Disclosures I have nothing to disclose Practical Gastrointestinal - - PowerPoint PPT Presentation

• 5/24/2013
• 1

Practical Gastrointestinal (and Liver) Pathology

Noon Slide Session Ryan M. Gill ryan.gill@ucsf.edu 415-476-3212

Disclosures

I have nothing to disclose

Summary

Colonic Adenomas Hepatocellular Adenomas

Colonic Adenomas – Diagnostic Issues

“Intramucosal adenocarcinoma” confusion Epithelial misplacement/pseudoinvasion vs

pT1

Lymphovascular invasion Risk stratification Unusual cell clusters IBD dysplasia

• 5/24/2013
• 2

“intramucosal adenocarcinoma” “intramucosal adenocarcinoma”

Tumor cells extend through BM into lamina propria,

but not through muscularis mucosa

Single cells, abortive gland formation, marked sheet

like growth

No metastatic risk

Pseudoinvasion

Misplaced (herniated) epithelium in submucoa Most often in pedunculated polyps in sigmoid (~ 86%) Usually > 1 cm Well circumscribed crypts, lobular architecture Surrounding rim of lamina propria No desmoplasia Hemorrhage/hemosiderin deposition in stroma

Differential diagnosis – Invasive adenocarcinoma, mucinous adenocarcinoma, localized colitis cystica profunda/prolapse

2012 Recommendations for Screening

• No polyps

10 years

• Small (<10 mm) HPs in rectum or sigmoid

10 years

• 1–2 small (<10 mm) tubular adenomas

5–10 years

• 3–10 tubular adenomas

3 years

• >10 adenomas

<3 years

• One or more tubular adenomas ≥10 mm

3 years

• One or more villous adenomas

3 years

• Adenoma with HGD

3 years

• Invasion in a pedunculated adenoma

0.5-1 year

• Inadequately removed or large sessile adenoma

2-6 months

• 5/24/2013
• 3

Colectomy?

Traditional pT1 treatment decisions:

Colectomy for unfavorable histology

(pedunculated), invasion in sessile polyp, invasion beyond stalk into bowel wall

Unfavorable histology (poorly differentiated, LVI,

<1-2 mm from margin), 20-43% recurrence +/- LN mets

Risk for pT1 tumors

Residual local disease (20% in R1 cases) Lymph node metastasis (10-15% in high risk cases) Distant metastasis (? Increased risk in poorly

differentiated tumors)

Risk is balanced against operative morbidity (age,

site, comorbidities) and mortality Risk Parameter Table (adapted, USCAP 2013, Prof

Kieran Sheahan)

Risk

Depth of tumor invasion from muscularis mucosa = 0.8 mm Low Tumor width = 2.8 mm Low Kikuchi level = Sm2 Low Radial margins = uninvolved Low Deep margin = negative, >1 mm Low Tumor budding level is low Low Lymphovascular invasion present (1 vein only by elastic stain) High Site = rectum High ? Morphology = Sessile Lesion High ?

IBD associated dysplasia CRC Risk

Sporadic Adenoma/ Adenoma-like DALM Low Non-adenoma DALM >40% Low grade flat dysplasia 20%* High grade flat dysplasia 20-50% Indefinite for dysplasia 9% (in 5 yrs)

PRELIMINARY DATA

SSA-like changes (n=29) 0% TSA-like changes (n=30) 77% “Hyperplastic polyp with cytologic atypia” (n=19) 53%

• 5/24/2013
• 4

Low grade dysplasia in Crohns Hepatic Adenomas – Diagnostic Issues

HCA vs FNH Subtyping of HCA Risk of HCC

Adenoma (HCA) Variants

HNF1α-inactivated HCA

Hallmark: Fatty change

β-catenin mutated HCA

Hallmark: Increased risk for HCC

Inflammatory adenoma

Hallmark: Obesity/metabolic syndrome association

(Variant 4 + ?)

Hallmark: No specific trait

Well Differentiated Lesion Algorithm

• History of a mass -> 1 H&E, 1 reticulin, and 8 unstained
• n first cut
• Portal tracts?

Yes

Atypia/reticulin abnormalities

• Yes early HCC vs partial sampling of HCA -> GS, SAA, BC,

LFABP, CD34, GPC3

• No Mass not sampled or FNH-like lesion -> GS

No

Well differentiated hepatocellular lesion

• FNH features present, no atypia/reticulin abnormalities

– Yes – FNH vs Inflammatory variant HCA -> GS, SAA, BC – No – HCA, requires stains for further subclassificaiton -> GS, SAA, BC, LFABP – If atypia/reticulin abnormalities, w/u early HCC as above

• 5/24/2013
• 5

Linda Ferrell MD Ryan Gill MD, PhD Sanjay Kakar MD Grace Kim MD Rageshree Ramachandran MD, PhD

Hepatocellular Adenoma diagnosis

Cases:

HCA, inflammatory variant Focal nodular hyperplasia HCA, HNF1 alpha inactivated variant HCA, beta catenin mutated variant HCC arising in HCA

• 5/24/2013
• 6

Current Risk Stratification

Low risk (no resection needed) – 40% of cases

No LVI Moderately to well differentiated No tumor budding

Current Risk Stratification

“High risk”/”unfavorable histology” (… it depends) –

60% of cases

LVI present, poorly differentiated and tumor

budding present warrants immediate surgery if possible

One or two risk factors present = uncertainty! In high risk cases that go to surgery ~80% of

patients will have no residual tumor or metastasis

Risk Factor Quantitation

Semi-quantitative

Haggitt level (0-4) - pedunculated Kikuchi level (sm1-3) – non-polypoid

Quantitative

Depth of tumor invasion Tumor width Distance from resection margin

Pseudoinvasion

• 5/24/2013
• 7

Pseudoinvasion? Colonic Adenoma

Cases

Tubular adenoma with pseudoinvasion Localized Colitis Cystica Profunda/prolapse Tubular adenoma with invasive adenocarcinoma Colorectal dysplasia (IBD associated)

Sinusoidal Infiltrates

Case

Primary DLBCL, sinusoidal predominant

• 5/24/2013
• 8

Sinusoidal Infiltrate

Differential Diagnosis

Lymphoid neoplasms Reactive infiltrate

Sinusoidal distention/cells pile up Single mature lymphoid cells Cytologic atypia Mixed acute and chronic inflammation Aberrant T-cell antigen loss Viral type injury Hemophagocytosis EBER in rare B-cells EBER positive tumor cells Other liver disease findings Geographic necrosis TCR PCR negative

Primary Hepatic Lymphoma

Rare diagnosis (0.06% of NHL) Wide age range, M:F (2:1) Hepatomegaly is common Mild transaminitis may be present, jaundice rare Solitary mass, multinodular, or diffuse DLBCL, Burkitt lymphoma, MALT lymphoma, LPL,

Follicular lymphoma, and PTCL most common

Sinusoidal Involvement

Mature B-cell neoplasms Mature T- and NK-cell neoplasms Burkitt lymphoma Adult T-cell leukemia/lymphoma B-cell prolymphocytic leukemia Aggressive NK cell leukemia CLL/SLL Anaplastic large cell lymphoma Diffuse large B-cell lymphoma Angioimmunoblastic T-cell lymphoma Follicular lymphoma EBV positive LPD of childhood Hairy cell leukemia Hepatosplenic T-cell lymphoma Lymphomatoid granulomatosis Other γ/δ T-cell lymphomas Lymphoplasmacytic lymphoma Mycosis fungoides/Sezary syndrome Mantle cell lymphoma Peripheral T-cell lymphoma, NOS Marginal zone lymphoma (MALT) PTLD PTLD T-cell LGL leukemia

• 5/24/2013
• 9

Atypical Sinusoidal Infiltrate

CD20

Pitfalls

Ductopenia due to lymphoma EBV hepatitis Atypical lymphoid infiltrates in a hepatocellular lesion

Atypical Sinusoidal Infiltrate?

• 5/24/2013
• 10

Hepatocellular Adenoma Inflammatory Variant

Key Points

Reactive infiltrates are common in the liver, most are

benign

Correlate with background GI and liver disease

findings

Cytologic atypia an important clue Immunohistochemical evaluation Molecular testing as needed

• 5/24/2013
• 11

Duodenum Benign MALT CD20 CD3

• 5/24/2013
• 12

CD10 BCL6 CD21 BCL2

• 5/24/2013
• 13

Small Intestine Follicular lymphoma CD20 CD3 CD10

• 5/24/2013
• 14

BCL6 CD21 CD43 BCL2

• 5/24/2013
• 15

Low grade (grade 2, scale 1-3)

• 5/24/2013
• 16

Approach to Sinusoidal Infiltrates

Sinusoidal infiltrate cell type? Out of proportion to primary liver disease? Cytologic atypia? Immunophenotype? Molecular testing if still uncertain.

Sinusoidal Infiltrate – Cell Type

Granulocytes/ immature myeloid Macrophages Blasts Mature lymphoid cells

Sinusoidal Infiltrate – Cell Type

Granulocytes/ immature myeloid

MPN Leukemoid reaction Surgical effect

Macrophages Blasts Mature lymphoid cells

• 5/24/2013
• 17

Myeloid Proliferation related to Down Syndrome Transient Abnormal Myelopoiesis Extramedullary Hematopoiesis in Polycythemia Vera Extramedullary Hematopoiesis in Polycythemia Vera

Megakaryocyte Erythroid Precursors

MPN/MDS

• 5/24/2013
• 18

Sinusoidal Infiltrate – Cell Type

Granulocytes/myeloid Macrophages

Immunologic (HLH) Infectious (Histoplasmosis, Cryptococcus,

visceral leishmaniasis)

Storage disorders (Gaucher disease, Niemann-

Pick disease, etc)

Blasts Mature lymphoid cells

CD163

Gill RM et al. Macrophage Infiltrate, Ch 18 Liver Pathology, eds Linda Ferrell and Sanjay Kakar, Demos 2011

Niemann-Pick Disease

Gill RM et al. Macrophage Infiltrate, Ch 18 Liver Pathology, eds Linda Ferrell and Sanjay Kakar, Demos 2011

Organisms

Gill RM et al. Macrophage Infiltrate, Ch 18 Liver Pathology, eds Linda Ferrell and Sanjay Kakar, Demos 2011

• 5/24/2013
• 19

Amastigotes of Visceral Leishmaniasis

Gill RM et al. Macrophage Infiltrate, Ch 18 Liver Pathology, eds Linda Ferrell and Sanjay Kakar, Demos 2011

Sinusoidal Infiltrate – Cell Type

Granulocytes/myeloid Macrophages Blasts

ALL AML CML blast crisis

Mature lymphoid cells

Suspicious Sinusoidal Infiltrate

Lymphoblasts

• 5/24/2013
• 20

CD34

Sinusoidal Infiltrate – Cell Type

Granulocytes/myeloid Macrophages Blasts Mature lymphoid cells

Reactive infiltrate B-cell neoplasms T-cells/NK cell neoplasms

CD20

Mature T and NK cell Neoplasms

Hepatosplenic T-cell lymphoma Aggressive NK cell leukemia EBV positive T cell lymphoproliferative disorder of

childhood

Peripheral T cell lymphoma, NOS

• 5/24/2013
• 21

Hepatosplenic T-cell lymphoma

Rare, <5% of PTCL, median age 35, male>female Medium sized lymphoid cells Marked sinusoidal infiltration/expansion of liver,

spleen and bone marrow

20% arise in setting of chronic immune

suppression or in patients treated with azathioprine and infliximab for Crohns disease

Portal and Sinusoidal Infiltrates

Atypical Sinusoidal T-cells Hepatosplenic T-cell lymphoma

CD3+, CD2+, TIA-1+, CD7+/-, CD56+/- CD4-/CD8- (or CD4-/CD8+) CD5-, TCRβF1-, granzyme B-, CD25-, CD30- Typically a large TCRγ clone by PCR and EBER is

negative

Recurrent cytogenetic abnormality (i7q) Aggressive disease with early relapse

• 5/24/2013
• 22

Aggressive NK Cell Leukemia

Similar presentation to HSTL and fulminant

course

NK cell neoplasm with a leukemic component CD2+, cCD3+, CD56+, TIA-1+. Granzyme B + T-cell markers negative (sCD3, CD5, CD4, CD8,

TCRβF1, CD7)

EBER positive, TCR genes germline Hemophagocytosis

Aggressive NK cell Leukemia

Atypical Sinusoidal Infiltrate

EBV positive T-cell LPD of childhood

Clonal EBV infected T-cell proliferation, often in

children and young adults

Geographic predisposition (most prevalent in Asia

and Latin America)

Aggressive clinical course with hemophagocytic

syndrome, multiple organ failure, and sepsis

Liver and spleen usually involved Rare form presents in “elderly” with generalized

lymphadenopathy and usually HBV or HCV infection

• 5/24/2013
• 23

EBV positive T-cell LPD of childhood

Sinusoidal and portal infiltration by medium sized

cells

Erythrophagocytosis, necrosis, steatosis, and

cholestasis

CD3+, CD2+, CD5+,TCRβF1+, TIA-1+, granzyme

B+, CD8+/-, CD4-/+, CD56-

EBER ISH is positive TCRγ clone can be demonstrated by PCR

EBV+ T-cell Lymphoproliferative Disorder

• f Childhood

EBV+ T-cell Lymphoproliferative Disorder of Childhood

Peripheral T-cell lymphoma, NOS

Monomorphous lymphocytes with dark smudgy

chromatin and cleared out cytoplasm

Portal based with focal extension into liver

parenchyma along sinusoids

Histiocytes and other inflammatory cells may be

present.

Usually CD3+, CD4+, TCRβF1+, CD8-, CD56-,

CD30-

Aberrant immunophenotype: CD7/CD5/ and/or

CD2 loss

Typically a large TCR clone by PCR and EBER is

negative by ISH

• 5/24/2013
• 24

Portal and Sinusoidal Infiltrate

Large Atypical Lymphoid Cells

Summary

Colonic Adenomas Extranodal B-cell lymphoma Hepatocellular adenomas Primary hepatic lymphoma Part 1 GI Part 2 Liver

• 5/24/2013
• 25

References

• Bowman SJ, Levison DA, Cotter FE, et al: Primary T cell lymphoma of the liver in a patient with Felty's syndrome. Br J

Rheumatol 1994; 33:157-160.

• Brugieres L, Deley MC, Pacquement H, et al: CD30+ anaplastic large-cell lymphoma in children: analysis of 82 patients enrolled in

two consecutive studies of the French Society of Pediatric Oncology. Blood 1998; 92:3591-3598.

• Bunn PA Jr et al. Clinical course of retrovirus-associated adult T-cell lymphoma in the United States. N Eng J Med. 1983;309:257-

264.

• Cai G. et al. Primary hepatic anaplastic large cell lymphoma diagnosed by fine needle aspiration biopsy. Diagn cytopathol.

2005;33:106-109.

• Chang SE et al. Cutaneous dissemination of nasal NK/T-cell lymphoma with bone marrow, liver, and lung involvement. Clin Exp
• Dermatol. 2002;27:120-122.
• Dogan A. et al. Angioimmunoblastic T-cell lymphoma. Br J Haematol. 2003;121:681-691.
• Falchook GS et al. Hepatosplenic gamma-delta T cell lymphoma: clinicopathologic features and treatment. Ann Oncol.

2009;20:1080-1085

• Ferrell, LD, Kakar S. eds. Liver Pathology, Consultant Pathology Series. Demos Medical, New York, 2011
• Gentile TC, Uner AH, Hutchison RE, et al: CD3+, CD56+ aggressive variant of large granular lymphocyte
• leukemia. Blood 1994; 84:2315-2321.
• Huang C-B, Eng H-L, Chuang J-H, et al: Primary Burkitt's lymphoma of the liver: report of a case with long-term survival after

surgical resection and combination chemotherapy. J Pediatr Hematol Oncol 1997; 19:135-138.

• Kikuma K et al. Etiological factors in primary hepatic B cell lymphoma. Virchows Arch 2012, 460:379-387.
• Kim JH, Kim HY, Kang I, et al: A case of primary hepatic lymphoma with hepatitis C liver cirrhosis. Am J

Gastroenterol 2000; 95:2377-2380.

• Isaacson PG, Banks PM, Best PV, et al: Primary low-grade hepatic B-cell lymphoma of mucosa-associated lymphoid tissue

(MALT)-type. Am J Surg Pathol 1995; 19:571-575.

• Jaffe ES et al. Hematopathology. Expert Consult. Elsevier, St. Louis, 2011
• Jaffe ES. Malignant lymphomas, pathology or hepatic involvement. Semin Liv Dis, 1987, 7:257-268.

References

• Le Deley MC, Reiter A, Williams D, et al: Prognostic factors in childhood anaplastic large cell lymphoma: results of a large

European intergroup study. Blood 2008; 111:1560-1566.

• Lukes RJ: Criteria for the involvement of lymph node, bone marrow, spleen and liver in Hodgkin's disease. Cancer

Res 1971; 31:1755-1767.

• Maes M, Depardieu J, Hermans M, et al: Primary low-grade B-cell lymphoma of MALT-type occurring in the liver. J

Hepatol 1997; 27:922-927.

• Memeo L, Pecorello I, Ciardi A, et al: Primary non-Hodgkin's lymphoma of the liver. Acta Oncol 1999; 38:655-658.
• Murakami J, Fukushima N, Ueno H, et al: Primary hepatic low-grade B-cell lymphoma of the mucosa-associated tissue type: a

case report and review of the literature. Int J Hematol 2002; 75:85-90.

• Osborne BM, Butler JJ, Guarda LA: Primary lymphoma of the liver. Ten cases and a review of the
• literature. Cancer 1985; 56:2902-2910.
• Ohsawa M, Aozasa K, Horiuchi K, et al: Malignant lymphoma of the liver. Report of five cases and review of the literature. Dig Dis

Sci 1992; 37:1105-1109.

• Page R, Romaguera J, Osborne B, et al: Primary hepatic lymphoma favorable outcome after combination
• chemotherapy. Cancer 2001; 92:2023-2029.
• Purtilo DR et al. EBV associated lymphoproliferative disorder. Lab invest 1992;67:5-23
• Quintanilla-Martinez L. et al. Fulminant EBV+ T-cell lymphoproliferative disorder following acute/chronic EBV infection: a distinct

clinicopathologic syndrome. Blood. 2000; 96(2):443-451.

• Rodriguez J, Rawls D, Speights V: Primary lymphoma of the liver mimicking metastatic liver disease. South Med J 1995; 88:677-

680.

• Scheimberg IB et al. Pathology of the liver in leukemia and lymphoma: A study of 110 autopsies: Histopathology. 1995;26:311-

312

References

• Stein H, Foss HD, Durkop H, et al: CD30+ anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical
• features. Blood 2000; 96:3681-3695.
• Swerdlow SH, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. IARC, Lyon 2008
• Walz-mattmuller R. et al. Incidence and pattern of liver involvement in haematological malignancies. Pathol Res Pract.

1998;194:781-789

• Ye M, Suriawinata A, Black C, et al: Primary hepatic marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type in

a patient with primary biliary cirrhosis. Arch Pathol Lab Med 2000; 124:604-608.

Differential Diagnosis

T-cell Large Granular Lymphocytic Leukemia

Indolent/assymptomatic, cytopenia, autoimmune

disease

LGL increased in peripheral blood CD2+, CD3+, CD5w+, CD7+, CD8+CD4-, CD56+/-

TCRβF1+, granzyme B+

TCRγ rearranged

• 5/24/2013
• 26

CD8 CD4 CD8

Portal Involvement

• 5/24/2013
• 27

Large Atypical Lymphoid Cells