This post focuses on the unique form of localized Langerhans cell histiocytosis that affects the lungs of adult cigarette smokers. 

This chapter is continuously updated. My eventual goal is to make this the best (and most often updated) free open-access online resource in the world on pulmonary Langerhans cell histiocytosis. 

Did I miss anything? Would you like me to address anything else or link to a helpful, accurate, free and open-access resource? Please suggest what I can add or clarify. Did I make any errors? Did you find this chapter helpful? Does it suck? Please let me know in the comments!

Don't have time to read the whole article? Need a quick summary? Here's the TL;DR version

Pulmonary Langerhans cell histiocytosis is a proliferation of Langerhans cells within the lung caused by cigarette smoking. It causes numerous small bilateral lung nodules and/or bilateral lung cysts in adult cigarette smokers. Definitive diagnosis often requires a lung biopsy. The best treatment is smoking cessation. 


Definition

Pulmonary Langerhans cell histiocytosis is defined by the presence of clusters/sheets of Langerhans cells within the interstitium of the lung (this is why this entity is considered a form of interstitial lung disease). It is important to define the disease in this way because isolated Langerhans cells are common in the lungs of cigarette smokers, but isolated cells (that do not form clusters/sheets in nodules) do not meet criteria for pulmonary Langerhans cell histiocytosis. 

What are Langerhans cells?

Langerhans cells (not to be confused with Langhans giant cells, found in true granulomas) are antigen-presenting dendritic cells that originate in the bone marrow and eventually enter the circulation and make their way to the skin (where they can be seen in the epidermis) and lung (very few in number in normal lungs). Unlike ordinary macrophages (histiocytes), which ingest (phagocytose) and destroy antigens,  the job of Langerhans cells is to detect antigens and present them on their surface to other cells of the immune system.

Langerhans cells are named after Paul Langerhans (1847-1888), a German pathologist who was mentored by Virchow. When Langerhans described these cells in 1868 using a gold chloride technique, he thought they were nerves of the skin (he was wrong). Here is a link to the paper. Warning: it's in German! https://zenodo.org/record/2319860#.Y9J7iezMK3I

Fun fact: other things named after Paul Langerhans are the islets of Langerhans (pancreas), Langerin (CD207), and the Langerhans cell layer (granular cell layer) of the skin.

Langerhans cells are positive for the immunohisotchemical markers S-100, CD1a, and Langerin (CD207).

Here is a beautiful image of Langerhans cells in the epidermis of the skin, stained with CD1a (positive = brown). The hair-like "tentacles" (these are dendritic cells, after all) are so gorgeous! Note that the neighboring epidermal epithelial cells (keratinocytes) are negative for CD1a.
https://kikoxp.com/posts/20196

You can read more about Langerhans cells in this open access review by Merad and collagues (ref: https://www.nature.com/articles/nri2455) 

Terminology

Old (obsolete) terms:
Eosinophilic granuloma
Histiocytosis X
Langerhans cell granulomatosis
Eosinophilic granulomatosis

History

Smoking and the lung (landmark papers over a century)
https://journals.lww.com/jdap/fulltext/2024/01010/smoking_and_the_lung__landmark_papers__1929_2023_.2.aspx
Good reference for the history of the disease (not lung specific): https://pubmed.ncbi.nlm.nih.gov/11841394/
Incredibly amazing anecdotes about the history of this entity by Drs. Christian Nezelof and Francoise Basset, pioneers in the field:
https://pubmed.ncbi.nlm.nih.gov/11484502/

1865: Possible first case described by Dr. Thomas Smith in a 4-year-old with impetigo and lytic lesions in the calvarium (for context, this is the year that the American Civil War ended)
1868: Langerhans cell discovered by Paul Langerhans (he was 21 years old, and Virchow was his mentor!)
1893: First definitive case reported by Alfred Hand (basis of the eponymous Hand-Schuller-Christian syndrome): exophthalmos, polydipsia, polyuria (reference: https://pubmed.ncbi.nlm.nih.gov/30281871/)
1915: Artur Schuller describes 2 cases with exophthalmos and map-like skull defects
1920: Henry Christian describes another case with exophthalmos
1924: Letterer describes a fulminant case (eponym: Letterer-Siwe syndrome)
1930: Mignon reports bone disease
1933: Siwe describes a case in a child
1940: Louis Lichtenstein and Henry Jaffe write a paper on "eosinophilic granuloma of bone" (Am J Pathol). The patient is a 4-year-old girl with a lesion in the femur. They remark on reports of similar lesions in the calvarium of boys, and the good prognosis of solitary bone lesions in children.
1941: Faber proposes that these are all variants of the same process
1951: Farinacci describes "eosinophilic granuloma of lung"
1953: Disease is re-named histiocytosis X; this proposal was made by Louis Lichtenstein
1961: Birbeck describes the ultrastructural features of Langerhans cells. PS: this eventually leads to decades of torture on the pathology board exams re: the famous zipper-like "Birbeck granules".
1973: Hashimoto and Pritzker: self-healing reticulohistiocytosis
1973: In the obscure European journal Biomedicine, French pathologists Nezelof, Basset and Rousseau propose that the condition then known as histiocytosis X was related to proliferation of Langerhans cells
1981: Landmark lung paper by Drs. Friedman, Liebow and Sokoloff: "eosinophilic granuloma of lung"
1981: First report of immunohistochemical markers of Langerhans cells. Anti-T6 (later called CD1a) by Murphy and colleagues, and S-100 by Cocchia et al (in the journal Nature!).
1987: The "Writing Group" of the Histiocyte Society groups all forms of the disease under the umbrella term "Langerhans cell histiocytosis" based on the work of Nezelof


Etiology

Cigarette smoking causes the vast majority of cases of lung-limited Langerhans cell histiocytosis in adults. The vast majority of adults with pulmonary Langerhans cell histiocytosis are heavy cigarette smokers (Reference: classic NEJM 2000 paper by Vassallo et al). In my experience, essentially 100% of lung cases occur in smokers. Rare cases in never-smokers are poorly documented, and are open to challenge since smoking history is self-reported. 

Is pulmonary Langerhans cell histiocytosis reactive or neoplastic?

This question has been debated for decades, and it has become fashionable to claim that pulmonary Langerhans cell histiocytosis is neoplastic on the basis of clonality and BRAF mutations in a small subset of cases. My take is that smoking-related pulmonary Langerhans cell histiocytosis is reactive because it does not behave like a neoplasm. The nodules almost never grow to more than a few millimeters in size, the cells do not invade locally or metastasize, and the lesions often spontaneously regress. Is this the behavior of a neoplasm? I do not buy the dubious claim that clonality in a small subset of cases means that this lesion is a neoplasm. Thankfully, despite the inclusion of this lesion in the WHO blue book (a mistake, in my opinion), clinicians treat this disease like a form of smoking-related interstitial lung disease, not as a neoplasm.   

Suri and colleagues have proposed that the lesional Langerhans cells are associated with local proliferation of the cells as opposed to another mechanism of accumulation (such as enhanced recruitment and survival, or delayed apoptosis) (Reference: https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-7-16). In line with my thought process, these authors speculate that the smoking-induced form of PLCH is a biologically distinct histiocytosis variant that is more consistent with a reactive rather than a clonal proliferative process. 

Pulmonary vs. extra-pulmonary Langerhans cell histiocytosis

The many ways in which Langerhans cell histiocytosis can present is an extremely complex topic. Extra-pulmonary Langerhans cell histiocytosis can involve the skin, bones and pituitary, and involvement can be single organ or multi-organ.  The smoking-related pulmonary form of the disease is not as well understood as other forms of this disease because most pathologists encounter the neoplastic form of Langerhans cell histiocytosis in non-pulmonary sites such as the bones or skin.

In what organs or tissue sites can Langerhans cell histiocytosis be encountered? Here is a list with some examples:
1. Lung (this chapter)
2. Bone
https://twitter.com/FelipePatologia/status/1613325759170641920?s=20&t=qK1607FlXpoM_lCMTs6DUw
https://twitter.com/mdlozanoe/status/1517465801678368768?s=20&t=qK1607FlXpoM_lCMTs6DUw
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1965122/pdf/amjpathol00526-0083.pdf
https://kikoxp.com/posts/17849 (nice example of imaging, lesion in clavicle)
https://kikoxp.com/posts/34174 (skull lesion)
3. Skin
https://twitter.com/JMGardnerMD/status/1571529602845089792?s=20&t=qK1607FlXpoM_lCMTs6DUw
https://twitter.com/DrBMcGinn/status/1478789360397045762?s=20&t=qK1607FlXpoM_lCMTs6DUw
4. Liver
5. Central nervous system
https://twitter.com/FelipePatologia/status/1573730634945683456?s=20&t=qK1607FlXpoM_lCMTs6DUw
6. Gastrointestinal tract
https://twitter.com/LizMontgomeryMD/status/1480664928683900929?s=20&t=qK1607FlXpoM_lCMTs6DUw
https://twitter.com/LizMontgomeryMD/status/1398425447654821890?s=20&t=qK1607FlXpoM_lCMTs6DUw

The vast majority of adult smokers with pulmonary disease have involvement limited to the lung. Cases with smoking-related pulmonary Langerhans cell histiocytosis and histologically confirmed extra-pulmonary disease are very rare, perhaps non-existent. Reader: please cite any literature that proves this assertion wrong :)

Langerhans cell histiocytosis in children

Although lung involvement (sometimes very striking) can occur in Langerhans cell histiocytosis in children, the disease that occurs in children is a completely different entity than pulmonary Langerhans cell histiocytosis in adult smokers. For a quick summary, see this tweet by Dr. Faheema Hasan:
https://twitter.com/faheema_hasan/status/1517496299117232130?s=20&t=qK1607FlXpoM_lCMTs6DUw

Clinical features

  1. Pulmonary Langerhans cell histiocytosis is a disease of adult cigarette smokers. It can occur at any age and affects both sexes. Langerhans cell histiocytosis in children features the same cells but is biologically a completely different disease. Similarly, Langerhans cell histiocytosis of the bones is a completely different clinical entity, although the cells are the same. I have been seeing cases of pulmonary Langerhans cell histiocytosis since 2002, but I have never seen a case of pulmonary Langerhans cell histiocytosis in an adult smoker that also had histologically documented bone (or other extrapulmonary) involvement. My colleague Dr. Scott Kilpatrick wrote a very highly cited paper on Langerhans cell histiocytosis of the bone, which is well worth a read (ref: https://pubmed.ncbi.nlm.nih.gov/8625073/).
  2. Many individuals with pulmonary Langerhans cell histiocytosis are asymptomatic, although Vassallo et al offer a number of only 25%. In patients who undergo lung biopsy, the disease is often discovered incidentally when lung nodules are noted during a chest CT performed for another reason. The frequency of asymptomatic pulmonary Langerhans cell histiocytosis in heavy smokers is probably greatly underestimated. As an example, pulmonary Langerhans cell histiocytosis has been reported as an incidental finding in lobectomies for lung cancer (reference: https://pubmed.ncbi.nlm.nih.gov/20004953/ ). 
  3. In symptomatic patients, typical symptoms are non-productive cough (most common), dyspnea, fatigue, weight loss and fever.
  4. Patients with advanced scarring may develop cough and shortness of breath. 
  5. Patients with cysts may present with a pneumothorax (pleuritic pain and acute shortness of breath).
  6. Here is an overview of clinical features from an expert clinician (YouTube): https://www.youtube.com/watch?v=gGgA4y62DYo
  7. Physical examination is usually unhelpful. Crackles and clubbing are both uncommon.

Imaging

Chest x-ray findings:
The usual findings are diffuse bilateral reticulonodular infiltrates with normal or increased lung volumes.

Chest CT findings:
  1. Bilateral lung nodules. The nodules are often centrilobular, cavitary and are almost invariably tiny (millimeter-sized). They may be so numerous as to raise the possibility of disseminated mycobacterial or fungal infection or disseminated malignancy on imaging. This differential diagnosis often prompts a lung biopsy.  Example: https://kikoxp.com/posts/21119
  2. Bilateral thin-walled cysts. These are usually - but not always - bilateral and upper and mid-lung  predominant. Relative sparing of lung bases is often cited in the imaging literature.
  3. Bilateral ground-glass opacities, probably attributable to macrophages and/or SRIF.
  4. Pneumothorax. 
  5. Theoretically, the combination of nodules and cysts might be so characteristic that the diagnosis can be made on the basis of chest CT alone and biopsy can be avoided. In practice, although radiologists often suggest the diagnosis in classic cases, most cases are biopsied for confirmation. Pathology is the gold standard for this diagnosis. 

Pathology

Features mandatory for a pathologic diagnosis
Sheets (clusters) of Langerhans cells within the interstitium forming multiple tiny (less than 1 cm, sometimes less than 1 mm) ill-defined nodules with irregular edges (stellate nodules). Pulmonary pathologists are very good at picking up this diagnosis at low magnification based on the typical shape of the nodules.
Here's what stellate nodules look like at low magnification:
https://kikoxp.com/posts/20261
https://kikoxp.com/posts/19143
https://kikoxp.com/posts/42030

What do Langerhans cells look like at high magnification? They are similar in some ways to ordinary macrophages (histiocytes), but their nuclei are more irregular and often have grooves.
Here are some images to illustrate this point:
https://kikoxp.com/posts/20190
https://kikoxp.com/posts/20337
https://kikoxp.com/posts/21268
https://kikoxp.com/posts/41922

To my eye, the nuclei of Langerhans cells resemble the kernel of a walnut. Cytoplasmic borders are somewhat poorly defined. One tip I find useful in practice is that Langerhans cells in lung lesions are often most numerous in the areas where the stroma looks slightly myxoid (like organizing pneumonia) (see https://kikoxp.com/posts/41922). In contrast, the more pink (collagenous/fibrous) the stroma becomes, the less likely it is that you will find Langerhans cells. Finally, in advanced lesions that are completely scarred, Langerhans cells are completely replaced by fibrous tissue, and cannot be demonstrated by immunohistochemistry. It is in these late stage scars that the opinion of an experienced pulmonary pathologist can be very helpful, as the diagnosis can be suggested on H&E based on the size and shape of the "stellate" nodules and smoking-related changes in the background lung.   

On frozen section, the reactive type 2 pneumocytes at the periphery of these nodules can be misinterpreted as adenocarcinoma. The appearance of pulmonary Langerhans cell histiocytosis at frozen section has been reported (https://pubmed.ncbi.nlm.nih.gov/38818706/).

Immunohistochemical stains are not mandatory for the diagnosis but most pathologists do perform them to confirm that the cells in question are indeed Langerhans cells. Langerhans cells are positive for S-100, CD1a  (https://kikoxp.com/posts/42030) and Langerin (CD207).

Variable pathologic findings
Very common finding: smoking-related changes in the background lung (example: https://kikoxp.com/posts/39249). The most common of these are pigmented macrophages within the alveolar lumens (airspaces). This has been called "respiratory bronchiolitis" or a "DIP-like reaction", both of which are suboptimal and misleading terms that fail to convey the true nature of the process. Other smoking-related changes that may be present in the background lung include emphysema and smoking-related interstitial fibrosis (SRIF).

What do you see within the interstitium in the stellate nodules? The mix of cells is quite variable and includes (in variable proportions) Langerhans cells, pigmented macrophages, eosinophils, and lymphocytes. There can be an occasional plasma cell or neutrophil but these are usually not prominent. These changes are admixed with variable amounts of collagen (fibrosis). In general, the more the collagen, the less the cells.

Eosinophils can be numerous within the nodules (for an image of what this looks like, see https://kikoxp.com/posts/20220) but are not mandatory. The occurrence of eosinophil-poor cases is one reason why "eosinophilic granuloma" was not a great term for this entity. Also, these lesions are NOT granulomas since they are collections of Langerhans cells, not epithelioid histiocytes. Clinicians might think this is a minor difference, but pathologists will recognize that granulomas and Langerhans cells collections are NOT the same thing and are (with good reason) defined as separate entities. For the same reason, "Langerhans cell granulomatosis" is incorrect terminology.

Vascular changes have been described by Melanie Bois and colleagues (ref: https://pubmed.ncbi.nlm.nih.gov/30040456/). These include intimal and medial thickening. I have also seen cases with significant eosinophil infiltrates within the walls of blood vessels, a finding that could potentially lead to misdiagnosis of a "true" vasculitis such as GPA or EGPA.

Scarred form of the disease
https://www.youtube.com/watch?v=ELnYD2tUmT4&t=97s

Immunohistochemistry
Langerhans cells are positive for S-100, CD1a and Langerin (CD207).

Molecular findings
BRAF V600E mutations are found in some but not all cases. In one study by Yousem and colleagues, 2/5 cases had a BRAF mutation.

Pathology specimens in which a diagnosis of pulmonary Langerhans cell histiocytosis can be made:
  1. Surgical lung biopsies: most commonly used, and most likely to be diagnostic
  2. Transbronchial lung biopsies. Of course, this method is subject to the possibility of sampling error. Reference: https://pubmed.ncbi.nlm.nih.gov/7514863/
  3. Core needle biopsies. This requires a really good interventional radiologist. Reference: https://pubmed.ncbi.nlm.nih.gov/20805183/ ; please also see a detailed case here: https://www.pulmonarypath.org/cotm/2023/mar/cotm_2303.html
  4. CD1a in BAL fluid is frequently cited as a way to make the diagnosis despite the fact that this is never diagnostic in practice, and there is no evidence to support this contention. This topic is well reviewed by Susan Vehar and colleagues. Reference: https://pubmed.ncbi.nlm.nih.gov/35730782/
  5. Lobectomies for cancer. In these specimens, the diagnosis is usually an incidental finding. Reference: https://pubmed.ncbi.nlm.nih.gov/20004953/  and pic: https://kikoxp.com/posts/39249

Treatment

Prognosis

There are several possible outcomes:
  1. Complete or partial resolution of disease with smoking cessation. Radiologic resolution is well documented in the literature. I have personally seen dramatic radiologic resolution, once in a patient who stopped smoking and in another occasion in an individual who continued to smoke!
  2. Recurrent pneumothoraces 
  3. Progressive scarring with lung function impairment.
  4. Secondary pulmonary hypertension.
  5. Smoking-related lung cancers. 
  6. Other malignancies such as lymphoma.
  7. Median survival was 12.5 years in a study of 102 adults. Ref: https://pubmed.ncbi.nlm.nih.gov/11844849/
Images
About the image attached to this post: I took this picture to show how small the nodules of pulmonary Langerhans cell histiocytosis are. Compare the tiny nodule in the lung to the size of the coin. The nodule is 2-3 mm in size, very tiny!! To the best of my recollection, this minute nodule was found incidentally in a lobectomy specimen for lung cancer. Note marked emphysema in the background lung.

Whole slide image (you can move around like you are seeing the slide through a microscope, and adjust magnification):
https://kikoxp.com/posts/20175
Langerhans cells at high magnification:
https://kikoxp.com/posts/20190
Eosinophils mixed with Langerhans cells
https://kikoxp.com/posts/20220

References

Melanie Bois and colleagues (vascular changes): https://pubmed.ncbi.nlm.nih.gov/30040456/

LANDMARK PAPER Paul Friedman, Averill Liebow and Joel Sokoloff: classic and very large study on pulmonary disease https://pubmed.ncbi.nlm.nih.gov/6975871/

Georgi Galev et al: list of landmark papers on smoking and the lung, described in chronological order
https://journals.lww.com/jdap/fulltext/2024/01010/smoking_and_the_lung__landmark_papers__1929_2023_.2.aspx

Housini et al (diagnosis in transbronchial biopsies) https://pubmed.ncbi.nlm.nih.gov/7514863/

Katzenstein et al: incidental PLCH in lobectomies for cancer.  https://pubmed.ncbi.nlm.nih.gov/20004953/

LANDMARK PAPER Scott Kilpatrick and colleagues (including the famous Dr. Krishnan Unni) on the bone form of the disease: https://pubmed.ncbi.nlm.nih.gov/8625073/

LANDMARK PAPER Lichtenstein and Jaffe describe a case in the femur of a 4-year-old girl  and call it "eosinophilic granuloma": https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1965122/pdf/amjpathol00526-0083.pdf

LANDMARK PAPER In 1953, Louis Lichtenstein (a famous bone pathologist who worked in New York city) groups Letterer-Siwe syndrome, Hand-Schuller-Christian syndrome and eosinophilic granuloma of bone under the umbrella term "histiocytosis X":
https://pubmed.ncbi.nlm.nih.gov/13057466/

Mendez and colleagues look at pneumothorax in a large cohort (Mayo Clinic): https://pubmed.ncbi.nlm.nih.gov/15006964/

Mogulkoc and colleagues (radiologic resolution with smoking cessation) https://pubmed.ncbi.nlm.nih.gov/10334170/

Sanjay Mukhopadhyay and colleagues (making the diagnosis of pulmonary LCH on core needle biopsies of lung nodules) https://pubmed.ncbi.nlm.nih.gov/20805183/

Sanjay Mukhopadhyay and Irene Sansano: recent review of pulmonary LCH as a form of smoking-related interstitial lung disease, along with historical notes https://pubmed.ncbi.nlm.nih.gov/38692802/

Sanjay Mukhopadhyay: appearance of pulmonary Langerhans cell histiocytosis at frozen section https://pubmed.ncbi.nlm.nih.gov/38818706/

Christian Nezelof and Francoise Basset recall the story of discoveries in LCH. Great read full of amazing details. Highly recommended!
https://pubmed.ncbi.nlm.nih.gov/11484502/

Anja Roden and colleagues (BRAF V600E mutation in 7/25 cases, 28%) https://pubmed.ncbi.nlm.nih.gov/24625419/

Harpreet Suri and colleagues lay down the case that pulmonary smoking-related Langerhans cell histiocytosis is a reactive process. https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-7-16

LANDMARK PAPER Robert Vassallo and colleagues (study of 102 patients, in NEJM); https://pubmed.ncbi.nlm.nih.gov/11844849/

Susan Vehar and colleagues (busting the BAL CD1a myth) https://pubmed.ncbi.nlm.nih.gov/35730782/

Samuel Yousem and colleagues (BRAF V600E mutations by NGS in 2/5 cases): https://pubmed.ncbi.nlm.nih.gov/23287985/