Gut and liver involvement in pediatric hematolymphoid malignancies

Table 1 Overview of gut and liver manifestations of hematolymphoid malignancies in children

	Overview of gut and liver manifestations
Infiltration	Intussusception; Adynamic ileus; Mucosal ulceration; Hemorrhage; Perforation; Protein-losing enteropathy; Jaundice (biliary wall infiltration); Hepatosplenomegaly; Acute liver failure; Vanishing bile duct syndrome; Portal hypertension; Ascites (peritoneal seeding, peritoneal lymphomatosis); Splenic infarction, rupture
Immunodeficiency	Necrotizing enterocolitis (typhlitis); Appendicitis; Wound infections; Perirectal abscess; Sepsis; Opportunistic infections; Esophageal and hepatic candidiasis; Herpes infections; Cytomegalovirus infections; Pseudomembranous colitis; Protozoal infections; Invasive fungemia; Hepatitis B and C reactivation
Drug toxicity	Mucositis; Gastritis and gastroparesis; Ileus; Pseudoobstruction; Bowel necrosis; Pancreatitis; Hepatotoxicity
Compression	Gastric outlet obstruction; Biliary obstruction; Secondary Budd-Chiari syndrome; Chylous Ascites
Miscellaneous:	Gastrointestinal haemorrhage (thrombocytopenia, coagulopathy, secondary hemophagocytic lymphohistiocytosis)

Table 2 Outcome of gastrointestinal lymphomas in children from world global registries

	SEER registry, United States (1973-2006)[75]	West midlands, United Kingdom (1957-2000)[82]	Egypt cancer registry; (1997-2003)[77]
n	265	44	43
Incidence	0.199/100000	0.9 million/yr	-
Age (yr)	< 10: 44%; > 10: 56%	3-14	0.4-17
Male: female	3:1	5.7:1	2.3:1
Distant involvement	7.5%	-	-
Surgery	83.4%	96%	91%
Radiation	12.5%	71%	-

Table 3 Workup in Langerhans cell histiocytosis

Workup
Mandatory investigations	Hemogram, complete liver function test (including coagulation), abdominal ultrasonography, chest Xray, skeletal survey (radiologic/nuclear), bone marrow examination
Optional	Complete body PET scan (at baseline and follow-up to monitor response and recurrence)
Special investigations
Liver/biliary dysfunction	Liver biopsy, magnetic resonance cholangiography
Lung involvement	HRCT, pulmonary function test, bronchioalveolar lavage, lung biopsy (if necessary)
Craniofacial involvement, aural discharge, visual anomalies	MRI head, HRCT temporal bone
Diabetes inspidus	Urine specific gravity, water deprivation test, MRI head
Short stature, pubertal issues	Hormonal assessment, MRI head
Spinal involvement	MRI spine, spinal biopsy

PET: Positron emission tomography; HRCT: High-resolution computed tomography; MRI: Magnetic resonance imaging.

Table 4 Common gastrointestinal manifestations with their clinical possibilities and recommendations for practice

Gut and liver manifestation	Possible reasons at diagnosis	Possible reasons during therapy	Recommendations
Jaundice	Tumor infiltration and necrosis of hepatocytes; Obstruction of biliary system by enlarged lymph nodes; Transfusion related viral hepatitis; Consider possibility of HLH as atypical presentation of hemato-lymphoid malignancies; Sclerosing cholangitis in a case of LCH	Chemotherapy induced liver injury (e.g., 6-MP, Methotrexate); Reactivation of viral infections (e.g., HBV, HCV, CMV, EBV)	Screen for HBV, HCV, HIV before starting chemotherapy; Safe transfusion practices; Exercise pharmacovigilance (chemotherapeutic drug dose modifications with underlying hepatic impairment, therapeutic drug monitoring-e.g., Methotrexate); Screen for genetic polymorphisms (e.g., TPMT, NUDT15 genotype for 6-MP)[104]; Abdominal imaging either CT angio or MRCP with MRI on clinical basis; Prioritize chemotherapy initiation for underlying malignancy over waiting for resolution of HLH with HLH treatment protocol[105]; Initiation of antivirals before chemotherapy for hepatitis B, hepatitis C infection as per standard guidelines[106,107]
Liver failure	Peculiar presentation with T-ALL, AML, TAM of newborn; Overwhelming sepsis at baseline due to poor immune reserve	Peculiar toxicity with L-asparaginase, high dose methotrexate and anthracyclines in predisposed individuals; Viral hepatitis especially hepatitis B reactivation	Early steroid initiation at presentation for preventing further liver cell necrosis in a case of ALL; Considering chemotherapy for TAM; FFP, cryoprecipitate product transfusions for hemostasis; Screen for hepatotrophic viral markers and appropriate antiviral therapy
Visceral perforation	Advanced stage lymphomas causing gut obstruction; Typhlitis due to severe neutropenia (e.g., AML); Appendicitis as presentation (especially with ALL)	Post chemotherapy initiation with high grade lymphomas of stomach or intestine; C. difficile infection	Abdominal girth, bowel sound monitoring stringently in suspect cases; Abdominal imaging by CECT enterography with oral positive contrast; Stool examination in colitis for C. difficile; Anticipatory surgical consultation in advanced lymphomas
Bowel obstruction	High grade lymphomas causing intussusception; Extrinsic nodal compression of gut	Vinca alkaloid induced paralytic ileus during therapy; Septic ileus during periods of neutropenia	Abdominal imaging with CECT enterography; Adequate broad spectrum antibiotic cover; Surgical consultation for intussusception; Continuous gastric /bowel drainage above the level of obstruction
GI bleed	Mucosal bleed due to thrombocytopenia at presentation; GI lymphoma[77]	Thrombocytopeniainduced mucosal bleeds; Drug induced coagulopathy (e.g., peg-asparaginase); Typhlitis; C. difficile colitis	Conservative management with blood products; Laparotomy only in uncontrolled bleed for surgical resection; In suspect cases of C.difficile colitis, stool for toxin assay, GDH and consider colonoscopy
Pancreatitis	Rare as initial presentation	Drug induced (Asparaginase preparations, cytarabine)	Do not rechallenge with the same drug in case of AAP; Genetic testing could have a future role in predicting the risk of drug induced pancreatitis
Ascites	High grade lymphomas at presentation; Peritoneal lymphomatosis; Chylous ascites in prolonged untreated Hodgkins lymphomas; Reported cases of secondary BCS due to Burkitts lymphoma; Pancreatic ascites in severe pancreatitis	Drug induced liver failure (ex. Anthracyclines at toxic dose, L-asparaginase)	Ascitic fluid for flow cytometry and malignant cytology can provide rapid diagnosis; MCT supplementation for chylous ascites; Octreotide and TPN for refractory chylous ascites; Lymphangiography if refractory chylous ascites

GI: Gastrointestinal; 6MP: 6Mercaptopurine; HBV: Hepatitis B virus; HCV: Hepatitis C virus; CMV: Cyto-megalo-virus; EBV: Epstein-Barr virus; HIV: Human immunodeficiency virus; LCH: Langerhans cell histiocytosis; T-ALL: T-cell acute lympoblastic leukemia; ALL: Acute lymphoblastic leukemia; AML: Acute myeloblastic leukemia; CT: Computed tomography; MRCP: Magnetic resonance cholangio-pancreatography; CECT: Contrast enhanced computerized tomography; FFP: Fresh frozen plasma; HLH: Hemophagocyticlymphohistiocytosis; TPMT: Thiopurinemethyltransferase; NUDT15: Nudix hydrolase-15; TAM: Transient abnormal myelopoiesis; GDH: Glutamate dehydrogenase; AAP: Asparaginase associated pancreatitis; MCT: Medium chain triglycerides; TPN: Total parenteral nutrition; BCS: Budd-Chiari syndrome; C. difficile: Clostridiodes difficile.