Clinical Pathological Conference Dr. David Gonzales May 5, 2006 - PowerPoint PPT Presentation

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Clinical Pathological Conference Dr. David Gonzales May 5, 2006

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Title: Clinical Pathological Conference Dr. David Gonzales May 5, 2006


1
Clinical Pathological Conference Dr. David
Gonzales May 5, 2006
2
  • 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 gt 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.

3
  • 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.

4
  • 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 gt 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.

5


  • 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

6
Labs
  •  
    8.3 \ 8.9  / 540
  •       
    / 27.1 \
  • N82, L8, M6,
    E1,Bands1, Metamyelocytes 2
  • Fe lt20 ug/dL, ferritin 316 ng/ml, transferrin
    171mg/dL, satlt 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
  • FENAlt 1           UA-wnl
  • Lipase 1391 U/L, amylase 302 U/L, Uric acid 14.6
    mg/dL

7
  • 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.

8
Radiology
  • CXR Small to moderate left pleural effusion with
    left basilar atelectasis.
  • CT Spine- Disc disease L5-S1-no fracture.
  • Other imaging was obtained..

9
CT Abdomen/Pelvis
  •  Massive retroperitoneal adenopathy, Moderate
    R
  • hydronephrosis, Prominent gastric
    folds/thickened gastric
  • wall.

10
A diagnostic procedure was performed.
11
CPC
  • David Gonzales
  • Presbyterian Hospital of Dallas
  • May 5, 2006

12
Case presentation
  • 49 year old male with epigastric pain x 2 months
  • Constant, severe
  • Early satiety
  • 20 pound weight loss, sweats, feeling hot

13
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

14
Case presentation
  • Sonogram (-)
  • No improvement with PPI
  • Pain extends to right flank and unilateral lower
    extremity weakness develops
  • Remainder of history not incredibly helpful

15
Differential Diagnosis
  • Tumor
  • Lymphoma
  • Biliary or other sites in GI tract
  • Infection with atypical organism
  • Gastritis/gastropathy

16
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

17
Labs
  • Microcytic anemia
  • Ferritin 316 (28-365)
  • Ironlt20, transferrin 171, 8 saturation
  • Mild thrombocytosis also argues for iron
    deficiency
  • Mild hyponatremia and renal insufficiency which
    corrected with hydration

18
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

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20
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

21
And hes got AIDS
  • CD 4 110
  • Abdominal pain is common in HIV
  • Opportunistic infection
  • Regular stuff (gastritis, cholecystitis, etc)
  • Medication related
  • Malignancy

22
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

23
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

24
Retroperitoneal Adenopathy
  • Retroperitoneal fibrosis
  • Testicular Cancer
  • Renal Cell Carcinoma
  • Opportunistic infection
  • Lymphoma

25
Enlarged Gastric Folds
  • Menetriers disease
  • Foveolar hyperplasia in the body and fundus of
    the stomach
  • Symptoms include pain, asthenia, anorexia
  • Often have hypoalbuminemia secondary to
    protein-losing enteropathy

26
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

27
Enlarged Gastric Folds
  • H. Pylori-associated gastritis
  • Anisakiasis
  • Adenocarcinoma
  • Lymphoma
  • GI vs. HIV-related

28
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

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30
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

31
HIV and lymphoma
  • Risk increases directly as CD4 count drops
  • 3 General types
  • Primary CNS lymphoma
  • Primary effusion lymphoma
  • Non-Hodgkins lymphoma

32
HIV and systemic lymphoma
  • Tend to be aggressive
  • High proliferation
  • Spontaneous cell death
  • 2 main histologic types
  • Diffuse large B cell
  • Burkitts or Burkitts-like

33
Burkitts lymphoma
  • 3 types
  • Endemic (African)
  • Non-endemic (American)
  • Immunodeficient
  • Translocation of C-myc is important

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37
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

38
Summary
  • Diagnostic test lymph node biopsy
  • EUS?

39
Diagnosis
  • AIDS-associated NHL, favor Burkitts
  • Rapid presentation
  • High cell turnover
  • Rare

40
M.C.
  • Diffuse high grade B-cell lymphoma,
  • Burkitt- like morphology
  • 2/1/06 Retroperitoneal core biopsy
  • 2/1/06 Bone marrow biopsy
  • 2/2/06 Duodenal mass biopsy
  • Gastric mass biopsy
  • 2/2/06 CSF cytology

41
M.C.
  • Pathology
  • Diffuse infiltrate B-cells (CD20)
  • Uniform intermediate size nuclei
  • Fine chromatin, nucleoli present
  • Basophilic cytoplasm with vacuoles
  • Numerous mitoses, admixed histiocytes

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47
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 (gt 90)

48
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

49
FISH
LSI IGH/MYC, CEP 8
LSI MYC break apart
50
Classic Burkitts 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

51
Classic Burkitts lymphoma
  • Immunophenotype
  • B-cell CD20, CD19, CD22
  • Surface monoclonal Ig
  • Positive CD10, CD43
  • Negative TdT, CD34, Bcl-2, CD138

52
Burkitt Lymphoma (BL)
  • Rare in non-immune depressed
  • lt 1 of NHL
  • HIV () 1000 fold incidence of BL

53
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

54
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

55
Lymphoma in HIV/AIDS
  • Clinical
  • CD4/CD8 lt 0.5
  • CD4 lymphocytes lt 100 mm3
  • Extra nodal location (60)
  • GI, CNS, liver, bone marrow
  • Advanced stage at presentation
  • Clinically aggressive
  • Short survival

56
Lymphoma in HIV/AIDS
  • Pathology
  • Aggressive histologic subtypes
  • Diffuse growth pattern
  • High proliferation rate
  • Mitoses
  • Ki-67 immunostain
  • Frequent necrosis
  • Cell debris/macrophages

57
Lymphoma in HIV/AIDS
  • Pathology
  • Diffuse large B-cell lymphoma (70)
  • Immunoblastic
  • Pleomorphic
  • (Burkiitts like/atypical Burkitts)
  • (Centroblastic)
  • Burkitts lymphoma (30)
  • Classic
  • Burkitts like/atypical Burkitts

58
Lymphoma in HIV/AIDS
  • Pathology
  • Rare subtypes (lt 1)
  • Primary effusion lymphoma
  • Oral cavity plasmablastic lymphoma

59
Lymphoma AIDS/HIV
60
NHL - AIDS
  • EBV Infection
  • 40-50 Burkitts lymphoma
  • 70 Diffuse large B cell lymphoma

61
Burkitts Lymphoma
  • 3 clinical variants
  • Endemic
  • Sporadic
  • Immunodeficiency associated
  • Common antecedents
  • Immunodeficiency
  • Antigenic stimulation
  • Genetic translocation/activation of MYC gene at
    chromosome 8q26

62
Burkitt Lymphoma
  • Molecular Genetics
  • Translocation c-myc gene ?activation
  • Increased c-myc protein
  • Transcription factor for many genes
  • Increased cell proliferation

63
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

64
Burkitts lymphoma
  • Morphology
  • 3 morphologic variants
  • Classic
  • Plasmacytoid Burkitt
  • Atypical Burkitt/Burkitt-like
  • All BL variants
  • High proliferation rate/growth fraction
  • MYC translocation

65
Burkitts lymphoma
  • Morphology
  • BL variants (non-classic)
  • Variable nucleoli
  • Variable nuclear size, shape, chromatin texture
  • Cytoplasm /- plasma cytoid
  • Histologic diagnosis of variants low
    reproducibility

66
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

67
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 gt 20-25 y.o.

68
Diffuse Large B-cell Lymphoma
  • Morphologic subtypes
  • Centroblastic
  • Immunoblastic
  • Pleomorphic/anaplastic
  • T-cell/histiocyte
  • Morphologic subtypes not reproducible
  • Marginal prognostic significance

69
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
  • Activated/post-germinal center immunophenotype
  • Express activation markers MUM1, CD-138
  • Worse prognosis/high grade

70
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

71
NHL-AIDSPost-HAART
  • Burkitts 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

72
Burkitt-like/Atypical Burkitts 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

73
Burkitt-like/Atypical Burkitts 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

74
Burkitt Lymphoma
  • Endemic
  • 100 EBV
  • Morphology classic
  • C-myc simple, non-complex translocation
  • Sporadic
  • lt 30 EBV
  • Morphology classic, atypical
  • C-myc translocation simple, complex
  • Immunodeficiency
  • 40-50 EBV
  • Morphology classic, atypical
  • C-myc translocation simple, complex

75
Burkitt Lymphoma
  • USA children homogenous entity
  • Classic morphology
  • Classic immunophenotype
  • Classic genotype single c-myc translocation
  • Classic clinical course
  • Good prognosis with modern treatment

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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

82
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 (lt 1 yr)
  • (-) c-myc similar to DLBL

83
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

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High grade B-cell LymphomaBurkitt-like/Atypical
Burkitt
  • Most cases in adults are ???
  • Diffuse large B-cell lymphoma
  • Atypical Burkitts/Burkitts like
  • Diffuse high grade B-cell lymphoma

86
Burkitts Lymphoma
  • EBV Infection
  • Endemic
  • 100 EBV
  • Morphology classic
  • Sporadic
  • 30 EBV
  • Morphology classic, atypical
  • Immunodeficiency
  • 40-50 EBV
  • Morphology classic, atypical
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