Abdominal complications of chemotherapy in pediatric malignancies:imaging findings☆
Nabil J. Khourya,⁎, Vladimir Kanja, Miguel Abboudb, Samar Muwakkitb,Ghina A. Birjawia, Maurice C. Haddada
aDepartment of Diagnostic Radiology, American University of Beirut Medical Center, Beirut, LebanonbChildren Cancer Center of Lebanon, American University of Beirut Medical Center, Beirut, Lebanon
With the increasing incidence of malignancies and theadvance in chemotherapeutic drugs, variable complicationsrelated to such therapy are being observed. Some particularcomplications were reported in relation to specific drugs orregimen used. Early detection and recognition of thesecomplications are crucial to improve patients' outcome.However, since their early use, these drugs were proven to bepotentially toxic resulting in variable side effects on differentorgans of the body. In this review, we are describing ourexperience in imaging findings of various abdominalcomplications encountered in young cancer patients follow-ing chemotherapy.
☆ The Children Cancer Center of Lebanon (CCCL) is affiliated with St.Jude's Cancer Center, Tennessee, USA.
⁎ Corresponding author. Department of Diagnostic Radiology, Amer-ican University of Beirut Medical Center, Bliss Street, Beirut, Lebanon.
For this purpose, we reviewed all the radiology files of243 patients diagnosed with malignancies treated in ourchildren cancer center (affiliated with St Jude's CancerCenter, Memphis, TN, USA) between April 2002 andDecember 2005. Abdominal imaging was performed in 164patients. Imaging studies, including ultrasound and CT scan,were performed either for regular follow-up for the patients'condition or because of nonspecific abdominal complaints.Ultrasounds were performed using a state-of-the-art sono-graphy machine (HDI 5000, ATL Ultrasound, Bothwell,WA, USA); CT scans were performed using a single-detectorhelical scanner (Tomoscan AV, Philips, Netherlands). Themedical records of patients with abnormal imaging studieswere reviewed, and correlation with pathology results, whenavailable, was done.
Out of the 164 patients with abdominal imaging, only 54patients had one or more abdominal disease processes that,after review of the medical charts, were not related to theprimary tumor or to other concomitant condition that maycause them and, hence, were considered as complications
NB: (1) Eight patients had two concomitant complications, and threepatients had three complications.(2) We have encountered a second patient with siderosis, treated for acutemyelogenous leukemia. However this was not included in our series becausethe patient had received significant amount of blood transfusions.
⁎ Two patients had spontaneous resolution of their gallstones on a 1-monthfollow-up ultrasound.
† One of these patients had previous gallstones that resolved prior to theepisode of cholecystitis.
‡ Neither of these patients had bone marrow transplantation or radiationtherapy prior to the appearance of this complication.
§ Six patients had no gallbladder disease. The remaining patientdeveloped gallbladder sludge after the onset of pancreatitis.
related only to chemotherapy. The male-to-female ratio was1:1.45 the range of age was 7 months–19 years 6 months(mean=10.5 years). Clinically, these patients were eitherasymptomatic or had nonspecific abdominal complaints.Table 1 summarizes the encountered abdominal complica-tions with the number of patients involved. Table 2 lists thesecomplications in relationship with the chemotherapy proto-cols that are summarized in the Appendix to Table 2. Table 3displays the variable malignancies in the patients' populationwe studied. In this review, we will discuss only theconditions encountered in our patient population.
2. Complications and imaging findings
2.1. Gallbladder disease
2.1.1. Gallstones, pseudolithiasis, crystals, and sludgeGallbladder stones, crystals, and sludge are rare in
children. Chemotherapeutic agents are responsible forabout 7.4% of this condition. Gallstones are mainly seenwith high dose of cytarabine and asparaginase and maydisappear spontaneously [1]. However, in cancer patients,there are other factors that predispose to gallstones includingsystemic infection, prolonged fasting, long-term totalparenteral nutrition, bone marrow transplantation, andradiotherapy [2]. Besides, high dose of ceftriaxone, fre-quently used in cancer patients suspected to have infections,can cause biliary pseudolithiasis since it is excreted in thebile forming a calcium–ceftriaxone complex precipitate [3].
On imaging, gallbladder crystals and sludge appear onsonography as echogenic foci without posterior shadowing(Figs. 1 and 2). On CT scan, mildly dense material is present(Fig. 3). Gallstones and pseudolithiasis are seen onultrasound as echogenic material with posterior shadowing(Fig. 4; see also Fig. 6A), which on CT scan appear as asignificantly dense or calcific material (Fig. 5).
2.1.2. Acalculous cholecystitisAlthough cholecystitis may occur as a complication of
stone disease, acalculous cholecystitis may occur due tochemotherapeutic agents, mainly in acute leukemia. Thedrugs involved include vincristine, cyclophosphamide, andcytosine-arabinoside. The etiology may be infectious orischemic [4].
On imaging, acalculous cholecystitis is diagnosed by thepresence of painful gallbladder showing wall edema with orwithout overdistention of the gallbladder (Figs. 6 and 7) andabsence of stones.
Several drugs have been implicated in liver injury thatmainly includes steatosis (fatty infiltration), fibrosis, andsiderosis (iron accumulation).
2.2.1.1. Steatosis and fibrosis. Steatosis is due to accumula-tion of triglycerides within the hepatocytes. It is commonlyseen in patients treated for acute lymphocytic leukemia(ALL) using mainly L-asparaginase [5]. Hepatic fibrosis isalso seen in the same population as evidenced by histopathol-ogy as well as in patients receiving methotrexate and 6-mercaptopurine [6,7]. On imaging, ultrasound typicallyshows increased liver echotexture in both steatosis andfibrosis relative to the kidneys [7,8] (Fig. 8). On nonenhancedCTscan, there is sharp contrast between the liver parenchymaand the hepatic vessels [8]. On intravenous-enhanced CTscan, the liver is hypodense in relationship with the spleen(Fig. 9). Hepatic fibrosis is not correlated with any CTchanges. On MR imaging, steatosis is best diagnosed onproton chemical shift imaging showing signal subtraction onthe opposed-phase images relative to the in-phase images [8].
2.2.1.2. Siderosis. Siderosis (or secondary hemochromatosis)is due to the accumulation of iron within the reticuloendothe-lial cells and in severe cases within the hepatocytes [9]. It hasbeen documented on pathology in 14–70% of patients treatedfor ALL [5,9]. However, siderosis can be due to frequentblood transfusions. On imaging, the liver is enlarged andshows diffuse increased density on nonenhanced CT scangreater than 75 Hounsfield units (Fig. 10). On MRI, there isdiffuse low signal intensity due to the paramagnetic effect ofthe ferritin and ferric irons, shortening T1 and T2 relaxationtimes [10].
Table2
Listof
protocolsim
plicated
inthevariouscomplications
Com
plication
CCCLALL
protocol
AML
POG—
#9421
AML
C9710
Neuroblastoma
A39
73Osteosarcom
aPGO
9351
Burkitt
lymphom
aSJB
CII
Acute
lymphob
lastic
lymph
omaPOG—
#9404
Hod
gkin
lymphom
aCCG-594
2Medulloblastoma
A99
61Allrelapse
protocol
Rhabdom
yosarcon
am
GBslud
geor
crystals
71
22
1GBston
esor
pseudo
lithiasis
41
21
Acalculou
scholecystitis
11
Liver
steatosis
171
11
21
Liver
siderosis
1Pancreatitis
61
Typh
litis
43
31
1Fun
galesop
hagitis
11
Veno-occlusiveof
liver
2
Note:
please
referto
“App
endixto
Table2”
fordetails
regardingthevariou
sprotocols.
CCCL=ChildrenCancerCenterof
Lebanon;AML=acutemyelogenous
leukem
ia.
255N.J. Khoury et al. / Clinical Imaging 33 (2009) 253–260
2.2.2. Veno-occlusive disease of the liverHepatic veno-occlusive disease (VOD) is a condition
affecting the hepatic sinusoids, characterized by endothelialinflammation and damage resulting in obstruction of theterminal hepatic and sublobular venules [11]. Local hyper-coagulable state is also induced with formation of aggregatesof fibrin and debris that occlude the endothelium pores. Thisresults in postsinusoidal portal hypertension. It may lead tohepatic necrosis and fibrous scarring [11]. Veno-occlusivedisease may complicate a variety of chemotherapy with themajor causative agent being the combination of dactinomycinand vincristine, and cyclophosphamide [12]. Portal veinthrombosis can rarely follow or have association with VOD[13]. Clinically, VOD presents with painful hepatomegaly,jaundice, and ascitis [11]. The diagnosis is confirmed bybiopsy [12]. On imaging, both sonography and CT scan showhepatomegaly, periportal edema, and ascitis [11] (Figs. 11 and12). Duplex Doppler sonography may show reversed portalvenous flow, high resistive index of the hepatic artery [14].
2.3. Pancreatic disease: pancreatitis
A large number of drugs have been shown to inducepancreatitis in children [15], in particular in the treatment ofacute lymphoblastic leukemia where the regimen usedcomprises doxorubicin, vincristine, and prednisolone [16].Adding L-asparaginase (in particular PEG-L-asparaginase) tothis therapy regimen further increases the incidence ofpancreatitis [16]. Pancreatitis induced by L-asparaginase maybe very severe resulting in necrosis. Besides, pancreatitismay have resulted from gallstones induced by other therapyregimen used in cancer patients. On imaging, there is diffuseenlargement of the pancreas on both ultrasound and CT scanwith some peripancreatic fat streaking and fluid (Figs. 13 and14). The diagnosis is confirmed by high blood levels ofamylase and lipase.
2.4. Gastrointestinal tract disease
The complications encountered in the gastrointestinaltract are related to the immunocompromised state induced bychemotherapeutic agents.
2.4.1. TyphlitisThis is an opportunistic infection due to pathogens that
are part of the patients' own intestinal flora [7]. It occursanywhere in the bowels but most commonly at the level ofthe cecum and terminal ileum [7]. It is associated withabdominal pain, tenderness, fever, and diarrhea. Theincidence in treated children for cancer is around 2.6%[17], being more common after 16 years of age. The patientsare usually neutropenic [6,7,17]. The mortality of typhlitisreaches 8%. On imaging (Figs. 15 and 16), there is bowelwall thickening ≥3 mm in size as measured by ultrasound orCT scan. Ultrasound was shown to be better than CT scan inthe assessment of bowel wall thickening in typhlitis and
Fig. 3. Gallbladder sludge seen on CT scan in a 7-year-old boy with ALL.There is dense material within the gallbladder lumen (asterisk). Ascitis ispresent in the perihepatic and pericholecystic region with secondarygallbladder wall thickening (arrowheads).
Fig. 4. Gallstones seen on ultrasound of a 5-year-old boy with ALL andabdominal pain. No changes in cholecystitis were present (arrow pointing tothe stones).
Fig. 5. Gallstones seen on CT scan as significantly dense material in thedependant portion of the gallbladder (arrow). The patient is a 10-year-oldboy with Hodgkin's lymphoma. The gallstones were incidental.
Table 3List of diagnoses in the 54 patients with abdominal complications
Fig. 1. Gallbladder crystals in a 6-year-old boy treated for ALL. Ultrasoundshows few echogenic movable foci within the gallbladder lumen.
Fig. 2. Gallbladder sludge and crystals in a 12-year-old female with ALL.Ultrasound showing significant echogenic material within the gallbladderwith no posterior shadow or changes in cholecystitis.
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hence for establishing the diagnosis and for follow-up [17].Besides, CT scan may show pneumatosis intestinalis,pericolonic fluid, and thickening of the fascial planes [6].Both ultrasound and CT scan are helpful in ruling out otherconditions that simulate typhlitis, such as appendicitis andbowel perforation.
2.4.2. Fungal esophagitisInfective esophagitis may be fungal, viral, or bacterial,
affecting immunocompromised children. The organisms areopportunistic and of low pathogenicity to normal individuals[7]. Fungal infection is seen in patients with severeneutropenia receiving chemotherapy [6]. Almost all drugsare implicated. Other risk factors include prolonged
Fig. 6. Cholecystitis in a 6-year-old boy with pelvic rhabdomyosarcoma. (A)Ultrasound performed as a routine screening showed incidental gallstoneswith no evidence of cholecystitis. The patient did not have upper abdominalpain. (B) One month later, the patient had right abdominal pain. Ultrasoundrevealed an overdistended gallbladder with diffuse wall edema andpericholecystic fluid. The gallstones have disappeared. Because ofnonresponse to antibiotics, cholecystectomy was performed. Pathologyconfirmed cholecystitis but no stones.
Fig. 7. Gallbladder wall edema (arrows) due to acalculous cholecystitis in a6-year-old girl with ALL. Gallbladder sludge is also noted. The patientpresented with abdominal pain.
hospitalization, radiation therapy, and administration ofbroad spectrum antibiotics [6]. The most frequentlyencountered fungus is candida and aspergillus [6]. Symp-toms include dysphagia, odynophagia, nausea, vomiting, andfever. On imaging, CT scan shows diffuse nonspecificesophageal wall thickening (Fig. 17). Diagnosis is made byendoscopy and biopsy.
In conclusion, we presented the imaging findings ofabdominal complications induced by chemotherapeutic
Fig. 8. Liver steatosis in a 17-year-old young man treated for ALL.Ultrasound performed 3 weeks after initiation of therapy shows diffuselyechogenic liver.
Fig. 9. Liver steatosis on a CT scan of a 16-year-old boy with ALL, 2 weeksafter the start of therapy. The liver is significantly hypodense. Note also thepresence of splenomegaly with splenic infarcts and/or leukemic infiltration(arrows).
agents and encountered in our pediatric cancer patientpopulation. We described and discussed these complicationsand their imaging findings. The chemotherapy regimen anddrugs implicated in our series did not differ from thosedescribed in the literature. Clinicians and radiologists shouldbe aware of these complications and recognize them toprovide early treatment and management to these patientswho suffer from high morbidity and mortality diseases.
Appendix to Table 2
Chemotherapy protocols used at Children Cancer Centerof Lebanon (CCCL)
CCCL ALL protocol
Fig. 10. Liver siderosis in a 12-year-old boy treated for ALL with impairedliver function tests and no history of frequent blood transfusion. None-nhanced CT scan shows significant increase in liver density in keeping withsiderosis. This was confirmed on histopathology following a liver biopsy.
Methotrexate (MTX), cytarabine-arabinoside (ara-C); dox-orubicin; prednisone; L-asparaginase; vincristine; IT (MTX,hydrocortisone ara-C); cyclophophamide; 6 mercaptopurine;dexamethasone; (PEG-asparaginase and Gleevec); leucovorin.
Fig. 11. Veno-occlusive disease of the liver of a 7-month-old girl known tohave neuroblastoma, presenting with increased abdominal girth. (A)Ultrasound of the abdomen reveals a hypoechoic enlarged liver withincreased periportal echoes due to edema. (B) Enhanced CT scan of theabdomen. The liver is enlarged slightly heterogeneous with significantperiportal edema (arrowheads). Liver biopsy confirmed VOD.
Fig. 12. Veno-occlusive disease of the liver of a 1-year-old boy with rightadrenal neuroblastoma. Patient had abnormal liver function tests. EnhancedCT scan of the abdomen shows again hepatomegaly and periportal edema.Neuroblastoma can be seen (star).
Fig. 14. Pancreatitis in an 11-year-old girl treated for ALL. Enhanced CTscan of the abdomen performed 2 weeks after the start of the therapy showsdiffusely enlarged, slightly heterogeneous pancreas, with peripancreaticfluid (cursor). Note also diffuse fatty liver infiltration.
Fig. 15. Typhlitis in a 1-year-old girl with ALL. Patient had abdominal pain.
259N.J. Khoury et al. / Clinical Imaging 33 (2009) 253–260
Fig. 13. Pancreatitis in a 4-year-old girl with ALL. Abdominal ultrasoundwas performed 1 month following the therapy initiation. The pancreaticbody (B) and tail (T) are enlarged with presence of peripancreatic fluid(arrows). Findings are consistent with pancreatitis and were proved bylaboratory data.
Enhanced CT scan performed 2 months following the start of chemotherapy.The ascending colon shows circumferential wall thickening. Minimalsurrounding fluid and ascitis are present (arrows).
Fig. 16. Typhlitis in a 13-year-old girl treated for ALL. Enhanced CT scanwas performed for abdominal pain. The rectosigmoid wall (RS) is thickened,an unusual location for typhlitis. The patient had also involvement of theascending colon (figure not shown). (S=sigmoid colon.)
Fig. 17. Esophagitis in a 9-year-old boy with acute myelogenous leukemia.The patient had dysphagia 2 weeks following the start of the chemotherapy.Enhanced CT scan showed diffuse esophageal wall thickening reaching thegastro-esophageal junction (arrows). The patient's symptoms responded toantiviral therapy.
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