Bumpy ride ahead?
Ten days later, you receive the pathology report. Analysis of the lymph node revealed a paracortical histiocytic infiltrate with antigen markers indicative of an immature dendritic cell tumor, or early-stage Langerhan cell histiocytosis. The mass did hide something sinister after all! Although the report confirms your suspicions, you still have questions about the disease and the prognosis.
You discuss the patient's history with the pediatric oncologist who participated in the analysis of the node. He proposes, in retrospect, that the earlier facial and inguinal rashes may have been transient cutaneous manifestations of histiocytic disease. He further explains that excision of the lymph node may have been curative and that chemotherapy isn't indicated. Full-body imaging is necessary, however, to detect any occult tumors or skeletal lesions. He also recommends periodic close follow-up at your office and with the staff of the oncology clinic.
Langerhan cell histiocytosis (LCH) is a disorder of abnormal dendritic cell proliferation characterized by the presence of pathologic Langerhan cells (a type of dendritic cell, or histiocyte) within the centers of proliferation. Once known as histiocytosis X, LCH is a disease of diverse clinical presentations that encompass several conditions once thought to be distinct pathologic entities, including:
eosinophilic granuloma (localized bone lesions)
Hand-Schuller-Christian disease (multiple organ involvement characterized by a classic triad of skull defects, diabetes insipidus, and exophthalmos)
Letterer-Siwe disease (visceral lesions involving multiple organs)
Hashimoto Pritzker variant (congenital skin lesions that may resolve by 2 or 3 months of age but can recur).
Other histiocytic disorders feature proliferation of cell types other than the Langerhan cell, such as hemophagocytic lymphohistiocytosis (HLH), histiocytoma with macrophage phenotype, and Rosai-Dorfman disease (benign painless cervical lymphadenopathy with occasional extra-nodal involvement).3 Although LCH is the most common form of childhood histiocytosis, it is rare, affecting only one in 25,000 children annually.
The initial clinical presentation of LCH is varied and depends on the organ systems involved. In single-system LCH, only one organ or tissue is affected. For example, skin rash is the only manifestation in approximately 10% of cases. The rash often appears on the scalp and in flexural areas as reddish papules that progress to vesicles, pustules, or ulcers, followed by depigmentation and, eventually, healing. Often, the rash is mistaken for seborrheic dermatitis in newborns and infants.
LCH can also present as disseminated disease that affects multiple organs and tissues. Osteolytic bone lesions, manifesting as painful swelling, are present in more than 80% of cases. Other affected organs can include bone marrow, liver, spleen, lung, the central nervous system, and, more rarely, the gastrointestinal and genitourinary systems. Lymph node enlargement occurs in only 10% of cases, usually at initial presentation.
When LCH—in any form—is suspected, guidelines recommend a comprehensive workup of chest radiography and a skeletal survey, CBC, coagulation studies, and a liver function panel. A bone scan or body computed tomography scan may be helpful in certain cases. Definitive diagnosis requires biopsy and histopathologic analysis of a suspected lesion. Hallmarks of LCH include positive staining for the histiocytic markers CD-1a and S-100, as well as the presence of the Langerhan cell organelle, or Birbeck granule, within pathologic histiocytes.
Management of LCH depends on the extent of organ system involvement. Mild cutaneous disease may require only close observation or treatment with local corticosteroids. Severe cutaneous disease or multisystem disease may require extensive chemotherapy. Outcome correlates well with extent of disease involvement: Patients whose disease is more disseminated at presentation are at greater risk of relapse and death.
When do you watch the big picture? Your patient's case illustrates the challenge faced by a primary care provider when addressing common complaints with a wide differential diagnosis. Although careful history-taking and physical examination are often helpful in narrowing possibilities, potentially lethal rare diseases such as LCH may, in an early stage, offer few, if any, clues to help distinguish them from more common, less serious conditions. Our recommendation is not to be overzealous in pursuing zebras but to give thoughtful attention to the big picture when a constellation of symptoms evolves over time, and to take every opportunity to re-evaluate the differential diagnosis.
How quickly should workup of a suspected unusual condition proceed? In the case of your patient, the decision to send her for prompt surgical evaluation arose from two critical factors: persistence and gradual enlargement of the mass over more than one month despite resolution of the perineal rash and the inability of US to definitively identify its nature or visualize the right ovary.
Plan of observation You call the baby's mother to deliver the news. She is alarmed to hear "tumor" but relieved that the disease may have been cured by the surgery. You prepare the family for her upcoming visit to the oncology clinic. Information offered by the oncologist proves helpful as you carefully explain the details of the diagnosis and address her mother's concerns.
The family returns two weeks later for the twins' 4-month-old health maintenance visit. Your patient has done well since her operation and has no complaints. Her sister remains healthy too. The physical exam is unremarkable—you find neither a rash nor lymphadenopathy. She has had her first oncology clinic appointment and has undergone several imaging studies since you saw her last. A skeletal survey showed no bony lesions, and a full-body CT scan revealed only five small pulmonary nodules on the right side, suggesting asymptomatic pulmonary histiocytic disease. There is no remaining evidence on imaging of the left-sided inguinal nodes that you observed. Repeat lab tests were normal. The baby will alternate seeing you and then the oncologist at least once a month, and she will undergo serial imaging study and lab testing every three months. If she remains symptom-free from her knotty problem—if things go smoothly now!—the frequency of visits and testing may, gradually, decrease over time. Although the oncologist does not believe that the twin sister is at elevated risk of LCH, you will monitor her for clinical signs of disease at her well-child visits.
DR. FINK is a third-year resident in pediatrics, and DR. SERWINT is director of pediatric resident education and associate professor of pediatrics, both at Johns Hopkins University School of Medicine, Baltimore.