Langerhans' cell histiocytosis: current trends and the role of the head and neck surgeon.
Langerhans' cell histiocytosis (LCH)--once called histiocytosis X--is a complex reticuloendothelial disease that often involves the head and neck. We discuss the current nomenclature of this disease and review its pathologic and clinical characteristics, with particular emphasis on the role of the head and neck surgeon. LCH can be challenging to diagnose, and the otolaryngologist must be familiar with its varied presentations. Because LCH usually responds well to medical therapy and extensive resection can easily cause more morbidity than the disease itself a minimalist approach to treatment usually provides the best outcome. We also discuss the case of a 9-month-old girl with LCH who presented with aggressive head and neck disease.
Like cancer, Langerhans' cell histiocytosis (LCH) can affect any organ system, and it can be progressive and fatal. In other cases, LCH is localized and self-limited. In most cases, LCH resolves with medical treatment, but the diagnosis cannot be made without analysis of a tissue sample, which is usually obtained by a surgeon or dermatologist. The disease is rare, but when it does occur, it often does so in the head and neck. The otolaryngologist should be familiar with the varied presentations of this disease and understand that it often masquerades as more common head and neck diseases. The head and neck surgeon therefore plays a critical role in the diagnosis of LCH and in following the patient once the diagnosis has been established.
In this article, we describe the case of a 9-month-old girl with undiagnosed LCH who had been referred to us by the emergency department for evaluation of an oral mass. We also discuss the current nomenclature of the disease and review its pathologic and clinical characteristics, with particular emphasis on head and neck involvement. Finally, we address new advances in treatment, and we present our philosophy on the role of the head and neck surgeon.
A mother brought her 9-month-old daughter to the emergency department for evaluation of an oral mass that had been growing for 2 weeks. The mother had first noticed the mass while her daughter was breast-feeding. She also noticed that the infant had not been feeding as much as usual. Otherwise, the child had been sleeping, crying, and developing normally. The infant's medical history was significant for a 4-month period of bilateral otitis externa, and she was responding minimally to neomycin/polymyxin B/hydrocortisone otic drops that had been prescribed by her primary care physician. The patient also had persistent scalp and diaper rashes that were not responding to over-the-counter creams. The remainder of the child's medical history was unremarkable.
On physical examination, the infant was well nourished. She had a robust cry and interacted normally. Her head and neck examination was notable for an eczematous scalp rash that involved the conchae of both ears. Her external auditory canals were edematous, and there was scant yellowish otorrhea bilaterally. Her tympanic membranes were intact. An exophytic, spongy, light-brown, palatal mass, approximately 3 x 1 cm in size, extended from the midline anteriorly along the left lateral aspect of the hard palate. A second lesion, 1 x 1.5 cm in size, was noted on the right lateral palate. The nasopharynx was normal. The remainder of the physical examination was normal except for the severe eczematous diaper rash and the similar rash on the scalp. The complete blood count and chemistry panels were normal, as was a chest x-ray. Computed tomography (CT) showed that the palatal mass involved the maxillary sinus and approached, but did not involve, the orbit (figure 1).
We took the patient to the operating room and obtained a biopsy of the palatal mass. Pathologic analysis led to a diagnosis of LCH (figure 2). A dermatologist obtained a biopsy of the groin rash, and the diagnosis was the same. The patient was referred to the hematology department, and she was started on weekly vinblastine and prednisolone. Hydrocortisone cream was prescribed for the rash, and the patient was kept on neomycin/polymyxin B/ hydrocortisone ear drops for her otitis externa.
The palatal mass resolved rapidly and the otitis externa responded, as well. However, the rash recurred following the completion of therapy, so the patient resumed the same chemotherapeutic medications for 3 months. Topical steroid therapy kept the rash under reasonable control, and at follow-up, the patient was doing well and developing normally.
Lichtenstein originated the term histiocytosis X in 1953 to describe a group of poorly understood diseases that differed in presentation but had a common pathologic characteristic: histiocyte proliferation. (1) At that time, histiocytosis X was subdivided into three types: (1) eosinophilic granuloma, an isolated osteolytic lesion: (2) Hand-Schuller-Christian disease, a multifocal version of eosinophilic granuloma that is often accompanied by systemic manifestations; and (3) Letterer-Siwe disease, a systemic, rapidly progressive form of histiocytosis X.
Several decades passed before a specific type of histiocyte--the Langerhans' cell--was identified as the culprit. (2-5) In 1987, the international Histiocyte Society changed the name of the disease from histiocytosis X to Langerhans' cell histiocytosis. (6) Authors of reports in the otolaryngology literature have been slow to adopt this new terminology, and many still refer to LCH by its former name.
Pathology. Strict diagnostic criteria have been published by the Histiocyte Society. (6) Fresh-tissue biopsy is required to diagnose the disease. In order to establish a definitive diagnosis, either Birbeck's granules must be identified on electron microscopy or the cells must be CD1a-positive. A less certain diagnosis can be made if biopsy reveals characteristic morphology and if two or more of the following are present on staining: characteristic peanut lectin binding, S-100 protein, alpha-D-mannosidase, and adenosine triphosphatase. A weaker presumptive diagnosis can be made if histologic characteristics are consistent with those reported in the literature.
Although the precise pathogenesis of LCH is unknown, Egeler et al have reported important information regarding the disease process. (7) Because Langerhans' cells are the only monoclonal cells in LCH, Egeler et al speculated that LCH is a type of neoplastic phenomenon. Therefore, the underlying cause of the disease may be a genetic defect, an abnormal response to infection, an autoimmune quirk, or a combination of these factors.
A histiocyte is an antigen-presenting immune cell that originates in the bone marrow and evolves into one of two cell types: macrophage or dendrite. Healthy Langerhans' cells circulate through the epidermis, lungs, and the vaginal and orobuccal epithelia seeking foreign antigens. (8) The dendritic nature of these cells may enhance their ability to capture and transport antigens (figure 3). (9) Both normal and diseased Langerhans' cells are CD1a--and S-100 protein-positive. They also contain Birbeck's granules, which are pentalaminar cytoplasmic inclusion bodies that sometimes have a dilated terminal ("tennis racquet" appearance).
Under normal circumstances, Langerhans' cells enter the lymphatic system and travel to the T-cell areas of the spleen and draining lymph nodes. Once there, these cells-now called interdigitating dendritic cells--present antigen to the T cells. (9) A bidirectional release of cytokines likely ensues as part of the immune response. (7) In the diseased state. Langerhans' histiocytes lose their healthy dendritic morphology and become less-capable round cells. These cells barely resemble their former manifestation as they assume a more macrophagic appearance, with vesicular nuclei and abundant, often vacuolated cytoplasm. (10) Angeli et al have noted that as LCH progresses, many of the diseased Langerhans' cells are replaced by fibrosis. (11) On routine pathologic staining, the "burned out" appearance of these diseased cells can lead the pathologist to confuse LCH with such conditions as osteomyelitis.
Egeler et al examined multiple LCH tissue specimens with antibody-based immunohistochemistry and double-staining techniques. (7) They concluded that in the diseased state, the normal production of cytokines by Langerhans' cells and CD3+ T cells becomes uncontrolled. They also noted that eosinophils produce cytokines in some lesions. In that study, cytokines were abundant in all of the specimens, regardless of the patient's age, sex, or lesion site. Furthermore, the site of the lesion did not significantly affect its histologic appearance, a finding that was consistent with those of others. (7,11,12) Egeler et al proposed that the cytokine storm produced by the combined effort of T cells and LCH cells allows the LCH lesion to grow and mature. (7) Systemic symptoms of LCH such as fever may also be the result of cytokine activity. In addition, several of the cytokines they identified are known to promote necrosis, fibrosis, and bone resorption--all of which are typical of LCH lesions.
The discovery that cytokines play an important role in the proliferation of LCH may open doors to new chemotherapeutic treatments, including recombinant cytokines. The purine analog 2-chlorodeoxyadenosine (2-CdA) is a promising new chemotherapeutic agent. (7) When cells attempt to incorporate 2-CdA into their DNA, the 2-CdA causes the cells' DNA strands to break. Cell death eventually occurs.
General head and neck manifestations. Roughly half of all LCH cases are diagnosed in children, most of whom are between 1 and 3 years of age. (13) Approximately 3 to 5.4 children per million population are diagnosed each year. (13,14) Like cancer, LCH can affect almost any organ system. Its systemic manifestations include weight loss, lever, chills, and fatigue. The seborrheic, scaly, erythematous rash seen in our patient was a typical presentation.
When LCH involves the orbital wall, proptosis may be the presenting sign. LCH that affects the mastoid can mimic mastoiditis. Mandibular disease may lead to fractures, "floating teeth," gingivitis, or localized soft-tissue swelling. When LCH affects the endocrine system, the most common presentation is diabetes insipidus. When the anterior pituitary gland is involved, the production of growth hormone may drop. Central nervous system (CNS) involvement usually occurs late in the disease process. Dysarthria, dysphagia, ataxia, nystagmus, and cranial nerve symptoms indicate CNS involvement.
Disease course. The course of LCH is unpredictable. In some cases, it resolves without treatment. On the other hand, it can recur even after the initial response to treatment was successful. A chronic intermittent course is sometimes seen before the disease resolves. Therefore, follow-up into early adulthood is important for all children with LCH. Monthly visits for 1 year followed by annual visits thereafter are usually adequate. (15)
Sites of disease. LCH is sometimes limited to a single site, while in other cases it involves multiple sites and organ systems. Patients with isolated lesions fare better. Solitary lesions most often affect the skin, bone, or a lymph node. LCH is considered to be disseminated when two or more organ systems are involved. The head and neck is frequently involved in LCH; one study showed that 87% of patients had disease in this region. (16)
Patients with disseminated disease tend to be younger. The systemic, progressive form of the disease usually arises in children younger than 2 years, while the more benign isolated bone lesions usually affect children between the ages of 5 and 15 years. (7) Disease that causes organ failure is associated with a poorer outcome; almost all of the 10% of LCH patients who die from this disease experience organ failure of one type or another.
Laboratory tests must be performed to help determine if organs such as the liver or bone marrow are involved. The choice of tests and procedures performed during the initial work-up depends on where the lesion is located. For example, if the patient has pulmonary symptoms, bronchoalveolar lavage should be performed. When gastrointestinal involvement is suspected, biopsies should be taken. When it appears that the patient has diabetes insipidus stemming from pituitary involvement, a water-deprivation test may be indicated.
Classification of disease. Alessi and Maceri reviewed the cases of 28 children (age range: birth to 16 yr) who were treated for head and neck LCH at Children's Hospital of Los Angeles and devised a straightforward classification system for LCH (17):
* Patients with type 1 (benign) disease were usually treated with curettage alone, and they did very well. Clear margins were not a primary surgical goal.
* Patients with type 2 (intermediate) disease had lesions at multiple sites. They required surgery or radiation therapy, and they tended to survive, albeit with varying degrees of morbidity.
* Patients with type 3 (disseminated) disease were youngest (age range: 2 wk to 2 yr). Bone marrow was usually involved. They were treated with chemotherapy, but none survived. Alessi and Maceri concluded that surgery might have a role in certain patients with disseminated disease, but only as a palliative measure.
Angeli et al reviewed a series of 25 cases of head and neck LCH in children aged 6 months to 17 years. (11) In this group, 16 patients had type 1 disease, 8 had type 2 disease, and 1 had type 3 disease:
* Of the 16 patients who had type 1 disease, 14 had skull involvement and 2 had mandibular involvement. Curettage was the mainstay of treatment. In 2 of these patients, surgery was limited because of orbital involvement, so postoperative radiation was administered as well. All patients in this group were disease-free at 11 years of follow-up.
* The 8 patients who had type 2 disease without visceral involvement underwent surgery when possible; otherwise, they were treated with radiation or chemotherapy. Most of these patients were alive with disease several years after presentation.
* The patient who had type 3 disease involving vital organs was 1 year old at presentation and died of LCH within 1 year.
Irving et al reported a retrospective study of LCH in 131 children aged 5 days to 16 years (male to female ratio: 1.7:1; mean follow-up: 5.2 yr). (15) Some 62% of these patients exhibited head and neck involvement at presentation, and 73% experienced head and neck manifestations during their disease course. The authors found that the most frequently affected area of the head and neck was the skull vault (48% of cases), followed by the meatal skin of the external auditory canal (24%) and the cervical lymph nodes (21%). The temporal bone was involved in 19% of cases, the maxilla in 10%, and the mandible in 6%. They found an association between meatal skin involvement and multisystem disease. They also found that 78% of patients with cervical node involvement had multisystem disease. Some 95% of the skull lesions resolved with treatment, regardless of whether the patient had multi-system disease. A poor outcome was associated with presentation at age 2 years or younger, vital organ dysfunction, and multisystem disease.
In the presence of multisystem disease, Irving et al found that head and neck lesions tended to resolve very well with medical treatment. (15) They recommended a 1-month course of prednisolone at 2 mg/kg/day, followed by a 2-month taper. Patients who fail to improve on this regimen should be given a course of either a vinca alkaloid or etoposide. Of course, it is important to consider the side effects of aggressive chemotherapy, which include secondary malignancy, sepsis, azoospermia, and immunosuppression. (18)
Watchful waiting may be the best approach to single-system disease involving the head and neck. In many cases, lesions regress spontaneously without treatment. (15,19) When treatment is necessary, a minimalist approach should be selected--one that includes a topical steroid, topical mustine (nitrogen mustard, an alkylating agent), and possibly steroid injections. According to Irving et al, surgery should be considered for treatment of head and neck disease only when there is progression despite medical treatment or when delicate structures such as the optic nerve or spinal cord are at risk. (15) When surgery is required, it can usually be limited to curettage or polypectomy. When a lesion cannot be reached surgically for example, in cases of deep temporal bone involvement or when surgery would threaten vital structures--radiation therapy may be administered. A dose of 550 to 600 cGy is safe, although as much as 1,000 cGy can be given without causing side effects. (15,20) Radiation therapy has been shown to be effective in treating these lesions, (21) but it can cause secondary malignancy, chronic otitis media, (22) and problems with bone growth in children. Irving et al recommended that radiation be used only as a last resort. (15)
Despite the high rate of head and neck involvement, Irving et al noted that LCH lesions cause relatively little morbidity. In their experience, morbidity related to head and neck disease was more likely to be caused by aggressive surgery than by the disease itself. Their study spanned 30 years, and the authors noted a change in their therapeutic approach over time. Initially, LCH was considered to be a type of malignancy and was therefore treated aggressively. Toward the latter part of their study, they came to view the disease as more akin to a reactive process, and it is now treated more conservatively at their institution. (23)
Otologic manifestations. Otologic manifestations have been reported to occur in 15 to 61% of patients with LCH. (3,24-27) Bilateral ear or temporal bone involvement has occurred in as many as 30% of reported cases. (3,22,27) Although the ear and temporal bone are commonly affected, the disease is often more significant in other areas; as a result, otologic LCH may be overlooked. (3)
Differentiating temporal bone disease from LCH otitis externa on physical examination can be challenging. (15) Temporal bone disease is more often a localized process that involves mastoid swelling and the presence of polyps or granulation tissue in the ear canal. Soft-tissue infiltration into the external ear canal can cause conductive hearing loss. Otorrhea and sometimes otalgia can be present. Polyps tend to originate in the mastoid and break through the canal wall in a posterosuperior direction. The tympanic membrane, ossicles, and middle ear are usually not involved. When the middle ear is involved, it is usually because of a secondary infection rather than direct extension. (15,24,28)
Otitis externa tends to appear in the presence of systemic disease and is often associated with extensive skin disease involving the scalp. (15) On examination, there is often so much debris present that it is difficult to determine whether the patient has otitis externa or polyps. In such cases, it is best to take the patient to the operating room for an examination under anesthesia. Overall, otologic LCH rarely presents with otalgia or facial nerve, inner ear, or ossicular chain involvement. It is important to keep in mind that LCH may mimic other diseases such as cholesteatoma. The only way to be certain is to obtain a tissue diagnosis.
Surgical intervention for otologic LCH has been associated with a high rate of complications. (15) Mastoid disease can obscure normal facial nerve landmarks, thereby putting this structure at undue risk. In addition, middle ear surgery could lead to inner ear involvement. (29) Aggressive disease can expose the sigmoid sinus and dura, (30) thereby increasing the risk of a dural tear if operative management is selected. Fistula is also a frequently reported complication of surgery. (15,27))
Irving et al found that the surgical complication rate was high and the rate of disease control was low. (15) Of the 8 surgical patients in their series who underwent some form of mastoidectomy, 2 developed a complete sensorineural hearing loss and 2 developed postauricular fistulae. All required further treatment. One patient ultimately died of multisystem disease. Also in that series, 17 patients with temporal bone involvement were treated conservatively. Nonmedical intervention in these patients was limited to aural polypectomy, plus radiation therapy in 1 patient. Disease was controlled in all cases, although 1 patient developed mild bilateral sensorineural hearing loss. The authors concluded that conservative treatment for otologic LCH is superior to surgery.
When surgery is chosen, the transcanal approach is often the most straightforward and least invasive means of obtaining a biopsy specimen. However, this approach may yield only superficial granulation tissue. Furthermore, there has been at least one report of facial nerve injury during the transcanal approach. (3) In that case, a prebiopsy CT would likely have shown erosion of the facial nerve canal and alerted the surgeon to a potentially displaced nerve. While Irving et a1 (15) found otherwise, the transmastoid approach may be a more reliable way of obtaining a definitive biopsy specimen. The lesion is usually present on the temporal bone surface and can be easily accessed. Lesions limited to the mastoid cortex can be treated with simple mastoidectomy, but they have also been reported to heal on their own. (31)
Otologic LCH usually responds well to medical therapy. In the series by Irving et al, patients who received systemic treatment experienced a resolution of their otitis externa. (15) The authors found that mustine drops were an effective treatment for otitis, although care must be taken when a tympanic membrane perforation is present because the drug can theoretically damage the inner ear. In patients with localized disease, researchers have found that only 50% responded to steroid drops while 100% responded to mustine drops (20 mg/dl). (15,32)
Some centers have used low-dose radiation both as an adjunctive treatment and as the sole treatment for temporal bone LCH. (22,33,34) By delivering a low but therapeutic dose, complications such as radiation otitis can usually he avoided. It is important to keep in mind that regardless of treatment, more than 90% of unifocal osseous lesions are cured. (35,36) Radiation therapy should therefore be used judiciously and rarely in type 1 disease of the temporal bone. Follow-up CT approximately 1 year following treatment has been recommended. (33)
Cunningham et al reported a series of 18 children, aged 2 months to 18 years, who had otologic symptoms of LCH. (3) Six of them presented with ear disease only, and 6 had bilateral temporal bone involvement. Manifestations were primarily otorrhea, conductive hearing loss, and postauricular swelling. Three patients had aural polyps. Only 1 patient had involvement of the otic capsule, as was demonstrated by presentation with vertigo, nystagmus, and sensorineural hearing loss. Another patient had disease-related facial paralysis. Cunningham et al pointed out that these patients were at risk for having their diagnosis missed and being treated for chronic ear disease. When an ear infection does not respond to standard treatment, a noninfectious cause such as LCH should be considered. Cunningham et al stressed that a temporal bone CT with contrast is a key study in such patients--not only to help establish a diagnosis, but also to provide guidance for surgical intervention or biopsy. In some cases, CT is also necessary to define radiation portals. In the series of Cunningham et al, 9 of the 18 patients were treated with radiation therapy. It is interesting that 11 of the 18 patients had systemic disease and were treated with chemotherapy. Cunningham et al thereby identified a positive association between otologic manifestations and systemic disease.
Radiologic evaluation. CT is the gold standard for imaging temporal bone LCH. Marioni et al pointed out that temporal bone CT usually identifies destructive mastoid lesions with indistinct margins; the middle ear, ossicles, and squamous part of the temporal bone are often spared. (37) There is usually a contrast-enhancing homogenous soft-tissue mass of variable size associated with the bony erosion. CT is helpful not only in helping establish the diagnosis, but also for follow-up.
In cases when there is erosion into the cranium, an intracranial soft-tissue mass may be visible on CT. In these situations, magnetic resonance imaging (MRI) can help delineate the relationship between the lesion and delicate intracranial structures. The soft-tissue mass will appear hyperintense on T2-weighted MRI and will range from isointense to hypointense on T1-weighted imaging. The mass will enhance with gadolinium and will often be associated with perilesional edema or inflammation. (37) Fernandez-Latorre et al reported a retrospective series of 14 LCH patients with temporal bone involvement from the radiologist's perspective. (38) All but 2 of these patients had temporal bone disease at presentation. Patients were evaluated by CT both initially and during a follow-up that ranged from 2 to 14 years (mean: 5). Four patients had bilateral disease. Bony destruction was obvious on CT in all patients, and all but 2 had an associated soft-tissue mass on CT. In 2 patients, the mass was heterogenous. Although the authors did not specify any treatment methods in their report, they noted that the lesions resolved in half of these patients. They also reported that patients with multisystem disease tended to have recurrent skull lesions that were more aggressive than the initial temporal bone lesions. These recurrent lesions tended to involve the greater wing of the sphenoid bone. In addition, 4 of the 6 patients with multisystem disease developed diabetes insipidus. The authors noted that resolution is heralded on CT when the soft-tissue mass disappears. Fernandez-Latorre et al also observed that reossification tended to occur approximately 1 year later. Although Marioni et al (37) found that LCH rarely involved the squamous part of the temporal bone, Fernandez-Latorre et a1 (38) found squamous lesions in 8 of their 14 patients.
According to Goldsmith et al, LCH of the temporal bone is rarely limited to the petrous apex, although they did describe 2 such cases in their series. (39) Nine of the 14 patients in the series by Fernandez-Latorre et al had middle ear lesions, and there was a relatively high rate of ossicular involvement (14.4%). (38)
Skeletal x-rays play an important role at the time of diagnosis and in surveying bony involvement of LCH. On x-ray, LCH lesions typically have a "shining" quality. They often show a beveled edge with sclerotic margins. The lesions may also appear to be well circumscribed. They may also have a punched-out appearance, (3,28) although this finding is hardly exclusive to LCH.
On bone scintigraphy, lesions may take up tracer material uniformly or they may appear to have a low-uptake focus with a high-uptake rim. Howarth et al found that the sensitivity and specificity for detecting LCH lesions were 100 and 61%, respectively, on x-ray; the corresponding figures for bone scintigraphy were 91 and 55%. (40) This suggests that x-ray is the more appropriate method for evaluating and following LCH.
In conclusion, we recommend a minimalist approach that is limited to biopsy whenever possible. More research needs to be conducted so that we may better understand the mechanisms of LCH and to help us predict when the disease will be benign and resolve on its own and when it will be aggressive and unremitting and require treatment.
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From the Department of Otolaryngology-Head and Neck Surgery, Keck School of Medicine, University of Southern California, Los Angeles.
Reprint requests: Dale H. Rice, MD, Department of Otolaryngology-Head and Neck Surgery, Keck School of Medicine, 1200 N. State St., Box 795, Los Angeles, CA 90033. Phone: (323) 226-7315; fax: (323) 226-2780; e-mail: email@example.com
Originally presented during the 14th annual conference of the Southern California chapter of the American College of Surgeons; Jan. 25, 2003; Santa Barbara, Calif.
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|Author:||Rice, Dale H.|
|Publication:||Ear, Nose and Throat Journal|
|Date:||May 1, 2004|
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