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

Summary: Langerhans cell sarcoma is a rare malignancy with only 1 pediatric case (less than 15 y of age) reported. Here, we report the second case of Langerhans cell sarcoma in a child who presented with cord compression. This patient was treated with extensive surgical resection, postoperative chemotherapy, and involved-field radiation therapy. She completed therapy and remains in remission for 27 months. A review and analysis of all 53 cases published in the world literature is provided to help guide physicians treating this disease. Recently discovered genetic mutation involving BRAF is also discussed. Key Words: Langerhans cell sarcoma, pediatric, treatment, world review

(J Pediatr Hematol Oncol 2014;36:419–425)

L

angerhans cell sarcoma (LCS), one of several malignant histiocytic disorders which also include histiocytic sarcoma and interdigitating dendritic cell sarcoma, is recognized by the World Health Organization (WHO) as a class III histiocytic process involving truly malignant histiocytes.1,2 This is supported by new evidence of BRAF mutations in some of these tumors.3,4 LCS differs from class I and II histiocytic disorders based on morphologic characteristics of lesional cellular make-up and is frequently a fatal disease. LCS is very rare and found mostly in adults, when reported. The Histiocyte Society has established classification, diagnostic criteria, evaluation, and suggested treatments for these disorders (http://www.histiocytesociety. org/). We recently evaluated and treated a pediatric patient diagnosed with LCS who presented with spinal cord compression and continues in complete remission for 27 months. Our goals for this report are: (1) to add information as an aid for other clinicians who may evaluate and treat this disease; (2) to undertake a review of the world literature; and (3) add to new molecular analysis of this tumor which may suggest better diagnostic criteria and allow rationale for treatment.

METHODS A literature search was conducted in PubMed under the search term “Langerhans Cell Sarcoma.” MeSH: Received for publication February 28, 2014; accepted April 30, 2014. From the *Miller Children’s Hospital, Long Beach; wDepartment of Pediatrics, University of California, Irvine, CA; and zChildren’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA. The authors declare no conflict of interest. Reprints: Ted Zwerdling, MD, Miller Children’s Hospital, 701 East 28th Street, Suite 202, Long Beach, CA 90806 (e-mail: [email protected]). Copyright r 2014 by Lippincott Williams & Wilkins

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Langerhans Cell Sarcoma; pathology, therapy, diagnosis, etiology. BRAF mutational analysis performed at Clarient Inc. (Aliso Viejo, CA) using polymerase chain reaction technique. Immunohistochemical staining was performed using standard techniques according to the manufacturers’ recommendations.

RESULTS Case Report and Clinical Outcome A 7-year-old girl presented to the emergency department 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 and she was taking no medications. In the emergency department, the patient was afebrile and examination found slight tenderness over the right thoracic paraspinal region which increased with movement and decreased sensation (pinprick and touch) in the lower extremities without a sensory line. Weakness involving the lower extremities, hyperactive reflexes, and bilateral Babinski signs were noted. The remainder of her examination, including a retinal examination, was normal. Magnetic resonance imaging of the spine demonstrated a left-sided, extradural soft-tissue mass with bony involvement of T5-T6 vertebral bodies. Initial treatment consisted of steroids, decompression laminectomy, and partial tumor resection. Pathologic evaluation of the resected material was diagnostic of LCS (Fig. 1). With residual tumor present, second surgery, with the goal of complete resection, was attempted. Additional tumor was removed in a piecemeal manner and it was unclear if the resection margins contained malignant cells. An extensive reconstruction of the operative site was performed with bone grafting and stabilization. Further evaluations including computed tomography (CT) scan, bilateral bone marrow aspirations and biopsies, and Tc99 radionuclide bone scan were negative for metastatic disease. The patient then went on to receive chemotherapy (Table 1). Five months into chemotherapy, a small area of residual mass at the primary site showed slight PET/CT activity. This was 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. Fourteen months after diagnosis and with continued healing of the bone graft, using intensity-modulated radiation therapy techniques, 4500 cGy, in 25 fractions, was delivered to the primary site of tumor. Subsequently, 2 additional courses of Maintenance Therapy completed approximately 17 months of treatment. End-of-treatment evaluations 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 demonstrate disease.

Pathologic Findings Soft tissue and bone measuring 1 cm in largest dimension were evaluated for histology from the primary tumor site. The neoplasm consisted of a uniform population of cells with enlarged, moderately pleomorphic nuclei, and occasional multinucleated cells. The degree of nuclear pleomorphism was atypical for Langerhans cell histiocytosis. Mitotic activity was over 20 mitoses in 10 hpf (Ki-67 of 10% to 30%, Fig. 2) and atypical, pyknotic nuclei were common with areas of tumor necrosis scattered throughout the neoplasm. The tumor invaded the bone and cartilage. Tissue was evaluated by electron microscopy and tumor cells identified by nuclear configuration and abundant cytoplasm. The tumor showed occasional cells with blunted pseudopodium, scattered numerous large lysosomes, and an electron-dense cytoplasm with ribosomes and occasional small profiles of rough endoplasmic reticulum. No intermediate-type filamentous whorls or Birbeck granules were identified. There were no features to suggest neuritic processes nor other features of a primitive neural TABLE 1. Treatment Schema Surgery Surgical resection 2 Induction Vincristine, IV, 2 mg/m2  1 dose Adriamycin, IV, 40 mg/m2  1 dose (S Adriamycin 320 mg/m2) Prednisone, PO, 40 mg/m2/d 7 d Cyclophosphamide, IV, 1000 mg/m2  1 dose with mesna 400 mg/m2  2 doses Cycles repeated every 3 wk, 9 Maintenance I Vincristine, IV, 2 mg/m2  1 dose Prednisone, PO, 40 mg/m2/d 7 d (held last 2 cycles) Cyclophosphamide, IV, 1000 mg/m2  2 doses with mesna 400 mg/m2  4 doses Cycles of chemotherapy repeated every 4 wk,  7 Radiation 4500 cGy to local site of disease Vincristine, IV, 2 mg/m2 X 1 dose, weekly X 6. Maintenance II Vincristine, IV, 2 mg/m2  1 dose Cyclophosphamide, IV, 1000 mg/m2  2 doses with mesna 400 mg/m2  4 doses Cycles of chemotherapy repeated every 4 wk,  2

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nor glial tumor. Immunohistochemical results are shown in Table 2 and Figure 2. Tumor tissue was subjected to analysis for BRAF and found to harbor a known mutation (V600E).

Literature Review and Discussion Tables 3 and 4 summarize 53 collected cases of LCS as published in the world literature as of January 2014. (We are also aware of 4 other cases involving children aged 2, 7, 15, and 18 years and 2 others in adults aged 22 and 31, but have insufficient information about these cases. These cases were reviewed by one of us (R.J.) and have never been published. However, attempts to gather additional information beyond the diagnosis were unsuccessful, and therefore, not included in our analysis.) Approximately 53% were reported to involve a single-site/single-organ. For patients with single-site/single-organ disease, 11 (39%) were reported to be in remission, as opposed to 5 of 25 with multisite/multiorgan disease (20%). Patients presenting with multisite/multiorgan disease fared very poorly with 64% dead and another 16% either alive with disease or without follow-up. It is likely that many of the patients reported as alive with disease eventually died from the process. For patients who presented with single-site/single-disease, lymph nodes, and skin were most frequently reported, similar to patients with multisite/multiorgan disease. Initiation of therapy and the actual treatment details are poorly reported precluding comparisons. Details of surgery, especially related to the intent to remove all known disease and the subsequent evaluation of resection margins for disease are absent in most of the cases reported to date. Less information regarding radiation therapy is given. Tables 5 and 6 summarizes treatment-related outcome as described for reported cases. Although all patients had lesional biopsy for diagnostic purposes, 43 (81%) went on to receive other treatments with either surgery only (n = 5), radiation only (n = 2), chemotherapy only (n = 19), or multimodality therapy (n = 17). Ten patients were either not treated or case reports did not so state. Three patients received liver (n = 1) or stem cell transplants. Two cases reported by Chung et al43 are not included in this analysis. In case 1, there is a lack of Ki-67 reporting and while the text described sarcomatous changes the CD1a illustration is poor and not convincingly membranous. They also describe widespread disease without any masses and no results of the bone marrow evaluation are given. r

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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 any illustrations. Langerhans cells are primarily charged with antigen recognition, processing, and presentation to T cells. First identified in 1868 using gold chloride staining technique, they were assumed to be of nerve origin based on morphology. It is now known, they are derived from fetal liverderived monocytes which populate the outer layer of the TABLE 2. Immunohistologic Results

Positively Reactive Immunostaining CEA (perinuclear, 10% of cells) CD1a (diffuse cytoplasmic, membranous) CD43 (diffuse, membranous) CD68 (perinuclear) INI-1 (strong, diffuse nuclear positivity)* Ki-67 60%-70% of tumor nuclei PGP 9.4 (faint, membranous) S-100 (diffuse, cytoplasmic, nuclear) Vimentin (diffuse, intense cytoplasmic) CD207

Nonreactive Immunostaining Synaptophysin EMA GFAP CD99, myeloperoxidase AE-1/AE-3 Myogenin, desmin CD34, CD117, CD3, CD15, CD20, CD21, CD23, CD30, CD35, CD45, CD56 HMB-45 Melan-A, tyrosine hydroxylase

*Normal (expected).

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epidermis before birth.44 During inflammatory states, they may be replaced by blood-derived Gr-1Hi monocytes. Other data support the separate ontogeny from other dendritic cells such as flt-3 independence, and required IL-34.45,46 Malignant Langerhans cells must be distinguished from class I histiocytes and include such morphologic features as increased nuclear:cytoplasmic ratio, nuclear pleomorphism, 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 microscopic identification of Birbeck granules. Alternatively, Birbeck granules may also be identified by CD207 reactivity (Langerin). CD207 appears to recognize a c-type lectin, found on Birbeck granules, but the pattern of staining clearly shows more than just the granule itself. This lectin participates in internalizing antigen and allows processing of antigen for presentation to T cells. However, Birbeck granules many not be observed in all cases of LCS.12 In reviewing the literature, it is apparent that LCS may arise de novo or be observed in other disorders. Several cases have been reported in myeloproliferative syndromes, other histiocytic disorders, B-lineage leukemia, follicular lymphoma, dermal lentigines, and after liver transplantation. Several authors provided details about chemotherapy given to these patients. Most used CHOP but several reports of MAID (mesna, doxorubicin, ifosphamide, dacarbazine) and other agents appear in the literature.8,10,37 In addition, Keklik et al,47 attempted to use 2-CDA for a primary tumor in the nasopharynx. However, new disease www.jpho-online.com |

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TABLE 3. Single-Site/Single-Organ Cases

References

Age (y)

Sex

1

5

21

M

Flank mass

Site

2

6

48

M

Skin

3

7

58

M

Skin

4

8

67

F

Lymph node

5

9

21

M

Lymph node

6

10

72

M

Skin

7

11

62

M

Lymph node

8 9

12 12

61 54

M M

10 11 12 13

13 14 15 15

60 34 17 10

M M F F

Skin Skin Myeloid leukemia Bone Lung Lymph node Skin

14 15 16 17

15 15 16 17

50 46 38 74

F M F F

Bone Lymph node Skin Skin

18 19 20 21 22

18 19 20 21 22

57 66 86

M F M

57

F

Lymph node Skin Lymph node Lymph node Bone

23 24 25 26 27 28

23 24 25 15 26 27

60 88 47 50 67 68

M M M F M F

Lymph node Skin Lung Skin Lymph node Lymph node chronic leukemia

was detected and treatment was changed to etoposide, ARA-C, cis-platin, and methylprednisolone without success. Chemotherapy for class I histiocytic disorders may consist of cyclosporine, prednisone, etoposide, and vinblastine, but only 1 report has been published for LCS.47 Some authors have suggested chemotherapy used for sarcomas treatment is suited for LCS and this was the approach used when treating our patient.40 However, reviewing the poor outcomes should raise concern about its efficacy, even in the setting of single-site/single-organ disease. Our initial impetus for this review was an attempt to design a treatment plan for this young patient reported. With the few patients reported, and virtually no data for young patients, we were left trying approaches which have proved successful for treating sarcomas in children and young adults. We therefore began therapy with aggressive surgical resection at the primary tumor site, returning the patient to the operating theater after definitive diagnosis and staging evaluation. The location of tumor, with extension near the spinal cord did not allow for a wide surgical excision with negative margins. However, this

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Therapy Surgery Radiotherapy Surgery Chemotherapy Surgery Liver transplant Radiotherapy Chemotherapy Chemotherapy Marrow transplant Chemotherapy Surgery Radiotherapy Chemotherapy Unknown Chemotherapy Stem cell transplant Radiotherapy Surgery Chemotherapy Surgery Radiotherapy Surgery Chemotherapy Surgery Surgery Radiotherapy Chemotherapy Chemotherapy Radiotherapy Unknown Surgery Radiotherapy Chemotherapy None Surgery Chemotherapy Not available Unknown Hospice care

Outcomes Alive Alive Alive Alive Alive Alive Alive Alive Alive Alive Alive Alive with disease Alive with disease Alive with disease Alive with disease Alive with disease Died at 14 mo Died at 7 mo Died of disease Died at 1 mo Dead Dead 10 mo Dead 3 mo Not available Not available Not available No data No data

approach did result in additional tumor removal during a second surgical procedure. With little data to choose chemotherapy, we decided on CHOP based on historical considerations and the fact that some of the drugs have been used to treat other histiocytic disorders. Once a cumulative dose of anthracycline equaled 320 mg/m2, we eliminated further doxorubicin, and continued therapy with vincristine, prednisone, and cyclophosphamide. One limitation of this approach was the possibility that steroids were slowing bone engraftment and healing at the site of surgical reconstruction. We felt it important to have adequate bone healing before initiating radiation therapy because of the long-term consequences related to bone graft demise. Therefore, 2 months before initiating local radiation therapy, prednisone was also discontinued. Furthermore, the extensive surgical grafting and possible slowing of bone healing by steroid therapy delayed local control measures. Most sarcoma therapy recommendations begin local control earlier in the course of therapy. Indeed, we were concerned that delaying radiotherapy might allow local recurrence and performed a PET/CT scan about 5 months into treatment. A site of modest activity near the r

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TABLE 4. Multisite/Multiorgan Disease Cases

References

Age (y)

Sex

1 2 3

28 29 30

33 47 74

M M F

Lymph nodes, skin Lymph nodes, skin Gall bladder, lymph nodes

Initial Sites

4

This study

7

F

Bone marrow, soft tissue

5

31

73

F

Lymph nodes

6 7

32 33

38 45

M F

Skin, lymph nodes, lung Skin, neck mass, lung

8 9 10 11 12 13 14 15 16 17 18 19

34 35 15 15 15 15 13 13 13 36 37 38

52 49 28 23 65 72 59 35 61 81 ? 75

M F M F F M M M F M M

Lymph nodes, lung, rib Lymph nodes, skin Mediastinum, liver, spleen Skin, lymph nodes, lung Skin, lymph nodes, lung, spleen Lymph nodes, lung, rib Spleen, skin, lymph nodes, bone marrow Bone marrow, lung, lymph nodes, liver Lymph nodes, liver, spleen Mediastinum, lung Skin, lymph nodes, lung Spleen, skin

20 21 22 23

12 12 39 40

63 88 77 41

F M F M

Skin, bone marrow Skin, neck Lymph nodes Subcutaneous

24 25

41 42

53 39

M M

Lung, lymph nodes, bone marrow Lymph nodes

primary tumor location was uncovered. Very little data are available to assess the role of PET/CT in this disease,41 so it was felt additional information would be of importance. Therefore, a CT-guided biopsy was performed. The tissue obtained did not show any evidence of tumor and chemotherapy proceeded for an additional 11 to 12 months. The rarity of LCS is likely to preclude any uniform clinical trials. However, the true incidence of LCS is unknown and it may be misdiagnosed as one of the other histiocytic disorders or even a granulocytic sarcoma. If the published reports regarding age distribution are accurate, many individuals may never receive therapy, especially for older patients where CHOP or other chemotherapy would be poorly tolerated. Recent reports of mutations in BRAF merit consideration and comment. BRAF, a serine/threonine protein TABLE 5. Treatment-related Outcome

Treatment Surgery only Radiation only Chemotherapy only Multimodality Unknown/ none Total

r

Number Dead 5 2 19

1 1 11

17 10 53

Alive With Disease 2

Alive Unknown

4

1 1 3

1

5 5

2 0

10 1

0 4

23

8

16

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1

Therapy Chemotherapy Chemotherapy Surgery Chemotherapy Surgery Radiotherapy Chemotherapy Chemotherapy Chronic myeloid leukemia Chemotherapy Surgery Chemotherapy Chemotherapy Chemotherapy None Chemotherapy Chemotherapy Chemotherapy Chemotherapy Chemotherapy Chemotherapy Chemotherapy Chemotherapy Radiotherapy Chemotherapy Unknown Surgery Unknown Radiotherapy Chemotherapy Not available Chemotherapy

Outcomes Alive Alive Alive Alive Alive Alive with disease Alive with disease Alive with disease Dead at 2 mo Dead at 3 wk Dead at 2 y Dead Dead Dead at 9 y Dead Dead at 10 mo Dead at 4 mo Dead at 5 mo Dead at 10 mo Dead Dead Dead Dead

at 3 mo 3 mo at 2 d at 1 y

Not available Dead at 7 mo

kinase, is recruited by activated RAS and transported to the cell membrane where it is then activated.3,27,48 Activated BRAF then activates MEK and eventually regulates gene expression via ERK. Mutations in the glycine-rich loop/ activation segment may lead to destabilization of inactive protein and result in a constitutively activated form of BRAF, which may increase MEK-ERK signaling by up to 700-fold.49 Many tumors have been described to have activating mutations in BRAF including melanoma, thyroid cancer, hairy cell leukemia, and sarcomas. A recent report by Chen et al,27 describes an activating BRAF mutation in LCS, the same mutation observed in our patient. Few other genetic abnormalities are known to exist in LCS tumors and given the poor outcome for these patients, we suggest BRAF testing be performed for future patients. Although this mutation has been reported in other histiocytic disorders and is not specific for LCS, it may help to distinguish this disorder from other tumors. Introduction of vemurafenib, a BRAF inhibitor, may allow rational exploitation of this mutation for treatment purposes, especially in older individuals where combined modality therapy is expected to be poorly tolerated.42,50 In summary, we report a young patient diagnosed with LCS. This is a highly aggressive neoplasm and patients who present with multisite/multiorgan disease are unlikely to benefit long-term from currently employed treatments. The best approach to treatment is unknown but some patients, especially with single-site/site-organ disease, may benefit from aggressive surgery, chemotherapy, and additional www.jpho-online.com |

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TABLE 6. Disease Outcome by Site

Disease

Total (%)

Alive (%)

Alive With Disease (%)

Dead (%)

Other (%)

28 (100) 25 (100)

11 (39) 5 (25)

5 (18) 3 (12)

7 (25) 16 (64)

5 (18) 1 (4)

Single-site/single-organ Multisites/multiorgans

local control with radiation. Tumor evaluation for BRAF mutations may allow better diagnosis, therapeutic options, and should be studied in this disease. REFERENCES 1. International Classification of Diseases for Oncology, 3rd Edition (ICD-O-3). C96.4. 2010. Available at: http://www. who.int/classifications/icd/en/. 2. Swerdlow SH, Campo E, Harris NL, et al. World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of Hematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008. 3. Badalian-Very G, Vergilio JA, Fleming M, et al. Pathogenesis of Langerhans cell histiocytosis. Annu Rev Pathol. 2013;8:1–20. 4. Subbiha V, Subbiah IM. Killing two birds with one stone: BRAF V600E inhibitor therapy for hairy cell leukemia and Langerhans/dendritic cell sarcoma. Ann Hematol. 2013;92:1149. 5. Au WY, Lai C, Trendell-Smith NJ, et al. Paraneoplastic disseminated lentigines heralding aggressive Langerhans cell sarcoma. Ann Hematol. 2013;92:419–420. 6. Li Y, Li B, Tian X, et al. Unusual cutaneous Langerhans cell sarcoma without extracutaneous involvement. Diagn Pathol. 2013;8:20–27. 7. Diaz-Sarrio C, Salvatella-Dane´s N, Castro-Forns M, et al. Langerhans cell sarcoma in a patient who underwent transplantation. JEADV. 2007;21:973–976. 8. Shimizu I, Takeda W, Kirihara T, et al. Long-term remission of Langerhans cell sarcoma by AIM regimen combined with involved-field irradiation. Rinsho Ketsueki. 2012;53:1911–1915. 9. Ratei R, Hummel M, Anagnostopoulos I, et al. Common clonal origin of an acute B-lymphoblastic leukemia and a Langerhans’ cell sarcoma: evidence for hematopoietic plasticity. Haematologica. 2010;95:1461–1466. 10. Uchida K, Kobayashi S, Inukai T, et al. Langerhans cell sarcoma emanating from the upper arm skin: successful treatment by MAID regimen. J Orthop Sci. 2008;13:89–93. 11. Nakayama M, Takahashi K, Hori M, et al. Langerhans cell sarcoma of the cervical lymph node: a case report and literature review. Auris Nasus Larynx. 2010;37:750–753. 12. Sagransky MJ, Deng AC, Magro CM. Primary cutaneous Langerhans cell sarcoma: a report of four cases and review of the literature. Am J Dermatopathol. 2012;35:196–204. 13. Kawase T, Hamazaki M, Ogura M, et al. CD56/NCAMpositive Langerhans cell sarcoma: a clinicopathologic study of 4 cases. Int J Hematol. 2005;81:323–329. 14. Lee JS, Ko GH, Kim HC, et al. Langerhans cell sarcoma arising from Langerhans cell histiocytosis: a case report. J Korean Med Sci. 2006;21:577–580. 15. Pileri SA, Gaidano G, Zinzani PL, et al. Tumours of histiocytes and accessory dendritic cells: an immunohistochemical approach to classification from the International Lymphoma Study Group based on 61 cases. Histopathology. 2002;41:1–29. 16. Misery L, Godard W, Hamzeh H, et al. Malignant Langerhans cell tumor: a case with a favorable outcome associated with the absence of blood dendritic cell proliferation. J Am Acad Dermatol. 2003;49:527–529. 17. Itoh H, Miyaguni H, Kataoka H, et al. Primary cutaneous Langerhans cell histiocytosis showing malignant phenotype in an elderly woman: report of a fatal case. J Cutan Pathol. 2001;28:371–378.

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18. Sumida K, Yoshidomi Y, Koga H, et al. Leukemic transformation of Langerhans cell sarcoma. Int J Hematol. 2008;87:527–531. 19. Muslimani A, Chisti MM, Blenc AM, et al. Langerhans/ dendritic cell sarcoma arising from hairy cell leukemia: a rare phenomenon. Ann Hematol. 2012;91:1485–1487. 20. Xu Z, Padmore R, Faught C, et al. Langerhans cell sarcoma with an aberrant cytoplasmic CD3 expression. Diagn Pathol. 2012;7:128–134. 21. Zhang J, Wang JS, Wei XJ, et al. Langerhans cell sarcoma: a case report and literature review. Zhonghua Xue Ye Xue Za Zhi. 2012;33:266–269. 22. Lian YL, He HY, Liao SL, et al. Langerhans cell sarcoma of talus: report of a case. Zhonghua Bing Li Xue Za Zhi. 2006;35:697–698. 23. West DS, Dogan A, Quint PS, et al. Clonally related follicular lymphomas and Langerhans cell neoplasms expanding the spectrum of transdifferentiation. Am J Surg Pathol. 2013;37:978–986. 24. Deng A, Lee W, Pfau R, et al. Primary cutaneous Langerhans cell sarcoma without Birbeck granules: indeterminate cell sarcoma? J Cutan Pathol. 2008;35:849–854. 25. Langfort R, Radzikowska E, Czarnowska E, et al. Langerhans cell sarcoma with pulmonary manifestation, mediastinum involvement and bronchoesophageal fistula. A rare location and difficulties in histopathological diagnosis. Pneumonol Alergol Pol. 2009;77:327–334. 26. Lo´pez-Ferrer P, Jime´nez-Heffernan JA. Fine needle aspiration cytology of Langerhans cell sarcoma. Cytopathology. 2008;19:59–64. 27. Chen W, Jaffe R, Zhang L, et al. Langerhans cell sarcoma arising from chronic lymphocytic lymphoma/small lymphocytic leukemia: lineage analysis and BRAF V600E mutation study. N Am J Med Sci. 2013;5:386–39. 28. Ferringer T, Banks PM, Metcalf JS. Langerhans cell sarcoma. Am J Dermatopathol. 2006;28:36–39. 29. Bohn OL, Ruiz-Argu¨elles G, Navarro L, et al. Cutaneous Langerhans cell sarcoma: a case report and review of the literature. Int J Hematol. 2007;85:116–120. 30. Zhao G, Luo M, Wu ZY, et al. Langerhans cell sarcoma involving gallbladder and peritoneal lymph nodes: a case report. Int J Surg Pathol. 2009;17:347–353. 31. Chang N-Y, Wang J, Wen MC, et al. Langerhans cell sarcoma in a chronic myelogenous leukemia patient undergoing imatinib mesylate therapy. A case study and review of the literature. Int J Surg Pathol. 2014. [Epub ahead of print]. 32. Lauritzen AF, Delsol G, Hansen NE, et al. Histiocytic sarcomas and monoblastic leukemias. A clinical, histologic, and immunophenotypical study. Am J Clin Pathol. 1994;102: 45–54. 33. Lee JY, Jung KE, Kim HS, et al. Langerhans cell sarcoma: a case report and review of the Literature. Int J Dermatol. 2013;53:1–3. 34. Yang CJ, Lee JY, Wu CC, et al. An unusual pulmonary mass with mediastinal invasion and multiple intrapulmonary nodules in a 52-year-old man. Chest. 2012;141: 253–258. 35. Tani M, Ishii N, Kumagai M, et al. Malignant Langerhans cell tumour. Br J Dermatol. 1992;126:398–403. 36. Ju¨lg BD, Weidner S, Mayr D. Pulmonary manifestation of a Langerhans cell sarcoma: case report and review of the literature. Virchows Arch. 2006;448:369–374. r

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37. Yoshimi A, Kumano K, Motokura T, et al. ESHAP therapy effective in a patient with Langerhans cell sarcoma. Int J Hematol. 2008;87:532–537. 38. Furmanczyk PS, Lisle AE, Caldwell RB, et al. Langerhans cell sarcoma in a patient with hairy cell leukemia: common clonal origin indicated by identical immunoglobulin gene rearrangements. J Cutan Pathol. 2012;39:644–650. 39. Wang Y-N, Zhou X, Wang Z. Langerhans cell sarcoma in the cervical lymph node: a case report and literature review. Act Haematologica. 2013;129:114–120. 40. Wang C, Chen Y, Gao C, et al. Multifocal Langerhans cell sarcoma involving epidermis: a case report and review. Diagn Pathol. 2012;7:99–103. 41. Chen YW, Chang CC, Hou PN, et al. The characteristics of FDG PET/CT imaging in pulmonary Langerhans cell sarcoma. Clin Nucl Med. 2012;37:495–497. 42. Machnicki MM, Stoklosa T. BRAF—a new player in hematological neoplasms. Blood Cells Mol Dis. 2014; pii:S1079-9796(14)00002-3. 43. Chung WD, Im SA, Chung NG, et al. Langerhans cell sarcoma in two young children: imaging findings on initial presentation and recurrence. Korean J Radiol. 2013;14:520–524.

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44. Berres Marie-Luise, Carl E. Allen, Miriam Merad: pathological consequence of misguided dendritic cell differentiation in histiocytic. In: Murphy KM, Merad M, eds. Advances in Immunology. Elsevier Inc.; 2013:127–161. ISSN 0065-2776. 45. Hoeffel G, Wang Y, Greter M, et al. Adult Langerhans cells derive predominantly from embryonic fetal liver monocytes with a minor contribution of yolk sac-derived macrophages. J Exp Med. 2012;209:1167–1181. 46. Greter M, Lelios I, Pelczar P, et al. Stroma derived Interleukin34 controls the development and maintenance of Langerhans cells and the maintenance of microglia. Immunity. 2012;37: 1050–1060. 47. Keklik M, Sivgin S, Kontas O, et al. Langerhans cell sarcoma of the nasopharynx: a rare case. Scott Med J. 2013;58:e17–e20. 48. Badalian-Very G, Vergilio JA, Degar BA, et al. Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood. 2010;116:1919–1923. 49. Ziai J, Hui P. BRAF mutation testing in clinical practice. Expert Rev Mol Diagn. 2012;12:127–138. 50. Garbe C, Abusaif S, Eigentler TK. Vemurafenib. Recent Results Cancer Res. 2014;201:215–225.

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Langerhans cell sarcoma: case report and review of world literature.

Langerhans cell sarcoma is a rare malignancy with only 1 pediatric case (less than 15 y of age) reported. Here, we report the second case of Langerhan...
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