Correspondence

Pulmonary Langerhans'-Cell Histiocytosis

N Engl J Med 2000; 343:1654-1656November 30, 2000

Article

To the Editor:

Vassallo et al. (June 29 issue)1 depict a central role for the alveolar macrophage in the pathogenesis of pulmonary Langerhans'-cell histiocytosis. We made several observations in a series of five patients with biopsy-proved, CD1a+ pulmonary Langerhans'-cell histiocytosis at our institution. The patients were all young adults (age range, 22 to 31 years) who had smoked cigarettes. On histologic analyses, there were CD68+ histiocytes, including macrophages with “smoker's granules,” admixed with Langerhans' cells; angiotensin-converting–enzyme (ACE) antigen was expressed on non–Langerhans'-cell histiocytes within the lesion and surrounding alveoli. Histiocytes from a lesion of Langerhans'-cell histiocytosis were positive for the latency-associated peptide of transforming growth factor β₁; and there were foci of myofibroblasts positive for α-smooth-muscle actin (Figure 1Figure 1Immunohistochemical Characterization of the Lesions of Pulmonary Langerhans'-Cell Histiocytosis.).

These data, when coupled with data from the literature, suggest a possible pathogenetic sequence for pulmonary Langerhans'-cell histiocytosis that includes smoking-induced up-regulation of ACE in alveolar macrophages, leading to the formation of angiotensin II,2 with activation of latent transforming growth factor β₁. The activation of transforming growth factor β₁ could result in chemotaxis of alveolar macrophages, contribute to the generation of histiocytes in Langerhans'-cell histiocytosis, and account for the foci of myofibroblastic proliferation with nodular fibrosis.1,3 There is evidence of a similar pathogenic sequence, involving macrophages that express ACE and histiocytes of Langerhans'-cell histiocytosis that express latency-associated peptides, in the development of the osteolytic lesions of Langerhans'-cell histiocytosis,4 a process that can be controlled with (antimacrophage) bisphosphonate therapy.5

Robert E. Brown, M.D.
Geisinger Medical Center, Danville, PA 17822

5 References

1
Vassallo R, Ryu JH, Colby TV, Hartman T, Limper AH. Pulmonary Langerhans'-cell histiocytosis. N Engl J Med 2000;342:1969-1978
Full Text | Web of Science | Medline

2
Sugiyama Y, Yotsumoto H, Okabe T, Takaku F. Measurement of angiotensin-converting enzyme activity in intact human alveolar macrophages and effect of smoking. Respiration 1988;53:153-157
CrossRef | Web of Science | Medline

3
de Boer WI, van Schadewijk A, Sont JK, et al. Transforming growth factor beta1 and recruitment of macrophages and mast cells in airways in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998;158:1951-1957
Web of Science | Medline

4
Brown RE. Angiotensin-converting enzyme, transforming growth factor β1, and interleukin 11 in the osteolytic lesions of Langerhans cell histiocytosis. Arch Pathol Lab Med 2000;124:1287-1290
Web of Science | Medline

5
Elomaa I, Blomqvist C, Porkka L, Holmstrom T. Experiences of clodronate treatment of multifocal eosinophilic granuloma of bone. J Intern Med 1989;225:59-61
CrossRef | Web of Science | Medline

To the Editor:

Whether genetic mechanisms are involved in Langerhans'-cell histiocytosis remains a matter of controversy. Vassallo et al. state that no further cases of familial clustering have been reported since the first one nearly 30 years ago, implying that virtually all cases are sporadic. In a recent survey of familial Langerhans'-cell histiocytosis, we found that the number of index patients with an affected relative was between 1 in 71 and 1 in 160, and this value is probably underestimated as a result of underreporting, the presence of mild or asymptomatic disease in a relative, and misdiagnosis.1 In three additional families, both a child and a parent were affected.2,3 With the mounting evidence that there may be a genetic component in at least a subgroup of patients with Langerhans'-cell histiocytosis, this possibility should be addressed in all patients by obtaining an accurate family history. In addition, chromosomal analysis of peripheral blood or lesional tissues should be included in the diagnostic workup.4 Whenever possible, constitutional and lesional DNA samples from patients with familial cases should be collected for further investigation. The results of such studies will facilitate counseling and provide tools to clarify the pathogenesis of Langerhans'-cell histiocytosis and to refine its treatment.

Maurizio Aricò, M.D.
Istituto di Recovero e Cura a Carattere Scientifico, Policlinico San Matteo, 27100 Pavia, Italy

Kim E. Nichols, M.D.
Children's Hospital of Philadelphia, Philadelphia, PA 19104

Cesare Danesino, M.D.
Università di Pavia, 27100 Pavia, Italy

4 References

1
Arico M, Nichols K, Whitlock JA, et al. Familial clustering of Langerhans cell histiocytosis. Br J Haematol 1999;107:883-888
CrossRef | Web of Science | Medline

2
de Chadarevian J-P, Pawel BR. Hereditary Langerhans cell histiocytosis: instances of apparent vertical transmission. Med Paediatr Oncol 1998;31:559-559
CrossRef | Medline

3
Aricò M, Haupt R, Spica Russotto V, et al. Langerhans' cell histiocytosis in two generations: a new family and review of the literature. Med Pediatr Oncol (in press).

4
Scappaticci MA, Danesino C, Rossi E, et al. Cytogenetic abnormalities in PHA-stimulated lymphocytes from patients with Langerhans cell histiocytosis. Br J Haematol 2000;110:1-6
CrossRef | Web of Science | Medline

To the Editor:

In their comprehensive review, Vassallo et al. suggest that patients with pulmonary Langerhans'-cell histiocytosis may be at increased risk for the development of concurrent cancers, including lymphoma. On the basis of our clinical experience and a review of reported cases, we found a potentially significant association between pulmonary Langerhans'-cell histiocytosis and previously treated Hodgkin's disease.

The two most recent cases of pulmonary Langerhans'-cell histiocytosis that were diagnosed at our institution occurred in patients who had Hodgkin's disease that was in remission. Including these, there have been nine reported cases of pulmonary Langerhans'-cell histiocytosis occurring during follow-up among patients with previously treated Hodgkin's disease.1,2 The diagnosis of pulmonary Langerhans'-cell histiocytosis was made after a median follow-up of one year. Unfortunately, smoking status was not universally reported. Although the diagnosis of pulmonary Langerhans'-cell histiocytosis may have been incidental and reflected the closeness of radiologic follow-up, similar results have not been reported in patients who were undergoing serial radiologic studies for other cancers. The rarity of both diseases suggests that this association is more than coincidental. An alternative explanation is that pulmonary Langerhans'-cell histiocytosis occurs as a therapy-related process, perhaps also reflecting the defect in cell-mediated immunity that occurs in Hodgkin's disease.3 The Histiocyte Society has established a registry to explore the association between these two rare diseases.

Anthony W. O'Regan, M.D.
Mary T. Brophy, M.D.
Boston University School of Medicine, Boston, MA 02118

3 References

1
Egeler RM, Neglia JP, Puccetti DM, Brennan CA, Nesbit ME. Association of Langerhans cell histiocytosis with malignant neoplasms. Cancer 1993;71:865-873
CrossRef | Web of Science | Medline

2
Flint A, Smid DM. Pulmonary Hodgkin's disease and Langerhans cell granulomatosis. Chest 1987;92:191-192
CrossRef | Web of Science | Medline

3
Slivnick DJ, Ellis TM, Nawrocki JF, Fisher RI. The impact of Hodgkin's disease on the immune system. Semin Oncol 1990;17:673-682
Web of Science | Medline

To the Editor:

The interesting and informative review of pulmonary Langerhans'-cell histiocytosis by Vassallo et al. had one glaring omission. Pneumothorax was not mentioned as a presenting symptom or a common complication. Indeed, the Images in Clinical Medicine in the same issue of the Journal involved a patient with Langerhans'-cell histiocytosis who presented with pneumothorax and who had bronchopleural fistula as a serious complication.1

Wallace T. Miller, M.D.
University of Pennsylvania Medical Center, Philadelphia, PA 19104

1 References

1
Arens R, Kramer SS. Pulmonary Langerhans'-cell granulomatosis (histiocytosis X). N Engl J Med 2000;342:1959-1959
Full Text | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: Drs. O'Regan and Brophy report on the occurrence of pulmonary Langerhans'-cell histiocytosis in two patients with Hodgkin's disease. We have also observed pulmonary Langerhans'-cell histiocytosis in association with a number of cancers, including hematologic and solid-organ cancers. The explanation for the association between cancer and pulmonary Langerhans'-cell histiocytosis is not clear and may be multifactorial. Cigarette smoking, the tendency of tumors to develop at sites of chronic pulmonary inflammation and scarring, and a history of the use of chemotherapeutic agents to treat Langerhans'-cell histiocytosis may all be factors that increase the risk of malignant neoplasms in these patients. Clarification of the relation between malignant tumors and pulmonary Langerhans'-cell histiocytosis in adults may be possible through the use of data from the patient registry established by the Histiocyte Society.

We agree with Dr. Aricò and colleagues that genetic mechanisms may be involved in occasional cases of Langerhans'-cell histiocytosis. However, in our experience involving more than 100 adults with histologically proved pulmonary Langerhans'-cell histiocytosis, we did not identify a single instance of familial clustering (unpublished observations). Thus, it is our opinion that pulmonary Langerhans'-cell histiocytosis in adults occurs in a sporadic fashion in the majority of patients. Although we agree that a careful family history should be elicited from all patients with pulmonary Langerhans'-cell histiocytosis, chromosomal and genetic testing is unlikely to be clinically helpful in the absence of a family history.

We greatly appreciate Dr. Miller's comment regarding pneumothorax as a presenting symptom. In our experience, approximately 10 percent of patients with pulmonary Langerhans'-cell histiocytosis have presented with a spontaneous pneumothorax.

Robert Vassallo, M.D.
Jay H. Ryu, M.D.
Andrew H. Limper, M.D.
Mayo Clinic and Foundation, Rochester, MN 55905

Citing Articles (3)

Citing Articles

1
Katharina Marten, David M. Hansell. (2005) Imaging of macrophage-related lung diseases. European Radiology 15:4, 727-741
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2
Esam H. Alhamad, Joseph P. Lynch, Fernando J. Martinez. (2001) PULMONARY FUNCTION TESTS IN INTERSTITIAL LUNG DISEASE. Clinics in Chest Medicine 22:4, 715-750
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3
Robert E. Brown. (2001) Bisphosphonates as antialveolar macrophage therapy in pulmonary langerhans cell histiocytosis?. Medical and Pediatric Oncology 36:6, 641-643
CrossRef