REVIEW ARTICLE

Langerhans Cell Sarcoma: Case Report and Review of World Literature

Ted Zwerdling, MD,* Eric Won, MD,w Lisa Shane, MD,* Ramin Javahara, MD,* and Ronald Jaffe, MDz

Langerhans Cell Sarcoma; pathology, therapy, diagnosis, Summary: Langerhans cell sarcoma is a rare malignancy with only etiology. 1 pediatric case (less than 15 y of age) reported. Here, we report the BRAF mutational analysis performed at Clarient Inc. second case of Langerhans cell sarcoma in a child who presented (Aliso Viejo, CA) using polymerase chain reaction with cord compression. This patient was treated with extensive technique. surgical resection, postoperative chemotherapy, and involved-field radiation therapy. She completed therapy and remains in remission Immunohistochemical staining was performed using for 27 months. A review and analysis of all 53 cases published in standard techniques according to the manufacturers’ the world literature is provided to help guide physicians treating recommendations. this disease. Recently discovered genetic mutation involving BRAF is also discussed. Key Words: Langerhans cell sarcoma, pediatric, treatment, world RESULTS review Case Report and Clinical Outcome (J Pediatr Hematol Oncol 2014;36:419–425) A 7-year-old girl presented to the emergency depart- ment with chest pain for 2 weeks and progressive difficulty walking for 3 days. She denied lower extremity pain, fevers, travel, or trauma. The family history was unremarkable angerhans cell sarcoma (LCS), one of several malignant and she was taking no medications. In the emergency histiocytic disorders which also include histiocytic sar- L department, the patient was afebrile and examination coma and interdigitating dendritic cell sarcoma, is recog- found slight tenderness over the right thoracic paraspinal nized by the World Health Organization (WHO) as a class region which increased with movement and decreased sen- III histiocytic process involving truly malignant histio- sation (pinprick and touch) in the lower extremities without cytes.1,2 This is supported by new evidence of BRAF a sensory line. Weakness involving the lower extremities, mutations in some of these tumors.3,4 LCS differs from hyperactive reflexes, and bilateral Babinski signs were class I and II histiocytic disorders based on morphologic noted. The remainder of her examination, including a ret- characteristics of lesional cellular make-up and is frequently inal examination, was normal. Magnetic resonance imaging a fatal disease. LCS is very rare and found mostly in adults, of the spine demonstrated a left-sided, extradural soft-tissue when reported. The Histiocyte Society has established mass with bony involvement of T5-T6 vertebral bodies. classification, diagnostic criteria, evaluation, and suggested Initial treatment consisted of steroids, decompression lam- treatments for these disorders (http://www.histiocytesociety. inectomy, and partial tumor resection. Pathologic evalua- org/). tion of the resected material was diagnostic of LCS (Fig. 1). We recently evaluated and treated a pediatric patient With residual tumor present, second surgery, with the goal diagnosed with LCS who presented with spinal cord com- of complete resection, was attempted. Additional tumor pression and continues in complete remission for 27 was removed in a piecemeal manner and it was unclear if months. Our goals for this report are: (1) to add informa- the resection margins contained malignant cells. An tion as an aid for other clinicians who may evaluate and extensive reconstruction of the operative site was performed treat this disease; (2) to undertake a review of the world with bone grafting and stabilization. Further evaluations literature; and (3) add to new molecular analysis of this including computed tomography (CT) scan, bilateral bone tumor which may suggest better diagnostic criteria and marrow aspirations and biopsies, and Tc99 radionuclide allow rationale for treatment. bone scan were negative for metastatic disease. The patient then went on to receive chemotherapy (Table 1). Five METHODS months into chemotherapy, a small area of residual mass at A literature search was conducted in PubMed under the primary site showed slight PET/CT activity. This was the search term “Langerhans Cell Sarcoma.” MeSH: biopsied and found to be fibrous tissue without evidence of LCS. Healing of the bone graft was found about 10 months into therapy and repeat metastatic evaluation was negative. Received for publication February 28, 2014; accepted April 30, 2014. From the *Miller Children’s Hospital, Long Beach; wDepartment of Fourteen months after diagnosis and with continued heal- Pediatrics, University of California, Irvine, CA; and zChildren’s ing of the bone graft, using intensity-modulated radiation Hospital of Pittsburgh of UPMC, Pittsburgh, PA. therapy techniques, 4500 cGy, in 25 fractions, was delivered The authors declare no conflict of interest. to the primary site of tumor. Subsequently, 2 additional Reprints: Ted Zwerdling, MD, Miller Children’s Hospital, 701 East 28th Street, Suite 202, Long Beach, CA 90806 (e-mail: courses of Maintenance Therapy completed approximately [email protected]). 17 months of treatment. End-of-treatment evaluations Copyright r 2014 by Lippincott Williams & Wilkins included PET/CT scan, cross-sectional imaging, and

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FIGURE 1. Hematoxylin and eosin staining of primary tumor (A: 20; B: 100). bilateral bone marrow aspirates and biopsies, did not nor glial tumor. Immunohistochemical results are shown demonstrate disease. in Table 2 and Figure 2. Tumor tissue was subjected to analysis for BRAF and Pathologic Findings found to harbor a known mutation (V600E). Soft tissue and bone measuring 1 cm in largest dimension were evaluated for histology from the primary Literature Review and Discussion tumor site. The neoplasm consisted of a uniform pop- Tables 3 and 4 summarize 53 collected cases of LCS as ulation of cells with enlarged, moderately pleomorphic published in the world literature as of January 2014. (We nuclei, and occasional multinucleated cells. The degree of are also aware of 4 other cases involving children aged 2, 7, nuclear pleomorphism was atypical for Langerhans cell 15, and 18 years and 2 others in adults aged 22 and 31, but histiocytosis. Mitotic activity was over 20 mitoses in 10 hpf have insufficient information about these cases. These cases (Ki-67 of 10% to 30%, Fig. 2) and atypical, pyknotic nuclei were reviewed by one of us (R.J.) and have never been were common with areas of tumor necrosis scattered published. However, attempts to gather additional infor- throughout the neoplasm. The tumor invaded the bone and mation beyond the diagnosis were unsuccessful, and cartilage. Tissue was evaluated by electron microscopy and therefore, not included in our analysis.) Approximately tumor cells identified by nuclear configuration and abun- 53% were reported to involve a single-site/single-organ. dant cytoplasm. The tumor showed occasional cells with For patients with single-site/single-organ disease, 11 (39%) blunted pseudopodium, scattered numerous large lyso- were reported to be in remission, as opposed to 5 of 25 with somes, and an electron-dense cytoplasm with ribosomes multisite/multiorgan disease (20%). Patients presenting and occasional small profiles of rough endoplasmic retic- with multisite/multiorgan disease fared very poorly with ulum. No intermediate-type filamentous whorls or Birbeck 64% dead and another 16% either alive with disease or granules were identified. There were no features to suggest without follow-up. It is likely that many of the patients neuritic processes nor other features of a primitive neural reported as alive with disease eventually died from the process. TABLE 1. Treatment Schema For patients who presented with single-site/single-dis- ease, lymph nodes, and skin were most frequently reported, Surgery similar to patients with multisite/multiorgan disease. Surgical resection2 Induction Initiation of therapy and the actual treatment details Vincristine, IV, 2 mg/m21 dose are poorly reported precluding comparisons. Details of Adriamycin, IV, 40 mg/m21 dose (S Adriamycin 320 mg/m2) surgery, especially related to the intent to remove all known Prednisone, PO, 40 mg/m2/d7d disease and the subsequent evaluation of resection margins Cyclophosphamide, IV, 1000 mg/m21 dose with mesna for disease are absent in most of the cases reported to date. 400 mg/m2 2 doses Less information regarding radiation therapy is given. Cycles repeated every 3 wk, 9 Tables 5 and 6 summarizes treatment-related outcome Maintenance I 2 as described for reported cases. Although all patients had Vincristine, IV, 2 mg/m 1 dose lesional biopsy for diagnostic purposes, 43 (81%) went on Prednisone, PO, 40 mg/m2/d7 d (held last 2 cycles) Cyclophosphamide, IV, 1000 mg/m2 2 doses with mesna to receive other treatments with either surgery only (n = 5), 400 mg/m2 4 doses radiation only (n = 2), chemotherapy only (n = 19), or Cycles of chemotherapy repeated every 4 wk, 7 multimodality therapy (n = 17). Ten patients were either Radiation not treated or case reports did not so state. Three patients 4500 cGy to local site of disease received liver (n = 1) or stem cell transplants. Vincristine, IV, 2 mg/m2 X 1 dose, weekly X 6. Two cases reported by Chung et al43 are not included Maintenance II in this analysis. In case 1, there is a lack of Ki-67 reporting Vincristine, IV, 2 mg/m21 dose 2 and while the text described sarcomatous changes the CD1a Cyclophosphamide, IV, 1000 mg/m 2 doses with mesna illustration is poor and not convincingly membranous. 400 mg/m2 4 doses Cycles of chemotherapy repeated every 4 wk, 2 They also describe widespread disease without any masses and no results of the bone marrow evaluation are given.

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CD1a (20X) CD207 (20X)

S100 (20X) Ki-67 (20X)

FIGURE 2. Immunohistologic reactivity of primary tumor.

The second case is incompletely documented and without epidermis before birth.44 During inflammatory states, they any illustrations. may be replaced by blood-derived Gr-1Hi monocytes. Other Langerhans cells are primarily charged with antigen data support the separate ontogeny from other dendritic recognition, processing, and presentation to T cells. First cells such as flt-3 independence, and required IL-34.45,46 identified in 1868 using gold chloride staining technique, Malignant Langerhans cells must be distinguished from they were assumed to be of nerve origin based on mor- class I histiocytes and include such morphologic features as phology. It is now known, they are derived from fetal liver- increased nuclear:cytoplasmic ratio, nuclear pleomorphism, derived monocytes which populate the outer layer of the and bizarre mitoses. Specific immunostaining is required for the accurate diagnosis of Langerhans cell neoplasms and may include CD4, CD1a, S-100, and/or the electron TABLE 2. Immunohistologic Results microscopic identification of Birbeck granules. Alter- Positively Reactive Nonreactive natively, Birbeck granules may also be identified by CD207 Immunostaining Immunostaining reactivity (Langerin). CD207 appears to recognize a c-type CEA (perinuclear, 10% of cells) Synaptophysin lectin, found on Birbeck granules, but the pattern of CD1a (diffuse cytoplasmic, EMA staining clearly shows more than just the granule itself. This membranous) lectin participates in internalizing antigen and allows CD43 (diffuse, membranous) GFAP processing of antigen for presentation to T cells. However, CD68 (perinuclear) CD99, myeloperoxidase Birbeck granules many not be observed in all cases of INI-1 (strong, diffuse nuclear LCS.12 In reviewing the literature, it is apparent that LCS positivity)* may arise de novo or be observed in other disorders. Sev- Ki-67 60%-70% of tumor AE-1/AE-3 nuclei eral cases have been reported in myeloproliferative syn- PGP 9.4 (faint, membranous) Myogenin, desmin dromes, other histiocytic disorders, B-lineage leukemia, S-100 (diffuse, cytoplasmic, CD34, CD117, CD3, CD15, follicular lymphoma, dermal lentigines, and after liver nuclear) CD20, CD21, CD23, CD30, transplantation. CD35, CD45, CD56 Several authors provided details about chemotherapy Vimentin (diffuse, intense HMB-45 given to these patients. Most used CHOP but several cytoplasmic) reports of MAID (mesna, doxorubicin, ifosphamide, CD207 Melan-A, tyrosine hydroxylase dacarbazine) and other agents appear in the literature.8,10,37 47 *Normal (expected). In addition, Keklik et al, attempted to use 2-CDA for a primary tumor in the nasopharynx. However, new disease r 2014 Lippincott Williams & Wilkins www.jpho-online.com | 421 Zwerdling et al J Pediatr Hematol Oncol Volume 36, Number 6, August 2014

TABLE 3. Single-Site/Single-Organ Cases References Age (y) Sex Site Therapy Outcomes 1 5 21 M Flank mass Surgery Alive Radiotherapy 2 6 48 M Skin Surgery Alive Chemotherapy 3 7 58 M Skin Surgery Alive Liver transplant 4 8 67 F Lymph node Radiotherapy Alive Chemotherapy 5 9 21 M Lymph node Chemotherapy Alive Marrow transplant 6 10 72 M Skin Chemotherapy Alive Surgery 7 11 62 M Lymph node Radiotherapy Alive Chemotherapy 8 12 61 M Skin Unknown Alive 9 12 54 M Skin Chemotherapy Alive Myeloid leukemia Stem cell transplant 10 13 60 M Bone Radiotherapy Alive 11 14 34 M Lung Surgery Alive 12 15 17 F Lymph node Chemotherapy Alive with disease 13 15 10 F Skin Surgery Alive with disease Radiotherapy 14 15 50 F Bone Surgery Alive with disease 15 15 46 M Lymph node Chemotherapy Alive with disease 16 16 38 F Skin Surgery Alive with disease 17 17 74 F Skin Surgery Died at 14 mo Radiotherapy 18 18 57 M Lymph node Chemotherapy Died at 7 mo 19 19 66 F Skin Chemotherapy Died of disease 20 20 86 M Lymph node Radiotherapy Died at 1 mo 21 21 Lymph node Unknown Dead 22 22 57 F Bone Surgery Dead 10 mo Radiotherapy Chemotherapy 23 23 60 M Lymph node None Dead 3 mo 24 24 88 M Skin Surgery Not available 25 25 47 M Lung Chemotherapy Not available 26 15 50 F Skin Not available Not available 27 26 67 M Lymph node Unknown No data 28 27 68 F Lymph node chronic Hospice care No data leukemia was detected and treatment was changed to etoposide, approach did result in additional tumor removal during a ARA-C, cis-platin, and methylprednisolone without suc- second surgical procedure. With little data to choose che- cess. Chemotherapy for class I histiocytic disorders may motherapy, we decided on CHOP based on historical consist of cyclosporine, prednisone, etoposide, and vin- considerations and the fact that some of the drugs have blastine, but only 1 report has been published for LCS.47 been used to treat other histiocytic disorders. Once a Some authors have suggested chemotherapy used for sar- cumulative dose of anthracycline equaled 320 mg/m2,we comas treatment is suited for LCS and this was the eliminated further doxorubicin, and continued therapy with approach used when treating our patient.40 However, vincristine, prednisone, and cyclophosphamide. One limi- reviewing the poor outcomes should raise concern about its tation of this approach was the possibility that steroids efficacy, even in the setting of single-site/single-organ were slowing bone engraftment and healing at the site of disease. surgical reconstruction. We felt it important to have ade- Our initial impetus for this review was an attempt to quate bone healing before initiating radiation therapy design a treatment plan for this young patient reported. because of the long-term consequences related to bone graft With the few patients reported, and virtually no data for demise. Therefore, 2 months before initiating local radia- young patients, we were left trying approaches which have tion therapy, prednisone was also discontinued. Fur- proved successful for treating sarcomas in children and thermore, the extensive surgical grafting and possible young adults. We therefore began therapy with aggressive slowing of bone healing by steroid therapy delayed local surgical resection at the primary tumor site, returning the control measures. Most sarcoma therapy recommendations patient to the operating theater after definitive diagnosis begin local control earlier in the course of therapy. Indeed, and staging evaluation. The location of tumor, with we were concerned that delaying radiotherapy might allow extension near the spinal cord did not allow for a wide local recurrence and performed a PET/CT scan about 5 surgical excision with negative margins. However, this months into treatment. A site of modest activity near the

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TABLE 4. Multisite/Multiorgan Disease Cases References Age (y) Sex Initial Sites Therapy Outcomes 1 28 33 M Lymph nodes, skin Chemotherapy Alive 2 29 47 M Lymph nodes, skin Chemotherapy Alive 3 30 74 F Gall bladder, lymph nodes Surgery Alive Chemotherapy 4 This study 7 F Bone marrow, soft tissue Surgery Alive Radiotherapy Chemotherapy 5 31 73 F Lymph nodes Chemotherapy Alive Chronic myeloid leukemia 6 32 38 M Skin, lymph nodes, lung Chemotherapy Alive with disease 7 33 45 F Skin, neck mass, lung Surgery Alive with disease Chemotherapy 8 34 52 M Lymph nodes, lung, rib Chemotherapy Alive with disease 9 35 49 F Lymph nodes, skin Chemotherapy Dead at 2 mo 10 15 28 M Mediastinum, liver, spleen None Dead at 3 wk 11 15 23 F Skin, lymph nodes, lung Chemotherapy Dead at 2 y 12 15 65 F Skin, lymph nodes, lung, spleen Chemotherapy Dead 13 15 72 M Lymph nodes, lung, rib Chemotherapy Dead 14 13 59 M Spleen, skin, lymph nodes, bone marrow Chemotherapy Dead at 9 y 15 13 35 M Bone marrow, lung, lymph nodes, liver Chemotherapy Dead 16 13 61 F Lymph nodes, liver, spleen Chemotherapy Dead at 10 mo 17 36 81 M Mediastinum, lung Chemotherapy Dead at 4 mo 18 37 ? Skin, lymph nodes, lung Chemotherapy Dead at 5 mo 19 38 75 M Spleen, skin Radiotherapy Dead at 10 mo Chemotherapy 20 12 63 F Skin, bone marrow Unknown Dead at 3 mo 21 12 88 M Skin, neck Surgery Dead 3 mo 22 39 77 F Lymph nodes Unknown Dead at 2 d 23 40 41 M Subcutaneous Radiotherapy Dead at 1 y Chemotherapy 24 41 53 M Lung, lymph nodes, bone marrow Not available Not available 25 42 39 M Lymph nodes Chemotherapy Dead at 7 mo

primary tumor location was uncovered. Very little data are kinase, is recruited by activated RAS and transported to the available to assess the role of PET/CT in this disease,41 so it cell membrane where it is then activated.3,27,48 Activated was felt additional information would be of importance. BRAF then activates MEK and eventually regulates gene Therefore, a CT-guided biopsy was performed. The tissue expression via ERK. Mutations in the glycine-rich loop/ obtained did not show any evidence of tumor and chemo- activation segment may lead to destabilization of inactive therapy proceeded for an additional 11 to 12 months. protein and result in a constitutively activated form of The rarity of LCS is likely to preclude any uniform BRAF, which may increase MEK-ERK signaling by up to clinical trials. However, the true incidence of LCS is 700-fold.49 Many tumors have been described to have unknown and it may be misdiagnosed as one of the other activating mutations in BRAF including melanoma, thyroid histiocytic disorders or even a granulocytic sarcoma. If the cancer, hairy cell leukemia, and sarcomas. A recent report published reports regarding age distribution are accurate, by Chen et al,27 describes an activating BRAF mutation in many individuals may never receive therapy, especially for LCS, the same mutation observed in our patient. Few other older patients where CHOP or other chemotherapy would genetic abnormalities are known to exist in LCS tumors be poorly tolerated. and given the poor outcome for these patients, we suggest Recent reports of mutations in BRAF merit consid- BRAF testing be performed for future patients. Although eration and comment. BRAF, a serine/threonine protein this mutation has been reported in other histiocytic dis- orders and is not specific for LCS, it may help to distinguish this disorder from other tumors. Introduction of vemur- TABLE 5. Treatment-related Outcome afenib, a BRAF inhibitor, may allow rational exploitation Alive With of this mutation for treatment purposes, especially in older Treatment Number Dead Disease Alive Unknown individuals where combined modality therapy is expected to 42,50 Surgery only 5 1 2 1 1 be poorly tolerated. Radiation only 2 1 1 In summary, we report a young patient diagnosed with Chemotherapy 19 11 4 3 1 LCS. This is a highly aggressive neoplasm and patients who only present with multisite/multiorgan disease are unlikely to Multimodality 17 5 2 10 0 benefit long-term from currently employed treatments. The Unknown/ 10 5 0 1 4 best approach to treatment is unknown but some patients, none especially with single-site/site-organ disease, may benefit Total 53 23 8 16 6 from aggressive surgery, chemotherapy, and additional r 2014 Lippincott Williams & Wilkins www.jpho-online.com | 423 Zwerdling et al J Pediatr Hematol Oncol Volume 36, Number 6, August 2014

TABLE 6. Disease Outcome by Site Disease Total (%) Alive (%) Alive With Disease (%) Dead (%) Other (%) Single-site/single-organ 28 (100) 11 (39) 5 (18) 7 (25) 5 (18) Multisites/multiorgans 25 (100) 5 (25) 3 (12) 16 (64) 1 (4)

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