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Unusual Presentations of Lymphomas

Unusual Presentations of Lymphomas. Aziza Shad MD Lombardi Comprehensive Cancer Center Georgetown University Hospital Washington, DC. Primary Central Nervous System Lymphoma (PCNSL). Rare form of non Hodgkin’s lymphoma Arises within and is confined to the CNS Previously classified as

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Unusual Presentations of Lymphomas

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  1. Unusual Presentations ofLymphomas Aziza Shad MD Lombardi Comprehensive Cancer Center Georgetown University Hospital Washington, DC

  2. Primary Central Nervous System Lymphoma (PCNSL) • Rare form of non Hodgkin’s lymphoma • Arises within and is confined to the CNS • Previously classified as • Perithelial sarcoma • Reticulum cell sarcoma • Microglioma • Advances in immunohistochemistry and histopathology have confirmed its lymphoid origin

  3. Primary Central Nervous System Lymphoma (PCNSL) • PCNSL is of particular interest for several reasons: • Its incidence has increased over the past several decades • Hence, it is now an increasingly important differential diagnosis of intracranial mass lesions • Unlike many primary brain tumors, PCNSL is very responsive to treatment • Aggressive management may lead to prolonged remission or cure • Long term consequences of aggressive therapy may result in significant neurological dysfunction

  4. PCNSL - Epidemiology • PCNSL accounts for approximately 1% of all primary brain tumors • Recent data suggest an increase in incidence in immunocompetant patients in USA • SEER data report a 10 fold increase between 1973 -1992 • Incidence of ocular lymphoma has also increased by 1.5 fold • This disproportionate increase in brain and eye lymphoma • Cannot be explained by advances in diagnostic techniques • ? Related to general aging of population • Increase in all age groups

  5. HIV associated PCNSL - Epidemiology • PCNSL is diagnosed in 1.6% - 9% of HIV affected individuals • 2nd most common intracranial mass lesion • Susceptibility to PCNSL is inversely proportional to CD4 count • HAART therapy may result in a decline in incidence

  6. PCNSL - Pathology • Grossly • Soft, granular, ill-defined lesion • Necrosis, hemorrhage, neovascularity uncommon except in AIDS-related PCNSL • Multi-focal in > 50% cases • Microscopically • Diffuse lesion with angiocentric growth pattern • Malignant lymphocytes freely invade normal surrounding brain Tumor infiltrated by reactive T lymphocytes

  7. PCNSL - Pathology • Histologically PCNSL is indistinguishable from systemic NHL • >90% are B-cell, high grade lymphomas • Diffuse large cell • Large cell immunoblastic • Lymphoblastic • 10% are primary T-cell type • Immunohistochemistry • Leukocyte common antigen + • B-cell markers CD20 and L26 + • T-cell markers CD3+, CD45RO+ • Genetically • Clonal abnormalities of chromosomes 1,6,7,14, del p15 and 16 • Immunoglobulin gene rearrangements

  8. PCNSL - Pathogenesis • Pathogenesis of PCNSL in immunocompetant patients is unknown • Hypotheses I • PCNSL may arise from seeding of a systemic lymphoma to the brain • Immune system has the capacity to eliminate the systemic tumor • Brain gives sanctuary to malignant lymphocytes –allowing tumor development • II. • Lymphocytes become trapped in CNS after inflammation and undergo malignant transformation • Inflammatory diseases usually attract T lymphocytes • PCNSL is usually B-cell in origin

  9. PCNSL – Clinical Features • Immunocompetant patient • Typical age – 55-70 yrs • Rare in children • Short duration between onset of symptoms and evaluation • Cognitive and personality changes common • Frontal lobes, corpus callosum and deep periventricular structures • Multi-focal in 1/3 of cases • Focal findings – hemiparesis, aphasia • Seizures -10% of patients • Important prognostic factors • Age < 60, excellent performance status

  10. PCNSL – Clinical Features • AIDS related PCNSL • Younger patient – 30 -40 years old • 25% cases –seizures • Median time from HIV diagnosis – 5 years • ? Higher incidence of multiple lesions • Leptomeningeal involvement • . 40% patients have leptomeningeal dissemination • Primary leptomeningeal lymphoma – rare • Increased IC pressure, multifocal cranial neuropathies, multi-level root involvement

  11. PCNSL – Clinical Features • Ocular involvement • 15% have ocular disease at presentation • 50-80% patients with isolated ocular lymphoma develop parenchymal disease • Ocular symptoms • Blurred vision • Decreased visual acuity • 50% may be asymptomatic • Dx may be delayed –misdiagnosis as chronic vitreitis or uveitis • Systemic lymphoma –uncommon • 2-3% patients with PCNSL and systemic disease

  12. PCNSL – Initial Evaluation • MRI of the brain with gadolinium • CSF cytology and immunohistochemistry • Opthalmologic evaluation including slit lamp • HIV serology • CT scans of chest, abdomen, pelvis • Bone marrow biopsy • Spinal MRI with gadolinium (if spinal symptoms present) • Tumor markers – LDH, β2 microglobulin • Stereotactic needle biopsy

  13. PCNSL - CT scan • Contrast-enhanced axial CT scan shows intensely enhancing masses of the midbrain • Occupy most of the right and some of the left cerebral peduncles. • Histologic analysis -large cell lymphoma

  14. PCNSL - CT scanTemporo-parietal large cell lymphoma

  15. PCNSL – MRILarge B-cell lymphoma • MR images show a hypo intense interhemispheric mass (m) separated bilaterally from brain parenchyma by a hypo intense line • Adjacent area of hyper intensity represents a focal area of infarction

  16. PCNSL - Differential Diagnosis Neoplastic disorders: Glioma - glioblastoma multiforme      Metastasis - extracranial primary brain-to-brain spread (primary glioblastoma multiforme)     Primitive neuroectodermal tumor - in childrenInfections:  Abscess - toxoplasmosis in HIV patients Sarcoidosis  Tuberculosis   Other granulomatous diseases Demyelinating disease     Multiple sclerosis (active plaques)

  17. PCNSL - Treatment • Surgery • Histopathological diagnosis • Stereotactic needle biopsy • Corticosteroids • Reduce vasogenic edema • Oncogenic effect – tumor lysis and radiological regression in 40% cases • Onset of response rapid with resolution of symptoms within 24-48 hours • Should be withheld till tissue obtained for diagnosis

  18. PCNSL - Treatment • Radiotherapy • PCNSL –radiosensitive tumor • Was standard treatment for many years • Whole brain radiation 40 -50 Gy • Craniospinal RT or boost to tumor does not improve survival • Ocular lymphoma: 36-40Gy to posterior 2/3 of globe • Median survival: 10-18 months

  19. PCNSL - Treatment • Chemotherapy • Significant improvement over radiation • Single agent High dose methotrexate: • single, most active agent • crosses blood brain barrier • > 1g/m2 – tumoricidal level in brain • > 3.5g/m2 – tumoricidal level in CSF • Doses of 1-8g/m2 commonly used alone or in combination with other agents or whole brain radiation • Combined modality approach - response rate close to 100% and median survival of 30 – 60 months • No difference in survival using MTX alone vs. combined modality approach • Less neurotoxicity with MTX alone

  20. PCNSL - Treatment • High dose chemotherapy with peripheral stem cell rescue • Used as consolidation following chemotherapy • Replaces standard dose radiation therapy • 2 trials in progress • Early results encouraging

  21. PCNSL – Treatment of AIDS associated lymphoma • Treatment dictated by clinical condition of patient • Early diagnosis critical - neurological deterioration may preclude ability to tolerate therapy • Aggressive combined modality therapy • Highly active anti-retroviral therapy (HAART) – remission reported • ? New important alternative

  22. PCNSL -Relapse • Risk of relapse following combined modality therapy is < 50% • Most recurrences occur within 2 years of completing therapy • Higher risk of relapse in patients with ocular or leptomeningeal disease at diagnosis • Relapse – local (common), leptomeningeal or systemic (10%) • Treatment – salvage chemotherapy, SCT, radiation • Prognosis is poor

  23. PCNSL – Treatment related neurotoxicity • Aggressive combined modality treatment • high dose MTX and cranial RT can cause significant delayed neurotoxicity • 90% of patients > 60 yrs old will be affected within 1 yr of treatment • Children • stroke like episodes acutely during treatment with MTX • Severe developmental delay later • Cerebro vascular disease in young adults • Progressive leucoencephalopathy • Accelerated atherosclerosis

  24. Primary Ocular Adnexal Lymphoma (POAL) in Pediatric Patients • Primary ocular adnexal lymphomas (POAL) originate from the ocular adnexa • the eyelid, conjunctiva, orbit, lacrimal gland, or lacrimal sac • There is no evidence of extraorbital disease • Are detected following a staging evaluation • The majority of POAL are non-Hodgkin’s lymphomas (NHL) • They are rare and represent approximately 8% of all extranodal lymphomas

  25. POAL - Pathology • REAL classification and WHO Classification • 5 main subtypes • extranodal marginal-zone lymphoma (EMZL) or mucosa-associated lymphoid tissue (MALT) lymphoma (60-70%) • diffuse large cell lymphoma (DLCL) (10-17%) • follicular lymphoma (10%) • lymphoplasmacytic lymphoma (2-5%) • plasmacytoma (2-5%) • rare: mantle cell lymphoma, lymphoblastic lymphoma, and peripheral T-cell lymphoma

  26. POAL in Pediatric Patients Differential Diagnosis • Reactive lymphoid hyperplasia • Majority of POAL are low-grade • Difficult to distinguish from their benign counterparts on conventional histology. • Immunohistochemical stains (IHS) and/or flow cytometric analysis (FCA) can be helpful • Polymerase chain reaction (PCR) for gene rearrangement

  27. POAL in Pediatric Patients Signs and Symptoms • Patients present with • mass • proptosis • chemosis • orbital swelling. • The development of symptoms in these patients is characterized by a chronic, progressive course

  28. CLINICAL FEATURES OF POAL IN PEDIATRIC PATIENTS Case Age/Sex Location Stage Diagnosis Therapy Followup Ref 1 10y/F Lacrimal IE MALT Radiation 7 m free of Stork sac disease 2 14y/M Orbit IE DLCL CT 2 y free of Stork disease lost to follow-up 3 13y/M Orbit IE DLCL Radiation 71 m free Hahn + CT of disease 4 17y/F Orbit IE MALT Surgery 23 m free Chen of disease 5 10y/M Orbital IE BPLL NA Extraorbital Jenkins adnexa spread during Rx

  29. POAL - Treatment • Surgical excision • Radiation • Only for Stage I MALT lymphoma • Chemotherapy • High grade lesions, low grade lesions with systemic symptoms • Combined modality treatment • Survival: Stage I >90%, Stage II 70%, Stages III/IV 40% • Late effects - cataracts

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