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