Successful Treatment of Adult Onset Langerhans Cell ...

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□ CASE REPORT □

Successful Treatment of Adult Onset Langerhans CellHistiocytosis with Multi-Drug Combination Therapy

Eri Matsuki 1, Yuiko Tsukada 1, Aya Nakaya 2, Kenji Yokoyama 1 and Shinichiro Okamoto 1

Abstract

Adult onset Langerhans cell histiocytosis (LCH) is a rare disorder. Its clinical features have been well de-

scribed in children, however remain poorly defined in adults. Optimal treatment strategy is still under debate.

We have encountered two cases of adult onset LCH, which obtained a durable disease control by combina-

tion chemotherapy using prednisone, vinblastine and 6-mercaptopurine. Herein, we report their clinical fea-

tures together with a review of the current literature.

Key words: Langerhans cell histiocytosis, combination chemotherapy, adults

(Intern Med 50: 909-914, 2011)(DOI: 10.2169/internalmedicine.50.4808)

Introduction

Langerhans cell hisitocytosis (LCH) is characterized by a

clonal proliferation of Langerhans cells that predominantly

occurs in infants and small children. Patients with localized

disease or diseases limited to single organ system have a

good prognosis, thus local therapy or close follow-up with-

out therapy would be an appropriate treatment choice. In

contrast, multisystem disease with multiple organ involve-

ment carries a poor prognosis requiring therapy with cyto-

toxic drugs and/or steroids (1-3). In one report of 101 chil-

dren with LCH, the overall survival rate was 79% at 1 year

and 71% at 5 years, however, in patients with liver or spleen

involvement, 1 year survival was 33% and 5 year survival

was 25% (4).

LCH in adults is extremely rare, therefore, its clinical pic-

ture is not fully understood and optimal treatment is not es-

tablished. Only a few reports describing a series of adult pa-

tients with LCH are currently available (5-8). We herein re-

port two cases of adult-onset multisystem LCH in Japanese,

which obtained a durable disease control by combination

chemotherapy together with a review of the current litera-

ture.

Case Report

Case 1

A 27-year-old man was admitted to our hospital for the

evaluation of multiple lung nodules in August 2007. The pa-

tient had noticed the appearance of skin rashes on his fore-

head since 2004. In 2006, he started complaining of tinnitus

and excessive thirst, and frequent urination. Head MRI was

performed and a diagnosis of diabetes insipidus (DI) was

made. CT scan of the head also showed destruction of his

temporal bone leading to the occlusion of his external ear

canal. During the work-up, multiple small lung nodules

were found on his chest X-ray. Needle biopsy of the tempo-

ral bone and transbronchial lung biopsy showed eosinophilic

granuloma. He was put on course observation with smoking

cessation, however, no clinical improvement was noted. The

patient was referred to our hospital for further treatment.

Upon admission, physical examination revealed a mass of

2 cm in his right neck. Skin eruptions of 3 to 5 mm with

partial impetigo-like lesions were scattered over his forehead

and scalp. Hepatosplenomegaly was not evident. He denied

any recent weight loss or persistent fever. The results of

blood analysis were all within normal limits except for an

increased CRP level (Table 1). Chest X-ray and CT scan

１Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Japan and ２Department of Internal Medicine,

Tokyo Dental College Ichikawa General Hospital, Japan

Received for publication November 8, 2010; Accepted for publication January 10, 2011

Correspondence to Dr. Eri Matsuki, [email protected]

Intern Med 50: 909-914, 2011 DOI: 10.2169/internalmedicine.50.4808

910

Table　1.　Laboratory Findings of the Two Patients

Case 1 Case 2 WBC (/ L) 7800 4300 Neutro (%) 70.5 59.1 Lymph (%) 19.8 26.3 Mono (%) 8.3 6 Eosino (%) 1.3 8.1Baso (%) 0.1 0.5

RBC (×106/ L) 4.72 4.75 Hb (g/dL) 13.7 13.2 Hct (%) 40.7 42.7

Plt (×104/ L) 37.6 31.8 TP (g/dL) 7.7 7.8

Cr (mg/dL) 0.8 0.8 LDH (IU/L) 223 249

CRP (mg/dL) 1.91 0.19 Na (mEq/L) 144.3 143.8 K (mEq/L) 3.6 4.3 Cl (mEq/L) 106 105

ADH (pg/mL) - 0.44 Ca (mg/dL) 9.1 9.6 Osmolality - 289

Urine Osmolality - 100

showed multiple small nodules with some emphysematous

change in his upper to middle lung fields. CT scan also

showed multiple lytic bone lesions in his cranial and pelvic

bones and solid masses in the thyroid gland and mediasti-

num (Fig. 1). Skin biopsy from his forehead showed prolif-

eration of Langerhans cells with indented nucleus; the cells

were positive for S-100 and CD1a by immunostaining. Pro-

liferation of lymphocytes and eosinophils was also seen.

Electronmicroscopy showed Birbeck granules within the

proliferating cells (Fig. 2). Based upon these findings, a di-

agnosis of multi-system LCH was made.

He was started on treatment with prednisone and vin-

blastine, according to the LCH-A1 protocol (briefly, vin-

blastine 6 mg/m2 i.v. once a week and oral prednisone 1 mg/

kg daily for four weeks, followed by tapering off of corti-

costeroids over two weeks period. Continuation therapy was

planned with mercaptopurine 30 mg/m2 orally every day

with vinblastine 6 mg/m2 i.v. every three weeks and predni-

sone p.o. 1 mg/kg on days 1-5 every three weeks up to six

months) (9). His skin eruptions had completely disappeared

by six weeks of treatment. CT scan three months after the

beginning of therapy showed improvement in the obstruction

of his external ear canal, however, no significant change was

seen on other mass lesions including multiple lung nodules.

The response to the treatment was considered as AD-better

(a state where the patient shows continuous regression of the

disease) according to the criteria by the Histiocyte Soci-

ety (10).

The patient self-discontinued his treatment at this point,

and returned to the clinic one month later, with reappear-

ance of the skin eruption over his forehead. CT scan at the

time confirmed no exacerbation of other systemic lesions.

He was placed on continuation treatment with 6-

mercaptopurine (6-MP), vinblastine and prednisone. After 6

months of continued therapy, he had again obtained AD-

better, where his lung and termporal bone lesions showed

further improvement and remained stable, but had not disap-

peared. After a total of 9 months of treatment, his treatment

was stopped as per protocol. One month after discontinu-

ation of therapy, he returned to the clinic again with reap-

pearance of the skin eruptions. No other exacerbation of

preexisting lesions was clinically noted. Prednisone 0.5 mg/

kg was restarted, resulting in marked improvement of his

skin lesion. He is currently being tapered from his steroid

treatment with no recurrence.

Case 2

A 43-year-old woman started complaining of right thigh

pain in early 2003. A solitary lytic bone lesion of the right

femur was found by CT scan; a needle biopsy was per-

formed that showed proliferation of Langerhans cells that

were positive for S-100 by immunostaining, with infiltrating

small lymphocytes and eosinophils (Fig. 3). A diagnosis of

LCH was made. Since systemic evaluation showed no other

lesions, she was put on observation as an outpatient. In June

2007, she gradually developed pain on her left buttock and

back, and was found to have multiple bone lesions in the

cranial and pelvic bone and spine by CT scan. She also

complained of frequent urination, excessive thirst and was

referred to our hospital for further treatment.

Upon admission, physical examination showed increased

deep tendon reflex on both upper and lower extremities,

pain on movement of the neck. Exophthalmos, skin rashes

and hepatosplenomegaly were not noted. The patient also

denied recent body weight change or persistent fever. Blood

analysis showed elevated eosinophil count and increased se-

rum osmolality with decreased urine osmolality (Table 1).

CT scan showed multiple bone lesions with a new lesion

identified in the scapula. Bone scan was performed that

showed consistent result with the multiple lytic bone lesions

on CT scan. MRI showed atlantoaxial subluxation with en-

hancement of the surrounding soft tissue, and absent signal

in the posterior pituitary gland on T1-weighted images

(Fig. 4). A diagnosis of DI was made.

Since the patient presented with pathological fracture of

the cervical spine, she was initially treated with radiation of

10 Gy (2 Gy ×5) and subsequently with systemic chemo-

therapy according to the LCH-A1 protocol.

During the initial treatment, the patient developed grade 3

peripheral neuropathy, and vinblstine was omitted from sub-

sequent treatment cycles. After six-weeks treatment with 6-

MP and prednisone, her back pain decreased that enabled

her to walk without support. Treatment was completed in

approximately 6 months and she was off therapy at the end

of March 2008. Radiologic examination at that time showed

disappearance of the enhancing soft tissue mass around her

cervical spine, with persistent bone lesions. Clinical symp-


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Figure　1.　Physical and radiographic findings of case 1. Skin eruptions of 3 to 5 mm with partial impetigo like lesions were seen over his forehead (a). CT scan showed partial emphysematous chang-es with multiple small granular lesions in the middle lobe of the lungs (b). Masses in the thyroid gland (3 cm in diameter) (c) and mediastinum (4 cm in diameter) (d) and multiple lytic bone lesions in the pelvic bone (e) and temporal bone (f).

(a)

(b)

(c)

(d)

(e)

(f)

toms of DI were unchanged. She was assessed to have ob-

tained NAD (no active disease) by the criteria of the Histio-

cyte Society. She has been followed up with no exacerbation

of the disease until July 2010.

Discussion

There are several reports with a reasonably good number

of patients on systemic treatment for LCH in children.

DAL-HX83 and DAL-HX90 regimens consist of initial

treatment with prednisone, vinblastine and etoposide, fol-

lowed by continuous treatment with oral mercaptopurine and

intermittent administration of prednisone, vinblastine,

etoposide and methotrexate, according to disease risk. The

initial response rate was 79% and the probability of reacti-

vation of the disease was 36% at a median follow up of 7.5

years (11). LCH-I study was the first international random-

ized prospective study that compared the efficacy of vin-

blastine or etoposide and 53% of the patients were judged

as responders. Reactivation of the disease was observed in

58% of the patients at a median of 9 months after achieving

CR (12). Comparing these results, the combination therapy

seemed to yield a better response with respect to the rates of

initial response and reactivation. Therefore, LCH-II was con-

ducted that stratified the patients into high-risk and no-risk

groups according to the extent of risk organ involvement (i.

e. involvement of the liver, spleen, lung or hematopoietic

system) and age. The high-risk group was randomized be-

tween initial treatment with the 2-(prednisone and vin-

blastine) or 3-(prednisone, etoposide and vinblastine) drug

arm followed by continuation therapy with 6-MP and pulses

of oral prednisone and vinblastine or the same regimen with

the addition of etoposide, respectively. Patients in the no-

risk group were assigned initially to the 2 drugs and subse-

quently received continuation therapy without 6-MP. Re-

sponse in the high-risk group improved to 67% compared to

43% in LCH-I. Mortality also decreased in this group with

44% in LCH-1 to 27% in LCH-II. Comparison between the

2- and 3-drug regimen in the high-risk group for LCH-II

showed similar outcomes in terms of rapid response (2-drug

vs 3-drug: 63%/71%), 5-year overall survival (74%/79%),

disease reactivation rate (46%/46%) and the occurrence of


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Figure　2.　Histological findings of the skin eruption over the forehead (a). Hematoxylin and Eosin staining showed a proliferation of Langerhans cells which were positive for both S-100 (b) and CD1a (c) by immunostaining. Electron microscopy confirmed typical Birbeck granules in the proliferating cells (d).

(a) (c)

(b) (d)

Figure　3.　Hematoxylin and Eosin staining of the biopsy of the bone at initial presentation in case 2.

permanent consequences (43%/37%). However, for those

with risk organ involvement, mortality was reduced in the 3-

drug regimen group with a hazard rate of 0.54 (95% CI =

0.29-1.00) (13). LCH-III study is currently ongoing to solve

the questions of whether longer treatment or more intense

treatment would benefit certain risk patients using regimens

including methotrexate.

In contrast to children, treatment of LCH in adults has

been challenging due to the small number of patients. Tsele

et al treated three patients with LCH with etoposide

alone (14). All patients achieved clinical remission lasting

for more than a year. Giona et al treated 11 patients with

LCH according to their clinical presentation (8). They were

treated with either localized surgery or some kind of com-

bined chemotherapy. Those who relapsed were treated with

interferon. Altogether 5 patients remained in complete re-

sponse at the time of last follow-up including those after

salvage therapy. Saven and Burian conducted a phase II trial

of cladribine, either at 0.1 mg/kg/day for 7 days by continu-

ous intravenous infusion or 0.14 mg/kg/day over 2 hours in-

travenously for 5 consecutive days, repeated every 4

weeks (15). Of the 12 evaluable patients, 7 had achieved

complete responses and 2, partial response. Derenzini et al

recently reported the efficacy of MACOP-B regimen in 7

adults with LCH (16). The overall response rate was 100%

with 57% of the patients remained in first CR with a me-

dian follow-up of 6.5 years. Although the number of pa-

tients enrolled was very small, it is plausible that a certain

population of LCH in adults may benefit from intensive che-

motherapy regimens.

Although it still remains to be elucidated whether previ-

ously identified poor risk factors such as the involvement of

certain risk organs (liver, spleen, lung and hematopoietic

system) at the time of diagnosis and response at 6 weeks of

treatment would allow for patient stratification and therapy

adjustment in pediatric patients, it needs to be determined

whether these risk factors are applicable to adults as well.

Treatment results of the present patients suggest that risk or-

gan involvement may also be a good prognostic marker for

adult patients. Also, Derenzini et al evaluated PET positivity

in four patients, and identified PET negativity as a possible

predicting factor for durable CR (16). The number of pa-


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Figure　4.　Radiographic findings at the time of admission in case 2. Multiple lytic bone lesions were noted on CT scan and bone scan (arrow head) (a), (d). MRI of the pituitary gland showed decreased intensity of the posterior pituitary gland on T1 weighed image (b). MRI also showed atlantoaxial subluxation with enhancement of the surrounding soft tissue in the cervical and thoracic spine (ar-row head) (c).

(a)(b)

(c)

(d)

tients is still very limited, and further study is necessary to

identify whether PET is useful to determine the duration of

the treatment response.

In conclusion, we present the treatment outcome of two

cases of adult LCH. Treatment with combination of cyto-

toxic drugs and prednisone as in LCH-A1 protocol seemed

effective with long lasting remission in one case. Treatment

of adult LCH needs further evaluation with identification of

associated risk factors. International registration and clinical

trials are clearly warranted in order to establish risk-

adjusted, optimal treatment.

The authors state that they have no Conflict of Interest (COI).

AcknowledgementWe thank Dr. Yukiko Tsunematsu (Hosen College of Child-

hood Education) for her meaningful advice on the selection of

treatment for our patients.

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