Abdominal Pain and IntermittentFevers in a 16-Year-Old GirlKristen Penberthy, PhD,a Joanne Mendoza, MD,b Michael Mendoza, MD,c Grant Harrison, MD,d Luke Lancaster, MD,e

Brian Belyea, MD,f Steven L. Zeichner, MD, PhDg,a

abstractA 16-year-old girl presented to the emergency department with intermittentfevers and worsening abdominal pain of 5 weeks duration. She had a historyof travel to a less developed country and exposure to possible infectiousdiseases. Abdominal imaging and blood tests revealed diffuse mesentericlymphadenopathy, elevated transaminases, and elevation of inflammatorymarkers. Gastroesophageal and colon endoscopies revealed gastric ulcers,and the patient was discharged with a presumptive diagnosis of systemicjuvenile idiopathic arthritis given the lymphadenopathy seen on imaging,serositis, sacroiliac joint stiffness noted on physical examination, and painrelief with celecoxib. She presented again 4 days later with worseningabdominal tenderness, elevated transaminases, and new-onset abdominaldistention. Tissue biopsy yielded the diagnosis and directed appropriatetreatment.

CASE HISTORY WITH SUBSPECIALTYINPUT

Dr Penberthy, Medical ScientistTraining Program Fourth-Year ClinicalMedical Student, Moderator

A 16-year-old girl with a 5-weekhistory of abdominal pain presented toour emergency department (ED) withintermittent fevers, up to 38.3°C, andworsening abdominal pain. Her fevershad no clear pattern in timing orduration. Her abdominal pain wassharp, constant, at the left upperquadrant and epigastric regions, andrelieved by nonsteroidalantiinflammatory drugs (NSAIDs) andacetaminophen. She denied havingconstipation, diarrhea, dark or bloodystools, emesis, or appetite changes. Shereported an enlarged, tender right-sided cervical lymph node thatappeared 2 to 3 months beforepresentation. Her last bowel movementwas 1 day and her last menstrualperiod was 2 weeks beforepresentation. She denied sexual activity,

drug, or alcohol use. She attendedsummer camp in Pennsylvania 1 weekbefore presentation where she swam ina lake and walked in the woods.

Her past medical history includedphysician-diagnosed, appropriatelytreated Lyme disease with Bell’s palsy2 years earlier. She reportedintermittent joint pain and muscleaches since. She had bilateral upperthird molar extractions 3 weeks beforepresentation. Her oral surgeonprescribed prophylactic amoxicillin,considered standard of care by the oralsurgeon; she developed a rash after9 days of amoxicillin. Her pediatricianprescribed prednisone for 9 days fora presumed allergic reaction 12 daysbefore presentation, after which herrash resolved, abdominal painimproved, and the neck lymph nodesubjectively decreased in size accordingto her parents.

Several physicians saw our patient forabdominal pain before her presentationto our ED. Her pediatrician tested for

Divisions of bGeneral Pediatrics, cGastroenterology andNutrition, fPediatric Hematology and Oncology, andgPediatric Infectious Diseases, Department of Pediatrics andDepartments of dPathology, eRadiology, and aMicrobiology,Immunology, and Cancer Biology, School of Medicine,University of Virginia, Charlottesville, Virginia

Dr Penberthy helped conceive the manuscript,provided initial organization and text, and helpededit the final manuscript; Dr Belyea helped conceivethe manuscript, supplied subspecialty-related text,and helped edit the final manuscript; Dr J. Mendozasupplied clinically related text; Drs M. Mendoza,Lancaster, and Harrison supplied subspecialty-related text and images; Dr Zeichner helped conceivethe manuscript, provided initial organization andtext, supplied subspecialty-related text, and helpededit the final manuscript; and all authors approvedthe final manuscript as submitted and agree to beaccountable for all aspects of the work.

DOI: https://doi.org/10.1542/peds.2019-0093

Accepted for publication Feb 7, 2019

Address correspondence to Steven L. Zeichner, MD,PhD, Division of Pediatric Infectious Diseases,Departments of Pediatrics and Microbiology,Immunology, and Cancer Biology, University ofVirginia, PO Box 801349, 409 Lane Rd, MR4, Room2118, Charlottesville, VA 22908-0386. E-mail:zeichner@virginia.edu

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online,1098-4275).

Copyright © 2019 by the American Academy ofPediatrics

FINANCIAL DISCLOSURE: The authors have indicatedthey have no financial relationships relevant to thisarticle to disclose.

To cite: Penberthy K, Mendoza J, Mendoza M, et al.Abdominal Pain and Intermittent Fevers in a 16-Year-Old Girl. Pediatrics. 2019;144(3):e20190093

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Helicobacter pylori, with a negativeresult, and prescribed pantoprazole.Three days before presenting to us,she went to another ED for abdominalpain. They performed an abdominalcomputed tomography (CT) scan,which revealed diffuselymphadenopathy, peritoneal freefluid, and stool in the rectal vault.Although the patient had notcomplained of constipation, given thefindings of stool in the rectal vault,the ED recommended a trial ofpolyethylene glycol for constipationand also prescribed dicyclomine. Shewas given intravenous (IV) ketorolac.

In our ED, our patient was insignificant distress because ofabdominal pain. Her vital signs wereas follows: blood pressure 105/69mmHg, heart rate 88 beats perminute, respiratory rate 20 beats perminute, and temperature of 35.8°C.Her examination was remarkable fora single 2-cm diameter, nontender,not-fixed right cervical lymph node.The examination was also remarkablefor abdominal tenderness andguarding, without rebound, over theleft upper quadrant, left lowerquadrant, and epigastrium. Theremainder of her examination wasunremarkable. Her initial laboratories(Table 1) were notable for anaspartate aminotransferase (AST) of96 U/L, an alanine aminotransferase(ALT) of 106 U/L, an erythrocytesedimentation rate (ESR) of 55 mm/hour, and a C-reactive protein (CRP)of 5.6 mg/dL. The ED physicians wereconcerned that the elevatedtransaminases might representacetaminophen toxicity, but anacetaminophen level was notelevated. Her heterophile antibodytest result was negative. She wasgiven ketorolac, which provided painrelief, and admitted to the generalpediatrics hospitalist service forfurther workup.

Dr J. Mendoza, what did the generalpediatric team think?

Dr J. Mendoza, Attending Physician,Pediatric Hospitalist Service

Abdominal pain in a postpubertal girlis common, with a wide differentialdiagnosis. Our patient had worsening,multiple-quadrant abdominal pain.We had concerns about herconstipation; abdominal,retroperitoneal, and cervicallymphadenopathy; fevers and chills;frequent use of acetaminophen andibuprofen with some possibly NSAID-induced gastritis; and elevatedinflammatory markers. Evaluatingwhich symptoms might be disease-related and which might be iatrogenicwas challenging. Indolent infectiousdisease; gastrointestinal (GI) diseasedue to inflammatory bowel disease(IBD), gluten enteropathy, orsensitivity to galactose-a-1,3-galactose; and an oncologic processwere on our differential. However,because there was not animmediately clear etiology, andbecause she evidenced considerableemotional distress, we alsoconsidered functional causes. Weaddressed her comfort whilesimultaneously pursuing a diagnosis.

We treated our patient with dioctylsodium sulfosuccinate, polyethyleneglycol 3350, famotidine, andondansetron. We continuedtreatment with NSAIDs whilerecognizing their potentialcomplications. We obtaineda complete blood count withdifferential, a complete metabolicpanel, lipase, lactate dehydrogenase(LDH), urinalysis, ESR, CRP,immunoglobulin A (IgA),transglutaminase IgA, deaminatedgliadin IgA, immunoglobulin E–a-1,3galactose, urinalysis with microscopy,acetaminophen level, 2-view chestradiograph, and requested that ourradiologist read her outside of CTscan. Table 1 shows her initiallaboratory results. We consulted theDivisions of Gastroenterology andHepatology, Pediatric InfectiousDisease, and Hematology andOncology.

Dr Penberthy

Dr Lancaster, what did the initialimaging studies reveal?

Dr Lancaster, Department ofRadiology

The initial CT scan revealed multipleenlarged mesenteric andretroperitoneal lymph nodes in theabdomen, with small volume ascitesin the abdomen and pelvis (Fig 1). Atthis point, the differential diagnosiswas broad,1–4 including infection,particularly those resulting ingranulomatous reactivelymphadenopathy (tuberculosis oratypical mycobacteria, cat scratchdisease, fungal infections), Epstein-Barr virus, systemic lupuserythematosus, sarcoidosis, systemicjuvenile idiopathic arthritis (SJIA),Langerhans cell histiocytosis(histiocytosis X), HIV, autoimmunelymphoproliferative disease(lymphoproliferation due to geneticcauses would be unlikely ina teenager), lymphoma (Hodgkin’s ornon-Hodgkin’s), or anothermalignancy.

Dr Penberthy

Dr M. Mendoza, many of our patient’ssigns and symptoms were GI. Whatwere the thoughts of thegastroenterology service?

Dr M. Mendoza, Division of PediatricGastroenterology and Nutrition

Although we considered IBD, thispatient had few specific symptomspointing toward IBD. Our patient hadcomplaints of epigastric abdominalpain, worsening over the previous 3months, but little else wascharacteristic of IBD. She hadlaboratory findings suggestive ofa chronic inflammatory process, thatis, an elevated ESR, but this isnonspecific. Our patient’s serumalbumin level was 3.8 g/dL; it issuggested in some data that albuminof ,4 may indicate mild or earlyIBD.5 It is also possible that gastric

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ulcer disease might result inabdominal lymphadenopathy.

Because of an absence of diagnosticlaboratory findings, we alsoconsidered that she might havea functional gastrointestinal disorder(FGID). FGIDs are a group ofdisorders classified by symptomsrelated to any combination ofa disturbance of GI motility, visceralhypersensitivity, altered mucosal andimmune function, altered gutmicrobiota, and altered centralnervous system processing. Using theRome IV criteria for FGIDs, ourpatient most appropriately fit witha diagnosis of epigastric painsyndrome,6,7 which can be treatedwith cyproheptadine.8 Epigastric painsyndrome is characterized byepigastric pain and burning severeenough to impact on usual activities.

Dr Penberthy

Dr Zeichner, what were the infectiousdiseases considerations among thispatient’s potential diagnoses?

Dr Zeichner, Division of PediatricInfectious Diseases

When we first interviewed the patientand her family, we learned there weremany potential exposures, forexample, the patient’s summer camp.However, with additionalinterviewing, we learned that ourpatient, who has family in Ecuador,took 3 trips there in the preceding2 years. In Ecuador, the family staysin homes on the outskirts of Quitoand at a family farm near SantoDomingo, an area with endemicChagas disease.9 When showna photograph of a reduviid bug (thevector for Trypanosoma cruzi), thefamily observed that “we saw theseall the time.” The farm raises cattle,horses, and poultry, although thepatient did not take part in the farmanimal activities. The family reportedthat there are bats in the area. Thefamily visited an “ecolodge” on anAmazon tributary and swam in riversand hot springs. They drank bottled

TABLE 1 Laboratory Tests Obtained on Admission

Test Value Reference Range

WBC, k/mL 6.17 4.40–8.10RBC, M/mL 4.62 4.20–5.20Hemoglobin, g/dL 12.3 12.0–16.0Hematocrit, % 38.1 35.0–47.0MCV, fL 82.5 83.0–95.0MCH, pg 26.6 28.0–32.0MCHC, g/dL 32.3 32.0–36.0RDW, % 13 11.0–14.0MPV, fL 10 9.0–12.0Platelets k/mL 255 150–450Lymphocytes, % 20.7 15.0–45.0Lymphocytes, k/mL 1.28 1.40–3.30Monocytes, % 10.4 2.0–12.0Monocytes, k/mL 0.64 0.00–1.00Eosinophils, % 4.5 0.0–6.0Eosinophils, k/mL 0.28 0.00–0.60Basophils, % 0.2 0.0–2.0Basophils, k/mL 0.01 0.00–0.20Neutrophils, % 64.2 47.0–82.0Neutrophils, k/mL 3.96 1.80–8.00Sodium, mmol/L 138 136–145Potassium, mmol/L 4.2 3.4–4.8Chloride, mmol/L 101 98–107CO2, mmol/L 25 20–28BUN, mg/dL 8 8–21Creatinine, mg/dL 0.7 0.6–0.9Glucose, mg/dL 86 74–99Calcium, mg/dL 10.1 8.5–10.5Total protein, g/dL 7.2 6.0–8.0Albumin, g/dL 3.8 3.2–5.2Total bilirubin, mg/dL 0.4 0.3–1.2Alkaline phosphatase, U/L 82 40–150AST, U/L 96 ,35ALT, U/L 106 ,55IgA, mg/dL 198.2 68.0–378.0CRP, mg/dL 5.6 ,0.5ESR 55 0–30 mm/hAcetaminophen level, mg/mL 14 Therapeutic Range: 10–20Color, urine Yellow YellowAppearance, urine Clear ClearSpecific gravity, urine 1.013 1.005–1.030pH, urine 7 5.0–8.0Protein, urine Negative NegativeGlucose, urine Negative NegativeKetone, urine Negative NegativeBilirubin, urine Negative NegativeBlood, urine Negative NegativeNitrite, urine Negative NegativeUrobilinogen, EU 0.2 0.2–1.0Leukocyte esterase Negative NegativeWBC urine, cells per HPF Rare ,3–5RBC urine, cells per HPF Negative ,3–5Cast urine, casts per LPF Negative NegativeEpithelial cells urine, cells per HPF Rare NegativeBacteria urine Negative NegativePregnancy test urine Negative Negative

CO2, carbon dioxide; EU, Ehrlich unit; HPF, high-power field; LPF, low-power field; MCH, mean corpuscular hemoglobin; MCHC,mean corpuscular hemoglobin concentration; MCV, mean cell volume; MPV, mean platelet volume; RBC, red blood cell;RDW, red blood cell distribution width; WBC, white blood cell.

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water while in the country. Thepatient typically ate shrimp, fish,pork, and beef. All meat wasreportedly well cooked. The patientconsumed local cheese and milk ofunknown pasteurization status. InEcuador, she experienced no diarrhea.

Given the extensive exposure historyand the possibility that infectiousdiseases could produce symptomsconsistent with the patient’spresentation and clinical course,10,11

we constructed a large infectiousdifferential diagnosis, although noneof the diseases we considered werecompletely consistent with thepresentation, and the presentationwas not consistent with the common,acute infectious disorders ofreturning travelers.12,13 Weconsidered Epstein-Barr virus andcytomegalovirus infections, with thepatient’s lymphadenopathy. Givenboth the fevers and thelymphadenopathy in the context ofher travel, we were concerned aboutthe possibility of tuberculosis. Amongother bacterial infections, we weremost concerned for chronic zoonoses.Among chronic parasitic diseases, weconsidered trichinella, because of hermeat consumption and findings ofelevated serum LDH, and Chagasdisease, although the lack of

eosinophilia would weigh againstthose diagnoses. We recommendedseveral studies to rule out possibleinfectious causes for her disease.

Dr Penberthy

Dr Belyea, can you please discuss howthe presentation and initial findingsmight support an oncologicdiagnosis?

Dr Belyea, Division of PediatricHematology and Oncology

When we first met this patient, wewere impressed by her abdominalpain. We reviewed her CT scan withradiology. Although lymphoma is onthe differential of a patient withmesenteric lymphadenopathy, 1 or 2large masses is more typical versuslarge numbers of mesenteric lymphnodes, which were all slightly largerthan normal. Her imaging showedsignificant inflammation with ascitesand stranding, more consistent withan inflammatory process. Finally, herremarkable improvement withNSAIDs is not typical of lymphomaand is more suggestive ofa rheumatologic or inflammatorydisease. A definitive diagnosis ofmalignancy can only be achieved bytissue biopsy. Biopsy of herabdominal nodes was not withoutrisk, and because other conditions

were possible (SJIA, sarcoidosis,gastric ulcers, and possible infectiousetiologies), we recommended closemonitoring with a plan to repeatimaging and reconsider biopsy as hersymptoms evolved.

Dr Penberthy

Dr J. Mendoza, can you please discusssome of the ongoing managementchallenges during hospitalization,particularly pain management, andfindings that complicated thediagnosis?

Dr J. Mendoza

During admission, the main concernwas pain control. She receivedketorolac with good analgesic effect,but this was not a long-term solution.Her H2-blocker was changed toa proton pump inhibitor. Carafate wasadded. When she lost her IV line, weswitched to oral ibuprofen and thenacetaminophen, with cyproheptadineadded. Pain control was insufficient,so the anesthesia pain team wasconsulted, and she was givengabapentin.

Dr Penberthy

Dr M. Mendoza, as her symptomscontinued and there was not yeta definitive diagnosis, her physicianscame to consider a primary GIprocess. The GI service performedendoscopic examinations. Can youplease comment?

Dr M. Mendoza

Although nonspecific, her chronicsymptoms, albumin of ,4,and elevated inflammatorymarkers prompted anesophagogastroduodenoscopy andcolonoscopy with biopsies to evaluatefor IBD (Fig 2). At endoscopy, she wasnoted to have well-defined antralulcers; in addition, colonoscopyrevealed Enterobius vermicularis(pinworm) infestation (SupplementalInformation), but no evidence for IBD.She was therefore started on high-dose IV acid suppression and

FIGURE 1Initial abdominal CT examinations. The figure shows the results from the initial abdominal CTexamination. A, Coronal view. B, Transverse view.

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treatment with 400 mg ofalbendazole.

We believed that NSAIDs were theprimary cause of her ulcers. Theincidence of GI ulcers in the setting ofchronic NSAID use is reported to beas high as 25%.14

Pinworm is the most common worminfection in the United States,typically presenting with perianalitching. Diagnosis is made by direct

visualization of eggs by using a tapetest or direct worm visualization.Stool examination is notrecommended; there are noserological tests. Treatment is a singledose of an antihelminthic, with repeattreatment in 2 weeks, and treatmentof all household members.15

Dr Penberthy

Dr Zeichner, did the infectious diseaseservice consider the finding ofpinworms on endoscopy significant?

Dr Zeichner

Although we found the endoscopyvideos intriguing, we did not believethat pinworms caused thecomplaints. There are isolated casereports of pinworms observed onendoscopy,16 and pinworms havebeen associated with diseases likeappendicitis, IBD, or diverticulitis,although these associations may beincidental.17

Although our index of suspicion forzoonosis and other infectiousdiseases was not high, even with the

exposure history, absent of anyother definitive diagnosis, wethought it was worthwhile to searchbroadly. The infectious workup wasunrevealing. Tables 2 and 3summarize the results. We did notbelieve that the result for tularemiawas significant; that diagnosiswould not have been consistentwith her clinical course. Weconcluded an infectious etiologywas unlikely.

Dr Penberthy

Dr J. Mendoza, please describe thehospital course and diagnosticconsiderations after endoscopy?

Dr J. Mendoza

She was assessed by physical andoccupational therapy. They noticedirregular posture and wereconcerned about stiffness of hersacroiliac joints, which, togetherwith the other signs, symptoms, andimaging studies indicating diffuseadenopathy, led to the addition ofSJIA to the differential. Pediatricrheumatology was consulted

FIGURE 2Upper endoscopy. The image shows a gastriculcer from the upper endoscopy.

TABLE 2 Additional Laboratory Testing for Infectious Organisms

Test Value Reference Range Notes

Babesia microti IgG antibody Negative NA —

Blastomyces antibody Negative NA —

Blood culture, acid-fast bacilli Negative NA —

Blood culture, bacterial Negative NA —

Blood culture, fungal Negative NA —

Borrelia burgdorferi IgG p41, p23, p18 bandsdetected

$5 bands for a positive IgG Previous testing positive: p66, p45, p41, p39,p23, p18 bands

Brucella abortus IgG antibody Negative NA —

B abortus IgM antibody Negative NA —

Coccidioides antibody Negative NA —

Francisella tularensis antibodies 1:40 ,1:20 negative; 1:20–1:80 equivocal; $1:160 positive

—

H pylori stool antigen Negative NA —

Histoplasma antibody Negative NA —

Histoplasma antigen Negative NA —

HIV-1/2 antibody Negative NA —

Mycobacterium tuberculosis(QuantiFERON gold)

Negative NA —

Stool ova and parasite examination E vermicularis eggsdetected

NA Stool ova and parasite examination otherwisenegative

Toxoplasma gondii IgG antibody ,3 IU/mL Negative ,10 IU/mL —

T gondii IgM antibody Negative — —

T cruzi IgG antibody Negative NA —

T cruzi IgM antibody ,1:16 Negative ,1:16 —

Urine culture Negative NA —

IgG, immunoglobulin G; IgM, immunoglobulin M; NA, not applicable; —, not available.

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because SJIA can present withfevers, serositis, andlymphadenopathy without painfuljoints. Rheumatology considered

recommending a lymph node biopsybut felt that the yield was low inSJIA. The patient was dischargedwith a working diagnosis of SJIA

after the patient achieved significantrelief on a trial of celecoxib.

Dr Penberthy

Four days after discharge, the patientpresented to the ED with abdominalpain and temperatures up to 39.4°C.She complained of nausea, emesis,night sweats, dark urine, andabdominal distention. Her parentsreported that she had been compliantwith her celecoxib, gabapentin, andproton pump inhibitor. Given herequivocal tularemia titer, she wasgiven a prescription for ciprofloxacinon discharge, but the family electednot to fill it.

The patient’s examination atreadmission revealed no subjectivechange in cervical lymphadenopathybut was remarkable for abdominaldistention and diffuse tenderness,both new from her previousadmission. She had persistentelevation of LDH (422), worseninghepatitis, with increasing elevation ofliver enzymes (ALT 474 U/L and AST218 U/L), with a newly elevated totalbilirubin (3.1 mg/dL), alkalinephosphatase (389 U/L),g-glutamyltransferase (366 U/L), andlipase (222 U/L). A right upperquadrant ultrasound revealed dilationof her biliary tree in the absence ofgallstones. A repeat CT scan of herabdomen was performed and she wasadmitted.

Dr Lancaster, can you please discussthe additional imaging studies?

Dr Lancaster

On her second CT scan, 17 days afterher initial study, herlymphadenopathy had progressed,with dramatically increased ascites.Our assessment was that this couldeither have been because of aninfectious or inflammatory processbecause those are more likely to showrapid changes or because ofa lymphoma (Fig 3).

TABLE 3 Laboratory Tests Obtained Subsequently

Test Value Reference Range

WBC, k/mL 8.43 4.40–8.10RBC, M/mL 4.63 4.20–5.20Hemoglobin, g/dL 11.5 12.0–16.0Hematocrit, % 36.1 35.0–47.0MCV, fL 78 83.0–95.0MCH, pg 24.8 28.0–32.0MCHC, g/dL 31.9 32.0–36.0RDW, % 14.3 11.0–14.0MPV, fL 10.2 9.0–12.0Platelets k/mL 425 150–450Lymphocytes, % 12.2 15.0–45.0Lymphocytes, k/mL 1.03 1.40–3.30Monocytes, % 8.3 2.0–12.0Monocytes, k/mL 0.70 0.00–1.00Eosinophils, % 0.5 0.0–6.0Eosinophils, k/mL 0.04 0.00–0.60Basophils, % 0.2 0.0–2.0Basophils, k/mL 0.02 0.00–0.20Neutrophils, % 78.8 47.0–82.0Neutrophils, k/mL 7.19 1.80–8.00Sodium, mmol/L 132 136–145Potassium, mmol/L 3.8 3.4–4.8Chloride, mmol/L 96 98–107CO2, mmol/L 28 20–28BUN, mg/dL 8 8–21Creatinine, mg/dL 0.6 0.6–0.9Glucose, mg/dL 112 74–99Calcium, mg/dL 9.8 8.5–10.5Total protein, g/dL 6.7 6.0–8.0Albumin, g/dL 3.5 3.2–5.2Total bilirubin, mg/dL 3.1 0.3–1.2Alkaline phosphatase, U/L 389 40–150AST, U/L 218 ,35ALT, U/L 474 ,55LDH, U/L 422 127–287GGT, U/L 366 ,38Lipase, U/L 222 8–78Color, urine Orange YellowAppearance, urine Cloudy ClearSpecific gravity urine 1.031 1.005–1.030pH urine 8.0 5.0–8.0Protein, urine 21 NegativeGlucose, urine Negative NegativeKetone, urine Large NegativeBilirubin, urine Moderate NegativeBlood, urine Negative NegativeNitrite, urine Positive NegativeUrobilinogen, EU 1.0 0.2–1.0Leukocytes esterase Small NegativeWBC urine, cells per HPF 3–5 ,3–5RBC urine, cells per HPF Rare ,3–5Epithelial cells urine, cells per HPF Occasional NegativeBacteria urine Occasional Negative

CO2, carbon dioxide; EU, Ehrlich unit; GGT, g-glutamyltransferase; HPF, high-power field; MCH, mean corpuscular hemo-globin; MCHC, mean corpuscular hemoglobin concentration; MCV, mean cell volume; MPV, mean platelet volume; RBC, redblood cell; RDW, red blood cell distribution width; WBC, white blood cell.

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Dr Penberthy

Dr J. Mendoza, what were yourthoughts about the changes in thepatient’s clinical status sincedischarge?

Dr J. Mendoza

With the patient’s worseningabdominal lymphadenopathy andnew ascites, our concern formalignancy increased. The teamdecided not to proceed with steroidtreatment of possible SJIA.

Dr Penberthy

Dr Belyea, can you please discussyour evolving approach?

Dr Belyea

Her second CT scan led us inoncology to increasingly suspecta malignancy. There was discussionwith the primary team about whetherto start steroids. Steroids would havepartially treated a lymphoma,confusing and/or delaying thatdiagnosis. We recommendedadditional imaging studies: a positronemission tomography (PET)–CTexamination. The PET-CT would helpdetermine if the lymphadenopathywas reactive or representeda malignancy, in which case the lymphnodes would appear hypermetabolic,particularly because we had ruled out

a large number of potential infectiouscauses for the lymphadenopathy. Webelieved that the PET-CT would alsohelp identify sites of disease thatmight be more amenable to biopsythan diffuse abdominallymphadenopathy. We alsorecommended following seriallaboratory values.

Dr Lancaster

We performed a fludeoxyglucosePET-CT 2 days after her second CTscan (Fig 4), which was remarkablefor intense tracer uptake in multipleabdominal lymph nodes and in a fewneck and pelvic lymph nodes. Lymphnode uptake that intense stronglysuggested malignancy and/orlymphoma and is unusual in infection.Although sarcoidosis can have intenseuptake, sarcoidosis is rare in childrenand does not show the rapid changesobserved.

Dr Belyea

From the oncological viewpoint, thePET-CT examinations revealinghypermetabolic right cervical andabdominal lymph nodes wereconcerning for lymphoma, buta tissue diagnosis was still needed.The most rapidly available way tosafely obtain tissue was throughinterventional radiology, done undersedation and local anesthesia. Theright cervical node was accessible forfine-needle aspiration (FNA) and corebiopsy, and we obtained those. TheFNA suggested a high-grademalignant neoplasm. However, theneedle core biopsies did not containthe neoplasm seen on FNA, anda definitive diagnosis could not bemade. After this procedure, hercervical node decreased significantlyin size and was no longer palpable.We considered an excisional nodebiopsy, but given the nondiagnosticcore sample and the decreasing sizeof this node, we were worried that anexcisional node biopsy still might notresult in a definitive diagnosis andwould delay her workup and ultimatetherapy further. Therefore, we

FIGURE 3Follow-up abdominal CT examinations compared to initial CT. The figure shows the results from thesecond abdominal CT examination. A, Coronal view from initial CT (as in Fig 1). B, Coronal view fromsecond CT; note increasing lymphadenopathy. C, Transverse view from initial CT (as in Fig 1). D,Transverse view from second CT; note increasing lymphadenopathy.

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requested a surgical consult fora biopsy of an abdominal lymph node.Although the FNA suggesteda malignant neoplasm, given the widepossible differential, we felt thatobtaining tissue would offer the bestopportunity to make a definitivediagnosis. Our surgeon colleagueswere concerned about theinflammation in her abdomen and thepossibility of poor wound healing andsuggested paracentesis before a moreinvasive procedure. Therefore, weproceeded with paracentesis toobtain ascites cells. We obtained 1 Lof fluid, with improvement in thepatient’s comfort. We examined thefluid with flow cytometry,cytopathology, bacterial Gram-stainand culture, fungal culture, acid-fastbacterial culture, LDH, protein, andlipase.

Dr Penberthy

Dr Harrison, can you please discussyour pathologic findings?

Dr Harrison, Department ofPathology

We processed 70 mL of yellowparacentesis fluid into a paraffin cellblock. Microscopic examinationrevealed numerous large atypicalcells in a background of small maturelymphocytes (Fig 5A). The atypical

cells had markedly irregular nuclearcontours, unevenly distributedchromatin, prominent nucleoli, andabundant eosinophilic cytoplasm,with apoptotic bodies and mitoticfigures. The morphologic differentialdiagnosis included anaplastic large-cell lymphoma (ALCL) and malignantmelanoma. Immunohistochemicalstains revealed cells negative forS100, evidence against the diagnosisof malignant melanoma. Atypical cellswere positive for the leukocytecommon antigen (CD45), confirmingthe diagnosis of large-cell lymphoma.CD3 was positive and CD20 wasnegative, confirming a T-cell–derivedneoplasm. Finally, the cells werepositive for CD2, CD5, CD30,anaplastic lymphoma kinase (ALK),perforin, and granzyme B, confirmingthe diagnosis of ALK 1 ALCL (Fig 5 Band C).

ALK 1 ALCLs typically havea variable proportion of cells withhorseshoe-shaped or kidney-shapednuclei. Some have nuclearpseudoinclusions. Althoughmorphology helps form a differentialdiagnosis, a chromosomaltranslocation involving the ALK geneand expression of ALK protein andCD30 defines ALCL.18 Otherimmunohistochemical stains are

helpful: ALCLs often retain CD2 andCD5 expression. ALCL cells sharesome features of mature cytotoxicT-cells because ALCL typicallyexpresses perforin and granzyme B.19

Dr Penberthy

Dr Belyea, can you please discuss theultimate diagnosis and course?

FIGURE 4PET-CT fluorodeoxyglucose uptake study. A, False color view. B, Black and white view. Note high-intensity uptake in abdominal lymph nodes.

FIGURE 5Histology and immunohistochemical studies. A,Hemotoxilin and eosin stain. The micrographshows numerous large atypical cells againsta background of small, mature lymphocytes.The atypical cells have markedly irregular nu-clear contours, unevenly distributed chromatin,prominent nucleoli, and abundant eosinophiliccytoplasm, with apoptotic bodies and mitoticfigures. B, Immunohistochemical staining forCD30 (or tumor necrosis factor receptor su-perfamily member 8), activated cell tumormarker for Hodgkin’s lymphoma and ALCL, andthe target for brentuximab. C, Immunohisto-chemical staining for ALK. The atypical cellsstain positive for ALK, the definitive marker forALCL.

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Dr Belyea

Patients with ALCL can have unusual,inflammatory presentations. Theyoften have a waxing and waningcourse, delaying diagnosis. Mostpatients present at advanced stages,with primary abdominal ormediastinal disease.20 They oftenhave systemic signs and symptoms(fever, weight loss, and night sweats)and frequently have extranodaldisease in skin, liver, lung, soft tissues,and bone.21 These inflammatorysymptoms can be troubling yetnonspecific. Inflammatory symptomsmay suggest to clinicians thata patient’s complaints havea functional component, as was theinitial case with our patient. It isimportant to remember that whenpatients feel ill, especially with anundiagnosed disease, they experiencegreat stress. Confusing disease-related stresses with functionaldisorders can distract from theessential diagnostic pursuit. A furtherconfounder for our patient is that sheexperienced significant, althoughtemporary, symptom improvementwith NSAIDs. These medications werelikely treating systemic inflammatoryprocesses that accompany ALCL. Ourpatient’s primary care physician alsotreated her with steroids fora presumed allergic reaction toamoxicillin prescribed by her dentist.Steroids likely provided someminimally effective antilymphomatherapy, further complicating ourinitial diagnostic efforts. Animportant lesson from this case isthat treating ill patients who do nothave a clear diagnosis with potentantiinflammatory agents, notablyincluding steroids but also high-potency NSAIDS, can mask importantaspects of the disease, complicatingdiagnosis and therapy. This is perhapsmost important when contemplatingsteroid treatment of patients forwhom neoplastic diseases are in thedifferential. We, and the patient, arefortunate in that we withheldadditional steroids for possible SJIA

and fortunate also in that diagnostichypotheses and managementsuggestions from the several differentservices were offered in a highlycollegial atmosphere, whichcontributed immeasurably to makingthe final diagnosis. In retrospect, weshould have also paid more attentionto her single, nontender, mobile,cervical lymph node. Her parents feltit decreased in size after antibiotics,but it more likely decreased aftersteroids.

ALCL is a non-Hodgkin’s lymphomasubtype, accounting for ∼10% to20% of pediatric lymphomas.22 ALCLis considered a peripheral T-celllymphoma; however, null-cell disease(cells not expressing of T- or B-cellmarkers) occurs. Most patients withALCL have a translocation involvingthe ALK gene and the nucleophosmingene, t(2;5)(p23;q35); indeed, .90%of patients with ALCL are positive forALK in children and young adults.23

This translocation yields aberrantALK expression, which drives cellproliferation and survival21 andyields ALK immunohistochemicalstaining, which is pathognomonic. Allsystemic ALCL cases express CD30.Our patient’s cells were positive forboth CD30 and ALK, establishing thediagnosis.

Before effective chemotherapyregimens, ALCL was uniformly fatal.Various regimens have been used totreat ALCL with good success.20

Current regimens involve 6 cycles ofalternating agents, typically includingdexamethasone, ifosfamide,cyclophosphamide, methotrexate,etoposide, cytarabine, anddoxorubicin. Typical side effectsinclude neutropenia, mucositis,nausea and/or vomiting, and anemia.Long-term event-free survival is∼70% to 75%.24 For patients whoselymphoma is not controlled by initialchemotherapy, salvage rates are high,especially with the addition ofcrizotinib,25 a small moleculeinhibitor of ALK, and brentuximab,26

a CD30-targeted antibody conjugatedto an antitubulin agent. Current trialsincorporate these drugs into first-linetherapy, which will likely changetreatment paradigms for this diseaseand further improve long-termoutcomes.20

Our patient had no involvement ofher bone marrow or central nervoussystem, and she had no skin lesions.Her signs and symptoms resolvedquickly with chemotherapy, witha complete response after 2chemotherapy cycles. She hascompleted treatment and remainssymptom free.

ACKNOWLEDGMENTS

We thank our patient and her familyfor enabling us to share in her careand present this diagnostic dilemmacase to the pediatric community andthank all our other colleagues whohelped in the diagnosis andmanagement of our patient.

ABBREVIATIONS

ALCL: anaplastic large-celllymphoma

ALK: anaplastic lymphoma kinaseALT: alanine aminotransferaseAST: aspartate aminotransferaseCRP: C-reactive proteinCT: computed tomographyED: emergency departmentESR: erythrocyte

sedimentation rateFGID: functional gastrointestinal

disorderFNA: fine-needle aspirationGI: gastrointestinalIBD: inflammatory bowel diseaseIgA: immunoglobulin AIV: intravenousLDH: lactate dehydrogenaseNSAID: nonsteroidal

antiinflammatory drugPET: positron emission

tomographySJIA: systemic juvenile idiopathic

arthritis

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FUNDING: Dr Penberthy’s studies were supported by a grant from the National Institutes of Health (T32 GM007267, the Medical Scientist Training Program to the

University of Virginia). Dr. Zeichner’s work was supported by by the Pendleton Pediatric Infectious Disease Laboratory, University of Virginia. Funded by the National

Institutes of Health (NIH).

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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Lancaster, Brian Belyea and Steven L. ZeichnerKristen Penberthy, Joanne Mendoza, Michael Mendoza, Grant Harrison, Luke

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