Association of langerhans cell histiocytosis with malignant neoplasms

865

Association of Langerhans Cell Histiocytosis with Malignant Neoplasms R. Maarten Egeler, M.D.,* Joseph P. Neglia, M.D., M.P.H.,* Diane M . Puccetti, M.D.,t Carroll A. Brennan, M.D.,* and Mark E. Nesbit, M.D.*

Background. The association of Langerhans cell histiocytosis (LCH) with a malignant neoplasm is rare and generally has been the subject of isolated case reports .

A recent case of LCH seen at the Univer- sity of Minnesota in combination with acute lymphoblastic leukemia led the authors to review their own charts from 1960 onward, in addition to the literature for other reported associations of LCH and malignant neoplasms.

Results. In addition to the presented case and 3 cases from the files of the authors, the literature con- tained 87 reported cases. Of the 91 patients, 39 had LCH with malignant lymphoma (ML); 25 of these cases were Hodgkin disease. In 11 of these 39 patients, the LCH was diagnosed from 12 months to 33 years after the ML was diagnosed. In 62% of the patients with LCH-ML (24 patients), the diagnosis was made concurrently and the Langerhans cells were found in the same lymph nodes. In the remaining four patients, the diagnosis of LCH preceded that of ML by 6-24 months. In 22 patients, including 2 patients in the files of the authors, LCH was reported in association with leukemia; 16 (73%) of these cases were associated with acute nonlymphoblastic leukemia. In two cases the leukemia preceded the LCH. In 6 patients both diagnoses were made concurrently, and in 14 patients (64%) the diagnosis of LCH preceded the diagnosis of leukemia by 8 months to 17 years. In the remaining 30 patients, LCH was associated with a variety of solid tumors, including a lung carcinoma in 12 patients. In all of these 12 cases the LCH was confined to the lung,

Methods.

From the *Section of Pediatric Hematology-Oncology, Depart- ment of Pediatrics, University of Minnesota School of Medicine, Min- neapolis, Minnesota; and the tDepartment of Pediatrics, Section of Pediatric Hematology-Oncology, Indiana University Hospitals, James Whitcomb Riley Hospital for Children, Indianapolis, Indiana.

Supported in part by the Children's Cancer Research Fund of the University of Minnesota; Dr. Egeler is supported by the Ter Meu- len Fonds, the Royal Academy of Arts and Sciences, Amsterdam, The Netherlands.

Address for reprints: R. Maarten Egeler, M.D., Section of Pediat- ric Hematology-Oncology, Department of Pediatrics, University Hos- pital of Minnesota, Box 484 UMHC, Harvard Street at East River Road, Minneapolis, MN 55455.

Accepted for publication July 20, 1992.

and in 75% (9 of 12) of patients the diagnoses were made concurrently. In the 16 patients in whom the LCH preceded the solid tumor, the malignant diseases in 69% (11 of 16) developed within the radiation field used for the treatment of the LCH.

Conclusions. The intimate andsimultaneous association of LCH with ML and lung carcinomas suggests strongly that the process that leads to the association is a reactive one. However, in the patients with leukemia and the other solid tumors, the latency of the malignant neoplasm after the diagnosis of LCH is suggestive of a therapy-related process. Cancer 1993; 71:865-73.

Key words: Langerhans cell histiocytosis, malignant lymphoma, leukemia, neoplasm, childhood.

Langerhans cell histiocytosis (LCH) may present in a variety of clinical situations, ranging from a solitary lesion of bone to a multisystem, life-threatening disorder.' It generally is believed that the diagnostic cell, the Langerhans cell, originates in the bone and represents a subset of a larger family of morphologi- cally distinctive cells, referred to as dendritic cells. These dendritic cells share properties with monocytes and macrophages but possess distinctive cytomorpho- logic, immunohistochemical, ultrastructural, immunophenotypic, and functional characteristics that permit their identification within the monocyte-macrophage lineage.'

Although widely disseminated variants of LCH clinically may resemble a malignant neoplasm, LCH is not believed to be a neoplastic disorder because cytolog- ically mitotic figures are sparse or absent.' In an attempt to quantify the percentage of cytologic atypia and mitotic activity in LCH, Risdall et al. reviewed 51 cases.' In half the cases (25 of 51), mild cytologic atypia was found. The mitotic rates were low, ranging from 0 to 23 per 10 high-power fields, with a median of 2. In most patients, DNA content analysis of LCH cells by flow cytometry has not shown aneuploid subpopulations.6 However, a case can show DNA aneuploidy sporadi- ally,^,^ and it must be investigated whether this pres-

866 CANCER February 1, 2993, Volume 71, No. 3

ence has any value in indicating the course and out- come of the d i ~ e a s e . ~

In general reviews of LCH, the association with a malignant neoplasm is discussed rarely; however, a recent case of LCH seen at the University of Minnesota in combination with acute lymphoblastic leukemia (ALL) led us to review our own charts from 1960 to the present, in addition to the literature, for other reported associations between LCH and malignant neoplasms.

Case Report

The patient, a 3.5-year-old boy, had a mild sore throat, lymphadenopathy, and splenomegaly. Laboratory investigations showed a leukocyte count of 328,500/mm2 and a lactic dehy- drogenase level of 3240 U/1. A bone marrow aspirate con- tained 88% blasts ( l O O o / ~ French-American-British L1) with T-cell markers. A diagnosis of ALL was made. Cytogenetic studies of the bone marrow showed 46XY with a 9p deletion.

The patient was treated with chemotherapy and received 18 Gy of cranial radiation therapy. Remission of ALL was documented at day 28 of therapy. Ten months later he was readmitted to the hospital with multiple skin lesions, consisting of raised cherry-red papules on the chest and back. Bone marrow and cytogenetic studies showed no evidence of a relapse. Results of a skin biopsy were reported as indicating cutaneous T-cell lymphoma/leukemia. Although reinduction chemotherapy was started, skin lesions persisted. Results of another skin biopsy performed 6 weeks later also were reported as indicating a T-cell leukemic infiltrate. Cytogenetic studies of this biopsy specimen showed the clonal change that was seen in the original diagnostic bone marrow study. However, the bone marrow at this time showed a different cytogenetic abnormality, consisting of 9q deletion. Reinduc- tion was begun for the third time, now with high-dose cyto- sine arabinoside, and the patient was referred for autologous bone marrow transplantation. Repeat biopsies of the skin were performed before bone marrow transplantation. At that time, the infiltrated cells had positive results for S-100, and Birbeck granules were seen on electron microscopic examination, consistent with LCH. Retrospectively, the first skin biopsy, 11 months after the initial diagnosis of leukemia, showed marginally positive results for 5-100 and positive results for peanut lectin with immunoperoxidase staining. Six months after transplant, brownish and crusted skin lesions were still present. A skin biopsy specimen again showed LCH. Repeated examination of the bone marrow aspirate and biopsy specimen have shown no recurrence of ALL 18 months after transplant; however, the clinical signs of LCH persist.

Review of University of Minnesota Cases

During the last 31 years (1961-1991), 116 patients with LCH were treated at the University of Minnesota Hospi- tal in Minneapolis. In addition to the patient in this case report, we found three patients in whom a malignant neoplasm developed in association with LCH:

One boy had recurrent disseminated LCH since he was 3 months old. He was treated with radiation therapy and several different chemotherapeutic agents, including vinblastine, cyclophosphamide, methotrexate, and etoposide. Nine years after the diagnosis of LCH, AML developed with a t(7;21). He died within 3 months of the AML diagnosis. An 18-month-old girl with disseminated LCH was treated with radiation therapy and vinblastine. A clinical remission was achieved. However, in 1988, 26 years after the radiation therapy was initiated, a basal cell carcinoma developed within the previous radiation port. This was removed surgically, and she is currently disease-free. A 9-month-old boy with disseminated LCH was treated in 1961 with several chemotherapeutic agents (prednisone, vinblastine, 5-fluorouracil, 6-mercaptopurine) and radiation therapy for bone lesions. After 3 years of therapy, he was disease- free. Fifteen years later, an ependymoma developed within the field of radiation. Despite surgery, radiation therapy, and chemotherapy, he died within 3 years of this latter diagnosis.

Literature Review

The literature was searched for any combination of LCH and a malignant neoplasm. Eighty-seven patients have been reported in 44 reference~.~.~-~l Our review included many articles published before 1987, and in some instances the published data were insufficient for us to determine whether the diagnosis of LCH would have met the histopathologic criteria as outlined by the Histiocyte Society.”

For the purpose of this review, the patients reported have been assigned to three groups and their cases are summarized in three tables: Table 1 contains the cases of LCH and malignant lymphoma (ML); Table 2 reflects the cases of LCH and leukemia; and Table 3 shows the cases of LCH with solid tumors. So that our information would be complete, we also added our four patients to the tables. Table 4 shows a summary of the timing of the malignant neoplasm and LCH for the three subsets mentioned above and for lung carcinomas.

Results

Group 1: LCH and ML

This group consisted of 39 patients. Twenty-five had LCH associated with Hodgkin disease, and 16 of these patients had the nodular sclerosing subtype (Table 1). Of the patients with Hodgkin disease, there were 14 male patients and 8 female patients, and in three cases

LCH and Malignant Neoplasms/Egeler et al. 867

Table ‘1. Review of Ihe Literature on the Association of Langerhans Cell Histiocytosis With Malignant Lymphoma

Type ML Age Treatment Time (histologic Treatment

Author Sex (yr) Site of LCH of LCH interval subtype) of ML F o I I o w - u ~

Sajjad and Luna’

L‘Hoste et al.” Lyon et al.”

Neumann and Frizzera12

Murray and Keen et aI.l4

Shanley et aI.l5

Coli et a1.16 lmamura et al.”

Concurrent diagnosis

Williams and Dorfman”

Kjeldsberg and Kim”

Burns et al.’”

Bonetti et al.”

Almanaseer et al.” Neumann and FrizzeraI2

Flint and Smid”

Malignant lymphoma preceding Langerhans cell histiocytosis

Langerhans cell histiocyolisis preceding malignant lymphoma

M 20 F 20 M 29 M 31

M 35 F 40 M 32 M 37

F 16

M 35 F 9

NA NA NA NA

F 27 M 45 M 42 F 29 F 23 M 26 M 18 F 25 M 27 M 31 F 33 M 46

F 63

M 47 M 20 M 24 M 76 M 29 M 40

NA

Lung None Lung Chem, rad Disseminated None Disseminated Steroids

Disseminated Chem Lung Steroids Lymph node Excision Bone Curettage

Lung None

Lung NA Disseminated Chem

Lymphnode NA Lymphnode NA Lymphnode NA Lymph node NA Lymphnode NA Lymphnode NA Lymphnode NA Lymphnode NA Lymphnode NA Lymphnode NA Lymphnode NA Lymphnode NA Lymphnode NA Lymphnode NA Lymphnode NA Lymphnode NA

Lymph node Skin Lymph node Lymph node Lymph node Lymph node Lymph node Lymph node Lung

NA

Chem Rad Chem, rad Chem, rad Chem Chem NA

3 + y r HD(NS) 6+ yr* HD (NS) 12+mo HD(MC) 12+ mo HD(NS)

5+ y r t NHL (MC) 12+ mo HD (NS) 24+mo HD(NS) 33+ yr HD(NS)

18+mo HD(NS)

7 + y r HD(MC) 12+ mo NHL (MH)

- HD (NA) - HD (NA) - NHL (NA) - NHL (NA) - NHL (MC) - NHL (MC)

NHL (NS) - HD (MC) - HD (MC) - HD (NS) - HD (NS) - HD (NS) - HD (NS) - HD (NS) - HD (MC) - NHL

(F & DM) - NHL (CL)$

-

- NHL (CL) - HD (NS) - HD (NS)

- HD (MC) - HD (NS) - HD (NA)

NHL (MC) -

Chem, rad Chem, rad Chem, rad Chem, rad

Chem, rad Chem, rad Chem, rad Rad

Chem

Chem, rad Chem

NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA

Alive, NED 4 yr DOD, 4 yr Alive, WD 2 yr Alive, with LCH

DOD, 9 yr Alive, NED 7 yr Alive, NED 1 yr Died, at the age

Alive, with LCH

NA DOD, 1 mo

2 Y‘

of 78 yr with LCH

4 mo

NA NA NA NA Alive, NED 2 yr Alive, NED 3 yr Alive, WD 2 yr Alive, NED 10 yr Alive, 3 mo DOD, 4 yr Alive, NED 7 yr Alive, NED 8 yr Alive, CUT DOD, 7 yr Alive, CUT Alive, NED 8 yr

NA Alive, WD 7 mo

Chem Alive, NED 20 mo Rad Alive, NED 7 yr Chem, rad Alive, NED 7 yr Chem, rad Alive, NED 5 yr Chem Alive, NED 1 yr Chem Alive, NED 2 yr NA NA

Frederiksen and F 20 Disseminated Rad ThommesenZ4 F 57 Bone Rad

F 24 mo Disseminated Chem

12+mo HD(NS) 6 + m o NHL(MH) 18+ mo NHL (MH)

NA DOD, 1 yr NA DOD, 1 yr NA Alive, WD 5 yr

Vol l~rn’~ F 89 Disseminated Steroids 24+ mo NHL (NA) NA DOD, 3 mo MC: mixed cellularity; NED: no evidence of disease; F & DM: follicular and diffuse mixed; CUT: currently under treatment; CL: composite lymphoma; LCH: Langrrhans cell histiocytosis; ML: malignant lymphoma; chem: chemotherapy; rad: radiation therapy; steroids: corticosteroids; HD: Hodgkin disease; NHL: non- Hodgkin lymphoma; NS: nodular sclerosis; MH: malignant histiocytosis; WD: with disease (malignant lymphoma); DOD: died of disease (malignant lymphoma); NA: not available. * LCH combined with HD on relapse, 6 years after first disease. t LCH combined with NHL on relapse, 5 years after first disease. i This composite lymphoma (two distinctive malignant lymphomas involving a single lymph node) developed eventually into chronic lymphocytic leukemia.

868 CANCER February 1, 1993, Volume 7 1 , No. 3

Table 2. Review of the Literature on the Association of Langerhans Cell Histiocytosis With Leukemia

Age Treatment Time Type of Treatment of Follow-up leukemia Author Sex (yr) Site of LCH of LCH interval leukemia

Leukemia precedine. Lanaerhans cell histiocvtosis

Kanter et al.” M 3 Current case report M 3


Gray and Taylof’ M 6 Pollak et al.” M 12mo Wood and Walkerz9 M 53 Thong et a].” F 18 mo Kaiserling and Horny3’ M 71

Claudy et M 75

Langerhans cell histiocytosis preceding leukemia

Texier and Maleville3’ M 44 M 53

Miller” M 21mo Greenberger et al.” F 18

M 2 M 8 mo M 16mo

Fontana et al.36 M 38 Mahoney et aL3’ F 3 mo Van Heerde and Egeler‘ M 17

Heitger et al.” M 6 Arico et al.39 M 3

F 7

Bone Skin

Disseminated Disseminated Lymph node Disseminated Skin

Skin

Disseminated Disseminated Disseminated Disseminated Disseminated Disseminated Disseminated Disseminated Disseminated Skin Bone Bone Bone

Curettage None

NA Steroids Surgery NA Steroids

Chem

NA NA Steroids Chem, rad Chem, rad Chem, rad Chem, rad Chem Chem Chem Chem None Chem

b+ mo 11+ mo

-

- -

- -

-

6+ yr 3+ yr 5+ yr 17+ yr 5 + yr 3+ yr 18+ mo 18+ mo 4.5+ yr 14+ yr 8+ mo 6+ yr 4+ yr

ALL AL

ANLL (AMoL) ANLL (AMoL) CLL ANLL (AMoL) CML

ANLL (AMoL)

ANLL (AMoL) ANLL (AMoL) ANLL (AML) ANLL (AML) ANLL (AUL) ANLL (AML) ANLL (AML) ANLL (AMoL) ANLL (AML) ANLL (AMoL) ALL ALL ANLL (AML)

Chem, rad Chem, ABMT

NA Chem Chem, rad NA NA

None

NA NA Chem NA NA NA NA Chem Chem Chem Chem, rad Chem Chem

DOD, 1 yr Alive, with

LCH 15 mo

DOD, 1 mo DOD, 2 mo Alive, NED 5 yr DOD, 1.5 mo Alive, CUT

DOD, 7 mo 2 mo

DOD. 6 yr DOD, 3 yr DOD, 9 mo DOD. same year Alive, CUT DOD, same year DOD, same year DOD, 1 yr DOD. 5 yr DOD, I yr Alive, NED 2 yr Alive, NED 3 yr DOD. 1 yr

Current series M 3 mo Disseminated Chem, rad 9+ yr ANLL (AML) None DOD, 3 mo

ABMT: autologous bone marrow transplantation; LCH: Langerhans cell histiocytosis; chem: chemotherapy; rad: radiation therapy; steroids: corticosteroids; ANLL: acute nonlymphoblastic leukemia; AMoL acute monocytic leukemia; AML acute myeloid leukemia; AUL acute undifferentiated leukemia; ALL: acute lymphoblastic leukemia; CLL: chronic lymphoblastic leukemia; CML: chronic myeloid leukemia; NED: no evidence of disease; DOD: died of disease (leukemia); CUT currently receiving treatment; N A not available.

the sex was not specified. The 14 patients with non- Hodgkin lymphoma had a variety of histologic sub- types. The patients with non-Hodgkin lymphoma included six male patients and six female patients, and in two cases the sex was not specified. Three patients in whom malignant histiocytosis was diagnosed were included in the group of patients reported to have non- Hodgkin lymphoma.’7r24 The age at first diagnosis ranged from 2 to 89 years (mean, 33.6 years) in the overall group. In 11 patients (28%), the diagnosis of ML preceded that of LCH, occurring from 1 to 33 years before the diagnosis of LCH (mean, 5.5 years). Twenty- four patients (62%) had LCH and the malignant disease in the same lymph node. In all but one of these patients, both diseases were diagnosed concurrently. In the remaining four patients, the LCH was diagnosed at 6, 12, 18, and 24 months before the ML.

In 33 of these patients (85%), the LCH was confined to one organ only, consisting of microscopic in-

volvement of lymph nodes (24 patients), lung (6 patients), bone (2 patients), and skin (1 patient). All patients were treated with either chemotherapy and/or radiation therapy for their lymphoma. In six patients, no follow-up information was presented. Of the remaining 33 patients, 8 (24%) were reported to have died of the ML; 4 of these patients had the combination LCH-Hodgkin disease. One patient died at 78 years of age with signs of LCH. In nine cases (27%), the patients were being treated or recurrent malignant disease had developed. Fifteen patients (45 YO) were being observed on a follow-up basis without evidence of either disease; the follow-up ranged from 1 to 10 years (median, 5 years).

Group 2: LCH and Leukemia

In 22 patients (including 2 of our patients), LCH had been reported in association with leukemia (Table 2).

LCH and Malignant NeoplasmslEgeler et al. 869

Table 3. Review of the Literature on the Association of Langerhans Cell Histiocytosis With Other Solid Tumors

Age Treatment Time Type of solid Treatment of !Sex (yr) Site of LCH of LCH interval tumor solid tumor FOllOW-UU Author

Solid tumor preceding Langerhans cell histiocytosis

Marshall" Murray and Hall" Lombard et al."

F F F

M F M F F M F F F

M M

56 37 58

39 70 53 74 56 77

58 78 1 mo

49 63

Bone Bone Lung

Chem Curettage NA

8+ yr Breast ca 6+ mo Breast ca 12+ mo Large cell ca

Mastectomy Alive, NA Mastectomy Alive, NED 1 yr Surgery, rad Alive, with LCH

5 Yr


Basset et al." Hammar et a1 '3

Lung Lung Lung Lung Lung Lung, bone Lung Lung Disseminated

Chem NA NA NA NA NA NA NA Chem

Adeno ca Adeno ca Adeno ca Adeno ca Adeno ca Adeno ca Adeno ca Adeno ca Retinoblastoma

Chem NA NA NA NA NA NA NA Enucleation,

Gashectomy Lobectomy

DOD, 10 mo Alive, NA Alive, NA Alive, NA Alive, NA Alive, NA Alive, NA Alive, NA

chem Poor condition,

NA NA

after 4 mo Orye et a]."

Arrinda et Lombard et al."

Stomach Lung

Surgery NA

- Gastric ca - Large cell ca

Langerhans cell histiocytosis preceding solid tumor

Mermann et al.'" M 2 M 1 2 m o

Bone, skin Bone,

Disseminated lymph node

Rad Antifolics, Steroids, rad Rad, chem

NA Chem Chem, rad Rad Rad Rad, chem Steroids None Curettage,

rad Rad Rad

chlorobutanol'

14+ yc Astrocytoma 3+ yr Medulloblastoma

NA DOD, same year NA DOD. same year

Grosfeld et a]." M 2 18+ yr Hepatoma None DOD, same year

Sims'' Creenherger et al."5

M 4 M 5 M 3 M 2 m o

NA NA

F 47 M 18 M 24mo

NA Bone Disseminated Disseminated Bone Bone Lung Lung Bone

21+ yr 14+ yr 12+ yr 28+ yr NA NA 12+ mo 14+ yr 20+ yr

Meningioma Hepatocell ca Thyroid ca Thyroid ca Thyroid ca Osteosarcoma Adeno ca Squam cell ca Apudoma

NA NA Surg NA NA NA Lobectomy, rad Pneumectomy Chem

Died, suicide DOD, same year Alive, NED 1 yr DOD. same year NA NA DOD, 1 yr NA DOD. 1 mo

Komp"

Lombard et al."

Egeler et

Dimentberg and Brown"

F 9 m o M 20mo

Bone Bone

17+ yr Chondrosarcoma 10+ yr Giant cell

26+ yr Basal cell ca glioblastome

NA DOD, same year NA DOD, same year

Authors F 1 8 m o M 9 m o

Disseminated Disseminated

Chem, rad Surg Alive, NED 3 yr Chem, rad 15+ yr Ependymoma Surg, chem, rad DOD, 3 yr

LCH: Langerhans cell histiocytosis; chem: chemotherapy; rad: radiation therapy; steroids: corticosteroids; NED; no evidence of disease; DOD: died of disease (solid tumor); N A not available. * I'itressin, Parke-Davis, Morris Plains, N].

Of these, 16 received the diagnosis of acute nonlymphoblastic leukemia; eight of these cases were acute monocytic leukemia. Four cases of ALL, one case of chronic lymphocytic leukemia, and one case of chronic myelocytic leukemia also were reported in association with LCH. There were two patients for whom the diagnosis of LCH fohwed the diagnosis of leukemia. In both patients, LCH developed within 1 year of the initial diagnosis of AILL. In 6 patients (27%) the diagnoses

of LCH and leukemia were made concurrently, and in the remaining 14 patients (64%) the diagnosis of LCH preceded the diagnosis of leukemia by more than 8 months.

In more than half of the cases (13 of 22), the patients were reported to have the disseminated form of LCH. All but four of the patients were male (male-female ratio = 4.5:l). The age at first diagnosis ranged from 3 months to 75 years (mean, 18.5 years). The LCH

870 CANCER February 1, 2993, Volume 71, No. 3

Table 4. Langerhans Cell Histiocytosis in Association With Malignant Neoplasms: The Number (and Percentages) of Cases of Langerhans Cell Histiocytosis After, Concurrent With, or Preceding the Malignant Neoplasm

Langerhans cell histiocvstosis

After the Preceding the Type of malignant malignant wudignarrt neoplasm neoplasm Concrrrrent neoplasm

Malignant lymphoma

Leukemia

Lung carcinoma

Solid tumor

(n = 39) 11 (28%) 24 (61%) 4 (loo/,)

(n = 22) 2 (9'10) 6 (27%) 14 (64%)

(n = 12) i(nvO) 9 (75%) 2 (1 7%)

(n = i n ) 2 (11%) 2 (11%) 14 (78%)

was treated with several different modalities, including surgery, topical nitrogen mustard, corticosteroids, or chemotherapy. In addition to our recent patient, five other patients are alive during follow-up. Three patients have no evidence of disease 2,3, and 5 years after the initial diagnosis; two are being treated for their leukemia. The patient reported above is free of leukemia but continues to have LCH of the skin, despite autologous bone marrow transplantation.

Group 3: LCH and Other Solid Tumors

In the remaining 30 patients, LCH was reported in association with a variety of solid tumors (Table 3). The malignant neoplasms in this group included 12 lung carcinomas, 3 cases of thyroid carcinoma, 2 breast carcinomas, and 1 case each of an astrocytoma, glioblas- toma, medulloblastoma, meningioma, ependymoma, chondrosarcoma, retinoblastoma, basal cell carcinoma, apudoma, hepatoma, hepatocellular carcinoma, gastric carcinoma, and osteosarcoma. In all cases of associated lung carcinoma and LCH, the diagnosis of LCH also was confined pathologically to the lung. In these 12 LCH-lung carcinoma associations, 9 were diagnosed concurrently. Of the remaining 18 patients with LCH and solid tumors, the diagnosis of LCH preceded the solid tumor by 1-28 years (mean, 15.7 years) in 14 patients (78%). Among these 14 patients in whom the LCH preceded the solid tumor, in 11 patients (79%) the malignant disease was reported to have developed within the radiation field used for the treatment of LCH.

Time of Diagnosis

Table 4 summarizes the time course of the LCH-malignant neoplasm association. Significant differences were

observed in the chronology of the association by cate- gory (chi-square, P < 0.001). For instance, in 61% of the LCH-lymphoma and 75% of the LCH-lung carcinoma cases, the diagnoses were made concurrently in contrast to only 27% of the LCH-leukemia cases and 11% of the LCH-solid tumor cases. Additionally, the diagnosis of a malignant neoplasm was much more likely to follow the diagnosis of LCH for the cases of leukemia (64%) and for other solid tumors (78%).

Discussion

Associations between malignant neoplasms and LCH, summarized in this review, appear more frequently than previously recognized, and it is likely that the occurrence is greater than that expected by chance alone. In our review of 116 patients with LCH at our institu- tion, we found 4 patients in whom a malignant neoplasm also was diagnosed (3.5%). In reviewing the organ systems involved in the cases of LCH, the characteristics of the malignant neoplasms, and the timing of both diagnoses, it is reasonable to postulate that this association appears to follow two distinct processes: a reactive one and/or a therapy-related one.

The number of cases in which the malignant neoplasm preceded the LCH was relatively small, especially for the LCH-leukemia and LCH-solid tumor cases. In more than half of the LCH-lymphoma cases, the LCH was diagnosed within 2 years of the development of the malignant neoplasm. When the time interval between occurrences is considered, it suggests that the LCH represents a reaction to the lymphoma. How- ever, the bulk of these associations do not show a distinct pattern.

In most of the cases of lymphoma and lung carcinoma, the LCH was intimately involved pathologically with the primary malignant neoplasm and the diagnoses usually were made concurrently (61% of the LCH-lymphoma cases and 75% of the LCH-lung carcinoma cases [Table 41). This focal intermingling of the two processes suggests that, in these cases, the LCH represents a reaction to the lymphoma or solid lung tumor, which has been suggested previously for lymphomas.'' In most of the cases of lymphoma-LCH, the bulk of the disease was related to the lymphoma, with only focal microscopic lesions of LCH being present in the draining lymph node. These patients have had no evidence of systemic spread of LCH beyond the draining lymph nodes. Although Kjeldsberg and Kim" considered LCH an incidental finding and unrelated to the lymphoma, Burns et a1.*' speculated that the lymphoma may be a direct or indirect stimulus for the proliferation of LCH. Similarly, in the cases in which LCH was associated with lung carcinoma, a reactive relationship has been postulated by analogy with "scar" carcinomas aris-

LCH and Malignant NeoplasmslEgeler et al. 871

ing in association with pulmonary fibrosis.41 In a combined light microscopic and ultrastructural study of 37 cases of bronchoalveolar cell carcinoma, Hammar et al.43 identified 7 cases in which Langerhans cells were associated closely with the tumor cells.

These reports demonstrate the possibility that the association is not between two distinct diseases, but rather a result of a specific dendritic cell reaction. Al- though in all the concurrently diagnosed cases of LCH with ML or lung carcinoma the tumor cells exhibited histochemical and immunophenotypic characteristics unique to Langerhans cells, none of the cases met the clinical criteria for the diagnosis of LCH as a disease entity. Because the respiratory tract and lymph nodes normally contain low numbers of Langerhans cells, biopsy and cytologic material must be evaluated cautiously. Here, quantity is important; in this setting there must be large numbers of Langerhans cells to warrant a diagnosis of LCH because the histopathologic presence of Langerhans cells alone is insufficient evidence to indicate the diagnosis LCH.53

In most of the rseported associations between leukemia and LCH and LCH and solid tumors other than lung carcinomas, the malignant condition followed the diagnosis of LCH. Table 4 shows that, in 64% of the patients with leukemia, this latter diagnosis was made after the diagnosis of LCH. This was even more striking in the cases of LCH associated with solid tumors; in 78% the malignaint neoplasm was diagnosed after the LCH.

An article by the Late Effects Study Group reported four cases in which a malignant neoplasm occurred after LCH was diagnosed in 215 patients.54 The types of treatment used and time interval between the development of LCH and leukemia, especially acute nonlymphoblastic leukemia (ANLL) and many of the solid tumors, suggest a causal relationship to therapy. The time between the diagnosis of LCH and the subsequent leukemia was relatively short, ranging from 8 months to 17 years, with a mean of 5.7 years. In the largest propor- tion of patients, the leukemia developed at least 2 years after the initial diagnosis of LCH. In the therapy data available, most of those patients were treated with chemotherapy because most of them had disseminated LCH. Recently, Pui et al.55 published a report that associated the occurrence of secondary acute myeloid leukemia after the use of epipodophyllotoxins. One of these agents, etoposide, is used commonly in the treatment of LCH.56,57 ,4lthough, until now, there have been no clear cases of etoposide-induced acute myeloid leukemia in patients with LCH, the previous association provides additional concern regarding the possibility of therapy-induced rnalignant neoplasms after LCH treatment. Additional evidence of the therapy-related association of LCH and malignant neoplasms is the relation-

ship observed in the 14 cases of solid tumors (excluding the lung carcinomas) that developed after LCH treatment (Table 3). In 11 patients (79%) with LCH who had radiation therapy for a lesion, a tumor later appeared at that site, within the port.

Also of interest are the age differences among the categories. Seventy-three percent (16 of 22) of the patients with LCH-leukemia and 78% (14 of 18) of the patients with LCH and other solid tumors were 18 years of age or younger at the time of diagnosis of the first condition (either LCH or malignant neoplasm). This contrasts significantly with the other two categories, in which 88% of the patients with LCH-lymphoma and 92% of the patients with LCH-lung carcinoma were older than 18 years of age. This would support the likeli- hood that a malignant condition (either leukemia or a solid tumor) may be an induced event after therapy for LCH that occurs at usual ages. The age distribution of patients in the LCH-lymphoma and LCH-lung carcinoma categories is unusual compared with that of primary LCH but not compared with that of the malignant neoplasms, also suggesting that in these instances the "LCH" was actually a local reactive process.

In conclusion, the data presented here suggest that LCH may be associated with lymphomas and lung tumors, in which the timing and unifocal involvement suggest a reactive process. Because none of those cases was consistent with the clinical criteria of LCH as a disease entity, we would rather designate those patients as having a malignant neoplasm in association with a reactive focal Langerhans cell proliferation. A second group of patients who had LCH associated with malignant neoplasms indicates that chemotherapy and radiation therapy used in the treatment of LCH may increase the risk of secondary leukemia or solid tumors. The Histiocyte Society is establishing a registry to collect cases of LCH associated with malignant neoplasms in the future. We hope this will lead to a better under- standing of the nature of the association of the two diseases.

References

Egeler RM, Nesbit ME Jr. Current concepts and treatment in Langerhans cell histiocytosis. In: VoGte PA, Barrett A, Lemerle I , editors. Cancer in children, clinical management. 3rd ed. Hei- delberg: Springer-Verlag, 1992:158-68. Perreault C, Pelletier M, Landry D, Gyger M. Study of Langer- hans cells after allogeneic bone marrow transplantation. Blood

Volc-Platzer B, Sting1 G, Wolff K, Hinterberg W, Schnedl W. Cytogenetic identification of allogeneic epidermal Langerhans cells in a bone-marrow graft recipient [letter]. N Engf I M r d 1984;

Van Heerde P, Egeler RM. The cytology of Langerhans cell histiocytosis (histiocytosis X). Cytopathology 1991; 2: 149-58.

1984; 63:807-11.

310:1123-4.

872 CANCER Februury 1, 1993, Volume 71, No. 3

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18

19

20

21

22

23

24

25

26

Risdall RJ, Dehner LP, Duray P, Kobinsky N, Robison L, Nesbit ME. Histiocytosis X (Langerhans’ cell histiocytosis). Arch Pathol Lab Med 1983; 107:59-63. Rabkin MS, Wittwer CT, Kjeldsberg CR, Piepkorn MW. Flow- cytometric DNA content of histiocytosis X (Langerhans cell histiocytosis). A m / Pathol 1988; 131:283-9. Ornvold K, Carstenseii H, Larsen JK, Christensen I], Ralfkiaer E. Flow cytometric DNA analysis of lesions from 18 children with Langerhans cell histiocytosis (histiocytosis X). A m I Pathol 1990;

Goldberg NS, Bauer K, Rosen ST, Caro WA, Marder RJ, Zuger- man C, et al. Histiocytosis X: flow cytometric DNA-content and immunohistochemical and ultrastructural analysis. Arch Dernra-

Sajjad SM, Luna MA. Primary pulmonary histiocytosis X in two patients with Hodgkin’s disease. Thorax 1982; 37.1 10-3. LHoste RJ, Arrowsmith WR, Leonard GL, McGaw H. Eosino- philic granuloma occurring in a patient with Hodgkin disease. Hum Patlrol 1982; 13:592-5. Lyon JM, Pezzimenti J, Kranwinkel RN. The development of histiocytosis X in patient with Hodgkin’s lymphoma. Corm Med

Neumann MI‘, Frizzera G. The coexistence of Langerhans’ cell granulomatosis and malignant lymphoma may take different forms. H u m Pathol 1986; 17:1060-5. Murray PA, Hall PA. Histiocytosis X mimicking recurrent malignant disease: a report of two cases. Clin Radiol 1988; 39:310-2. Keen CE, Philip G, Parker BC, Souham RL. Unusual bony lesions in histiocytosis X in a patient previously treated for Hodg- kin’s disease. Patliol Res Pract 1990; 186:519-25. Shanley DJ, Lerud KS, Luetkehans TJ. Development of pulmonary histiocytosis X after chemotherapy for Hodgkin disease.

Coli A, Bigotti G, Ferrone S. Histiocytosis X arising in Hodgkin‘s disease: immunophenotypic characterization with a panel of monoclonal antibodies. Virrhows Arch [A] 1991; 418:369-73. Imamura M, Sakamoto S, Hanazono H. Malignant histiocytosis: a case of generalized histiocytosis with infiltration of Langer- hans‘ granule-containing histiocytes. Cancer 1971; 28:467-75. Williams JW, Dorfman RF. Lymphadenopathy as the initial manifestation of histiocytosis X. Am I Surg Pathol 1979; 3:405- 21. Kjeldsberg CR, Kim H. Eosinophilic granuloma as an incidental finding in malignant lymphoma. Arch Pathol Lab Med 1980;

Burns BF, Colby TV, Dorfman RF. Langerhans‘ cell granulomatosis (histiocytosis X) associated with malignant lymphomas. Am ] Surg Pafhol 1983; 7:529-33. Bonetti F, Knowles DM, Chilosi M, Pisa R, Fiaccavento S, Riz- zuto N, et al. A distinctive cutaneous malignant neoplasm ex- pressing the Langerhans cell phenotype. Cancer 1985; 55:2417- 25. Almanaseer IY, Kosova L, Pellettiere EV. Composite lymphoma with immunoblastic features and Langerhans’ cell granulomatosis (histiocytosis X). A m / Chi Pathol 1986; 85:111-4. Flint A, Smid DM. Pulmonary Hodgkin’s disease and Langer- hans’ cell granulomatosis [letter]. Chest 1987; 92:191-2. Frederiksen P, Thommesen P. Histiocytosis X: 111. Clinical value of serial biopsies. Acta Radiol [Oncol] 1978; 17:362-8. Vollum D1. Letterer-Siwe disease in the adult. Clin Exp Dermatol 1979; 4:395-406. Kanter HM, Lin LM, Goepp RA, Olson RE. Mandibular histiocytosis X and acute lymphoblastic leukemia. Oral Surg 1976; 42:221-30.

136:1301-7.

tol 1986; 122:446-50.

1985; 49:354-6.

AJR 1990; 1551741-2.

104:137-40.

27.

28.

29. 30.

31.

32.

33.

34.

35.

36.

3 7.

38.

39.

40.

41.

42.

43.

44.

45.

Gray JD, Taylor S. Acute systemic reticulo-endotheliosis termi- nating as a monocytic leukemia. Cancer 1953; 6:333-7. Pollak A, Radaszkiewicz R, Weissenbacher G. Untersuchung zur Frage der Verwandtschaft zwischen Histiozyten und Mono- zyten an Hand einer Letterer-Siweschen Erkrankung mit uber- gang in Monozytenleukamie. Wieiz Klin Wochenschr 1973;

Wood JK, Walker F. Letter. Histopathology 1977; 1:315-6. Thong YH, Sinniah D, Kaur K, Yadav M, Chong KC. A Chinese with features of Letterer-Siwe disease, histiocytic medullary re- ticulosis and monocytic leukemia. Singapore Med / 1977; 18: 147- 50. Kaiserling E, Horny HP. Dermal Langerhans‘ cell tumor in chronic myelomonocytic leukemia. Ultrastruct Pathol 1988;

Claudy AL, Larbre B, Colomb M, Levigne V, Deville V. Letterer- Siwe disease and subacute monocytic leukemia. ] A m Acad Der-

Texier L, Maleville J . Periorificial and pulmonary eosinophilic granuloma (histiocytosis X) and monocytic leukemia. Br ] Der-

Miller DR. Raised foetal haemoglobin in childhood leukaemia. Br Hneniatol 1969; 17:103-12. Greenberger JS, Crocker AC, Vawter G, Jaffe N, Cassady JR. Results of treatment of 127 patients with systemic histiocytosis (Letterer-Siwe syndrome, Schuller-Christian syndrome and multifocal eosinophilic granuloma). Medicine 1981; 60:311-38. Fontana J, Koss W, McDaniel D, Jenkins J, Welton W. Histiocy- tosis X and acute monocytic leukemia. A m ] Med 1987; 82:137- 42. Mahoney DH Jr., McClain KL, Hanson IC, Taylor LD, Steuber CP. Acquired immune deficiency, myelodysplasia, and acute nonlymphocytic leukemia associated with monosomy 7 and t(3;3)(q21;q26) in a child with Langerhans cell histiocytosis. A m ] Pediatr Hematol Oncol 1989; 11:153-7. Heitger A, Mann G, Dengg K, Kreczy A, Stauder R, Wicke K, et al. Localized Langerhans cell histiocytosis (LCH) developing during maintenance therapy for T-cell acute lymphoblastic leukemia (T-ALL): a case report [abstract]. Proceedings of the An- nual Meeting of the Histiocyte Society, Chicago, Illinois, 1991:29. Aric6 M, Comelli A, Bossi G, Raiteri E, Piombo A, Egeler RM. Langerhans cell histiocytosis and acute leukemia: unusual association in two cases. Mcd Pcdiatr Orrcol 1992; 20. Marshall ME. Breast carcinoma, eosinophilic granuloma of bone and dermatomyositis in a single patient. ] Ky Med Assoc 1983;

Lombard CM, Medeiros J, Colby TV. Pulmonary histiocytosis X and carcinoma. Arch Pafhol Lab Med 1987; 111:339-41. Basset F, Soler P, Wyllie L, Abelanet R, Le Charpentier M, Kreis B, et al. Langerhans cells in a bronchiolar-alveolar tumour of lung. Virchorus Arch [A] 1974; 362315-30. Hammar SP, Bockus D, Remington F, Hallman KO, Winter- bauer RH, Hill LD, et al. Langerhans cells and serum precipitat- ing antibodies against fungal antigens in bronchioloalveolar cell carcinoma: possible association with pulmonary eosinophilic granuloma. Ultrastruci Pathol 1980; 1:19-37. Orye E, Benoit Y, Coppieters R, Jeannin PH, Vercruysse C, De- laey J, et al. A case of retinoblastoma, associated with histiocytosis-X and mosaicism of a deleted D-group chromosome (13q14 - q31). Clzn Genet 1982; 2237-9. Arrinda JM, Vilanova JR, Zabalza IE, Ortega FJ, Bilbao FJ, Ri- vera-Pomar JM. Solitary Langerhans’ cell granulomatosis of the stomach associated with gastric carcinoma. Virchows Arch [A]

85:841-4.

121209-19.

tllafol 1989; 2 1: 1 105-6.

n~atol 1966; 78~51-2.

81:91-3.

1985; 408:323-8.

LCH and Malignanl NeoplasmslEgeler e t af. 873

46.

47.

48.

49.

50.

51.

52

Mermann AC, Dargeon HW. The management of certain non- lipid reticulo-endothelioses. Cancer 1955; 8:112-22. Grosfeld JL, Fitzgerald JF, Wagner VW, Newton WA, Baehner RL. Portal hypertension in infants and children with histiocytosis X. Am ] Surg 1976; 131:108-13. Sims DG. Histiocy'tosis X: follow-up of 43 cases. Arch Dis Child

Komp DM. Long-term sequelae of histiocytosis X. Am Pediafr

Egeler RM, de Kraker J, Vofite PA. Langerhans cell histiocytosis (histiocytosis X): 20-years' experience at the Emma Kinderzie- kenhuis, Amsterdam (1969-1988) [abstract]. Proceedings of the Fourth Annual Meeting of the American Society of Pediatric Hematology and Oncology, Chicago, Illinois, 1991:22. Dimentberg RA, Brown KLB. Diagnostic evaluation of patients with histiocytosis X. Pediatr Orthop 1990; 10:733-41. Writing Group of the Histiocyte Society. Histiocytosis syn- dromes in children. Laticet 1987; 60:208-9.

1977; 52:433-40.

Hrnirifol OtiCOl 1981; 31165-8.

53. Favara BE. A review on the article: the histiocytosis: clinical pre- sentation and differential diagnosis by Gonzalez CL and Jaffe

Tucker MA, Meadows AT, Boice JD, Hoover RN, Fraumeni JF (for the Late Effects Study Group). Cancer risk following treatment of childhood cancer. In: Boice JD, Fraumeni JF, editors. Radiation carcinogenesis: epidemiology and biological signifi- cance. New York: Raven Press, 1984:211-24.

55. Pui CH, Ribeiro RC, Hancock ML, Rivera GK, Evans WE, Rai- mondi SC, et al. Acute myeloid leukemia in children treated with epipodophyllotoxins for acute lymphoblastic leukemia. N Eiigl ]Men 1991; 325:1682-7. Ceci A, De Terlizzi M, Colella R, Balducci D, Grazia Toma M, Grazia Zurlo M, et al. Etoposide in recurrent childhood Langer- hans cell histiocytosis: an Italian cooperative study. Caiicrr 1988;

Broadbent V, Pritchard J, Yeomans E. Etoposide (VP16) in the treatment of multisystem Langerhans cell histiocytosis (histiocytosis X). Med Pcdiatr Oiicol 1989; 17:97-100.

ES. OtICOlOgy 1990; 4160-1. 54.

56.

62:2528-31. 57.

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Association of langerhans cell histiocytosis with malignant neoplasms