metastatic process. The brainstem was not involved, and careful review of postcontrast MRI showed no evidence of leptomeningeal disease. Systemic metastatic workup, including CT of the thorax, abdomen, and pelvis, mammography, and bone scan, was negative. Cerebrospinal fluid (CSF) analysis was unremarkable. One sample of CSF was sent for cytology and returned negative for malignancy. Flow cytometry could not be performed because of insufficient cell count. Nasopharyngoscopy revealed a polyp in the right nasal cavity. Transsphenoidal biopsies of the nasal polyp and sellar mass were performed.
Preliminary pathology of the sellar tissue was consistent with normal pituitary tissue, with areas of focal necrosis suggestive of “mild pituitary apoplexy”; final pathology was deferred pending immunohistochemical staining. Meanwhile, the nasal polyp pathology returned consistent with sinonasal hemangiopericytoma. Ectatic vascular spaces within the hemangiopericytoma contained large malignant lymphoid cells (Fig. 2A) that stained positively with B-cell markers (Fig. 2B–D). Final pathology of the pituitary gland did reveal focal areas of infarction (Fig. 3A), while immunohistochemistry also demonstrated endovascular malignant lymphoid cells (Fig. 3B). The presence of identical endovascular malignant lymphoid cells within both the pituitary gland and the hemangiopericytoma confirmed the final diagnosis of IVL.
The patient was treated with 3 cycles of cyclophosphamide, doxorubicin, vincristine, prednisolone, and rituximab (CHOP-R) chemotherapy. Repeat MRI after 3 cycles of CHOP-R, approximately 2 months after initial presentation, revealed resolution of the mass (Fig. 1C). At follow-up 6 months later, the patient had a right third nerve palsy, but the remainder of her bilateral ophthalmoplegia had resolved.
Our patient demonstrated a rare presentation of IVL with sellar and bilateral cavernous sinus involvement. This precipitated the abrupt onset of bilateral ophthalmoplegia mimicking pituitary apoplexy. Our literature review revealed no previous cases of IVL involving the pituitary gland presenting with neuro-ophthalmic findings.
Arriving at a diagnosis of IVL is challenging since it is established postmortem in 53% of cases (15). Although peripheral blood smear is nondiagnostic, and CSF often does not reveal malignant cells (16), the diagnosis of IVL can sometimes be made antemortem by skin biopsy, provided the disease is suspected. The clinical presentation, laboratory results, and neuroimaging of our patient were initially consistent with apoplectic pituitary macroadenoma. Pituitary biopsy revealed areas of necrosis, consistent with pituitary apoplexy. The key pathological finding in this case, the presence of endovascular malignant lymphoid cells, was almost overlooked on the pituitary biopsy. The detection of these cells within a nasal polyp, incidentally biopsied on the transsphenoidal approach to the pituitary gland, allowed the diagnosis of intravascular large B-cell lymphoma to be made.
Leptomeningeal involvement in IVL is largely confined to areas overlying enhancing parenchymal lesions (17). Pachymeningeal involvement is a more common neuroimaging and pathological finding in IVL, resulting from lymphomatous infiltration of meningeal blood vessels causing a mix of inflammation and ischemia (18). Cranial nerve involvement, when it occurs in IVL, may be on the basis of mass effect from nearby tumor, as in our patient, or from small vessel ischemia caused by intravascular tumor infiltration (19).
There have been no previous reported cases of parasellar IVL presenting with cranial nerve findings. Schleinitz et al (20) described 2 cases of IVL causing hypopituitarism; one patient diagnosed by skin biopsy had normal-sized pituitary, and the other patient, who was diagnosed by bone marrow biopsy, had an enlarged pituitary on MRI. Kraus et al (12) reported 2 patients with hypopituitarism and a normal MRI of the pituitary. IVL patients have also been reported (14,20) with hypopituitarism and empty sella on MRI of the pituitary (14,20).
Systemic IVL can spread to the pituitary gland without mass formation and cause pituitary dysfunction (12–14). The lack of tissue-specific vascular homing receptors, CD29 and CD54, has been reported in patients with IVL and may contribute to the intravascular and disseminated distribution pattern of the neoplasm (21). In our patient, spread of IVL to the cavernous sinuses would explain her initial right third nerve palsy and Horner syndrome, followed by development of bilateral ophthalmoplegia.
Chemotherapy is the current treatment for IVL. Anthracycline-based regimens have shown clinical benefit, with CHOP being the most commonly used (22–24). A case series by Ferreri et al (1) examined 38 cases of IVL and revealed a response rate of nearly 60% and a 3-year survival of 32% after anthracycline-based chemotherapy. Several studies have demonstrated the benefit of adding rituximab, a CD20 monoclonal antibody, to anthracycline-based regimens in the treatment of IVL (3,25,26). One such study compared rituximab to placebo as an adjuvant to CHOP-based chemotherapy (3). There was no difference in the rate of treatment-related deaths, but at 18 months, the rituximab group showed higher rates of complete response, 2-year progression-free survival, and 2-year overall survival. Thus, the current recommended first-line therapy for IVL is an anthracycline-based regimen, such as CHOP, along with rituximab.
Since 35%–40% of IVL patients present with neurological symptoms, and one third of IVL relapses involve the CNS, some authors argue that first-line chemotherapy should include CNS-penetrating agents, such as methotrexate (MTX), either systemically or intrathecally (23,26–28). Other treatment modalities including autologous stem cell transplantation (1,29–35) and radiotherapy (36,37) have shown limited efficacy to date.
Our patient had a complete MRI response after 3 cycles of CHOP-R chemotherapy, with resolution of the sellar mass and no features of tumor recurrence. At 6-month follow-up, she had a residual partial right third nerve palsy, presumably on the basis of axonal damage, but the remainder of her complete bilateral ophthalmoplegia had resolved. She is to receive 3 more cycles of CHOP-R with intrathecal MTX.
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