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Primary central nervous system lymphoma of the optic chiasm

Published:November 10, 2018DOI:https://doi.org/10.1016/j.jcjo.2018.08.015
      Primary CNS lymphoma (PCNSL) is a rare form of extranodal, high-grade, non-Hodgkin lymphoma (NHL), accounting for approximately 3% of newly diagnosed brain tumors and 2 to 3% of all NHL.
      • Rubenstein JL
      • Gupta NK
      • Mannis GN
      • Lamarre AK
      • Treseler P
      How I treat CNS lymphomas.
      PCNSL can also arise from posttransplant lymphoproliferative disorder (PTLD), a disorder in patients with secondary immunodeficiency after a solid organ or hematopoietic stem cell transplant.
      • Torlakovic EE
      • Bailey D
      Post-transplant lymphoproliferative disorders.
      PCNSL is characterized by rapid growth usually confined to the CNS and can originate in the brain, leptomeninges, spinal cord, or eyes. Sixty-five percent of cases present as a solitary supratentorial mass, while 35% of cases present as multiple lesions and regions.
      • Rubenstein JL
      • Gupta NK
      • Mannis GN
      • Lamarre AK
      • Treseler P
      How I treat CNS lymphomas.
      PCNSL is rarely seen in the optic chiasm.
      • Tsutsumi K
      • Horiuchi T
      • Aoyama T
      • Hongo K
      Isolated primary malignant lymphoma arising from the optic chiasm.
      We present 2 cases of PCNSL of the optic chiasm. Although both cases are rare due to the chiasmal presentation, to our knowledge, case 2 is the first case of PTLD-induced PCNSL presenting in the optic chiasm in the English ophthalmologic literature.

      Case 1

      A 25-year-old, previously healthy male presented with a 1-week history of severe headaches and changes in vision. He reported recent decreased libido, polyuria, polydipsia, and emotional lability. Ophthalmologic examination showed a best corrected visual acuity of 20/30 at distance in each eye. Ishihara color plates were correctly identified in 14/14 plates in the right eye (OD) and 13/14 in the left eye (OS). External, extraocular motility, intraocular pressure, and slit-lamp biomicroscopic and fundus examinations were normal in both eyes (OU). Automated perimetry (Humphrey 24-2) showed a bitemporal hemianopsia.
      Computed tomography (CT) scan of the head showed a poorly defined hypothalamic and right parasagittal subcortical mass. An endocrinologic evaluation showed panhypopituitarism with low serum levels of adrenocorticotrophic hormone, cortisol, thyroid stimulating hormone, luteinizing hormone, and follicle stimulating hormone levels. Serum prolactin levels were normal. Cranial magnetic resonance imaging (MRI) showed multifocal circumscribed thick rim-enhancing masses with restricted diffusion-weighted imaging involving the right posterior body-splenium of corpus callosum, hypothalamus, and posterior third ventricle (Fig. 1). MRI of the spine was negative for metastasis. Scrotal ultrasound and CT of the body were negative for dysgerminoma, other metastasis, or other primary tumors. A bone marrow aspirate did not reveal tumour cells or lymphoid infiltrate. Human immunodeficiency virus (HIV) testing was negative.
      Fig 1
      Fig. 1Case 1: MRI of the brain shows multifocal circumscribed thick rim-enhancing masses involving the right posterior body-splenium of corpus callosum, hypothalamus, and posterior third ventricle, lesions demonstrated relatively reduced diffusion. There was moderately marked vasogenic edema surrounding the larger lesions. Findings are shown in A and B, Sagital T1 postcontrast; C and D, Axial T1 postcontrast; E, Coronal T1 postcontrast; and F, Diffusion-weighted imaging.
      A right-sided craniotomy with ventriculostomy was performed and showed an infiltrative tumour within the optic chiasm and hypothalamus. The biopsy showed high-grade, diffuse, nongerminal center type, large B-cell lymphoma. Copy gains of MYC and BCL2 were detected by fluorescent in situ hybridization (FISH). The tumour also had perivascular involvement typical for PCNSL (Fig. 2). Immunohistochemical studies were positive for CD45, CD20, CD79a, PAX-5, and MUM-1 (Fig. 2) and negative for CD10, an immunophenotype consistent with nongerminal center type, large B-cell lymphoma, and activated B-cell type lymphoma. The lymphoma was negative for TdT, CD34, CD3, synaptophysin, GFAP, and OCT 3-4. Ki-67 proliferation fraction was 90%, and BCL2 expression was extensive (Fig. 2). After surgery, the patient completed 5 cycles of chemotherapy with intravenous (IV) rituximab, IV methotrexate, and R-MV vincristine followed by 23.4 Gy whole brain radiation therapy. Three months later, a follow-up cranial CT scan showed resolution of the lesion. Lumbar puncture was normal and cytology was negative. The patient, however, did not return for neuro-ophthalmic examination.
      Fig 2
      Fig. 2Case 1: Left: hemotoxylin and eosin stain (400 ×) and B-cell markers expression by immunohistochemistry: Infiltrating intermediate to large-sized atypical lymphocytes with perivascular space involvement. V, vessel; white arrow, mitotic figure. A, CD20 is variably expressed in the majority of lymphoma cells (100 ×). B, CD79a is extensively expressed (400 ×). C, PAX-5 nuclear expression is extensive (400 ×). D, MUM-1 is also extensively expressed, the expression of MUM-1 with absence of CD10 expression is consistent with a nongerminal center type large B-cell lymphoma (400 ×). E, Immunophenotypic features identified that may be seen with high-grade B-cell lymphoma with rearrangements or extra copies (gains) of MYC and BCL2. V, vessel. Ki-67 proliferation fraction of approximately 90% (400 ×). F, Extensive expression of BCL2 (400 ×).

      Case 2

      A 61-year-old Hispanic female with a 3-week history of cognitive impairment and headache presented with painless, right-sided vision loss. Her past medical history was significant for chronic back pain, lumbar and thoracic compression factures, hypothyroidism, and type 2 diabetes mellitus with nonproliferative diabetic retinopathy OU. Her surgical history included hysterectomy without salpingo-oophorectomy, left breast lumpectomy for a benign tumour, substernal, partial thyroidectomy for an unknown etiology, right parotid gland removal for a parotid gland tumour, and most significantly, a liver transplantation for nonalcoholic steatohepatitis that was completed 2 years earlier. Her medications included immunosuppression with cyclosporine 25 mg twice daily and mycophenolate 500 mg twice daily, as well as gabapentin 100 mg twice daily, calcium carbonate oyster shell 500 mg thrice daily, ergocalciferol 50 000 units twice a week, insulin lispro 10 unit injection thrice daily, levothyroxine 75 mcg daily, losartan 25 mg daily, lisinopril 5 mg daily, pravastatin 20 mg daily, escitalopram 20 mg, quetiapine 50 mg daily, and omega-3 acid ethyl esters 1 g twice daily. She reported an allergic, itching reaction to hydrocodone-acetaminophen. She denied tobacco, excessive alcohol, and illicit drug use. Her mother had dementia. Her review of systems revealed musculoskeletal weakness and was otherwise unremarkable.
      Neuro-ophthalmologic examination revealed best corrected visual acuity of 20/70 OD and 20/25 OS. Ishihara colour plates were correctly identified in 10/14 plates OD and 14/14 OS. Humphrey visual field testing revealed a superior altitudinal field defect and inferior arcuate with a mean deviation of −9.80 decibels (dB) OD. Nonspecific scatter and a mean deviation of −2.75 dB was noted OS. A right relative afferent pupillary defect (RAPD) was present.
      Ophthalmoscopy revealed optic atrophy OD. Optical coherence tomography (OCT) showed a global retinal nerve fiber layer thickness that was reduced to 77 microns OD but was normal at 101 microns OS. Fundus examination showed scattered dot and blot hemorrhages bilaterally, consistent with nonproliferative diabetic retinopathy.
      MRI of the brain revealed multiple bihemispheric, hyperintense, enhancing lesions with surrounding vasogenic edema. Notably, a hyperintense, enhancing lesion with surrounding vasogenic edema was also present in the optic chiasm (Fig. 3). A right-sided craniotomy was performed for biopsy of the optic chiasm lesion. Tissue pathology revealed a diagnosis of posttransplant lymphoproliferative disorder, with CNS involvement (Fig. 4). Large B-cell lymphoma tested positive for Epstein-Barr virus (EBV) via EBV-encoded RNA in situ hybridization. Cerebrospinal fluid showed mild lymphocytic pleocytosis with 6 white blood cells (normal less than 5). Glucose was 44 mg/dL, and protein was elevated at 112 mg/dL with increased IgG synthesis rate. No oligoclonal bands were present. Immunosuppression medications were discontinued, and the patient was treated with 4 900 mg weekly doses of rituximab and prednisone 20 mg daily, followed by cranial radiotherapy.
      Fig 3
      Fig. 3Case 2: An initial axial T1 postcontrast and T2 FLAIR MRI brain scan revealed multiple bihemispheric, hyperintense, enhancing lesions with surrounding vasogenic edema, including a lesion in the optic chiasm. A posttreatment axial T1 postcontrast and T2 FLAIR MRI brain scan performed 9 months later showed complete resolution of the lesions.
      Fig 4
      Fig. 4Case 2: A, periodic acid–Schiff (600 ×) and B, hemotoxylin and eosin stains (600 ×) show infiltrating intermediate to large-sized atypical lymphocytes with perivascular space involvement. C, Epstein-Barr virus was confirmed by an Epstein–Barr virus-encoded small RNA in situ hybridization study. D, CD79a is extensively expressed. E, A scale bar was provided for reference.
      Six months after a 4-week rituximab treatment and radiotherapy, a follow-up magnetic resonance scan of the brain showed resolution of the majority of the lesions, including the lesion in the optic chiasm (Fig. 3). At her latest neuro-ophthalmologic examination, approximately 9 months after treatment, the patient presented with visual acuity without corrective lenses of 20/40 at distance in each eye. Colour plates were correctly identified in 6/14 plates OD and 11/14 OS. A right RAPD was present. Humphrey visual field testing showed a mean deviation of −15.33 dB OD and −8.01 dB OS. There was a residual superior and inferior arcuate defect OD. OCT global RNFL thickness was 67 microns OD and 99 microns OS. The rest of her examination was otherwise unchanged.

      Discussion

      Diffuse large B-cell lymphoma (DLBCL) in the optic chiasm is rare. A review of the prior reported cases is summarized in Table 1. Approximately 40% of all B-cell lymphomas are characterized by recurrent, reciprocal chromosome translocations that activate multiple oncogenes, known as “double hit” lymphomas; the most common translocation involves the MYC and BCL2 genes. “Double hit” lymphomas carry a worse prognosis due to traditional chemotherapy resistance.
      • Friedberg JW
      How I treat double-hit lymphoma.
      B-cell lymphomas with extra copies, or “gains” of MYC and BCL2 without translocation can occur,
      • Li S
      • Seegmiller AC
      • Lin P
      • et al.
      B-cell lymphomas with concurrent MYC and BCL2 abnormalities other than translocations behave similarly to MYC/BCL2 double-hit lymphomas.
      as in our case one.
      Table 1A summary of atypical and typical features of our cases
      PCNS-DLBL cases.
      compared with previous
      PatientPresentationLocationExamination
      No.SexPresentation (Age in Years)Signs and SymptomsSymptom Duration in WeeksCNS Large B-cell LymphomaLesion LocationsSlit LampMRI EnhancementEnhancement Type
      Case 1: Go et al.
      PCNS-DLBL cases.
      1Male25Bitemporal hemianopsia

      Headache

      Decreased libido

      Polyuria

      Polydipsia

      Emotional lability
      1YesLobar

      basal ganglia

      Callosal

      Ventricle contact

      Optic chiasm
      UnremarkableYesHeterogeneous
      Case 2: Go et al.
      PCNS-DLBL cases.
      1Female61Blurred vision

      Headache

      Cognitive impairment
      3YesLobar

      Periventricular

      Cerebellar

      (not shown in Fig. 3)

      Optic chiasm
      PCIOL in both eyes,

      DBH in the macula and periphery of both eyes,

      PCO in the right eye
      YesHomogeneous
      Tsutsumi et al.
      • Tsutsumi K
      • Horiuchi T
      • Aoyama T
      • Hongo K
      Isolated primary malignant lymphoma arising from the optic chiasm.
      1Male59Right superior quadrantic hemianopia OD

      Right hemianopia OS
      Not availableYesOptic nerve

      Optic tract

      Optic chiasm
      Not availableYesHomogeneous
      Cavaliere et al.
      • Cavaliere R
      • Petroni G
      • Lopes MB
      • Schiff D
      Primary central nervous system post-transplantation lymphoproliferative disorder: an international primary central nervous system lymphoma collaborative group report.
      3465% male,

      35% female
      Median:

      43
      34% Headache

      33% Hemiparesis

      29% Ataxia

      26% Seizures

      20% Aphasia

      36% Other
      Median:

      3
      Yes85% Lobar

      40% Meningeal

      39% Basal ganglia

      36% Periventricular

      33% Infratentorial

      14% Callosal

      10% Spinal cord

      10% Ventricle contact
      100% Unremarkable97% Yes

      3% No
      56% Heterogeneous

      41% Homogenous



      29% Ring pattern
      Izadi et al.
      • Izadi M
      • Fazel M
      • Saadat SH
      • Taheri S
      Radiotherapy is the best treatment method in post-transplant lymphoproliferative disorders localizing in brain: a review of the literature.
      7951% male,

      49% female
      Mean:

      39.7 ± 17.2
      Not availableNot availableYesNot availableNot availableNot availableNot available
      Papanastasiou et al.
      • Papanastasiou L
      • Pappa T
      • Dasou A
      • et al.
      Case report: primary pituitary non-Hodgkin's lymphoma developed following surgery and radiation of a pituitary macroadenoma.
      1Female60Muscle weakness

      Ptosis

      Headache
      4YesIntrasellar

      Suprasellar

      Cavernous sinus

      Optic canal

      Optic chiasm

      Pons
      Not availableYesHeterogeneous
      Ozdemir et al.
      • Ozdemir ES
      • Yildirim AE
      • Can AY
      Primary central nervous system lymphoma of optic chiasma: endoscopic endonasal treatment.
      1Male76Headache

      Dizziness

      Loss of appetite

      Syncope
      4YesOptic tract

      Third ventricle

      Optic chiasm
      Not availableYesHomogeneous
      Lee et al.
      • Lee AG
      • Tang RA
      • Roberts D
      • Schiffman JS
      • Osborne A
      Primary central nervous system lymphoma involving the optic chiasm in AIDS.
      1Male42Headache

      Diplopia

      Bilateral vision loss
      3YesSuprasellar

      Optic nerves

      Optic chiasm
      UnremarkableYesHomogeneous
      Cellina et al.
      • Cellina M
      • Fentooni V
      • Baron P
      • Orsi M
      • Oliva G
      Unusual primary central nervous system lymphoma location involving the fourth ventricle and hypothalamus.
      1Male65Headache

      Weight loss

      Blurred vision

      Asthenia

      Walking impairment
      2YesSupratentorial

      Infratentorial

      Periventricular

      Thalamus

      Hypothalamus
      Not availableYesHomogeneous
      GeneticsPTLDManagement
      Genetic AbnormalityPTLD RelatedEBV StatusPrior Maintenance ImmunosuppressionTransplant OrganMonths from Transplant to DiagnosisChemotherapyRadiotherapyPosttreatment Results with Radiotherapy
      Case 1: Go et al.
      PCNS-DLBL cases.
      Copy gains: MYC, BCL2NoNot availableN/AN/AN/AMethotrexate

      Rituximab

      Vincristine
      YesSurvived with resolution of lesions
      Case 2: Go et al.
      PCNS-DLBL cases.
      Not availableYesPositiveCyclosporine

      Mycophenolate
      Liver24RituximabYesSurvived with resolution of lesions
      Tsutsumi et al.
      • Tsutsumi K
      • Horiuchi T
      • Aoyama T
      • Hongo K
      Isolated primary malignant lymphoma arising from the optic chiasm.
      Not availableNoNot availableN/AN/AN/ACytarabine

      Methotrexate
      NoSurvived with resolution of lesions
      Cavaliere et al.
      • Cavaliere R
      • Petroni G
      • Lopes MB
      • Schiff D
      Primary central nervous system post-transplantation lymphoproliferative disorder: an international primary central nervous system lymphoma collaborative group report.
      Not availableYesNot available55% Cyclosporine

      55% Mycophenolate

      52% Corticosteroids

      38% Tacrolimus

      24% Azathioprine

      10% OKT3
      56% Kidney

      15% Liver

      6% Lung

      23% Other or combination
      Median:

      52
      30% Systemic chemotherapy

      15% Intrathecal chemotherapy
      24% Yes

      76% No
      63% complete response

      25% partial response

      12% no response
      Izadi et al.
      • Izadi M
      • Fazel M
      • Saadat SH
      • Taheri S
      Radiotherapy is the best treatment method in post-transplant lymphoproliferative disorders localizing in brain: a review of the literature.
      Not availableYes65% Yes

      35% No
      Not available68% Kidney

      10% Bone marrow

      8% Liver

      6% Pancreas

      5% Heart

      3% Lung
      Mean:

      47.4 ± 66.1
      59% Yes

      41% No
      53% Yes

      47% No
      73% remission episode

      27% no remission episode
      Papanastasiou et al.
      • Papanastasiou L
      • Pappa T
      • Dasou A
      • et al.
      Case report: primary pituitary non-Hodgkin's lymphoma developed following surgery and radiation of a pituitary macroadenoma.
      Not availableNoN/AN/AN/AN/AMethotrexate

      Procarbazine

      Rituximab

      Vincristine
      NoDeceased due to hospital-acquired infection
      Ozdemir et al.
      • Ozdemir ES
      • Yildirim AE
      • Can AY
      Primary central nervous system lymphoma of optic chiasma: endoscopic endonasal treatment.
      Not availableNoN/AN/AN/AN/AUnspecified chemotherapyNoNot available
      Lee et al.
      • Lee AG
      • Tang RA
      • Roberts D
      • Schiffman JS
      • Osborne A
      Primary central nervous system lymphoma involving the optic chiasm in AIDS.
      Not availableNoN/AN/AN/AN/AUnspecified chemotherapyYesTransferred to skilled nursing facility
      Cellina et al.
      • Cellina M
      • Fentooni V
      • Baron P
      • Orsi M
      • Oliva G
      Unusual primary central nervous system lymphoma location involving the fourth ventricle and hypothalamus.
      Not availableNoN/AN/AN/AN/ARituximabNoRegression of lesions
      MRI, magnetic resonance imaging; PTLD, posttransplant lymphoproliferative disorder; EBV, Epstein-Barr virus; N/A, not applicable; PCIOL, posterior chamber intraocular lens; DBH, dob blot hemorrhage; PCO, posterior capsule opacification.
      low asterisk PCNS-DLBL cases.
      The median age of presentation for DLBCL due to PCNSL is typically greater than 65 years for nonimmunocompromised patients, although PCNSL can occur in younger, HIV-positive patients.
      • Rubenstein JL
      • Gupta NK
      • Mannis GN
      • Lamarre AK
      • Treseler P
      How I treat CNS lymphomas.
      • Sierra del Rio M
      • Rousseau A
      • Soussain C
      • Ricard D
      • Hoang-Xuan K
      Primary CNS lymphoma in immunocompetent patients.
      Activated, nongerminal center type diffuse large B-cell lymphomas have a worse clinical outcome compared with germinal center type diffuse large B-cell lymphomas.
      • Swerdlow SH
      • Campo E
      • Pileri SA
      • et al.
      The 2016 revision of the World Health Organization classification of lymphoid neoplasms.
      BCL2 and Ki-67 overexpression and gains are also associated with a poor prognosis.
      • Li S
      • Seegmiller AC
      • Lin P
      • et al.
      B-cell lymphomas with concurrent MYC and BCL2 abnormalities other than translocations behave similarly to MYC/BCL2 double-hit lymphomas.
      A recent retrospective analysis of patients with double-hit lymphoma who received various chemotherapeutic regimens (e.g., R-CHOP, R-EPOCH, or R-HyperCVAD/MA) reported 2-year, event-free survival rates of 25%, 67%, and 32%, respectively; 13% of these patients had lymphomas with CNS involvement.
      • Friedberg JW
      How I treat double-hit lymphoma.
      Due to the presence of MYC rearrangements, some retrospective studies advocate more aggressive management, mirroring Burkitt lymphoma treatment.
      • Friedberg JW
      How I treat double-hit lymphoma.
      Treatment of PCNS lymphomas with high-dose methotrexate has been reported but remains controversial because of neurotoxic effects.
      • Rubenstein JL
      • Gupta NK
      • Mannis GN
      • Lamarre AK
      • Treseler P
      How I treat CNS lymphomas.
      • Sierra del Rio M
      • Rousseau A
      • Soussain C
      • Ricard D
      • Hoang-Xuan K
      Primary CNS lymphoma in immunocompetent patients.
      We report atypical age and outcome in case 1, a 25-year-old patient who received 3 cycles of chemotherapy and whole brain radiation therapy with good short-term results.
      PTLD is a common transplant-related neoplasia, second in frequency only to nonmelanoma skin carcinomas.
      • Torlakovic EE
      • Bailey D
      Post-transplant lymphoproliferative disorders.
      The incidence of PTLD in solid organ transplants ranges between 1 and 16% based on sex,
      • Torlakovic EE
      • Bailey D
      Post-transplant lymphoproliferative disorders.
      age, organ transplanted, and immunosuppression regimen.
      • San-Juan R
      • Comoli P
      • Caillard S
      • Moulin B
      • Hirsch HH
      • Meylan P
      Epstein-Barr virus-related post-transplant lymphoproliferative disorder in solid organ transplant recipients.
      • Cavaliere R
      • Petroni G
      • Lopes MB
      • Schiff D
      Primary central nervous system post-transplantation lymphoproliferative disorder: an international primary central nervous system lymphoma collaborative group report.
      More than 70% of cases test positive for Epstein-Barr virus.
      • San-Juan R
      • Comoli P
      • Caillard S
      • Moulin B
      • Hirsch HH
      • Meylan P
      Epstein-Barr virus-related post-transplant lymphoproliferative disorder in solid organ transplant recipients.
      PCNSL due to PTLD is rare, especially in isolation,
      • Cavaliere R
      • Petroni G
      • Lopes MB
      • Schiff D
      Primary central nervous system post-transplantation lymphoproliferative disorder: an international primary central nervous system lymphoma collaborative group report.
      but often presents in subcortical white matter and basal ganglia of cerebral hemispheres after a median time of 4.4 years after surgery.
      • Torlakovic EE
      • Bailey D
      Post-transplant lymphoproliferative disorders.
      In case 2, our patient's presentation 2 years after transplantation was atypical compared with the 4.4-year median time frame reported in literature (Table 1).
      Optimal management for PCNS-PTLD has not been established for several reasons. First, its low disease prevalence limits data collection. Second, treatments often involve a combination of therapies,
      • Cavaliere R
      • Petroni G
      • Lopes MB
      • Schiff D
      Primary central nervous system post-transplantation lymphoproliferative disorder: an international primary central nervous system lymphoma collaborative group report.
      preventing isolated study of individual therapeutics, such as rituximab.
      • Izadi M
      • Fazel M
      • Saadat SH
      • Taheri S
      Radiotherapy is the best treatment method in post-transplant lymphoproliferative disorders localizing in brain: a review of the literature.
      However, one widely recognized treatment of PCNS-PTLD is radiotherapy, with literature reporting 1-year and 5-year patient survival rates of 71% and 37% with radiotherapy, compared with 41% and 28% in a control group.
      • Torlakovic EE
      • Bailey D
      Post-transplant lymphoproliferative disorders.
      • Cavaliere R
      • Petroni G
      • Lopes MB
      • Schiff D
      Primary central nervous system post-transplantation lymphoproliferative disorder: an international primary central nervous system lymphoma collaborative group report.
      Consistent with prior literature, our patient's treatment with rituximab, radiotherapy, and corticosteroids was successful in case 2 (Table 1).

      Conclusion

      In summary, we report 2 rare cases of PCNSL of the optic chiasm. Both cases illustrate the role of FISH techniques and cytogenetics in the evaluation and management of these tumours. To our knowledge, case 2 is the first reported case of PTLD of the chiasm in the English language ophthalmic literature. Clinicians should be aware of the possibility of chiasmal lymphoma in patients presenting with an intra-axial lesion of the optic apparatus.

      Disclosure

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

      Patient consent

      This report does not contain any personal information that could lead to the identification of the patient. Thus, consent to publish these cases was not obtained.

      Acknowledgements

      The authors would like to thank Dr. Matthew Cykowski, Department of Pathology and Genomic Medicine at Houston Methodist Hospital, for providing pathologic images.

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