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1108 Part VIII: Monocytes and Macrophages Chapter 71: Inflammatory and Malignant Histiocytosis 1109

Marrow failure secondary to LCH or from therapy is rare but is are (in order of decreasing frequency) dyspnea or tachypnea, polydip-
associated with a higher risk of malignancy. Patients with LCH may sia and polyuria, bone pain, lymphadenopathy, weight loss, fever, gin-
97
have a higher than normal risk of developing secondary cancers. Leu- gival hypertrophy, ataxia, and memory problems. Among the signs of
kemia (usually acute myelogenous) occurs after treatment as does lym- LCH are skin rash, scalp nodules, soft-tissue swelling near bone lesions,
phoblastic lymphoma. Concurrent LCH and a malignancy have been lymphadenopathy, gingival hypertrophy, hepatosplenomegaly. Patients
reported in a few patients, and some patients have had their malignancy who present with isolated DI should be carefully observed for onset
initially followed by development of LCH. Three patients with T-cell of other symptoms or signs characteristic of LCH. At least 80 percent
acute lymphoblastic leukemia (T-ALL) and aggressive LCH, for which of patients with DI had involvement of other organ systems: bone
the two disorders had shared clonal markers have been reported. 98,99 (68 percent), skin (57 percent), lung (39 percent), and lymph nodes
Two cases had clonality of the same T-cell receptor genotype. The (18 percent). 107
authors considered the plasticity of lymphocytes permitting develop- Many patients have a papular rash with brown, red, or crusted areas
ment into LCs. The other patient with LCH after T-ALL had the same ranging in size from a pinhead to a dime. In the scalp the rash is similar
T-cell receptor gene rearrangements and activating mutations of the to seborrhea. Skin in the inguinal region, genitalia, or around the anus
NOTCH1 gene in the patient’s DCs and acute lymphoblastic leukemia may have open ulcers that do not heal after antibacterial or antifungal
(ALL) blasts. A series of four patients with acute leukemia of ambiguous therapy. In the mouth, swollen gums or ulcers along the cheeks, roof
100
or myeloid lineage with intermingling LCH cells have been reported. of the mouth, or tongue occur. In a series of 18 patients with skin LCH
The authors speculated the two diseases shared a common hematopoi- collected from 5 centers in the Netherlands followup revealed 5 devel-
etic stem cell as had been suggested earlier during investigation of the oped malignancies which included 2 with myelomocytic leukemia,
BRAF V600E mutation in the marrow of LCH patients. 6 1 with histiocytic sarcoma, and 2 with lymphomas. A literature review
produced 6 additional cases of adults who had skin LCH and subse-
ADULT LANGERHANS CELL HISTIOCYTOSIS quently developed hematologic malignancies. 108
Incidence The sites of bone involvement in adults differ from that of children.
It is estimated that one to two adult cases of LCH occur per 1 million Lesions in the mandible occur in 30 percent of adults versus in 7 percent
population. The true incidence of this disease is difficult to assess of children, and skull lesions in occur 21 percent of adults versus in
101
102,109
because large published studies usually are from referral centers and 40 percent of children. The frequency of LCH lesions in the verte-
the disorder often is underdiagnosed. A survey from Germany reported brae (13 percent), pelvis (13 percent), extremities (17 percent), and ribs
that 66 percent of the adult LCH patients were women with an average (6 percent) of adults is similar to that found in children.
age of 43.5 years. 102 Pulmonary LCH is slightly more prevalent in smokers than in non-
smokers and the male-to-female ratio may be near unity depending on
Pathogenesis the incidence of smoking in the population studied. 44,102,110 Patients with
There are no studies to compare the biology of LCH in adults and chil- pulmonary LCH usually present with cough, dyspnea, or chest pain,
dren. The association of adult pulmonary LCH with smoking and evi- although nearly 20 percent of adults with lung involvement have no
111
dence that the incidence of BRAF V600E mutations in adult LCH tissue is symptoms. The sudden onset of chest pain may indicate a spontane-
not the same as in the pediatric population indicates some differences. ous pneumothorax. The most frequent pulmonary function abnormality
The LCs in adult lung lesions are mature DCs expressing high levels of finding (80 percent of patients) with pulmonary LCH is a reduced carbon
the accessory molecules CD80 and CD86, unlike LCs found in other monoxide diffusing capacity. 112,113 A long-term retrospective study of 49
lung disorders. Molecular studies have shown pulmonary LCH in pulmonary LCH patients showed that lung function deteriorated within
103
adults is primarily a reactive process, rather than a clonal proliferation 2 years in 60 percent of patients and the forced expiratory volume in 1
as seen in childhood LCH. Subsequent investigations by this group second (FEV ) and diffusing capacity in lung for carbon dioxide (DLCO)
104
1
114
with the Ion AmpliSeq technology showed two of five adult pulmonary were the parameters that most often declined. Airway obstruction
LCH patients had the BRAF V600E mutation. An analysis of BRAF V600E was the most important functional pattern observed, which correlated
105
expression by immunohistochemistry (IHC) and molecular techniques with the percent predicted FEV . In this series, the investigators found
1
(allele-specific polymerase chain reaction [PCR] and Sanger sequenc- pulmonary function tests much better than serial CTs for following the
ing) has also been reported for a series of adults with isolated pulmo- disease course and response to therapy. A high-resolution CT scan can
nary LCH and others with nonpulmonary lesions. Of the pulmonary uncover cysts and nodules, usually in the upper lobes characteristic of
106
LCH cases 7 of 25 (28 percent) were positive for BRAF V600E expression LCH. Despite the typical CT findings, a lung biopsy is needed to confirm
115
by IHC. The cumulative pack-years of smoking was significantly higher the diagnosis. The presence of cystic abnormalities on high-resolution
116
in the BRAF-positive adult pulmonary LCH patients than in the wild- CT scans does not predict which patients will have progressive disease.
type BRAF cases. Only 19 of 54 (35.2 percent) of the nonpulmonary Adults with pulmonary LCH can have multisystem disease, including
cases had the BRAF mutation. The frequency of BRAF V600E mutation in bone (18 percent) or skin (13 percent) lesions and DI (5 percent).
North American pediatric series ranged from 57 to 65 percent based
on deep sequencing and quantitative PCR. It is possible that techni- Therapy
5,19
cal differences in sensitivity underlie the relatively decreased reported Although adult patients have been treated with vinblastine and pred-
frequency of BRAF V600E in adult cases of LCH. Further studies in adult nisone, vinblastine often causes significant neuropathy in adults when
patients will be needed to determine if age or ethnicity influence the role given weekly for 6 weeks, and glucocorticoids are not tolerated as well
of BRAF mutations in LCH pathogenesis. by adults as children. Alternative approaches in adults for initial ther-
apy include either intravenous cytarabine or intravenous cladribine. The
Clinical Findings latter is effective for adults with skin, bone, lymph node, and probably
Adult LCH patients may have symptoms and signs for many months pulmonary and mass lesions in the CNS. 79,117,118 A review of 58 adults
before a definitive diagnosis is made and treatment instituted. LCH in with bone lesions compared the efficacy and toxicity of intravenous vin-
adults is often similar to that in children, except that isolated adult pul- blastine plus oral prednisone to intravenous cladribine or cytarabine.
119
monary LCH is closely associated with smoking. Presenting symptoms In this retrospective review, cytarabine had the best outcomes, with 21

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