Abdominal Pain and Intermittent Fevers in a 16-Year-Old Girl

A 16-year-old girl presented with fevers and abdominal pain. She had histories of exposure to possible infections, lymphadenopathy, and elevated transaminases and inflammatory markers.

Abstract

A 16-year-old girl presented to the emergency department with intermittent fevers and worsening abdominal pain of 5 weeks duration. She had a history of travel to a less developed country and exposure to possible infectious diseases. Abdominal imaging and blood tests revealed diffuse mesenteric lymphadenopathy, elevated transaminases, and elevation of inflammatory markers. Gastroesophageal and colon endoscopies revealed gastric ulcers, and the patient was discharged with a presumptive diagnosis of systemic juvenile idiopathic arthritis given the lymphadenopathy seen on imaging, serositis, sacroiliac joint stiffness noted on physical examination, and pain relief with celecoxib. She presented again 4 days later with worsening abdominal tenderness, elevated transaminases, and new-onset abdominal distention. Tissue biopsy yielded the diagnosis and directed appropriate treatment.

Case History With Subspecialty Input

Dr Penberthy, Medical Scientist Training Program Fourth-Year Clinical Medical Student, Moderator

A 16-year-old girl with a 5-week history of abdominal pain presented to our emergency department (ED) with intermittent fevers, up to 38.3°C, and worsening abdominal pain. Her fevers had no clear pattern in timing or duration. Her abdominal pain was sharp, constant, at the left upper quadrant and epigastric regions, and relieved by nonsteroidal antiinflammatory drugs (NSAIDs) and acetaminophen. She denied having constipation, diarrhea, dark or bloody stools, emesis, or appetite changes. She reported an enlarged, tender right-sided cervical lymph node that appeared 2 to 3 months before presentation. Her last bowel movement was 1 day and her last menstrual period was 2 weeks before presentation. She denied sexual activity, drug, or alcohol use. She attended summer camp in Pennsylvania 1 week before presentation where she swam in a lake and walked in the woods.

Her past medical history included physician-diagnosed, appropriately treated Lyme disease with Bell’s palsy 2 years earlier. She reported intermittent joint pain and muscle aches since. She had bilateral upper third molar extractions 3 weeks before presentation. Her oral surgeon prescribed prophylactic amoxicillin, considered standard of care by the oral surgeon; she developed a rash after 9 days of amoxicillin. Her pediatrician prescribed prednisone for 9 days for a presumed allergic reaction 12 days before presentation, after which her rash resolved, abdominal pain improved, and the neck lymph node subjectively decreased in size according to her parents.

Several physicians saw our patient for abdominal pain before her presentation to our ED. Her pediatrician tested for Helicobacter pylori, with a negative result, and prescribed pantoprazole. Three days before presenting to us, she went to another ED for abdominal pain. They performed an abdominal computed tomography (CT) scan, which revealed diffuse lymphadenopathy, peritoneal free fluid, and stool in the rectal vault. Although the patient had not complained of constipation, given the findings of stool in the rectal vault, the ED recommended a trial of polyethylene glycol for constipation and also prescribed dicyclomine. She was given intravenous (IV) ketorolac.

In our ED, our patient was in significant distress because of abdominal pain. Her vital signs were as follows: blood pressure 105/69 mm Hg, heart rate 88 beats per minute, respiratory rate 20 beats per minute, and temperature of 35.8°C. Her examination was remarkable for a single 2-cm diameter, nontender, not-fixed right cervical lymph node. The examination was also remarkable for abdominal tenderness and guarding, without rebound, over the left upper quadrant, left lower quadrant, and epigastrium. The remainder of her examination was unremarkable. Her initial laboratories (Table 1) were notable for an aspartate aminotransferase (AST) of 96 U/L, an alanine aminotransferase (ALT) of 106 U/L, an erythrocyte sedimentation rate (ESR) of 55 mm/hour, and a C-reactive protein (CRP) of 5.6 mg/dL. The ED physicians were concerned that the elevated transaminases might represent acetaminophen toxicity, but an acetaminophen level was not elevated. Her heterophile antibody test result was negative. She was given ketorolac, which provided pain relief, and admitted to the general pediatrics hospitalist service for further workup.

TABLE 1.

Laboratory Tests Obtained on Admission

Test	Value	Reference Range
WBC, k/μL	6.17	4.40–8.10
RBC, M/μL	4.62	4.20–5.20
Hemoglobin, g/dL	12.3	12.0–16.0
Hematocrit, %	38.1	35.0–47.0
MCV, fL	82.5	83.0–95.0
MCH, pg	26.6	28.0–32.0
MCHC, g/dL	32.3	32.0–36.0
RDW, %	13	11.0–14.0
MPV, fL	10	9.0–12.0
Platelets k/μL	255	150–450
Lymphocytes, %	20.7	15.0–45.0
Lymphocytes, k/μL	1.28	1.40–3.30
Monocytes, %	10.4	2.0–12.0
Monocytes, k/μL	0.64	0.00–1.00
Eosinophils, %	4.5	0.0–6.0
Eosinophils, k/μL	0.28	0.00–0.60
Basophils, %	0.2	0.0–2.0
Basophils, k/μL	0.01	0.00–0.20
Neutrophils, %	64.2	47.0–82.0
Neutrophils, k/μL	3.96	1.80–8.00
Sodium, mmol/L	138	136–145
Potassium, mmol/L	4.2	3.4–4.8
Chloride, mmol/L	101	98–107
co2, mmol/L	25	20–28
BUN, mg/dL	8	8–21
Creatinine, mg/dL	0.7	0.6–0.9
Glucose, mg/dL	86	74–99
Calcium, mg/dL	10.1	8.5–10.5
Total protein, g/dL	7.2	6.0–8.0
Albumin, g/dL	3.8	3.2–5.2
Total bilirubin, mg/dL	0.4	0.3–1.2
Alkaline phosphatase, U/L	82	40–150
AST, U/L	96	<35
ALT, U/L	106	<55
IgA, mg/dL	198.2	68.0–378.0
CRP, mg/dL	5.6	<0.5
ESR	55	0–30 mm/h
Acetaminophen level, μg/mL	14	Therapeutic Range: 10–20
Color, urine	Yellow	Yellow
Appearance, urine	Clear	Clear
Specific gravity, urine	1.013	1.005–1.030
pH, urine	7	5.0–8.0
Protein, urine	Negative	Negative
Glucose, urine	Negative	Negative
Ketone, urine	Negative	Negative
Bilirubin, urine	Negative	Negative
Blood, urine	Negative	Negative
Nitrite, urine	Negative	Negative
Urobilinogen, EU	0.2	0.2–1.0
Leukocyte esterase	Negative	Negative
WBC urine, cells per HPF	Rare	<3–5
RBC urine, cells per HPF	Negative	<3–5
Cast urine, casts per LPF	Negative	Negative
Epithelial cells urine, cells per HPF	Rare	Negative
Bacteria urine	Negative	Negative
Pregnancy 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.

Dr J. Mendoza, what did the general pediatric team think?

Dr J. Mendoza, Attending Physician, Pediatric Hospitalist Service

Abdominal pain in a postpubertal girl is common, with a wide differential diagnosis. Our patient had worsening, multiple-quadrant abdominal pain. We had concerns about her constipation; abdominal, retroperitoneal, and cervical lymphadenopathy; fevers and chills; frequent use of acetaminophen and ibuprofen with some possibly NSAID-induced gastritis; and elevated inflammatory markers. Evaluating which symptoms might be disease-related and which might be iatrogenic was challenging. Indolent infectious disease; gastrointestinal (GI) disease due to inflammatory bowel disease (IBD), gluten enteropathy, or sensitivity to galactose-α-1,3-galactose; and an oncologic process were on our differential. However, because there was not an immediately clear etiology, and because she evidenced considerable emotional distress, we also considered functional causes. We addressed her comfort while simultaneously pursuing a diagnosis.

We treated our patient with dioctyl sodium sulfosuccinate, polyethylene glycol 3350, famotidine, and ondansetron. We continued treatment with NSAIDs while recognizing their potential complications. We obtained a complete blood count with differential, a complete metabolic panel, lipase, lactate dehydrogenase (LDH), urinalysis, ESR, CRP, immunoglobulin A (IgA), transglutaminase IgA, deaminated gliadin IgA, immunoglobulin E–α-1,3 galactose, urinalysis with microscopy, acetaminophen level, 2-view chest radiograph, and requested that our radiologist read her outside of CT scan. Table 1 shows her initial laboratory results. We consulted the Divisions of Gastroenterology and Hepatology, Pediatric Infectious Disease, and Hematology and Oncology.

Dr Penberthy

Dr Lancaster, what did the initial imaging studies reveal?

Dr Lancaster, Department of Radiology

The initial CT scan revealed multiple enlarged mesenteric and retroperitoneal lymph nodes in the abdomen, with small volume ascites in the abdomen and pelvis (Fig 1). At this point, the differential diagnosis was broad,^1–4 including infection, particularly those resulting in granulomatous reactive lymphadenopathy (tuberculosis or atypical mycobacteria, cat scratch disease, fungal infections), Epstein-Barr virus, systemic lupus erythematosus, sarcoidosis, systemic juvenile idiopathic arthritis (SJIA), Langerhans cell histiocytosis (histiocytosis X), HIV, autoimmune lymphoproliferative disease (lymphoproliferation due to genetic causes would be unlikely in a teenager), lymphoma (Hodgkin’s or non-Hodgkin’s), or another malignancy.

FIGURE 1.

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

Dr Penberthy

Dr M. Mendoza, many of our patient’s signs and symptoms were GI. What were the thoughts of the gastroenterology service?

Dr M. Mendoza, Division of Pediatric Gastroenterology and Nutrition

Although we considered IBD, this patient had few specific symptoms pointing toward IBD. Our patient had complaints of epigastric abdominal pain, worsening over the previous 3 months, but little else was characteristic of IBD. She had laboratory findings suggestive of a chronic inflammatory process, that is, an elevated ESR, but this is nonspecific. Our patient’s serum albumin level was 3.8 g/dL; it is suggested in some data that albumin of <4 may indicate mild or early IBD.⁵ It is also possible that gastric ulcer disease might result in abdominal lymphadenopathy.

Because of an absence of diagnostic laboratory findings, we also considered that she might have a functional gastrointestinal disorder (FGID). FGIDs are a group of disorders classified by symptoms related to any combination of a disturbance of GI motility, visceral hypersensitivity, altered mucosal and immune function, altered gut microbiota, and altered central nervous system processing. Using the Rome IV criteria for FGIDs, our patient most appropriately fit with a diagnosis of epigastric pain syndrome,^6,7 which can be treated with cyproheptadine.⁸ Epigastric pain syndrome is characterized by epigastric pain and burning severe enough to impact on usual activities.

Dr Penberthy

Dr Zeichner, what were the infectious diseases considerations among this patient’s potential diagnoses?

Dr Zeichner, Division of Pediatric Infectious Diseases

When we first interviewed the patient and her family, we learned there were many potential exposures, for example, the patient’s summer camp. However, with additional interviewing, we learned that our patient, who has family in Ecuador, took 3 trips there in the preceding 2 years. In Ecuador, the family stays in homes on the outskirts of Quito and at a family farm near Santo Domingo, an area with endemic Chagas disease.⁹ When shown a photograph of a reduviid bug (the vector for Trypanosoma cruzi), the family observed that “we saw these all the time.” The farm raises cattle, horses, and poultry, although the patient did not take part in the farm animal activities. The family reported that there are bats in the area. The family visited an “ecolodge” on an Amazon tributary and swam in rivers and hot springs. They drank bottled water while in the country. The patient typically ate shrimp, fish, pork, and beef. All meat was reportedly well cooked. The patient consumed local cheese and milk of unknown pasteurization status. In Ecuador, she experienced no diarrhea.

Given the extensive exposure history and the possibility that infectious diseases could produce symptoms consistent with the patient’s presentation and clinical course,^10,11 we constructed a large infectious differential diagnosis, although none of the diseases we considered were completely consistent with the presentation, and the presentation was not consistent with the common, acute infectious disorders of returning travelers.^12,13 We considered Epstein-Barr virus and cytomegalovirus infections, with the patient’s lymphadenopathy. Given both the fevers and the lymphadenopathy in the context of her travel, we were concerned about the possibility of tuberculosis. Among other bacterial infections, we were most concerned for chronic zoonoses. Among chronic parasitic diseases, we considered trichinella, because of her meat consumption and findings of elevated serum LDH, and Chagas disease, although the lack of eosinophilia would weigh against those diagnoses. We recommended several studies to rule out possible infectious causes for her disease.

Dr Penberthy

Dr Belyea, can you please discuss how the presentation and initial findings might support an oncologic diagnosis?

Dr Belyea, Division of Pediatric Hematology and Oncology

When we first met this patient, we were impressed by her abdominal pain. We reviewed her CT scan with radiology. Although lymphoma is on the differential of a patient with mesenteric lymphadenopathy, 1 or 2 large masses is more typical versus large numbers of mesenteric lymph nodes, which were all slightly larger than normal. Her imaging showed significant inflammation with ascites and stranding, more consistent with an inflammatory process. Finally, her remarkable improvement with NSAIDs is not typical of lymphoma and is more suggestive of a rheumatologic or inflammatory disease. A definitive diagnosis of malignancy can only be achieved by tissue biopsy. Biopsy of her abdominal nodes was not without risk, and because other conditions were possible (SJIA, sarcoidosis, gastric ulcers, and possible infectious etiologies), we recommended close monitoring with a plan to repeat imaging and reconsider biopsy as her symptoms evolved.

Dr Penberthy

Dr J. Mendoza, can you please discuss some of the ongoing management challenges during hospitalization, particularly pain management, and findings that complicated the diagnosis?

Dr J. Mendoza

During admission, the main concern was pain control. She received ketorolac with good analgesic effect, but this was not a long-term solution. Her H2-blocker was changed to a proton pump inhibitor. Carafate was added. When she lost her IV line, we switched to oral ibuprofen and then acetaminophen, with cyproheptadine added. Pain control was insufficient, so the anesthesia pain team was consulted, and she was given gabapentin.

Dr Penberthy

Dr M. Mendoza, as her symptoms continued and there was not yet a definitive diagnosis, her physicians came to consider a primary GI process. The GI service performed endoscopic examinations. Can you please comment?

Dr M. Mendoza

Although nonspecific, her chronic symptoms, albumin of <4, and elevated inflammatory markers prompted an esophagogastroduodenoscopy and colonoscopy with biopsies to evaluate for IBD (Fig 2). At endoscopy, she was noted to have well-defined antral ulcers; in addition, colonoscopy revealed Enterobius vermicularis (pinworm) infestation (Supplemental Information), but no evidence for IBD. She was therefore started on high-dose IV acid suppression and treatment with 400 mg of albendazole.

FIGURE 2.

Upper endoscopy. The image shows a gastric ulcer from the upper endoscopy.

We believed that NSAIDs were the primary cause of her ulcers. The incidence of GI ulcers in the setting of chronic NSAID use is reported to be as high as 25%.¹⁴

Pinworm is the most common worm infection in the United States, typically presenting with perianal itching. Diagnosis is made by direct visualization of eggs by using a tape test or direct worm visualization. Stool examination is not recommended; there are no serological tests. Treatment is a single dose of an antihelminthic, with repeat treatment in 2 weeks, and treatment of all household members.¹⁵

Dr Penberthy

Dr Zeichner, did the infectious disease service consider the finding of pinworms on endoscopy significant?

Dr Zeichner

Although we found the endoscopy videos intriguing, we did not believe that pinworms caused the complaints. There are isolated case reports of pinworms observed on endoscopy,¹⁶ and pinworms have been associated with diseases like appendicitis, IBD, or diverticulitis, although these associations may be incidental.¹⁷

Although our index of suspicion for zoonosis and other infectious diseases was not high, even with the exposure history, absent of any other definitive diagnosis, we thought it was worthwhile to search broadly. The infectious workup was unrevealing. Tables 2 and 3 summarize the results. We did not believe that the result for tularemia was significant; that diagnosis would not have been consistent with her clinical course. We concluded an infectious etiology was unlikely.

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 bands detected	≥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 eggs detected	NA	Stool ova and parasite examination otherwise negative
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.

TABLE 3.

Laboratory Tests Obtained Subsequently

Test	Value	Reference Range
WBC, k/μL	8.43	4.40–8.10
RBC, M/μL	4.63	4.20–5.20
Hemoglobin, g/dL	11.5	12.0–16.0
Hematocrit, %	36.1	35.0–47.0
MCV, fL	78	83.0–95.0
MCH, pg	24.8	28.0–32.0
MCHC, g/dL	31.9	32.0–36.0
RDW, %	14.3	11.0–14.0
MPV, fL	10.2	9.0–12.0
Platelets k/μL	425	150–450
Lymphocytes, %	12.2	15.0–45.0
Lymphocytes, k/μL	1.03	1.40–3.30
Monocytes, %	8.3	2.0–12.0
Monocytes, k/μL	0.70	0.00–1.00
Eosinophils, %	0.5	0.0–6.0
Eosinophils, k/μL	0.04	0.00–0.60
Basophils, %	0.2	0.0–2.0
Basophils, k/μL	0.02	0.00–0.20
Neutrophils, %	78.8	47.0–82.0
Neutrophils, k/μL	7.19	1.80–8.00
Sodium, mmol/L	132	136–145
Potassium, mmol/L	3.8	3.4–4.8
Chloride, mmol/L	96	98–107
co2, mmol/L	28	20–28
BUN, mg/dL	8	8–21
Creatinine, mg/dL	0.6	0.6–0.9
Glucose, mg/dL	112	74–99
Calcium, mg/dL	9.8	8.5–10.5
Total protein, g/dL	6.7	6.0–8.0
Albumin, g/dL	3.5	3.2–5.2
Total bilirubin, mg/dL	3.1	0.3–1.2
Alkaline phosphatase, U/L	389	40–150
AST, U/L	218	<35
ALT, U/L	474	<55
LDH, U/L	422	127–287
GGT, U/L	366	<38
Lipase, U/L	222	8–78
Color, urine	Orange	Yellow
Appearance, urine	Cloudy	Clear
Specific gravity urine	1.031	1.005–1.030
pH urine	8.0	5.0–8.0
Protein, urine	2+	Negative
Glucose, urine	Negative	Negative
Ketone, urine	Large	Negative
Bilirubin, urine	Moderate	Negative
Blood, urine	Negative	Negative
Nitrite, urine	Positive	Negative
Urobilinogen, EU	1.0	0.2–1.0
Leukocytes esterase	Small	Negative
WBC urine, cells per HPF	3–5	<3–5
RBC urine, cells per HPF	Rare	<3–5
Epithelial cells urine, cells per HPF	Occasional	Negative
Bacteria urine	Occasional	Negative

co₂, carbon dioxide; EU, Ehrlich unit; GGT, γ-glutamyltransferase; HPF, high-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.

Dr Penberthy

Dr J. Mendoza, please describe the hospital course and diagnostic considerations after endoscopy?

Dr J. Mendoza

She was assessed by physical and occupational therapy. They noticed irregular posture and were concerned about stiffness of her sacroiliac joints, which, together with the other signs, symptoms, and imaging studies indicating diffuse adenopathy, led to the addition of SJIA to the differential. Pediatric rheumatology was consulted because SJIA can present with fevers, serositis, and lymphadenopathy without painful joints. Rheumatology considered recommending a lymph node biopsy but felt that the yield was low in SJIA. The patient was discharged with a working diagnosis of SJIA after the patient achieved significant relief on a trial of celecoxib.

Dr Penberthy

Four days after discharge, the patient presented to the ED with abdominal pain and temperatures up to 39.4°C. She complained of nausea, emesis, night sweats, dark urine, and abdominal distention. Her parents reported that she had been compliant with her celecoxib, gabapentin, and proton pump inhibitor. Given her equivocal tularemia titer, she was given a prescription for ciprofloxacin on discharge, but the family elected not to fill it.

The patient’s examination at readmission revealed no subjective change in cervical lymphadenopathy but was remarkable for abdominal distention and diffuse tenderness, both new from her previous admission. She had persistent elevation of LDH (422), worsening hepatitis, with increasing elevation of liver enzymes (ALT 474 U/L and AST 218 U/L), with a newly elevated total bilirubin (3.1 mg/dL), alkaline phosphatase (389 U/L), γ-glutamyltransferase (366 U/L), and lipase (222 U/L). A right upper quadrant ultrasound revealed dilation of her biliary tree in the absence of gallstones. A repeat CT scan of her abdomen was performed and she was admitted.

Dr Lancaster, can you please discuss the additional imaging studies?

Dr Lancaster

On her second CT scan, 17 days after her initial study, her lymphadenopathy had progressed, with dramatically increased ascites. Our assessment was that this could either have been because of an infectious or inflammatory process because those are more likely to show rapid changes or because of a lymphoma (Fig 3).

FIGURE 3.

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

Dr Penberthy

Dr J. Mendoza, what were your thoughts about the changes in the patient’s clinical status since discharge?

Dr J. Mendoza

With the patient’s worsening abdominal lymphadenopathy and new ascites, our concern for malignancy increased. The team decided not to proceed with steroid treatment of possible SJIA.

Dr Penberthy

Dr Belyea, can you please discuss your evolving approach?

Dr Belyea

Her second CT scan led us in oncology to increasingly suspect a malignancy. There was discussion with the primary team about whether to start steroids. Steroids would have partially treated a lymphoma, confusing and/or delaying that diagnosis. We recommended additional imaging studies: a positron emission tomography (PET)–CT examination. The PET-CT would help determine if the lymphadenopathy was reactive or represented a malignancy, in which case the lymph nodes would appear hypermetabolic, particularly because we had ruled out a large number of potential infectious causes for the lymphadenopathy. We believed that the PET-CT would also help identify sites of disease that might be more amenable to biopsy than diffuse abdominal lymphadenopathy. We also recommended following serial laboratory values.

Dr Lancaster

We performed a fludeoxyglucose PET-CT 2 days after her second CT scan (Fig 4), which was remarkable for intense tracer uptake in multiple abdominal lymph nodes and in a few neck and pelvic lymph nodes. Lymph node uptake that intense strongly suggested malignancy and/or lymphoma and is unusual in infection. Although sarcoidosis can have intense uptake, sarcoidosis is rare in children and does not show the rapid changes observed.

FIGURE 4.

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

Dr Belyea

From the oncological viewpoint, the PET-CT examinations revealing hypermetabolic right cervical and abdominal lymph nodes were concerning for lymphoma, but a tissue diagnosis was still needed. The most rapidly available way to safely obtain tissue was through interventional radiology, done under sedation and local anesthesia. The right cervical node was accessible for fine-needle aspiration (FNA) and core biopsy, and we obtained those. The FNA suggested a high-grade malignant neoplasm. However, the needle core biopsies did not contain the neoplasm seen on FNA, and a definitive diagnosis could not be made. After this procedure, her cervical node decreased significantly in size and was no longer palpable. We considered an excisional node biopsy, but given the nondiagnostic core sample and the decreasing size of this node, we were worried that an excisional node biopsy still might not result in a definitive diagnosis and would delay her workup and ultimate therapy further. Therefore, we requested a surgical consult for a biopsy of an abdominal lymph node. Although the FNA suggested a malignant neoplasm, given the wide possible differential, we felt that obtaining tissue would offer the best opportunity to make a definitive diagnosis. Our surgeon colleagues were concerned about the inflammation in her abdomen and the possibility of poor wound healing and suggested paracentesis before a more invasive procedure. Therefore, we proceeded with paracentesis to obtain ascites cells. We obtained 1 L of fluid, with improvement in the patient’s comfort. We examined the fluid with flow cytometry, cytopathology, bacterial Gram-stain and culture, fungal culture, acid-fast bacterial culture, LDH, protein, and lipase.

Dr Penberthy

Dr Harrison, can you please discuss your pathologic findings?

Dr Harrison, Department of Pathology

We processed 70 mL of yellow paracentesis fluid into a paraffin cell block. Microscopic examination revealed numerous large atypical cells in a background of small mature lymphocytes (Fig 5A). The atypical cells had markedly irregular nuclear contours, unevenly distributed chromatin, prominent nucleoli, and abundant eosinophilic cytoplasm, with apoptotic bodies and mitotic figures. The morphologic differential diagnosis included anaplastic large-cell lymphoma (ALCL) and malignant melanoma. Immunohistochemical stains revealed cells negative for S100, evidence against the diagnosis of malignant melanoma. Atypical cells were positive for the leukocyte common antigen (CD45), confirming the diagnosis of large-cell lymphoma. CD3 was positive and CD20 was negative, confirming a T-cell–derived neoplasm. Finally, the cells were positive for CD2, CD5, CD30, anaplastic lymphoma kinase (ALK), perforin, and granzyme B, confirming the diagnosis of ALK + ALCL (Fig 5 B and C).

FIGURE 5.

Histology and immunohistochemical studies. A, Hemotoxilin and eosin stain. The micrograph shows numerous large atypical cells against a background of small, mature lymphocytes. The atypical cells have markedly irregular nuclear contours, unevenly distributed chromatin, prominent nucleoli, and abundant eosinophilic cytoplasm, with apoptotic bodies and mitotic figures. B, Immunohistochemical staining for CD30 (or tumor necrosis factor receptor superfamily member 8), activated cell tumor marker for Hodgkin’s lymphoma and ALCL, and the target for brentuximab. C, Immunohistochemical staining for ALK. The atypical cells stain positive for ALK, the definitive marker for ALCL.

ALK + ALCLs typically have a variable proportion of cells with horseshoe-shaped or kidney-shaped nuclei. Some have nuclear pseudoinclusions. Although morphology helps form a differential diagnosis, a chromosomal translocation involving the ALK gene and expression of ALK protein and CD30 defines ALCL.¹⁸ Other immunohistochemical stains are helpful: ALCLs often retain CD2 and CD5 expression. ALCL cells share some features of mature cytotoxic T-cells because ALCL typically expresses perforin and granzyme B.¹⁹

Dr Penberthy

Dr Belyea, can you please discuss the ultimate diagnosis and course?

Dr Belyea

Patients with ALCL can have unusual, inflammatory presentations. They often have a waxing and waning course, delaying diagnosis. Most patients present at advanced stages, with primary abdominal or mediastinal disease.²⁰ They often have systemic signs and symptoms (fever, weight loss, and night sweats) and frequently have extranodal disease in skin, liver, lung, soft tissues, and bone.²¹ These inflammatory symptoms can be troubling yet nonspecific. Inflammatory symptoms may suggest to clinicians that a patient’s complaints have a functional component, as was the initial case with our patient. It is important to remember that when patients feel ill, especially with an undiagnosed disease, they experience great stress. Confusing disease-related stresses with functional disorders can distract from the essential diagnostic pursuit. A further confounder for our patient is that she experienced significant, although temporary, symptom improvement with NSAIDs. These medications were likely treating systemic inflammatory processes that accompany ALCL. Our patient’s primary care physician also treated her with steroids for a presumed allergic reaction to amoxicillin prescribed by her dentist. Steroids likely provided some minimally effective antilymphoma therapy, further complicating our initial diagnostic efforts. An important lesson from this case is that treating ill patients who do not have a clear diagnosis with potent antiinflammatory agents, notably including steroids but also high-potency NSAIDS, can mask important aspects of the disease, complicating diagnosis and therapy. This is perhaps most important when contemplating steroid treatment of patients for whom neoplastic diseases are in the differential. We, and the patient, are fortunate in that we withheld additional steroids for possible SJIA and fortunate also in that diagnostic hypotheses and management suggestions from the several different services were offered in a highly collegial atmosphere, which contributed immeasurably to making the final diagnosis. In retrospect, we should have also paid more attention to her single, nontender, mobile, cervical lymph node. Her parents felt it decreased in size after antibiotics, but it more likely decreased after steroids.

ALCL is a non-Hodgkin’s lymphoma subtype, accounting for ∼10% to 20% of pediatric lymphomas.²² ALCL is considered a peripheral T-cell lymphoma; however, null-cell disease (cells not expressing of T- or B-cell markers) occurs. Most patients with ALCL have a translocation involving the ALK gene and the nucleophosmin gene, t(2;5)(p23;q35); indeed, >90% of patients with ALCL are positive for ALK in children and young adults.²³ This translocation yields aberrant ALK expression, which drives cell proliferation and survival²¹ and yields ALK immunohistochemical staining, which is pathognomonic. All systemic ALCL cases express CD30. Our patient’s cells were positive for both CD30 and ALK, establishing the diagnosis.

Before effective chemotherapy regimens, ALCL was uniformly fatal. Various regimens have been used to treat ALCL with good success.²⁰ Current regimens involve 6 cycles of alternating agents, typically including dexamethasone, ifosfamide, cyclophosphamide, methotrexate, etoposide, cytarabine, and doxorubicin. Typical side effects include neutropenia, mucositis, nausea and/or vomiting, and anemia. Long-term event-free survival is ∼70% to 75%.²⁴ For patients whose lymphoma is not controlled by initial chemotherapy, salvage rates are high, especially with the addition of crizotinib,²⁵ a small molecule inhibitor of ALK, and brentuximab,²⁶ a CD30-targeted antibody conjugated to an antitubulin agent. Current trials incorporate these drugs into first-line therapy, which will likely change treatment paradigms for this disease and further improve long-term outcomes.²⁰

Our patient had no involvement of her bone marrow or central nervous system, and she had no skin lesions. Her signs and symptoms resolved quickly with chemotherapy, with a complete response after 2 chemotherapy cycles. She has completed treatment and remains symptom free.

Glossary

ALCL

anaplastic large-cell lymphoma

ALK

anaplastic lymphoma kinase

ALT

alanine aminotransferase

AST

aspartate aminotransferase

CRP

C-reactive protein

CT

computed tomography

ED

emergency department

ESR

erythrocyte sedimentation rate

FGID

functional gastrointestinal disorder

FNA

fine-needle aspiration

GI

gastrointestinal

IBD

inflammatory bowel disease

IgA

immunoglobulin A

IV

intravenous

LDH

lactate dehydrogenase

NSAID

nonsteroidal antiinflammatory drug

PET

positron emission tomography

SJIA

systemic juvenile idiopathic arthritis