Case 11-2013 — A 4-Year-Old Boy with Fever and Abdominal Pain
Daniel P. Ryan, M.D., Alison M. Friedmann, M.D., Matthew D. Schmitz, M.D., and Russell J.H. Ryan, M.D.
N Engl J Med 2013; 368:1435-1444April 11, 2013DOI: 10.1056/NEJMcpc1209304
PRESENTATION OF CASE
Dr. Nicolas V. Currier (Pediatrics): A 4-year-old boy was admitted to this hospital because of fever and abdominal pain.
The night before admission, the patient awoke in the night, reported pain with urination, and urinated only in small quantities. The temperature was 37.8°C. His mother administered ibuprofen to him, and he returned to sleep. In the morning, he slept 3 hours longer than usual. During the morning, he had two episodes of nonbloody diarrhea. On examination later that day, his pediatrician palpated a mass in the abdomen. The patient was sent to the emergency department at another hospital.
The patient rated the pain at 4 on a scale of 0 to 10, with 10 indicating the most severe pain. On examination, he appeared pale. The temperature was 39.1°C, the blood pressure 106/62 mm Hg, the pulse 119 beats per minute, the respiratory rate 24 breaths per minute, and the oxygen saturation 98% while he was breathing ambient air. The weight was 17.5 kg. A mass, approximately 4 cm in diameter, was palpated in the right lower quadrant, and there was pain in the genital area on palpation. The remainder of the examination was normal. Urinalysis revealed 2+ ketones and 1+ blood, with 0 to 3 red cells per high-power field, and was otherwise normal. Ibuprofen in an oral suspension was administered. A radiograph of the abdomen showed a nonspecific bowel-gas pattern. Ultrasonography (Figure 1AFIGURE 1Imaging of the Abdomen (First Admission).) revealed a heterogeneous lobular mass (6 cm in diameter) in the pelvis. The patient was transferred to this hospital.
The patient's mother reported that, on the day of admission, his appetite was decreased and he refused solids. He had had eczema as an infant and had delayed speech. Medications included ibuprofen, acetaminophen, and a multivitamin. His immunizations were current. He had no known drug allergies. He lived with his mother and other relatives and did not attend day care. His brother had hypospadias, and his maternal grandfather had lymphoma.
On examination, the patient appeared well developed and in no distress. The temperature was 37.2°C, the blood pressure 103/53 mm Hg, the pulse 94 beats per minute, the respiratory rate 18 breaths per minute, and the oxygen saturation 99% while he was breathing ambient air. The abdomen was soft, without distention. A mass, 3 cm by 2 cm, was palpated in the right lower quadrant, which was tender to palpation, without guarding, rebound, or tap tenderness. The remainder of the examination was normal. Blood levels of glucose, total protein, albumin, globulin, amylase, and lactate dehydrogenase were normal, as were the results of tests of renal and liver function; other test results are shown in Table 1TABLE 1Laboratory Data..
Computed tomography (CT) of the abdomen and pelvis after the administration of contrast material revealed a heterogeneous, lobulated mass, 5.7 cm by 6.5 cm, in the pelvis (Figure 1B); a fat plane delineated the lesion from the bladder. The proximal appendix was visualized. CT-guided incision of the mass was performed, and approximately 10 ml of purulent fluid was aspirated; a drain was placed. Ampicillin, gentamicin, and metronidazole were administered. Gram's staining of the aspirate revealed abundant polymorphonuclear leukocytes, gram-negative and gram-positive rods, and moderate gram-positive cocci in pairs. A culture grew moderate Escherichia coli and abundant mixed anaerobic bacteria.
During the next 6 days, yellow serosanguineous fluid was recovered from the drain. Fever resolved on the third hospital day. A peripherally inserted central venous catheter was placed on the fifth day; the administration of piperacillin and tazobactam was begun, and other antibiotics were stopped. Results of laboratory tests are shown in Table 1. On the seventh day, the drain was flushed and small amounts of dark, bloody drainage were aspirated. The abdominal mass was no longer palpable. The patient was discharged on the eighth day, after removal of the drain, with a combination of piperacillin and tazobactam administered intravenously every 8 hours for 7 days and with supervision by a visiting nurse. The antibiotics were completed 16 days after presentation, and the central catheter was removed.
Seven days later, diarrhea and abdominal pain recurred. The next day, the patient returned to the other hospital. He rated the pain at 7 out of 10 and was unwilling to walk. On examination, the weight was 16.8 kg, the temperature 37.2°C, the blood pressure 112/67 mm Hg, the pulse 128 beats per minute, the respiratory rate 26 breaths per minute, and the oxygen saturation 97% while he was breathing ambient air. There was central abdominal distention and pain with palpation; gait was not tested. The remainder of the examination was normal. During the next 2 hours, the temperature rose to 39.1°C. Acetaminophen was administered rectally by suppository. The patient was transferred to this hospital and readmitted.
On examination, the temperature was 39.3°C, the blood pressure 112/62 mg Hg, and the pulse 140 beats per minute. Bowel sounds were normal; a nontender mass, approximately 12 cm by 15 cm, extended from the right lower quadrant past the midline. The remainder of the abdomen was soft, with mild tenderness surrounding the mass; there was erythema in the perianal area. Laboratory-test results are shown in Table 1. Vancomycin (one dose), metronidazole, gentamicin, and ampicillin were administered intravenously. Ultrasonography revealed a large heterogeneous mass, 8.4 cm by 10.8 cm by 7.1 cm, occupying the entire lower abdomen. CT of the abdomen and pelvis after the administration of intravenous and rectal contrast material revealed a heterogeneous mass, 8.2 cm by 10.7 cm by 8.7 cm, in the lower abdomen and pelvis, with compression of the ureters and mild bilateral hydronephrosis, as well as displacement of the sigmoid colon, partial obstruction of the descending colon, circumferential wall thickening of the descending and rectosigmoid colon, compression of the bladder, and multiple mesenteric and perirectal lymph nodes measuring up to 10 mm in diameter.
A diagnostic procedure was performed.
Dr. Daniel P. Ryan: I cared for this patient and am aware of the diagnosis. This 4-year-old boy initially presented with abdominal pain of approximately 1 day's duration, with a palpable mass on examination. May we see the initial imaging studies?
Dr. Matthew D. Schmitz: Radiographs of the abdomen were obtained at the other hospital with the patient in the supine and upright positions. These radiographs showed no definite abnormality and an essentially normal bowel-gas pattern. Focused ultrasonography performed at the other hospital (Figure 1A) revealed a large, heterogeneous, rounded mass in the right lower quadrant. The mass could not be seen to be arising from any specific normal abdominal structure.
After the patient's admission to this hospital, CT with the intravenous and oral administration of contrast material (Figure 1B) revealed that the mass was approximately 6 cm by 6 cm, contained fluid, and was clearly separated from the bladder by a fat plane. The mass was not seen to arise distinctly from any adjacent normal structure. The proximal appendix was seen, but not the distal portion. The remainder of the CT examination was normal.
Dr. Daniel Ryan: The initial clinical history and imaging studies suggested an infectious process, most likely perforating appendicitis, with an abscess and phlegmon in the lower abdomen and pelvis. However, a necrotic tumor could not be ruled out. The initial diagnostic test, performed by the interventional radiology service, was incision of the mass, which revealed that the mass was filled with purulent fluid. Aspiration was followed by placement of a drain in the cavity and cultures of the fluid, which grew enteric organisms.
Appendicitis with Perforation
In this patient with fever and no signs of diffuse peritonitis, the most likely cause of the large phlegmon and fluid collection seen on imaging studies is a perforated appendix. The risk of perforation is 2% or less among patients with appendicitis who have had untreated symptoms for less than 36 hours; the rate of perforation rises to approximately 5% if symptoms are left untreated for 36 hours or more.1 This child had speech delay, and the illness started during a holiday weekend, so the onset of symptoms may not have been recognized by his family, and the patient may have had a longer course than was evident by his history.
One option for initial treatment of this child who has possible perforating appendicitis and abscess is drainage with the use of a minimally invasive image-guided technique, followed by supportive care and the administration of antibiotics. Another option is immediate surgery to drain the abscess and remove the appendix. Treatment of a perforated appendix and an appendiceal abscess without immediate surgery, followed later by elective appendectomy, has a long record of good results2; the presence of diffuse peritonitis would preclude this approach. Up to 30% of patients who receive initial nonoperative treatment need surgery before the planned elective appendectomy, because of worsening clinical status or recurrence of severe symptoms after an initial period of improvement. For surgeons who proceed directly to surgery to drain the abscess and remove the appendix, the operations can be difficult because of the inflammation and infection. Surgery also carries the risk of spreading the infection throughout the abdominal cavity with the manipulation, leading to more problems with intraabdominal abscesses, adhesions, and bowel obstruction. In one randomized study involving children, early appendectomy was compared with initial nonoperative treatment followed by an appendectomy in 6 to 8 weeks (a so-called interval appendectomy). The study showed that the early operation was associated with less time away from normal activities and a lower adverse event rate than was the interval appendectomy.3
If early appendectomy is selected, the surgical approach could be laparoscopy with removal of the appendix, even in cases of complicated appendicitis,4 or the open technique. The surgical approach in cases of very inflamed appendixes may need to be changed from a laparoscopic to an open operation because of obliteration of the tissue planes or bleeding.
If an initial nonoperative approach is chosen, an area of controversy involves what to do next. Some authors advise performing an interval appendectomy, or removal of the appendix after the inflammation has resolved, usually between 4 and 12 weeks after the acute presentation. Other authors have suggested that the risk of recurrent appendicitis with observation is low enough to warrant continued observation and surgery only on those with symptoms. Unfortunately, most studies involve adults, and their applicability to children is not clear. One review and meta-analysis showed that 1.2% of patients (mostly adults) treated for an appendiceal mass or phlegmon had a malignant disease.5
The plan was for this patient to have an interval appendectomy a few weeks after his initial presentation. However, he presented with recurrent symptoms and an enlarging mass before his scheduled follow-up examination.
Dr. Schmitz: Ultrasonography of the abdomen performed on the second admission revealed a large, heterogeneous mass occupying essentially the entire lower abdomen. CT of the abdomen with the intravenous and rectal administration of contrast material (Figure 2FIGURE 2Imaging of the Abdomen (Second Admission).) showed an abdominal and pelvic mass measuring up to 10.7 cm in greatest dimension, with areas of central fluid. The mass caused partial obstruction of both ureters and severe compression of the urinary bladder (with resultant mild bilateral hydronephrosis), as well as partial obstruction of the descending colon. Multiple slightly enlarged mesenteric and perirectal lymph nodes were also seen.
Dr. Daniel Ryan: The imaging at this point did not suggest a recurrent abscess but instead revealed a large, solid mass with central necrosis. The differential diagnosis of a mass in the abdomen of a 5-year-old is very broad, and the imaging narrows the field of possibilities.
Abdominal Masses in Children
Trauma can cause a hematoma of the abdominal wall or psoas muscle that may present as a mass. Injury to other structures in the area with secondary infection may present as a tender mass. Usually there will be a history to suggest this cause, except perhaps in a case of nonaccidental trauma. There was no such history in this case. Congenital malformations may present as a mass in the abdomen. These could include a duplication of the gastrointestinal tract, lymphatic malformation, and renal malformation (e.g., an obstructed duplicated ureter or an ectopic kidney). Vascular malformations (hemangioma or lymphangioma) in this area are very unusual and have a distinct appearance on imaging.
Infection is probably the most common cause of abdominal masses in children. Examples of such masses are acute ileitis from infection or Crohn's disease, perforation of the bowel or appendix by a foreign body, or inflammation of a Meckel's diverticulum. Intussusception may present with a palpable mass, but patients usually have crampy abdominal pain. A primary psoas abscess is rare and usually is not associated with a palpable mass. By far the most common cause of a mass in the right lower quadrant in a child is acute appendicitis.
In this patient, because the imaging reveals a large, mainly solid mass that progressed in size over a period of just a few weeks, a neoplastic disease is most likely. In children, the most common intestinal neoplasms are lymphomas, principally Burkitt's lymphoma and diffuse large-B-cell lymphoma. Other primary bowel tumors, such as carcinoid tumors, adenocarcinomas, or sarcomas, are unusual. Tumors of the iliac crest, such as osteosarcoma or Ewing's sarcoma, can present as an abdominal mass, as can rhabdomyosarcoma of the abdominal wall or retroperitoneal muscles.Patients with neuroblastoma commonly present with a primary tumor in the abdomen, but tumors that arise outside the adrenal glands tend to occur in the midline, arising from the area of the aortic bifurcation; in this patient, the mass was in the right lower quadrant. Metastasis to the iliac nodes would be an unusual presentation in a child. Testicular tumors could be a source of metastasis to nodes in this area, but these tumors are usually readily apparent on physical examination and are more common in older children and young adults.
The very rapid growth of this lesion gives us a clue about the diagnosis. Burkitt's lymphoma has the shortest doubling time of cancers in humans and thus was our leading diagnosis. We proceeded with a biopsy and resection of the mass. At exploration, the mass involved the appendix but was mainly in the mesentery of the distal sigmoid colon and the proximal rectum. There was central necrosis but no residual abscess. We thought it best to remove as much of the possibly infected tumor as possible, because of the need for chemotherapy, and also to relieve the partial ureteral and colonic obstruction.
DR. DANIEL P. RYAN'S DIAGNOSIS
Malignant tumor of the appendix, most likely Burkitt's lymphoma, with appendiceal perforation and abscess.
Dr. Russell J.H. Ryan: The abdominal mass was removed in two parts. The first part included a partially necrotic tumor, 12 cm in greatest dimension, and the ligated stump of the proximal appendix. The second part included the remainder of the tumor, 5.5 cm in greatest dimension, as well as mesentery, a segment of sigmoid colon, and the distal appendiceal tip.
Microscopical evaluation revealed that the tumor was contiguous with the proximal and distal portions of the appendix, and sections through the middle portions of the tumor showed a necrotic appendix within the tumor (Figure 3AFIGURE 3Pathological Features of the Resected Abdominal Mass.). These findings suggested that the tumor arose from the midportion of the appendix. The tumor involved the mesentery and mesenteric lymph nodes and invaded the wall of the sigmoid colon, with focal projection into the lumen.
The tumor comprised sheets of medium-size lymphoid cells with scattered tingible-body macrophages (macrophages containing apoptotic cellular debris) that had abundant pale cytoplasm. This created a “starry sky” appearance (Figure 3B). The tumor cells were monomorphic, with a high nuclear-to-cytoplasmic ratio, cytoplasmic molding, coarse chromatin, inconspicuous nucleoli, and many mitotic figures (Figure 3C). Flow cytometry revealed a predominant population of CD19+ and CD20+ B cells that expressed CD10 but not CD23 or CD5 and had monotypic expression of lambda immunoglobulin light chain. Immunohistochemical analysis showed that the tumor cells were negative for terminal deoxynucleotidyl transferase, a marker of lymphoid precursor cells. The tumor cells had the immunophenotype of germinal-center B cells in that they were positive for CD10 and the transcription factor Bcl-6 but negative for the antiapoptotic protein Bcl-2. The Ki-67 proliferation index was greater than 90% (Figure 3D). The tumor cells were negative for Epstein–Barr virus (EBV)–encoded RNA by means of in situ hybridization. Cytogenetic analysis (Figure 3E) showed a balanced translocation involving the long arms of chromosomes 8 and 14, a feature consistent with involvement of the MYC oncogene at 8q24 and the immunoglobulin heavy-chain locus at 14q32. No other chromosomal abnormalities were identified. These morphologic, immunophenotypic, and cytogenetic findings are diagnostic of Burkitt's lymphoma.
Burkitt's lymphoma is an aggressive mature B-cell lymphoma that occurs in patients of all ages.The malignant cells resemble germinal-center B cells (centroblasts) in their morphologic features, immunophenotype,6 and gene-expression profile,7,8 although controversy remains about the identity of the true cell of origin.9,10 Burkitt's lymphoma occurs in three distinct epidemiologic clusters. Endemic Burkitt's lymphoma occurs in children living in geographically and climatologically defined regions of sub-Saharan Africa, presents most commonly in the jaw or facial bones, and is usually positive for EBV. This patient has the sporadic form of Burkitt's lymphoma, which occurs worldwide in children and adults. The disease often arises in abdominal organs, such as the gastrointestinal tract (in particular, the ileocecal region), kidneys, or ovaries, and is EBV-positive in only 30% of cases. Immunodeficiency-associated Burkitt's lymphoma is often seen in patients with the human immunodeficiency virus (HIV), frequently involves lymph nodes and bone marrow, and is EBV-positive in 25 to 40% of cases.
Nearly all cases of Burkitt's lymphoma have rearrangement of the MYC oncogene with the immunoglobulin heavy-chain (or, less often, the light-chain) locus, leading to up-regulation of MYCexpression by immunoglobulin enhancer elements. As in this case, pediatric Burkitt's lymphoma typically has a simple karyotype aside from the MYC translocation, in contrast to the heterogeneous and often complex alterations seen in diffuse large-B-cell lymphoma.
DISCUSSION OF MANAGEMENT
Dr. Alison M. Friedmann: In the United States, Burkitt's lymphoma accounts for 40 to 50% of pediatric non-Hodgkin's lymphomas.11 A small percentage of patients with Burkitt's lymphoma present as if they had acute leukemia, with extensive bone marrow and peripheral-blood involvement. This form of leukemia accounts for only 1 to 2% of cases of childhood acute lymphoblastic leukemia. More commonly, patients with Burkitt's lymphoma present either as this child did, with a large abdominal mass and abdominal pain and distention, or with intussusception of the small bowel related to lymphoma involving the terminal ileum. Although the initial finding of a periappendiceal abscess in this case was unusual, manifestation of Burkitt's lymphoma as appendicitis or periappendiceal abscess has been reported.12,13
Seven days after this patient was discharged with no palpable mass, he had an abdominal mass that was 10 cm in greatest dimension and caused ureteral and colonic obstruction. Such rapid growth is typical of Burkitt's lymphoma, which has a tumor doubling time of 12 to 24 hours and thus may constitute a true oncologic emergency. Patients such as this one need to be evaluated and treated urgently because of the risk of metabolic derangements, the tumor lysis syndrome, and organ compromise from massive intraabdominal disease. The first step is to establish a tissue diagnosis. The role of surgery is usually limited to procurement of a tissue sample that is adequate for making a definitive diagnosis, but sometimes more extensive surgery is indicated by the clinical presentation, such as in this case, or when there is intussusception.
Staging for a patient with Burkitt's lymphoma, such as this one, includes imaging of the involved sites (usually with CT for chest or abdominal involvement and magnetic resonance imaging for head and neck sites), chest radiography, and examination of the bone marrow and cerebrospinal fluid. In this patient, bone marrow aspiration and biopsy and lumbar puncture revealed no malignant cells. Blood tests were performed to assess tumor burden, organ function, and metabolic abnormalities. The tests included a complete blood count, tests of liver and renal function, testing for HIV infection, and measurement of levels of electrolytes, lactate dehydrogenase, and uric acid. The blood uric acid level was normal, and the lactate dehydrogenase level was mildly elevated at 247 U per liter (reference range, 110 to 210). Testing for HIV was negative.
Treatment of Burkitt's Lymphoma
Burkitt's lymphoma is highly curable,14 and the majority of children with the disease are cured with relatively short courses of systemic multiagent chemotherapy. A risk-adapted treatment strategy is important in planning the intensity and duration of treatment for patients with Burkitt's lymphoma. Several groups that conduct clinical trials have developed risk-stratification systems comprising two to four risk groups that incorporate tumor stage, extent of disease and surgical resection, and serum lactate dehydrogenase level. Patients with the most limited disease (completely resected abdominal disease or stage I extraabdominal disease) have a prognosis that approaches 100% event-free survival after very brief, low-intensity treatment, such as two or three cycles of chemotherapy. This patient, who has more extensive disease, would benefit from more dose-intensive chemotherapy. Effective treatment is the most challenging in patients with overt bone marrow and central nervous system (CNS) involvement, which this patient did not have. Therapy directed at the CNS (in the form of intrathecal chemotherapy) is an essential component of treatment for all patients. Supportive care is also crucial, because of the risk of the tumor lysis syndrome in patients with a large tumor burden; rasburicase (recombinant urate oxidase) has improved our ability to effectively manage this complication.15
This patient had a stage III Burkitt's lymphoma with extensive and incompletely resected abdominal involvement. His risk was classified as intermediate, and we treated him according to a Children's Cancer Group regimen (CCG-5961) — consisting of cyclophosphamide, vincristine, prednisone, doxorubicin, and methotrexate, with intrathecal methotrexate — that built on the successful experience of an earlier U.S. and European cooperative clinical trial.16 The 4-year event-free survival among patients in this patient's risk group was more than 90%. When relapses occur in Burkitt's lymphoma, they happen very early, within the first year after diagnosis, and thus survival curves at 4 years are very stable. In this patient, chemotherapy was delivered over a period of 3 months and incorporated several doses of intrathecal chemotherapy. The patient had no adverse events during therapy and remains well and in complete remission more than 2 years after the initial diagnosis. The cumulative doses of alkylating agents and anthracyclines were quite low, and thus he is at relatively low risk of serious long-term side effects of treatment.
Dr. Nancy Lee Harris (Pathology): Are there questions or comments?
Dr. Ronald L. Kleinman (Pediatrics): Would it have been worthwhile to perform imaging studies before the patient's first discharge?
Dr. Daniel Ryan: We typically do not perform follow-up imaging unless there is persistent purulent drainage, a mass, or concern about a fistula to the small bowel or cecum, none of which was present in this child.
A Physician: Why does the treatment protocol include intrathecal methotrexate when the cerebrospinal fluid is negative for tumor cells?
Dr. Friedmann: Occult disease in the CNS is common. Since most systemic chemotherapy does not penetrate the CNS well, CNS relapses used to be a common cause of treatment failure. Now, however, prophylaxis with intrathecal chemotherapy is a critical component of treatment.
A Physician: Why is EBV involved in the disease in equatorial Africa but less so in other areas?
Dr. Russell Ryan: Although EBV does encode growth-promoting proteins that act as oncogenes in other cancers, it is not clear that such factors are expressed and play an oncogenic role in Burkitt's lymphoma. It has been suggested that concurrent infection with EBV and malaria may be important in driving the emergence of endemic Burkitt's lymphoma, possibly by stimulating B-cell proliferation in the context of an altered immune response.
Burkitt's lymphoma, arising in the appendix, with involvement of the mesentery, lymph nodes, and the sigmoid colon.