FINAL DIAGNOSIS: Langerhans Cell Histocytosis (LCH or Histiocytosis X)
The prior clinical knowledge of this patient's previously diagnosed LCH was not provided in the clinical history in order to illustrate another possible etiology for the differential diagnosis of end-stage lung and liver disease. From available medical records, this disorder was clinically suspected in this patient as an adolescent, and several liver biopsies performed were interpreted as consistent with LCH, but never diagnostic. The opportunity to confirm the diagnosis was provided at autopsy by current immunoperoxidase and ultrastructural studies as described above.
The clinical entity long known as Histiocytosis X has a well-documented potential to show a progressive nature in many afflicted patients, as illustrated by this case. A recent review of 238 cases of Histiocytosis X spanning 50 years of clinical follow-up, presents an argument to rename this entity Langerhans cell histocytosis (LCH). The suggested revision is presented to avoid confusion regarding the term "Histiocytosis X," since substantial evidence indicates that the origin of the Langerhans cell is within the dendritic cell family, and not the tissue macrophage system. The authors of this long-term study also contend that in their experience, the disease is reactive in nature rather than clonal.
The term LCG would also allow for inclusion of the disease spectrum covered by the term Histiocytosis X. These are known traditionally as eosinophilic granuloma, Hand-Schuller-Christian (HSC) disease, and Letterer-Siwe disease. Eosinophilic granuloma can be unifocal or multifocal, and is characterized by destructive aggregates of Langerhans cells usually found within the medullary cavities of bones (calvarium, ribs, femur). The associated inflammation includes eosinophils, lymphocytes, plasma cells, and neutrophils, and can occur in the lungs, gastrointestinal tract, or skin. Letterer-Siwe disease is an acute disseminated variant with seborrheic cutaneous lesions of the trunk and scalp. Hepatosplenomegaly, lung lesions, lymphadenopathy, and destruction of bone are also seen. This form usually develops before 2 years of age, and is fatal without treatment. HSC disease is classically described as a triad of calvarial bone defects, exophthalmos, and diabetes insipidus. This form usually initially presents in childhood as fever associated with skin eruptions (scalp), otitis media (recurrent), and upper respiratory infections. Later in the course, lymphadenopathy and hepatosplenomegaly may develop. As one can see, a large degree of overlap exists in these three variants, which has led to the current belief that they are forms of expression of the same primary process.
The multifocal nature of the current case correlates best with HSC disease, where in 50% of patients involvement of the posterior pituitary stalk and the hypothalamus leads to diabetes insipidus. 85 of the 238 cases reviewed in the long-term follow-up study were reclassified as "multifocal" LCH, which are known to present during childhood, mainly in males, with initial onset usually as bony lesions. 19 of the 85 multifocal LCG cases also developed diabetes insipidus, regarded as one of the classic triad findings in HSC disease (bone lesions, exophthalmos, and diabetes insipidus). The authors describe the pulmonary findings for these 85 cases as ranging from multiple 2-3 mm stellate, irregular white nodules, to extensive honeycombing fibrosis. It is significant to note that in a number of the 85 multifocal cases, follow-up autopsy examination often failed to note residual LCH activity. In the current case, we were fortunate to detect the residual disease process by CD1a expression, and the Birbeck granules (also known as HX bodies, with a "tennis-racket" appearance) seen on electron microscopy.
Finally, it is interesting to note that despite the compelling evidence for LCH having an inflammatory basis in the 50 year follow-up study discussed above, some studies have indicated a possible clonal nature for LCH, indicating it maybe neoplastic rather than reactive. One study used X-linked polymorphic DNA probes to verify the clonal nature of the proliferating Langerhans cell in various forms of the disease. The authors demonstrated that 9 of 10 subject tissues showed clonal Langerhans cell populations, and that the percentage of clonal cells is approximately equal to the number of CD1a positive cells when directly compared. This suggests that an underlying genetic mutation is now detectable, and may lead to better therapies for this disease in the future.
Contributed by Douglas R. Johnson, MD