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Triple-hit lymphoma of the cavernous sinus

Published:August 28, 2018DOI:https://doi.org/10.1016/j.jcjo.2018.06.007
      Diffuse large B-cell lymphoma (DLBCL) is the most common non–Hodgkin-type lymphoma in adults, and the myriad of clinical presentations is well known to neuro-ophthalmologists.
      • Akyurek N
      • Uner A
      • Benekli M
      • Barista I
      Prognostic significance of MYC, BCL2, and BCL6 rearrangements in patients with diffuse large B-cell lymphoma treated with cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab.
      Traditionally, DLBCL was treated with standard chemotherapy, including R-CHOP (i.e., rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Newer cytogenetic, fluorescent in situ hybridization (FISH), and next-generation sequencing (NGS) techniques, however, have shown the presence of genomic abnormalities that have significant treatment and prognostic implications. For example, alterations in the MYC gene (e.g., “single-hit” MYC+ lymphoma) confer resistance to standard R-CHOP therapy and have a worse prognosis. “Double-hit” lymphomas (DHL) are uncommon (5%) and involve gene rearrangements in MYC and BCL2and/or BCL6. Triple-hit lymphomas (THL) are even more rare and are defined as high-grade B-cell lymphoma with rearrangements of MYC and BCL2and/or BCL6 in the 2016 World Health Organization (WHO) classification of lymphoid neoplasias.
      • Quintanilla-Martinez L
      The 2016 updated WHO classification of lymphoid neoplasias.
      THLs are highly aggressive and recalcitrant to traditional chemotherapy regimens such as R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab).
      • Akyurek N
      • Uner A
      • Benekli M
      • Barista I
      Prognostic significance of MYC, BCL2, and BCL6 rearrangements in patients with diffuse large B-cell lymphoma treated with cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab.
      Consequently, researchers are investigating novel therapeutic approaches.
      • Akyurek N
      • Uner A
      • Benekli M
      • Barista I
      Prognostic significance of MYC, BCL2, and BCL6 rearrangements in patients with diffuse large B-cell lymphoma treated with cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab.
      • Kaplan JB
      • Gordon LI
      • Infante JR
      • et al.
      Updated results from a phase 1 study of TAK-659, an investigational and reversible SYK inhibitor, in patients (pts) with advanced solid tumor or lymphoma malignancies.
      Central nervous system (CNS) prophylaxis is necessary due to the propensity of THL to affect the CNS.
      • Cheah CY
      • Oki Y
      • Westin JR
      • Turturro F
      A clinician's guide to double hit lymphomas.
      Unfortunately, CNS prophylaxis with current regimens can be inadequate for THL. Understanding and recognizing the signs and symptoms suggesting THL progression to the CNS is important in order to promptly initiate high-dose intrathecal chemotherapy and radiation regimens to reduce associated morbidity and mortality.
      We report a patient with stage IV, triple-hit DLBCL who presented with painless, bilateral, complete ptosis, complete ophthalmoplegia, proptosis, and fixed pupils and was found to have metastases to the cavernous sinuses. The metastases showed regression after focused radiation to the cavernous sinuses combined with intrathecal therapy. Although cavernous sinus lymphoma is well known to neuro-ophthalmologists, to our knowledge, this is the first triple-hit DLBCL affecting bilateral cavernous sinuses. Neuro-ophthalmologists should be aware of the newer cytogenetic and FISH techniques in lymphoma in order to improve diagnostic, treatment, and prognostic information for patients with DLBCL.

      Case Report

      A 54-year-old Caucasian male presented to the Houston Methodist Hospital neuro-ophthalmology department for acute painless bilateral sequential and rapidly progressive complete ophthalmoplegia over a 3-week period. His medical history was significant for well-controlled hypertension. He denied tobacco, alcohol, or drug use. He worked as a chemical trader. He denied a family history of neoplasm.
      Ten months before presentation, he developed a painless right iliac mass. Biopsy revealed DLBCL. The tumour showed protein overexpression of the cell proliferation index, Ki-67 of 95%. Cytogenetics and FISH was positive for C-MYC, BCL2, and BCL6 gene rearrangements. Immunohistochemistry was positive for CD20 and negative CD30. A diagnosis of triple-hit DLBCL was made and the patient was treated with numerous chemotherapy regimens, including hyper-CVAD (cyclophosphamide, vincristine, doxorubicin (i.e., adriamycin), and dexamethasone), intrathecal methotrexate and cytarabine, rituximab, R-EPOCH (rituximab, etoposide phosphate, prednisone, vincristine sulphate, cyclophosphamide, doxorubicin hydrochloride), and 2 cycles of TAK659, a tyrosine kinase inhibitor under research for treatment against lymphoma. However, the patient's lymphoma continued to progress, and the patient developed bone, soft tissue, and epidural metastases.
      On examination in the neuro-ophthalmology clinic, best-corrected visual acuity was 20/40 OD and 20/30 OS. The right pupil measured 8 mm and was fixed and dilated, and the left pupil measured 6 mm and was minimally reactive. No relative afferent pupillary defect was noted. External examination showed bilateral ptosis and proptosis (Fig. 1). Slit-lamp biomicroscopy, intraocular pressure measurements, visual field testing, and ophthalmoscopy were normal OU. On motility assessment, the patient had complete bilateral ophthalmoplegia (Fig. 4 and VIdeo 1, available online).
      Fig 1
      Fig.1External photograph of right and left pupil. The right pupil is fixed and dilated at 8mm and the left pupil is fixed and dilated at 7mm.
      Magnetic resonance imaging (MRI) of the brain and orbit revealed bilateral cavernous sinus infiltration (Fig. 2). Positron emission tomography (PET) scan also revealed abnormal uptake in the skull base (Fig. 3) and significant progression in disease with involvement of lymph nodes in the abdomen, pelvis, and several osseous structures.
      Fig 2
      Fig.2Bilateral proptosis. An external photograph showing bilateral proptosis. (A) A view from lateral and (B) a worm's-eye view. The patient had complete ptosis and required assistance in order to elevate the upper eyelids.
      Fig 3
      Fig.3Radiology studies. (A) Magnetic resonance imaging brain and orbit showing mild fullness greater in the left than in the right cavernous sinus region. (B) Computer Tomography (CT) orbits with and without contrast showing increased density in the cavernous sinus region compatible with diffuse lymphoma involvement of the cavernous sinus. (C) A positron emission tomography scan showing abnormal uptake at the skull base, correlating with previous CT findings, compatible with infiltration by lymphoma.
      Fig 4
      Fig.4External photographs of the patient in primary position, up gaze, down gaze, right gaze, and left gaze.
      Cerebrospinal fluid (CSF) cell composition showed normal cell count, protein, and glucose, but flow cytometry showed CD10-positive, kappa light chain–restricted B cells consistent with DLBCL.
      During the patient's hospitalization, the patient was started on intravenous dexamethasone, intrathecal methotrexate, and cytarabine. He received intensity-modulated stereotactic radiotherapy to the cavernous sinus. The patient was started on tyrosine kinase inhibitor ibrutinib. However, during the patient's hospitalization, he developed neutropenia and sepsis. The patient and his family elected for inpatient hospice, and the patient passed away within 1day of discharge from the hospital. It is unclear whether an autopsy was performed. There was no documentation in the electronic medical record that an autopsy was offered to the family or performed.

      Discussion

      The differential diagnosis of bilateral cavernous sinus involvement is broad. The cavernous sinus may be affected by infectious, neoplastic, vascular, and infiltrating lesions. Clinically, patients with cavernous sinus involvement present with ophthalmoplegia due to the involvement of cranial nerves 3, 4, and 6 with sensory deficits from the trigeminal nerve.
      • Nambiar R
      • Nair S
      Cavernous sinus syndrome.
      On MRI, many of the different processes mentioned above may have significant overlapping and nonspecific features. For example, meningiomas and cavernous hemangiomas are one of the most common primary cavernous sinus tumours. However, they usually present with slow growth. Meningiomas are usually hypointense to mildly hyperintense in relation to grey matter but are well delineated by contrast in MRI sequences.
      • Watts J
      • Box G
      • Galvin A
      • Brotchie P
      • Trost N
      • Sutherland T
      Magnetic resonance imaging of meningiomas: a pictorial review.
      Cavernous hemangiomas are hypointense in T1-weighted images and hyperintense in T2-weighted images and show homogenous enhancement after contrast.
      • Sohn CH
      • Kim SP
      • Kim IM
      • Lee JH
      • Lee HK
      Characteristic MR imaging findings of cavernous hemangiomas in the cavernous sinus.
      Lymphomas have no specific MRI findings except for contrast enhancement but the diagnosis is made by coupling the other imaging studies (such as PET) with clinical results, such as the case with the aforementioned patient with his symptoms, signs, and clinical course.
      THL, a rare subtype of DLCBCL, is defined by chromosomal rearrangements in the c-MYC BCL2, and BCL6 genes. Using the Hans algorithm, majority of them have a germinal centre B cell–like (GCB) immunophenotype. THL are associated with an extremely poor prognosis with a median survival after diagnosis of only 9 months.
      • Akyurek N
      • Uner A
      • Benekli M
      • Barista I
      Prognostic significance of MYC, BCL2, and BCL6 rearrangements in patients with diffuse large B-cell lymphoma treated with cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab.
      THLs are aggressive lymphomas and have a propensity to invade the CNS and thus are of particular interest to neuro-ophthalmologists.
      • Rosenthal A
      • Younes A
      High grade B-cell lymphoma with rearrangements of MYC and BCL2and/or BCL6: double hit and triple hit lymphomas and double expressing lymphoma.
      • Oki Y
      • Noorani M
      • Lin P
      • et al.
      Double hit lymphoma: the MD Anderson Cancer Center clinical experience.
      Cheah et al. in 2015 proposed giving intrathecal methotrexate to reduce the rate of CNS progression.
      • Cheah CY
      • Oki Y
      • Westin JR
      • Turturro F
      A clinician's guide to double hit lymphomas.
      • Liu D
      • Mamorska-Dyga A
      Syk inhibitors in clinical development for hematological malignancies.
      Focused radiation to the cavernous sinuses can reduce also ocular symptoms from metastases.
      • Pinnix CC
      • Andraos TY
      • Dabaja B
      • et al.
      Diffuse large B-cell lymphoma in very elderly patients over 80years old: incorporating consolidative radiation therapy into management decisions.
      Our patient received TAK-659, an investigational spleen tyrosine kinase (SYK) inhibitor. SYK is important in B-cell receptor signalling-driven tumourigenesis. The inhibition of SYK induces apoptosis and inhibits the prosurvival, chemoresistant, proliferative microenvironment. SYK inhibitors, including TAK-659, are being studied for various B-cell malignancies.
      • Liu D
      • Mamorska-Dyga A
      Syk inhibitors in clinical development for hematological malignancies.
      Early reports of a phase 1 study of TAK-659 have shown favourable results with 46% of patient achieving an objective response as per the International Working Group (IWG) response criteria.
      • Kaplan JB
      • Gordon LI
      • Infante JR
      • et al.
      Updated results from a phase 1 study of TAK-659, an investigational and reversible SYK inhibitor, in patients (pts) with advanced solid tumor or lymphoma malignancies.
      In summary, clinicians should be aware of newer cytogenetic, FISH, and NGS techniques to detect genetic alterations in lymphoma, including single-, double-, and triple-hit (MYC, BCL2, BCL6) DLBCL. Genomic status provides important risk stratification and prognostic information that may be of value when evaluating and treating neuro-ophthalmology patients (e.g., ophthalmoplegia or visual loss) with DLBCL.

      Disclosure

      The authors have no proprietary or commercial interest in any materials discussed in this article.

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