HEIDI C. WERNER
HISTORY OF PRESENT ILLNESS
The patient, a 3-year-old boy, was well until approximately 9 months prior to admission. At this time he developed discomfort and difficulty with passage of large stools, which led to further stool withholding; all during the time he was starting to toilet-train. The patient had bowel movements in his pull-ups, but would refuse to sit on the toilet. When stools were passed they were of normal texture, but he would complain of pain. The patient received several enemas followed by mineral oil orally and since then has had passage of stool on a daily basis. However, 1.5 months ago the patient developed perianal irritation. This started as a small pustule around the anus and evolved to a larger lesion. The patient was admitted to an outlying hospital 1 month prior to this admission at which time the anus was described as having 3-4 cm raised, red excoriating lesion concentrically around the anus. The patient was diagnosed with perianal cellulitis and he was treated for cellulitis with intravenous clindamycin followed by an oral first-generation cephalosporin. After a medical and social evaluation, sexual abuse was excluded. The patient continued to have constipation. He subsequently began to complain of neck pain.
The patient’s birth history was unremarkable. The patient has had no other hospitalizations or significant illnesses other than those mentioned previously.
T 37.0°C; RR 22/min; HR 122 bpm; BP 94/61 mmHg
Weight 16.2 kg (50th percentile); Height 98 cm (25%)
The patient was alert and in no acute distress. The examination was remarkable for mild neck stiffness with neck pain with extension. There was no neck pain or resistance to flexion or lateral motion. There was a 2 cm circumferential lesion around the anus. The lesion was erythematous and there was purulent exudate soiling in the underpants. A digital rectal examination could not be performed due to the lack of patient cooperation with the examination.
Laboratory studies showed a WBC count of 9000 cells/mm3 (45% segmented neutrophils, 49% lymphocytes, and 6% monocytes); hemoglobin, 11.0 g/dL; and platelets, 400 000/mm3. The mean corpuscular volume was 73 fL and the red cell distribution width was elevated at 19.1. The erythrocyte sedimentation rate was 55 mm/h. Electrolytes, blood urea nitrogen, creatinine, and liver function tests were all normal. The cholesterol was 265 mg/dL.
COURSE OF ILLNESS
The patient underwent an endoscopy and colonoscopy for suspected Crohn disease. On colonoscopy, a verrucous mass was visualized, which was circumferential to the anus up to the anal verge. Multiple biopsies were taken. The descending colon, sigmoid, and rectum appeared normal. The esophagus, stomach, and duodenum were also normal.
During the week following the biopsy the patient developed a rash on his back that, in the clinical context, suggested a diagnosis (Figure 12-3). He was also noted to have increased “swelling” around the eye. On examination, he had left eye proptosis with mild ptosis. Red reflexes were noted, but a full fundoscopic examination could not be obtained. The lateral neck radiograph and CT showed erosion of the third cervical vertebral body (Figure 12-4). The biopsy results became available that same day confirming the diagnosis suggested by the rash and radiologic imaging.
FIGURE 12-3. Photo of a rash.
FIGURE 12-4. Neck A. Radiograph. B. CT demonstrating lytic destruction of the third cervical vertebral body with preservation of the posterior elements and trans-verse foramina. The adjacent disk spaces are preserved. There is also mild bulging of the prevertebral soft tissues in this region.
DISCUSSION CASE 12-2
In any 3-year-old boy presenting with difficulty stooling, functional constipation will be first on a differential diagnosis. However, this patient had complicating factors that forced a provider to widen the differential. The perianal lesion should lead us to consider sexual abuse. Inflammatory bowel disease can also present with perianal lesions, but there were no other symptoms such as diarrhea or bloody stools to support that diagnosis. A child with inflammatory bowel disease would also most likely present with other symptoms such as fevers or poor weight gain. Obviously, the symptoms of proptosis and ptosis are worrisome and require additional evaluation. The differential diagnosis of an orbital mass includes leukemia, neuroblastoma, and orbital abscess.
While vertebral osteomyelitis is a diagnostic consideration, this diagnosis would not explain the rash or other findings. Furthermore, lytic destruction of the vertebral body in osteomyelitis would typically include encroachment on the disc spaces rather than their preservation.
The rash consisted of infiltrated, crusted papules and petechiae (Figure 12-3). The biopsy results revealed cells consistent with Langerhans cell histiocytosis (LCH). Magnetic resonance imaging of the head demonstrated multiple lytic lesions around the skull in the frontal and parietal areas with a left retro-orbital sphenoid mass. The findings of exophthalmos and multiple lytic bone lesions were also characteristic of LCH.
INCIDENCE AND EPIDEMIOLOGY
Langerhans cell histiocytosis (LCH) includes clinical entities such as eosinophilic granuloma, Hand-Schuller-Christian Disease, and Letterer-Siwe disease. Normally, the Langerhans cell is an antigen-presenting cell of the skin. The hallmark of LCH is the presence of a clonal proliferation of cells of the monocyte lineage containing the characteristic electron microscopic findings of Langerhans cells. LCH is not a malignancy, but rather a manifestation of complex immune dysregulation. The proliferation of these “normal” cells causes destruction or impairment of other organ systems.
LCH affects approximately 4 per million persons with a male to female ratio of 2 to 1. Only 2% of cases are known to be familial but many researchers suspect a genetic basis for the disease. Features that implicate a genetic cause include (1) a greater than expected incidence of malignant disease preceding the onset of LCH, (2) a younger age at onset for identical twins with LCH than for other family pairs, and (3) the finding of monoclonality of the pathologic Langerhans cell in LCH. There is no seasonal or geographic distribution.
LCH has an extremely variable presentation depending on sites and extent of involvement (Table 12-3). Approximately 55% of patients have single site disease while the remainder present with multisystem disease. The skeleton may often be the only affected site. Lytic bone lesions may be singular or numerous and are seen most commonly in the skull. These lesions may be asymptomatic or associated with pain and local swelling. Lesions can involve weight-bearing long bones and may result in fractures. Exophthalmos, when present, is often bilateral and caused by retro-orbital accumulation of granulomatous disease. Hypertrophic gingivitis and loose teeth signify underlying mandibular LCH.
TABLE 12-3. Common sites of presentation of Langerhans cell histiocytosis.
Skin involvement usually presents as a seborrheic dermatitis of the scalp or diaper region, which can spread to involve the back, palms, and soles. The rash frequently consists of infiltrated, crusted papules with areas of hemorrhage. Lymphadenopathy may be part of disseminated disease or associated with local disease affecting adjacent skin or bone. Various degrees of hepatic malfunction can also occur, including jaundice and ascites. In severe cases, liver fibrosis and failure occur. Lung involvement is common in multisystem disease. Children with uncontrolled LCH can develop pulmonary cysts, pneumothorax, and chronic respiratory failure. Central nervous system involvement may also occur. Approximately 15% of children develop diabetes insipidus as a consequence of hypothalamic and pituitary histiocytic involvement. Subtle neurologic defects such as hyporeflexia, ataxia, vertigo, nystagmus, and tremor may develop later during the course of illness. Early treatment may prevent the development of some of these features.
The most severely affected patients may have systemic manifestations such as fever, weight loss, malaise, irritability, and failure to thrive. Bone marrow involvement causes anemia and thrombocytopenia. Mortality is highest in patients presenting with disseminated LCH and organ dysfunction within the first 2 years of life.
Plain radiography. Plain radiography remains the first-line approach for detecting bone lesions. Chest radiography may reveal nodular or inter-stitial infiltrates with relative sparing of the costophrenic angles. Skeletal radiograph may reveal irregularly marginated lytic lesions, usually with adjacent soft tissue swelling. Common sites of bone involvement in multifocal LCH include the skull, mandible, vertebrae, and humerus.
Other radiologic studies. Fluorodeoxyglucose positron emission tomography (FDG PET) may be useful in identifying multiple sites of activity as well as measuring response to treatment. There is high FDG uptake in bone lesions with high concentrations of histiocytes, and thus FDG PET delineates metabolically active LCH. Technetium bone scanning may show lesions before plain radiography but has limited sensitivity in identifying bone lesions compared with FDG PET and MRI. MRI or CT of the head and spine will identify skull and vertebral lesions.
Bone marrow biopsy. Bone marrow infiltration occurs in 18% of patients with multisystem disease and in 33% of patients with hematologic system involvement.
Tissue biopsy. Diagnostic tissue biopsy is easiest to perform on skin or bone lesions.
Other studies. Once the diagnosis has been made, a thorough clinical and laboratory evaluation should be undertaken. This should include a series of laboratory tests (complete blood count, liver function tests, coagulation studies, chest X-ray, urine osmolality, and skeletal survey) and a detailed evaluation of any affected organ system as suspected by history, physical examination, or the above studies.
TREATMENT AND PROGNOSIS
Single-system disease carries a high chance of spontaneous remission, and is generally benign. Therefore, treatment should be minimal and focus on arresting the progression of a lesion that could result in permanent damage. Local radiation therapy is the treatment of choice for single-system disease.
For multisystem or systemic disease, chemotherapy is the treatment of choice. The intensity of the regimen is modified after risk stratification. Children with no organ dysfunction have a better prognosis than those with one or more involved organs. The initial response rate of children without pulmonary, hepatosplenic, or hematopoietic involvement is 90% with a survival rate of 100%. In those with an unfavorable prognosis, the mortality rate ranges from 20%-50%. The mortality rate is more than 90% in children with multisystem LCH who had a poor response to initial therapy with prednisolone, vincristine, and etoposide. Other chemotherapeutic agents with activity against LCH include glucocorticoids, vinblastine, and methotrexate.
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