liver involvement in hematological malignancy liver involvement in... · linical presentation of...

Liver involvement in Hematologic malignancy

Dr Taya Kitiyakara

Ramathibodi hospital

Mahidol University

For THASL, 21-23 Mar 2013

Hematologic malignancy

Lymphoma

Leukaemia

Myeloma

Myeloproliferative diseases

Grouping of liver involvement

Diagnosis

(Pre-Rx) Treatment Long-term

post Rx

Diagnosis Treatment Post-treatment long-term

Liver infiltration Infections Chronic GVH

Acute liver failure Drugs Fe overload

Amyloidosis Sinusoidal

obstruction syndrome

NRH; FNH

Primary hepatic lymphoma

Acute Graft-versus-Host disease (GVH)

Others: Infections

Haem recurrence PTLD

Splanchnic venous thrombosis

Biliary tract obstruction/

infection Cirrhosis, HCC

Direct and indirect infiltration of the liver in hematologic malignancy

• All leukaemia, lymphoma, myeloma can cause infiltration of the liver

• Problems include abnormal LFT (AlkP and γGT), biliary obstruction, hepatomegaly and liver failure

• Myeloma can produce amyloid

• Primary hepatic lymphoma

• (Hepato-splenic T cell lymphoma)

Liver infiltration by lymphoma

Infiltration of the liver by hematologic cells is common

• Hodgkin’s Lymphoma: 5% of patients have infiltration at diagnosis, 50% at autopsy

(Jaundice more from tissue infiltration> biliary obstruction)

• NHL: 20-45% of patients have liver

infiltration (Jaundice from biliary obstruction>

infiltration)

• Myeloma: 25-40% infiltration on autopsy

Infiltration into sinusoids (vs portal area in autoimmune hepatitis)

Immunoperoxidase staining for lambda light chains of sinusoidal plasma cells C Barth et al. Z Gastroenterol 2005 MJ Birrer et al Semin Liver Dis 1987 KI Lei et al Leuk Lymph 1998

Biliary obstruction from infiltration

Patient with Lymphoma in Ramathibodi hospital

Hematologic malignancy as cause of liver failure

• Costa F et al, Chronic lymphocytic leukemia Leuk Lymphoma 1998 • Esfahani K et al Chronic lymphocytic leukemia Current Oncol 2011 • Padilla GF et al non-Hodgkin lymphoma Acta Gastroenterol Latinoam 2008. • Dellon ES et al natural killer–like T-cell leukemia/ Lymphoma World JGastroenterol 2006;

• Kojima H, et al Lennert’s lymphoma Leuk Lymphoma 2003.

• Santos ES et al Primary hepatic non-Hodgkin’s lymphomas Am J Gastroenterol 2003 • Lettieri CJ et al non-Hodgkin’s lymphoma Am J Gastroenterol 2003. • Thompson DR, malignant lymphoma Clin Lymphoma 2001

• Yeshurun M et al low-grade NHL transformation into large-cell lymphoma Leuk Lymphoma 2001 • Morali GA et al relapsing non-Hodgkin’s lymphoma Eur J Gastroenterol Hepatol 2001 • Anderson SH et al acute leukaemia Liver 2001 • Stewart KS, et al. Non-Hodgkin lymphoma in pregnancy Obstet Gynecol 1999. • Suzuki N et al. Ki-1 lymphoma Am J Gastroenterol 1998

• Souto P haematological malignancy Eur J Gastroenterol Hepatol 1997;

• Yoshikawa M, hepatosplenic B-cell non-Hodgkin’s lymphoma J Gastroenterol 1996

• Woolf GM et al. Lymphoma Dig Dis Sci 1994 • Zafrani ES et al Primary lymphoma of the liver Liver 1993. • Salo J et al. non-Hodgkin’s lymphoma. Am J Gastroenterol 1993 • Rahhal FE et al Myeloma. World J Gastroenterol 2009

Liver failure from hematologic malignancy

• Rare

• Time-scale from presentation to liver failure varies (from days to weeks)

• Jaundice, coagulopathy, encephalopathy

• Elevated LDH, lactic acidosis and recurrent hypoglycaemia also seen

• Urgent Transjugular liver biopsy needed for rapid diagnosis and treatment (if other tissue can not be obtained) K Esfahani et al Current Oncol 2011






NRH; FNH



Others: Infections





Amyloidosis (AL) associated with multiple myeloma

• Manifestation of hepatic amyloidosis: – Hepatosplenomegaly – ALKP ↑ – Splenomegaly – Ascites – PT prolong (acquired

factor X deficiency) – Cholestasis – Jaundice – Acute liver failure – Spontaneous rupture

Heart failure Renal failure Neuropathy rash

JH Pinney et al Ann Clin Biochem 2012 T Cross et al Postgrad Med J 2006

Diagnosis: Histology showing Amyloid deposition: fat pad

aspiration, rectal biopsy, liver biopsy Imaging Scintigraphy with 123I-human serum amyloid P

(SAP) component TREATMENT: Suppression of B cells/underlying clonal disease Autologous stem cell transplantation OUTCOME: Untreated: <5% survival in 10yrs Variable survival with treatment, Related to extent organ damage Reported 42% survival in 4 years

Kumar SK et al Mayo Clin Proc 2011 Pinney JH et al Ann Clin Biochem 2012






NRH; FNH



Others: Infections





Primary Hepatic lymphoma

• DEFINITION:

• PHL as a lymphoma localized and limited to the liver without extrahepatic involvement.

• Symptoms should be explainable by involvement of the liver.

• Furthermore, superficial lymphadenopathy, splenomegaly, abnormal hematological parameters, spleen or bone marrow localization cannot be present for at least 6 mo after appearance of the hepatic lesion

EJA Steller et al World J Radiol 2012

Clinical presentation of 1⁰ hepatic lymphoma

• Clinical presentation of PHL is nonspecific.

• Most often fever, loss of weight and night sweats (also known as ‘B’ symptoms) occur.

• Alternative symptoms described are: right upper abdominal pain, epigastric pain, abdominal distension, nausea- vomiting, anorexia, asthenia or itch.

• Jaundice and hepatomegaly (rarely ascites) can be found in some patients.

• Blood tests can show abnormal AST, ALT, AlkP, total and direct bilirubin and LDH

Common cell types: B-cell NHL (63%) and T-cell lymphoma (25%)

• Solitary liver nodule • Multiple nodules • Diffuse infiltrating

On CT: • hypo- or iso-

attenuating • Hypointense on

contrast injection or rim enhancement

On MRI: • Hypointense T1 • Slight enhancement

of signal T2

1/3 each

Noronha V et al Crit Rev Oncol/Hematol 2005

Treatment for 1⁰ Hepatic lymphoma

• Chemotherapy is the treatment of choice

• Many will have had surgery, and chemotherapy should be used adjunctively

• No randomised controlled trials

• However, outcomes were not good in case series.

EJA Steller et al World J Radiol 2012






NRH; FNH



Others: Infections





Clinical presentation

• Budd-chiari syndrome: ascites, abdominal pain, encephalopathy, upper GI bleeding

• Abnormal AST/ALT

• Portal vein thrombosis: abdominal pain, nausea, dyspepsia, loose stool. Less commonly: small bowel infarction

• Severity of symptoms depends on extent and speed of thrombus

• Diagnosis often by Doppler, CT contrast scan, MRI

40.9%

27.7% 41.1%

31.5%

JS Smallberg et al Blood 2012

Distribution of Myeloproliferative disorder subtypes in non-cirrhotic

Splanchnic Thrombosis

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Budd-Chiari Portal V thrombosis

JAK2V617F+ only

unclassified MPN

MF

ET

PV


Treatment

• Anticoagulation • Angioplasty/ shunt/ stent • TIPS when angioplasty and medical treatment

fails • Liver transplantation

• Treatment of MPN disorder • Unclear whether any MPN-specific treatment

should be given to solitary JAK2 patients other than close observation

Baveno V consensus workshop on portal hypertension. J Hepatol 2010


A common problem for hepatologists: ….abnormal LFT’s /jaundice after stem

cell transplantation?!? 1. Sepsis related cholestasis 2. Acute graft versus host

disease 3. Sinusoidal obstruction

syndrome 4. Tumour infiltration 5. Liver infection 6. Cardiac failure 7. Antibiotics/antifungals 8. Ciclosporin 9. TPN 10. Biliary obstruction/infection

Timetable for common complications after stem cell transplantation for

hematologic malignancies

HH Tuncer et al World J Gastroenterol 2012






NRH; FNH



Others: Infections





Liver infections

Bacteria

mycobacterium

Non-opportunistic /

Biliary tract

Virus

CMV

HSV

HHV-6

VZV

adenovirus

EBV

(PTLD)

HBV

HCV

Fungus

Aspergillosis

Candida

(krusei, galbrata)

Molds:

Scopulariopsis

Trichosporon

Pseudallescharia

Fusarium

mucor

CMV and Herpes family virus

นพ. วชัรศกัดิ์ โชติยะปตุตะ

Acute viral infection: Dengue and Herpes infection

Adenovirus hepatitis

Extensive liver necrosis can occur with adenovirus.

Patients often have

combinations of: fever, respiratory distress,

diarrhea, and liver dysfunction.

Note the "smudgy" appearance of the nucleus(arrows), they are characterized by a crowding of chromatin towards the nuclear membrane. Immunohistochemical staining are confirmatory

Diagnosis with DNA blood test or immunohistochem’. Treatment is with cidofovir

Neofytos D et al Biol Blood Marrow Transplant 2007

On the left, a sterile healing abscess with a

necrotic center devoid of fungal elements, surrounded by inflammatory cells and a pseudo-capsule (asterisk) On the right, an acute abscess with a small focus of red-staining fungal elements (arrow) in a field of degenerative neutrophils, surrounded by a pseudo-capsule

Fungal infections: •Fever with tender enlarged hepatomegaly •Micro-abscesses may be missed by CT scan •Liver biopsy often needed •Prophylaxis antifungal treatment often select triazole resistant fungi and molds •Restoration of granulocyte count is the most important factor in recovery

GB MacDonald Hepatology 2010






NRH; FNH



Others: Infections





Commonly used and reported drugs

Hepatitic picture

• cyclophosphamide infusions,

• liposomal amphotericin,

• trimethoprim-sulfamethoxazole,

• itraconazole, voriconazole

• imatinib

Cholestatic picture

• Cyclosporin

• Tacrolimus

• trimethoprim-sulfamethoxazole,

• itraconazole, voriconazole, fluconazole, posaconazole

• TPN

“..in many cases, attribution to a single drug is mostly guesswork because every patient receives multiple drugs”.

GB MacDonald et al Hepatology 2010






NRH; FNH



Others: Infections





Sinusoidal obstruction syndrome (SOS) aka. Hepatic veno-occlusive disease

• Early onset after starting myeloablative therapy for stem cell transplantation

• Clinical features: tender hepatomegaly, hyperbilirubinaemia, fluid retention with weight gain

• Diagnostic criteria by investigators in Seattle and Baltimore

• Risk factors related mainly to myeloablative therapy

Diagnostic criteria for SOS Seattle group criteria Baltimore group criteria

Diagnosis requires 2 out of 3, within 20 days of transplantation

Hyperbilirubinemia (>2mg/dl) plus 2 or more of:

Bilirubin >2mg/dl Hepatomegaly, usually painful

Hepatomegaly or RUQ pain from liver

≥5% weight gain

>2% weight gain due to fluid accumulation

Ascites

McDonald GB et al Ann Intern Med 1993 Jones RJ et al Transplantation 1987

Risk factors for SOS Liver disease at base line Specific conditioning regimens Other drugs during

conditioning

HBV or HCV Cyclophosphamide(CY) based Itraconazole

NASH Cy 120mg/kg + TBI (esp with

higher TBI doses)

Sirolimus

(rapamycin)

Alcoholic hepatitis BCV (Cy+ BCNU+ VP-16) Norethisterone

Fibrosis/cirrhosis Cy+ BU

Extramedullary hemapoiesis

with sinusoidal fibrosis Mephalan (Mel) based

Intrahepatic cholestasis with

jaundice Mel + BU

Prior History Other regimens

Prior SOS BU + TBI

Prior liver irradiation

Gemtuzumab ozogamicin-

containing myeloablative

regimens

TBI= total body irradiation BU= busulfan

Prior myeloablative

hematopoietic cell transplant

High dose radiolabelled antibody

myeloablative regimen

HH Tuncer et al World J Gastroenterol 2012

Pathogenesis of Sinusoidal obstruction syndrome

Chemotherapy Irradiation other drugs

Pathogenesis of Sinusoidal obstruction syndrome

•Intrahepatic coagulation not thought to be main cause of disease •Other biochemical changes: NO, glutathione, matrix metalloproteinase-9, F-actin

Histology of SOS

• A. Zone 3 of the liver acinus in an early phase of SOS, with disruption of sinusoidal anatomy, red blood cells extending through the space of Disse, hepatocyte necrosis, and subendothelial edema in a patent central vein (CV) (H&E).

• B. Extensive hepatocyte necrosis and dropout, disruption of sinusoids, extravasation of red blood cells throughout zone 3, and subendothelial fibrosis (Masson trichrome).

GB MacDonald Hepatology 2010

Sinusoidal obstruction Syndrome

Evaluation

• Clinical (rapidity of symptom development)

• Level of abnormal LFT (bilirubin, AST>750u/l)

• USS doppler (reverse flow in PV, thrombosis)

• HVPG >20mmHg

• Other organ failure

Treatment

• Supportive

• No effective treatment

• Prophylaxis with Heparin does NOT work

• Prophylactic Defibrotide?

• PREVENTIVE- by avoiding high risk myeloablative regimens

Outcome

• 70% of patients resolve spontaneously

• Death usually from renal and cardiopulmonary failure

• “Reverse” cirrhosis can occur in survivors

‘Normal’ cirrhosis: fibrosis occurring around portal tracts and spreading to other portal tracts

CV

Histology of chronic SOS

• F. confluent fibrosis in and around adjacent central veins, with central to central bridges forming a picture of “reverse” cirrhosis two months after transplant.

Trichrome : Intimal and perisinusoidal fibrosis

GB MacDonald Hepatology 2010 Photo courtesy of Dr N Angkathunyakul






NRH; FNH



Others: Infections





Acute Graft-versus-Host disease (aGVH)

• Arises when donor T cells respond to genetically different proteins on host cells (so starts at engraftment)

• Frequency directed related to the degree of mismatch in HLA proteins

• Non-HLA proteins also involved

• (30-40% incidence in HLA matched related donors , 60-80% incidence with one HLA Ag mismatch unrelated donors)

• 3 main organs: Skin, Gastrointestinal tract and Liver

JLM Ferrara et al Lancet 2009

aGVH: a common sequence

Skin

Maculopapular rash

Bullous lesions

GI tract

Watery diarrhoea

Abdominal pain

Liver

Cholestatic LFT

Jaundice

Hepatitic variant After donor lymphocyte

infusion JLM Ferrara et al Lancet 2009

http://www.google.co.th/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&docid=mNBEn6sKN8RBgM&tbnid=cV8VTP_rLQ-39M:&ved=0CAUQjRw&url=http://dermaamin.com/site/atlas-of-dermatology/9-g/589-graft-versus-host-disease-&ei=S-BKUbSBCsiZiQfiQw&psig=AFQjCNH3joIYsTONc9q6mwQci6oRcGjxAw&ust=1363947932607441

Evaluating aGVH Staging of acute Graft versus Host disease

(modified Keystone criteria)

stage Skin GI tract Liver

0 No rash Diarrhea <500mL/d Bilirubin <2.0mg/dL

1 Maculopapular rash <25% of

body surface

Diarrhea 501-

1000mL/d or nausea

(+/- vomiting)

Bilirubin 2.0-

3.0mg/dL

2 Maculopapular rash 25-50% of

body surface

Diarrhea 1001-

1500mL/d

Bilirubin 3.1-

6.0mg/dL

3 Generalized erythroderma Diarrhea >1501mL/d Bilirubin 6.1-

15mg/dL

4 Generalized erythroderma

with blister/bullous formation

and desquamation

Severe abdominal

pain +/- ileus Bilirubin >15mg/dL

Grade: Severe Grade: life-threatening

Diagnosis

• Clinical symptoms with associated histopathology

• Often histopathology difficult to obtain from the liver (low platelet count)

• Easier to obtain tissue from skin or upper/lower GI tract

• Important findings: – lymphocytic infiltration and – apoptosis in crypts

Diffuse cholestasis with bile duct damage (lymphocytic infiltrate, Nuclear pleomorphism and Vacuolization of bile duct epithelium )

Histology of hepatic Acute GVHD

Important features (simplified): 1. lymphocytic infiltration of bile duct 2. Bile duct epithelial damage 3. bile duct degeneration and 4.cholestatis

Photo courtesy of Dr N Angkathunyakul

Treatment

• Ursodeoxycholic acid improves bilirubin level

• High dose corticosteroids is the mainstay of treatment (complete response in 30-50%)

• Other immunosuppressive regimens for non-responders

• Many progress to become cGVHD

Modified from S Aria et al J Hematotherapy Stem cell Res 2002

Mini-summary and algorithm in peri-transplant period

Liver dysfunction

Bili>2.5

AST/ALT>200

ALP>300

hepatomegaly

Symptoms

Weight

Drugs?

Blood for testing/smear

Restrict Na 2g/g

TPN holiday

ciclosporin→tacro’

Cultures

Viral DNA

Imaging:

Normal

Imaging: Biliary tract

disease

Imaging:

Focal mass/lesion

Imaging:

Hepatomegaly

(ascites)

VOD? Micro-

abscesses biopsy

Rx Surgical consult

Infection?: Rx. Follow LFT 3 days-worse?

Worse :biopsy If not worse:

observe, …assess in 3

days: better?

If not:biopsy

Phew! The immediate stem cell transplant period is over…






NRH; FNH



Others: Infections





Chronic GVHD • Definition: arbitary cut-off at 100 days

• Major cause of late non-relapse death

• Risk factors: old age and acute GVHD

• Hepatic manifestations:

– Abnormal ALT ALP γGT

– Slowly progressive jaundice

– Acute hepatitic picture

• Liver biopsy often needed

• Treatment with

– UDCA

– Immunosuppression

JLM Ferrara et al Lancet 2009

Liver histology in chronic GVHD

• E. A portal space showing absence of recognizable bile duct epithelium in a patient with longstanding refractory chronic GVHD (H&E).

Important features: Lobular hepatitis Portal inflammation Loss of small bile ducts

MacDonald GB Hepatology 2010






NRH; FNH



Others: Infections





Nodular Regenerative hyperplasia

NRH: Nodular architecture without intervening fibrosis A response to vascular injury from malignancy or its treatment Clinically silent but may produce portal hypertension


Central fibrous scar Reported to be up to 12% of survivors

Focal nodular hyperplasia







NRH; FNH



Others: Infections





Fever

Tender hepatomegaly

Predominantly Elevated ALP (Jaundice)

Summary

Sepsis Biliary disease

Fungus Abscess

Viral infection

SOS

Infiltration cGVHD

Cardiac failure

Budd-Chiari

Mycobacterial infection

Drugs aGVHD

Fe overload NRH FNH Cirrhosis/HCC

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