Transcript Clinical Pathological Conference Dr. David Gonzales May 5, 2006

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.
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Pain is epigastric, constant, severe, disturbs sleep, no radiation, worse
with meals and associated with early satiety.
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Associated with nausea, had emesis x 2 two months ago.
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He reports black stools for 2 weeks but denies BRBPR.
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He has had poor PO intake and reports losing > 20 lbs over 2 months.
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He also c/o constipation.
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No abdominal distention. No jaundice or acholic stools.
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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.
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PMHx: No PCP
H/o MVA x 2 with R elbow #.
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PSHx: none
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Allergies: NKDA
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Medications:
Pantoprazole 40 mg po qd
Hydrocodone/APAP as needed
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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.
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Family History: Mother with DM, HTN; Father with HTN
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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…..
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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:
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CXR: Small to moderate left pleural effusion with left basilar
atelectasis.
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CT Spine- Disc disease L5-S1-no fracture.
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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
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Constant, severe
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Early satiety
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20 pound weight loss, sweats, “feeling hot”
Management of dyspepsia
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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
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Sonogram (-)
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No improvement with PPI
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Pain extends to right flank and unilateral
lower extremity weakness develops
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Remainder of history not incredibly helpful
Differential Diagnosis
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Tumor
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Lymphoma
Biliary or other sites in GI tract
Infection with atypical organism
Gastritis/gastropathy
Physical Exam
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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
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Microcytic anemia
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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
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Alkaline Phosphatase about 5 x normal with
normal bilirubin
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Lipase and amylase elevated
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Mild transaminitis
Ca 19-9 moderately elevated
LDH and uric acid very elevated
SPEP
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A screening test for
plasma cell disorders
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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…
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CD 4 = 110
Abdominal pain is common in HIV
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Opportunistic infection
Regular stuff (gastritis, cholecystitis, etc)
Medication related
Malignancy
55 yo AA male with AIDS and
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Abdominal pain with fever, weight loss, and
sweats
Abdominal mass
Iron-deficiency anemia
Markers of high cell turnover
Pancreaticobiliary abnormalities
Imaging
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CXR: small left pleural effusion with
atelectasis
CT Abdomen/Pelvis
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Massive retroperitoneal adenopathy
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Moderate R hydronephrosis
Prominent gastric folds
No info on liver, pancreas, or kidney: assume
normal
Retroperitoneal Adenopathy
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Retroperitoneal fibrosis
Testicular Cancer
Renal Cell Carcinoma
Opportunistic infection
Lymphoma
Enlarged Gastric Folds
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Menetrier’s disease
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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
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Zollinger-Ellison (gastrinoma)
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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
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H. Pylori-associated gastritis
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Anisakiasis
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Adenocarcinoma
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Lymphoma
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GI vs. HIV-related
Gastrointestinal lymphoma
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Defined as localized disease in the GI tract or
presentation predominantly in the GI tract
Role of MALT
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Spread from adjacent nodes
Diffuse large B-cell lymphoma also seen
HIV and malignancy
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Increased incidence similar to transplant
recipients
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Length and degree of immunosuppression
likely play roles
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Role of HIV and other viruses including EBV
HIV and lymphoma
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Risk increases directly as CD4 count drops
3 General types
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Primary CNS lymphoma
Primary effusion lymphoma
Non-Hodgkin’s lymphoma
HIV and systemic lymphoma
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Tend to be aggressive
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High proliferation
Spontaneous cell death
2 main histologic types
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Diffuse large B cell
Burkitt’s or Burkitt’s-like
Burkitt’s lymphoma
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3 types
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Endemic (African)
Non-endemic (American)
Immunodeficient
Translocation of C-myc is important
To summarize
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55 year old male with AIDS
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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
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Suspect nerve root and ureteral compression from
adenopathy
Summary
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Diagnostic test: lymph
node biopsy
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EUS?
Diagnosis
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AIDS-associated NHL, favor Burkitt’s
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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
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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.
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Diagnosis
Diffuse high grade B-cell lymphoma, Burkittlike morphology
Definitive diagnosis pending FISH studies for
c-myc translocation
c-myc FISH results
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1st lab: negative
2nd lab: positive
FISH
LSI IGH/MYC, CEP 8
LSI MYC break apart
Classic Burkitt’s lymphoma
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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
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B-cell – CD20, CD19, CD22
Surface monoclonal Ig
Positive: CD10, CD43
Negative: TdT, CD34, Bcl-2, CD138
Burkitt Lymphoma (BL)
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Rare in non-immune depressed
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< 1% of NHL
HIV (+) – 1000 fold incidence of BL
Lymphoma in HIV/AIDS
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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
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HIV virus is not directly lymphomagenic
Deficient immune surveillance/cellular
immunity
HIV associated infections
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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
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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
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Pathology
Aggressive histologic subtypes
Diffuse growth pattern
High proliferation rate
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Mitoses
Ki-67 immunostain
Frequent necrosis
Cell debris/macrophages
Lymphoma in HIV/AIDS
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Pathology
Diffuse large B-cell lymphoma (70%)
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Immunoblastic
Pleomorphic
(Burkiitt’s like/atypical Burkitt’s)
(Centroblastic)
Burkitt’s lymphoma (30%)
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Classic
Burkitt’s like/atypical Burkitt’s
Lymphoma in HIV/AIDS
Pathology
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Rare subtypes (< 1%)
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Primary effusion lymphoma
Oral cavity plasmablastic lymphoma
Lymphoma AIDS/HIV
Age
BL
Large cell lymphoma
Younger
Older
Lower (< 100 mm3)
CD4 level
Higher
Location
Nodal
Extra-nodal
Often (-)
Usually present advanced
AIDS
Syndrome
NHL - AIDS
EBV Infection
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40-50% Burkitt’s lymphoma
70% Diffuse large B cell lymphoma
Burkitt’s Lymphoma
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3 clinical variants
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Common antecedents
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Endemic
Sporadic
Immunodeficiency associated
Immunodeficiency
Antigenic stimulation
Genetic translocation/activation of MYC gene at
chromosome 8q26
Burkitt Lymphoma
Molecular Genetics
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Translocation c-myc gene →activation
Increased c-myc protein
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Transcription factor for many genes
Increased cell proliferation
Burkitt Lymphoma
Molecular Genetics
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Balanced translocation of c-myc oncogene on
chromosome 8q24 into
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Ig heavy chain gene 14q32
Kappa light chain gene 2q11
Lambda light chain gene 22q11
Burkitt’s lymphoma
Morphology
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3 morphologic variants
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Classic
Plasmacytoid Burkitt
Atypical Burkitt/Burkitt-like
All BL variants
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High proliferation rate/growth fraction
MYC translocation
Burkitt’s lymphoma
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Morphology
BL variants (non-classic)
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Variable nucleoli
Variable nuclear size, shape, chromatin
texture
Cytoplasm +/- plasma cytoid
Histologic diagnosis of variants low
reproducibility
Burkitt/Burkitt-like Lymphoma
Morphology
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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
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Morphology
Cases in immunocompetent adults are
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(2/3) Diffuse large B-cell lymphoma
c-myc negative
 Prognosis similar to DLBCL
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(2/3) True atypical Burkitt/Burkitt-like
lymphoma
c-myc positive
 Complex c-myc translocations
 Extremely poor prognosis
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Classic Burkitt very rare > 20-25 y.o.
Diffuse Large B-cell Lymphoma
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Morphologic subtypes
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Centroblastic
Immunoblastic
Pleomorphic/anaplastic
T-cell/histiocyte
Morphologic subtypes not reproducible
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Marginal prognostic significance
Diffuse Large B-cell Lymphoma
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Prognosis
postulated cell of origin
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2 major subtypes by gene expression
Germinal center immunophenotype
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Germinal center
Post germinal center/activated
Bcl-6/CD-10 immunostain (+)
Better prognosis/intermediate grade
Activated/post-germinal center immunophenotype
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Express activation markers MUM1, CD-138
Worse prognosis/high grade
NHL-AIDS/HIV
HAART
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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
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Large B-cell lymphoma (activated)
Improved survival
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Diffuse large B-cell lymphoma
NHL-AIDS
Post-HAART
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Burkitt’s lymphoma no improvement in
prognosis
Unresolved issues:
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Prognostic significance of BL variants
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Improved survival of DLCL
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Simple vs complex c-myc variants
Less frequent activated subtypes
Relative increase in germinal center subtype
Most appropriate therapy for BL
Burkitt-like/Atypical Burkitt’s
Lymphoma
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Diffuse, high mitotic rate
Nuclei ≥ size of macrophage nuclei
Amphophilic/plasmacytoid cytoplasm
Variable
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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
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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
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Endemic
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Sporadic
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100% EBV
Morphology classic
C-myc simple, non-complex translocation
< 30% EBV
Morphology: classic, atypical
C-myc translocation: simple, complex
Immunodeficiency
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40-50% EBV
Morphology: classic, atypical
C-myc translocation: simple, complex
Burkitt Lymphoma
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USA children – homogenous entity
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Classic morphology
Classic immunophenotype
Classic genotype – single c-myc translocation
Classic clinical course
Good prognosis with modern treatment
Mature B-cell Compartments
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Pre-germinal center (virgin) B-cells
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Germinal center B-cells
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No somatic mutation IgV, Bcl-6
Somatic hypermutation Bcl-6
+/or somatic hypermutation IgV
Post-germinal center B-cells
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Somatic hypermutation Bcl-6 +/or IgV
Expression of activation markers MUM-1, CD-138
Burkitt-like/Atypical Burkitt
Lymphoma
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Adult, median 68 (20-90)
Extra nodal ~ 50%
Variable:
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1/3 c-myc translocation
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Immunophenotype
Genotype
Single translocation
Complex
Prognosis related to c-myc translocation
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(+) c-myc – very poor prognosis (< 1 yr)
(-) c-myc similar to DLBL
High grade B-cell Lymphoma
Burkitt-like/Atypical Burkitt
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Many but not all morphologic features of
classic BL
Shared features:
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Distinguishing features
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High mitotic rate
Dispersed macrophages (starry sky)
Greater/variable nuclear size/shape
Not reproducible entity
No standardized/reproducible diagnostic
criteria
High grade B-cell Lymphoma
Burkitt-like/Atypical Burkitt
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Most cases in adults are ???
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Diffuse large B-cell lymphoma
Atypical Burkitt’s/Burkitt’s like
Diffuse high grade B-cell lymphoma
Burkitt’s Lymphoma
EBV Infection
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Endemic
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Sporadic
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100% EBV
Morphology – classic
30% EBV
Morphology – classic, atypical
Immunodeficiency
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40-50% EBV
Morphology – classic, atypical