clinical pathological conference dr. david gonzales may 5, 2006
TRANSCRIPT
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 Ca 8.6 mg/dL 4.6 │24 │1.7 \
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
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.
More tests were ordered…..
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
Lipase and amylase elevated Ca 19-9 moderately 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 protein-losing 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
2 main histologic types Diffuse large B cell Burkitt’s or Burkitt’s-like
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 Retroperitoneal core biopsy2/1/06 Bone marrow biopsy2/2/06 Duodenal mass biopsy
Gastric mass biopsy2/2/06 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, CD38Negative: CD34, CD117, CD3, Tdt, Bcl-2,
CD138, CD5, CD23, CD56
Light chain restriction: KappaKi-67 proliferative index = high (> 90%)
M.C.
Diagnosis Diffuse high grade B-cell lymphoma, Burkitt-
like morphology Definitive diagnosis pending FISH studies for
c-myc translocation c-myc FISH results
1st lab: negative 2nd lab: positive
LSI IGH/MYC, CEP 8 LSI MYC break apart
FISH
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/AIDSPathology
Diffuse large B-cell lymphoma (70%) Immunoblastic Pleomorphic (Burkiitt’s like/atypical Burkitt’s) (Centroblastic)
Burkitt’s lymphoma (30%) Classic Burkitt’s like/atypical Burkitt’s
Lymphoma in HIV/AIDSPathology
Rare subtypes (< 1%) Primary effusion lymphoma
Oral cavity plasmablastic lymphoma
Lymphoma AIDS/HIV
BL Large cell lymphoma
Age Younger Older
CD4 level Higher Lower (< 100 mm3)
Location Nodal Extra-nodal
AIDS
SyndromeOften (-)
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
Common antecedents Immunodeficiency Antigenic stimulation
Genetic translocation/activation of MYC gene at chromosome 8q26
Burkitt LymphomaMolecular Genetics
Translocation c-myc gene →activation Increased c-myc protein
Transcription factor for many genes Increased cell proliferation
Burkitt LymphomaMolecular 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
All BL variants High proliferation rate/growth fraction MYC translocation
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 LymphomaMorphology
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 LymphomaMorphology
Cases in immunocompetent adults are (2/3) Diffuse large B-cell lymphoma
c-myc negativePrognosis similar to DLBCL
(2/3) True atypical Burkitt/Burkitt-like lymphoma
c-myc positiveComplex c-myc translocationsExtremely poor prognosis
Classic Burkitt very rare > 20-25 y.o.
Diffuse Large B-cell Lymphoma
Morphologic subtypes Centroblastic Immunoblastic Pleomorphic/anaplastic T-cell/histiocyte
Morphologic subtypes not reproducible Marginal prognostic significance
Diffuse Large B-cell LymphomaPrognosis
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
Activated/post-germinal center immunophenotype Express activation markers MUM1, CD-138 Worse prognosis/high grade
NHL-AIDS/HIVHAART
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) Improved survival
Diffuse large B-cell lymphoma
NHL-AIDSPost-HAART
Burkitt’s lymphoma no improvement in prognosis
Unresolved issues: Prognostic significance of BL variants
Simple vs complex c-myc variants Improved survival of DLCL
Less frequent activated subtypes Relative increase in germinal center subtype
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
Sporadic < 30% EBV Morphology: classic, atypical C-myc translocation: simple, complex
Immunodeficiency 40-50% EBV Morphology: classic, atypical C-myc translocation: simple, complex
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
Germinal center B-cells Somatic hypermutation Bcl-6 +/or somatic hypermutation IgV
Post-germinal center B-cells Somatic hypermutation Bcl-6 +/or IgV Expression of activation markers MUM-1, CD-138
Burkitt-like/Atypical Burkitt Lymphoma Adult, median 68 (20-90) Extra nodal ~ 50% Variable:
Immunophenotype Genotype
1/3 c-myc translocation Single translocation Complex
Prognosis related to c-myc translocation (+) c-myc – very poor prognosis (< 1 yr) (-) c-myc similar to DLBL
High grade B-cell LymphomaBurkitt-like/Atypical Burkitt Many but not all morphologic features of
classic BL Shared features:
High mitotic rate Dispersed macrophages (starry sky)
Distinguishing features Greater/variable nuclear size/shape
Not reproducible entity No standardized/reproducible diagnostic
criteria
High grade B-cell LymphomaBurkitt-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 LymphomaEBV Infection
Endemic 100% EBV Morphology – classic
Sporadic 30% EBV Morphology – classic, atypical
Immunodeficiency 40-50% EBV Morphology – classic, atypical