CPC case and path Burkitts Lymphoma

Clinical Pathological Conference Dr. David Gonzales May 5, 2006 CC: Abdominal pain x 2 months PMH: 49 y/o AAM with h/o abdominal pain x 2 months.  Pain is epigastric, constant, severe, disturbs sleep, no radiation, worse with meals and associated with early satiety. Associated with nausea, had emesis x 2 two months ago. He reports black stools for 2 weeks but denies BRBPR.    He has had poor PO intake and reports losing > 20 lbs over 2 months. He also c/o constipation. No abdominal distention. No jaundice or acholic stools. He denied fever or chills but did say he “felt hot” and had some sweats.    He went to the ER at another facility 2 months ago and was given an unknown medication after X rays and sonogram of the abdomen were done; reportedly negative. His pain worsened and he developed back pain radiating down both lower extremities. He returned to the ER a few weeks later and was given hydrocodone/APAP and a PPI and asked to f/u with a PCP. His PCP continued the PPI but pain persisted. He then developed a new R flank pain, pain radiating down R LE worsened and he complained of R LE weakness. He went back to the ER at the other hospital and after further workup was transferred to our hospital.  PMHx: No PCP H/o MVA x 2 with R elbow #. PSHx: none Allergies: NKDA Medications: Pantoprazole 40 mg po qd Hydrocodone/APAP as needed     Social History: Single. Lives with his parents. Will not disclose sexual orientation but has not been sexually active for > 1 year, no h/o STDs. Occasional tobacco-cigars for 3 years, occasional ETOH, denies recreational drug use. Family History: Mother with DM, HTN; Father with HTN ROS: Positive for fatigue, weakness, “feeling hot”, sweats and weight loss as above. Also reports hiccups and R LE weakness , otherwise negative.   PHYSICAL EXAM Gen: emaciated 49 y/o AA male BP 138/92. HR 111, RR 18, Wt 68.5 kg, T-afebrile HEENT: Normocephalic, atraumatic, PERRL, EOMI, OP clear, slightly dry. Neck- Supple. No JVD, bruit, LAD, thyromegaly. Lungs: CTAB Cv: RRR. S1S2+, no murmur, gallop, rub. Tachycardia+ Abd: Periumbilical and RUQ fullness, Prominent veins above the umbilicus, NABS+. Liver edge palpable, firm, nontender-span 11 cms. Ill defined mass about 8x8 cm palpable in the periumbilical area, lower right border rounded, other borders poorly defined, firm, non tender. No splenomegaly. No shifting dullness. Rectal- Normal sphincter tone. Brown, guaiac –ve stool Neuro: CNS II-XII grossly intact, DTRs 2/4,, sensation intact, F-to-N intact. Strength 5/5 b/l UEs, RLE prox 3+/5, distal 4/5, LLE prox 4/5, distal 4+/5. Gait not evaluated Skin: No rash. Lymphatic: No significant LAD; Ext: Warm, perfused, no LEE. . Labs 8.3 \ 8.9 / 540 / 27.1 \ N82%, L8%, M6%, E1%,Bands1%, Metamyelocytes 2% Fe <20 ug/dL, ferritin 316 ng/ml, transferrin 171mg/dL, % sat< 8. MCV was 78%, his stool occult blood was initially negative but turned positive 3 days later. RDW 14.9% 129 │98 │23 / 73 4.6 │24 │1.7 \ Ca 8.6 mg/dL Tp 8.1 g/dL Alb 3.4 g/dL Glob 3.7g/dL AST 78 U/dL ALT 79 u/dL AlkP 686 u/dL Tbili 0.6 mg/dL  SPEP-protein 6.8-high Alpha 1 globulin 0.32, low albumin FENA< 1 UA-wnl Lipase 1391 U/L, amylase 302 U/L, Uric acid 14.6 mg/dL LDH 2952 U/L , CEA< 0.5 ng/ml, CA 19-9 – 130 U/ml More tests were ordered…..     Fecal H. pylori Antigen -ve; HIV status +ve; CD4-absolute 110, %- 29% The creatinine and sodium normalized with hydration The alkaline phosphatase dropped to the 190s later. Radiology:  CXR: Small to moderate left pleural effusion with left basilar atelectasis. CT Spine- Disc disease L5-S1-no fracture.   Other imaging was obtained….. CT Abdomen/Pelvis Massive retroperitoneal adenopathy, Moderate R hydronephrosis, Prominent gastric folds/thickened gastric wall. A diagnostic procedure was performed…. CPC David Gonzales Presbyterian Hospital of Dallas May 5, 2006 Case presentation  49 year old male with epigastric pain x 2 months  Constant, severe Early satiety 20 pound weight loss, sweats, “feeling hot”   Management of dyspepsia           Unintended weight loss Persistent vomiting Dysphagia/Odynophagia Anemia Hematemesis Palpable mass iron deficiency anemia Family history of upper gastrointestinal cancer Previous gastric surgery Jaundice Case presentation  Sonogram (-)  No improvement with PPI Pain extends to right flank and unilateral lower extremity weakness develops Remainder of history not incredibly helpful   Differential Diagnosis  Tumor   Lymphoma Biliary or other sites in GI tract   Infection with atypical organism Gastritis/gastropathy Physical Exam     Mild tachycardia Emaciated Periumbilical/RUQ fullness with firm, 8cm mass; liver palpable Right leg 3/5 prox, 4/5 distal; left leg 4/5; sensation and reflexes normal Labs  Microcytic anemia    Ferritin 316 (28-365) Iron<20, transferrin 171, 8% saturation Mild thrombocytosis also argues for iron deficiency  Mild hyponatremia and renal insufficiency which corrected with hydration Labs  Alkaline Phosphatase about 5 x normal with normal bilirubin  Mild transaminitis Ca 19-9 moderately elevated  Lipase and amylase elevated   LDH and uric acid very elevated SPEP  A screening test for plasma cell disorders   A clone secretes a homogenous (M for monoclonal) protein If M protein is found, it must be characterized by immunofixation  This patient had high alpha-1 globulin and low albumin And he’s got AIDS…   CD 4 = 110 Abdominal pain is common in HIV     Opportunistic infection Regular stuff (gastritis, cholecystitis, etc) Medication related Malignancy 55 yo AA male with AIDS and      Abdominal pain with fever, weight loss, and sweats Abdominal mass Iron-deficiency anemia Markers of high cell turnover Pancreaticobiliary abnormalities Imaging   CXR: small left pleural effusion with atelectasis CT Abdomen/Pelvis  Massive retroperitoneal adenopathy  Moderate R hydronephrosis   Prominent gastric folds No info on liver, pancreas, or kidney: assume normal Retroperitoneal Adenopathy      Retroperitoneal fibrosis Testicular Cancer Renal Cell Carcinoma Opportunistic infection Lymphoma Enlarged Gastric Folds  Menetrier’s disease    Foveolar hyperplasia in the body and fundus of the stomach Symptoms include pain, asthenia, anorexia Often have hypoalbuminemia secondary to proteinlosing enteropathy Enlarged Gastric folds  Zollinger-Ellison (gastrinoma)     High gastrin output causes acid hypersecretion  ulcers, primarily in the duodenum and distally Often associated with diarrhea (3/4 of pts) Weight loss only present in 17% MEN 1 Enlarged Gastric Folds  H. Pylori-associated gastritis  Anisakiasis Adenocarcinoma Lymphoma    GI vs. HIV-related Gastrointestinal lymphoma   Defined as localized disease in the GI tract or presentation predominantly in the GI tract Role of MALT  Spread from adjacent nodes  Diffuse large B-cell lymphoma also seen HIV and malignancy  Increased incidence similar to transplant recipients Length and degree of immunosuppression likely play roles Role of HIV and other viruses including EBV   HIV and lymphoma   Risk increases directly as CD4 count drops 3 General types    Primary CNS lymphoma Primary effusion lymphoma Non-Hodgkin’s lymphoma HIV and systemic lymphoma  Tend to be aggressive   High proliferation Spontaneous cell death Diffuse large B cell Burkitt’s or Burkitt’s-like  2 main histologic types   Burkitt’s lymphoma  3 types    Endemic (African) Non-endemic (American) Immunodeficient  Translocation of C-myc is important To summarize  55 year old male with AIDS     Abdominal pain from a large, fast-growing retroperitoneal mass B symptoms (probably) Evidence of high cell turnover (uric acid and LDH LE motor weakness and R hydronephrosis  Suspect nerve root and ureteral compression from adenopathy Summary  Diagnostic test: lymph node biopsy  EUS? Diagnosis  AIDS-associated NHL, favor Burkitt’s    Rapid presentation High cell turnover Rare M.C. Diffuse high grade B-cell lymphoma, Burkitt- like morphology 2/1/06 2/1/06 2/2/06 2/2/06 Retroperitoneal core biopsy Bone marrow biopsy Duodenal mass biopsy Gastric mass biopsy CSF cytology M.C. Pathology      Diffuse infiltrate B-cells (CD20+) Uniform intermediate size nuclei Fine chromatin, nucleoli present Basophilic cytoplasm with vacuoles Numerous mitoses, admixed histiocytes M.C. Immunophenotype Positive: CD20, CD79, CD10, Bcl-6, CD38 Negative: CD34, CD117, CD3, Tdt, Bcl-2, CD138, CD5, CD23, CD56 Light chain restriction: Kappa Ki-67 proliferative index = high (> 90%) M.C.    Diagnosis Diffuse high grade B-cell lymphoma, Burkittlike morphology Definitive diagnosis pending FISH studies for c-myc translocation c-myc FISH results   1st lab: negative 2nd lab: positive FISH LSI IGH/MYC, CEP 8 LSI MYC break apart Classic Burkitt’s lymphoma       Morphology Diffuse, monomorphic cells Interspersed macrophages – “starry sky” Neoplastic nuclei are uniform, round intermediate size Multiple (2-5) small distinct nucleoli – uniform Moderate amount basophophilic vacuolated cytoplasm Frequent mitoses, apoptotic bodies Classic Burkitt’s lymphoma Immunophenotype     B-cell – CD20, CD19, CD22 Surface monoclonal Ig Positive: CD10, CD43 Negative: TdT, CD34, Bcl-2, CD138 Burkitt Lymphoma (BL)  Rare in non-immune depressed  < 1% of NHL  HIV (+) – 1000 fold incidence of BL Lymphoma in HIV/AIDS      NHL in 4-10% AIDS patients Relative risk for NHL 60-200 fold 10% of all NHL in USA NHL affects all AIDS groups equally HL relative risk 10 fold in AIDS Lymphoma in HIV/AIDS    HIV virus is not directly lymphomagenic Deficient immune surveillance/cellular immunity HIV associated infections   Activation/proliferation B-cells B-cell genetic instability: mutations, deletions, translocation of tumor suppressor genes/oncogenes   Clonal expansion of genetically altered B-cells B-cell NHL Lymphoma in HIV/AIDS Clinical        CD4/CD8 < 0.5 CD4 lymphocytes < 100 mm3 Extra nodal location (60%) GI, CNS, liver, bone marrow Advanced stage at presentation Clinically aggressive Short survival Lymphoma in HIV/AIDS    Pathology Aggressive histologic subtypes Diffuse growth pattern High proliferation rate   Mitoses Ki-67 immunostain   Frequent necrosis Cell debris/macrophages Lymphoma in HIV/AIDS  Pathology Diffuse large B-cell lymphoma (70%)     Immunoblastic Pleomorphic (Burkiitt’s like/atypical Burkitt’s) (Centroblastic) Classic Burkitt’s like/atypical Burkitt’s  Burkitt’s lymphoma (30%)   Lymphoma in HIV/AIDS Pathology  Rare subtypes (< 1%)  Primary effusion lymphoma  Oral cavity plasmablastic lymphoma Lymphoma AIDS/HIV BL Age CD4 level Location AIDS Syndrome Younger Higher Nodal Often (-) Large cell lymphoma Older Lower (< 100 mm3) Extra-nodal Usually present advanced NHL - AIDS EBV Infection   40-50% Burkitt’s lymphoma 70% Diffuse large B cell lymphoma Burkitt’s Lymphoma  3 clinical variants    Endemic Sporadic Immunodeficiency associated Immunodeficiency Antigenic stimulation  Common antecedents    Genetic translocation/activation of MYC gene at chromosome 8q26 Burkitt Lymphoma Molecular Genetics   Translocation c-myc gene →activation Increased c-myc protein  Transcription factor for many genes  Increased cell proliferation Burkitt Lymphoma Molecular Genetics  Balanced translocation of c-myc oncogene on chromosome 8q24 into    Ig heavy chain gene 14q32 Kappa light chain gene 2q11 Lambda light chain gene 22q11 Burkitt’s lymphoma Morphology  3 morphologic variants    Classic Plasmacytoid Burkitt Atypical Burkitt/Burkitt-like High proliferation rate/growth fraction MYC translocation  All BL variants   Burkitt’s lymphoma  Morphology BL variants (non-classic)    Variable nucleoli Variable nuclear size, shape, chromatin texture Cytoplasm +/- plasma cytoid  Histologic diagnosis of variants low reproducibility Burkitt/Burkitt-like Lymphoma Morphology      Cases in non-AIDS/HIV children “Sporadic” Burkitt in USA Classic Burkitt morphology, uniform immunophenotype Simple, non-complex c-myc translocation Prognosis excellent Burkitt/Burkitt-like Lymphoma  Morphology Cases in immunocompetent adults are  (2/3) Diffuse large B-cell lymphoma c-myc negative  Prognosis similar to DLBCL   (2/3) True atypical Burkitt/Burkitt-like lymphoma c-myc positive  Complex c-myc translocations  Extremely poor prognosis   Classic Burkitt very rare > 20-25 y.o. Diffuse Large B-cell Lymphoma  Morphologic subtypes     Centroblastic Immunoblastic Pleomorphic/anaplastic T-cell/histiocyte Marginal prognostic significance  Morphologic subtypes not reproducible  Diffuse Large B-cell Lymphoma  Prognosis postulated cell of origin   Germinal center Post germinal center/activated   2 major subtypes by gene expression Germinal center immunophenotype   Bcl-6/CD-10 immunostain (+) Better prognosis/intermediate grade Express activation markers MUM1, CD-138 Worse prognosis/high grade  Activated/post-germinal center immunophenotype   NHL-AIDS/HIV HAART       Preliminary Data Incidence NHL declined Longer history of AIDS diagnosis Less frequent 1° CNS lymphoma Histology shift to intermediate grade NHL Fewer high grade large B-cell lymphomas  Large B-cell lymphoma (activated) Diffuse large B-cell lymphoma Improved survival  NHL-AIDS Post-HAART   Burkitt’s lymphoma no improvement in prognosis Unresolved issues:  Prognostic significance of BL variants  Simple vs complex c-myc variants Less frequent activated subtypes Relative increase in germinal center subtype  Improved survival of DLCL    Most appropriate therapy for BL Burkitt-like/Atypical Burkitt’s Lymphoma     Diffuse, high mitotic rate Nuclei ≥ size of macrophage nuclei Amphophilic/plasmacytoid cytoplasm Variable     nuclear size nuclear shape Nucleoli Imunophenotype   FISH confirmation of c-myc translocation or complex c-myc signal Extremely aggressive clinical course* * HIV/AIDS * Sporadic adults Burkitt-like/Atypical Burkitt’s Lymphoma Morphology     FISH negative for c-myc translocation/complex pattern Not Burkitt or/atypical Burkitt lymphoma Diffuse B-cell lymphoma NOS Prognosis similar to diffuse large B-cell lymphoma Burkitt Lymphoma  Endemic    100% EBV Morphology classic C-myc simple, non-complex translocation < 30% EBV Morphology: classic, atypical C-myc translocation: simple, complex 40-50% EBV Morphology: classic, atypical C-myc translocation: simple, complex  Sporadic     Immunodeficiency    Burkitt Lymphoma  USA children – homogenous entity      Classic morphology Classic immunophenotype Classic genotype – single c-myc translocation Classic clinical course Good prognosis with modern treatment Mature B-cell Compartments   Pre-germinal center (virgin) B-cells  No somatic mutation IgV, Bcl-6 Somatic hypermutation Bcl-6 +/or somatic hypermutation IgV Somatic hypermutation Bcl-6 +/or IgV Expression of activation markers MUM-1, CD-138 Germinal center B-cells    Post-germinal center B-cells   Burkitt-like/Atypical Burkitt Lymphoma    Adult, median 68 (20-90) Extra nodal ~ 50% Variable:   Immunophenotype Genotype Single translocation Complex (+) c-myc – very poor prognosis (< 1 yr) (-) c-myc similar to DLBL  1/3 c-myc translocation    Prognosis related to c-myc translocation   High grade B-cell Lymphoma Burkitt-like/Atypical Burkitt   Many but not all morphologic features of classic BL Shared features:   High mitotic rate Dispersed macrophages (starry sky) Greater/variable nuclear size/shape   Distinguishing features   Not reproducible entity No standardized/reproducible diagnostic criteria High grade B-cell Lymphoma Burkitt-like/Atypical Burkitt  Most cases in adults are ???    Diffuse large B-cell lymphoma Atypical Burkitt’s/Burkitt’s like Diffuse high grade B-cell lymphoma Burkitt’s Lymphoma  EBV Infection Endemic   100% EBV Morphology – classic 30% EBV Morphology – classic, atypical 40-50% EBV Morphology – classic, atypical  Sporadic    Immunodeficiency  