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remains the

mainstay of diagnosing rare dendritic

and histiocytic . Collaborative

efforts are needed to better treat patients

with these rare disorders.

Mushroom Biome. Photograph courtesy of Sherri Damlo. www.damloedits.com.

Dendritic Cell and Histiocytic Neoplasms: Biology, Diagnosis, and Treatment Samir Dalia, MD, Haipeng Shao, MD, PhD, Elizabeth Sagatys, MD, Hernani Cualing, MD, and Lubomir Sokol, MD, PhD

Background: Dendritic and histiocytic cell neoplasms are rare malignancies that make up less than 1% of all neoplasms arising in lymph nodes or soft tissues. These disorders have distinctive disease biology, clinical presentations, pathology, and unique treatment options. Morphology and immunohistochemistry evaluation by a hematopathologist remains key for differentiating between these neoplasms. In this review, we describe tumor biology, clinical features, pathology, and treatment of follicular , interdigitating dendritic cell sarcoma, indeterminate dendritic cell sarcoma, , fibroblastic reticular cell tumors, and disseminated . Methods: A literature search for articles published between 1990 and 2013 was undertaken. Articles are reviewed and salient findings are systematically described. Results: Patients with dendritic cell and histiocytic neoplasms have distinct but variable clinical presentations; however, because many tumors have recently been recognized, their true incidence is uncertain. Although the clinical features can present in many organs, most occur in the lymph nodes or skin. Most cases are unifocal and solitary presentations have good prognoses with surgical resection. The role of adjuvant therapy in these disorders remains unclear. In cases with disseminated disease, prognosis is poor and data on treatment options are limited, although chemotherapy and referral to a tertiary care center should be considered. Excisional biopsy is the preferred method of specimen collection for tissue diagnosis, and immunohistochemistry is the most important diagnostic method for differentiating these disorders from other entities. Conclusions: Dendritic cell and histiocytic cell neoplasms are rare hematological disorders with variable clinical presentations and prognoses. Immunohistochemistry remains important for diagnosis. Larger pooled analyses or clinical trials are needed to better understand optimal treatment options in these rare disorders. Whenever possible, patients should be referred to a tertiary care center for disease management.

From the Departments of Medical (SD), Hematopathology Submitted December 20, 2013; accepted May 1, 2014. and Laboratory Medicine (HS, ES), and Malignant Hematology (LS) at Address correspondence to Samir Dalia, MD, Mercy Clinic Oncol- the H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, ogy-Hematology, 3001 McClelland Boulevard, Joplin, MO 64804. the University of South Florida Morsani College of Medicine (SD, HS), E-mail: [email protected] Tampa, Florida, and IHCFLOW (HC), Lutz, Florida. No significant relationships exist between the authors and the com- Dr Dalia is now affiliated with Mercy Clinic Oncology-Hematology, panies/organizations whose products or services may be referenced Joplin, Missouri. in this article.

290 Cancer Control October 2014, Vol. 21, No. 4 Introduction nodes or the extranodal ectopic lymphoid tissue, Dendritic and histiocytic neoplasms are rare hema- including lymphoid nodules in the marrow. tological malignancies that involve common immune Through the formation of immune complexes, these accessory or mesenchymal cells. These tumors are cells store and retain and serve as a nidus typically placed into 2 main groups based on their for B-cell proliferation and differentiation, along with derivation from either precursors or help from T cells.5-7 FDCs are mesenchymal in origin mesenchymal cells. Histiocytic sarcoma (HS), Lang- and similar to . Although FDCs are not erhans cell (LCH), and interdigitating derived from bone marrow progenitors, they express dendritic cell sarcoma (IDCS) are derived from bone antigens related to bone marrow stroma. Hence, these marrow precursors, while follicular dendritic cell sar- cells typically express markers of FDC differentiation, coma (FDCS), indeterminate dendritic cell sarcoma including CD21, CD23, and CD35.8 (INDCS), fibroblastic reticular cell tumors (FRCTs), Although FDCS is mesenchymal in origin, it is and disseminated juvenile xanthogranuloma (DJX) clonally related to follicular , possibly are histogenetically of stromal-derived dendritic cells through transdifferentiation of the follicular lympho- or mesenchymal in origin.1,2 Divergent differentiation ma clone.3 The disease has also been associated with from marrow precursors is the normal histogenesis, Castleman disease, paraneoplastic pemphigus, and although hybrid or transdifferentiation from neoplas- myasthenia gravis.9-13 FDCS may arise in lymph nodes tic lymphoid clones has also been proposed in IDCS, that harbor dysplastic FDCs in Castleman disease, with HS, or FDCS.2-4 Together, dendritic and histiocytic neo- some studies reporting clonal expansion of FDCs in plasms make up less than 1% of neoplasms presenting these patients.14,15 FDCS and non-neoplastic FDCs of in the lymph nodes or soft tissues. Castleman disease express epidermal growth factor re- The rarity of these tumors makes them difficult ceptor, which may promote FDC persistence and allow to accurately diagnose and treat, and they are often for mutations that may result in FDCS.16 In addition, mistaken as non-Hodgkin lymphoma or other lymph- a correlation exists between FDCS and the presence oproliferative disorders. Patients with suspected den- of Epstein–Barr virus (EBV).17 Because FDCs express dritic and histiocytic neoplasms require hematopathol- CD21 (acting as a receptor for EBV), the virus could ogy consultation and should be referred to a tertiary gain entry into these cells.18-20 The differential diagno- care cancer center when possible. The diagnosis of sis of FDCS remains broad and includes B- and T-cell these rare disorders is based on differential features , myeloid , melanoma, carcino- in morphology and immunohistochemistry. Recent mas, and other dendritic and histiocytic disorders, such advances in immunohistochemistry have helped in a as blastic plasmacytoid dendritic cell neoplasms and better classification of dendritic cell and histiocytic LCH (Table 1). Rarely, peripheral nerve sheath tumors neoplasms and have improved our knowledge of their and malignant fibrous are mistaken for tumor biology and histogenesis, which may be helpful FDCS; immunohistochemistry might help in the diag- in the management of these rare diseases. The aim of nosis of these entities.21,22 this review is to provide clinicians with the current scientific framework to better understand the tumor Clinical Features biology, clinical features, pathology, and treatment of FDCS presents in a wide range of ages, but it shows FDCS, IDCS, INDCS, HS, FRCT, and DJX. adult predominance (mean age, 44 years).23,24 Local- We performed a literature search for articles pub- ized FDCS has a benign course, a median survival lished between January 1, 1990, and December 1, 2013, rate of 168 months (range, 2–360 months), and risks to find research related to tumor biology, clinical fea- of local recurrence and distant metastasis of 27% to tures, pathology, and treatments for each of these rare 28%, respectively.10 Larger tumor size (≥ 6 cm), the disorders. We referred to the text and references of the presence of coagulative necrosis, high mitotic count fourth edition of the WHO Classification of Tumours (≥ 5 per 10 HPF), and cytological atypia are associated of Haematopoietic and Lymphoid Tissues1 as a basis to with a poor prognosis.8,10,25 Stage did not significantly comprehensively cover these disorders. Although LCH impact overall survival rates in patients with FDCS.10 is integral in understanding these entities, it has been Saygin et al10 reported that 2-year survival rates for separately reviewed by Dr Grana on page 328 of this early, locally advanced, and distant metastatic disease issue and will not be covered here. were 84.2%, 80%, and 42.8%, respectively. In the majority of cases, FDCS presents as a Follicular Dendritic Cell Sarcoma slow-growing mass, usually with the most frequent Tumor Biology location in the head and neck or abdominal lymph FDCS is a very rare clonal of follicular nodes. Approximately one-half of patients will present dendritic cells (FDCs). FDCs are stromal-derived cells with a local cervical and intra-abdominal mass.10,26 normally found in the germinal centers of lymph Although rare, most extranodal involvement occurs

October 2014, Vol. 21, No. 4 Cancer Control 291 Table 1. — Differential Diagnosis of Dendritic Cell Sarcomas

FDCS and IDCS FRCT HS INDCS JXG

Anaplastic large cell lymphoma FDCS Anaplastic large cell LCH IDCS (for FDCS) or FDCS IDCS lymphoma Pityriasis rosea Eruptive (for IDCS) INDCS Diffuse large B-cell Scabies LCH Inflammatory pseudotumors lymphoma Palisaded T-cell lymphomas Intranodal myofibroblastoma Hemophagocytic myofibroblastoma (cutaneous T-cell hyperplasia, Papular LCH lymphohistiocytosis mycosis fungoides) Sarcoma Spitz nevus Non-Hodgkin lymphoma LCH Tuberous xanthoma Peripheral nerve sheath tumors Lymphoma True histiocytic lymphomas Metastatic carcinoma or melanoma

FDCS = follicular dendritic cell sarcoma, FRCT = fibroblastic reticular cell tumor, HS = histiocytic sarcoma, IDCS = interdigitating dendritic cell sarco- ma, INDCS = indeterminate dendritic cell sarcoma, JXG = juvenile xanthogranuloma, LCH = histiocytosis. in the liver, lungs, tonsils, or .10 Workup for pression of CD68 can be seen.5,8,28 Clusterin is strong- patients with FDCS should include computed tomog- ly positive in FDCS and is negative or weakly posi- raphy (CT) scans with contrast from the neck to the tive in other dendritic cell tumors.21,29 Desmoplakin, pelvis to evaluate other sites of disease, complete vimentin, fascin, epidermal growth factor receptor, counts, bone marrow aspiration, and biopsy. CD45, and HLA-DR can be variably positive.5,16,28,30 In certain patients, HIV, EBV, and hepatitis testing can Immunoglobulin and T-cell receptor genes are in a be considered to exclude concurrent viral infection. germline configuration.30 Cytogenetic data in patients Core needle biopsy or excisional biopsy (preferred) with FDCS are limited and do not aid in diagnosis.31 of the tumor mass is necessary for an accurate diag- The major clinical and pathological findings for nosis of FDCS. Fine needle aspiration biopsy should FDCS are outlined in Table 2. be avoided. Treatment Pathology Surgical resection remains the mainstay of treatment in Cytomorphology of a biopsied/resected lesion is FDCS. A Surveillance, Epidemiology, and End Results characterized as spindled to ovoid cells that form database study reported that 94% of patients with fascicles, whorls, diffuse sheets, or nodules (Fig 1). localized disease had surgical resection as the initial Individual cells generally show indistinct cell borders and a moderate amount of eo- sinophilic cytoplasm. Nuclear pseudoinclusions are common and binucleated, and multinu- cleated tumor cells are seen.1 Long cytoplasmic projections and desmosomal junctions are seen on electron microscopy; and numer- ous are not present.5 Lymphoplasmacytic infiltration is present in more than 90% of cases.10 Rarely, Reed-Sternberg– like cells can lead to a mistaken diagnosis of Hodgkin disease.27 Immunohistochemistry is the most important work- up to help differentiate FDCS Fig 1. — Follicular dendritic cell sarcoma. This spindle cell proliferation was identified on a retroperitoneal from other histiocytic tumors. mass in a 79-year-old man. The spindle cells form fascicles with occasional whorls. Several mitotic figures In FDCS, CD21, CD23, CD35, were seen (lower right panel), which, in combination with the intra-abdominal location and large size of the mass, suggested an increased risk for recurrence. A few small are seen in the background, which R4/23, Ki-FDC1p, and KiM4 is typical for this entity. By immunohistochemistry the spindle cells were positive for CD21, CD23, CD68, and are positive and a variable ex- D2-40. The cells were negative for CD117 (c-), S100, desmin, cytokeratin, and CD34.

292 Cancer Control October 2014, Vol. 21, No. 4 treatment.26 The benefit of adjuvant therapy for fully tation in FDCS is unclear. One study reported relapses resected lesions in patients with limited stage disease within 1 year in 2 patients treated with allogeneic is debatable. Two large analyses both reported no ben- transplantation for FDCS.32 efit for adjuvant radiation therapy in patients with lo- calized FDCS.10,26 Soriano et al32 reported in a series of Interdigitating Dendritic Cell Sarcoma 14 cases with FDCS that 3 patients treated with surgery Tumor Biology followed by adjuvant chemotherapy and radiotherapy Normal interdigitating dendritic cells (IDCs) are anti- had complete remission, while 3 patients given che- gen-processing cells usually located in the motherapy alone showed no complete response. The paracortex, a major T-cell region. These cells present role of adjuvant chemotherapy or radiation therapy antigens to T cells and regulate cellular immune re- in localized FDCS remains controversial and should sponse.10,34-38 IDCs originate from marrow hematopoi- be considered on a case-by-case basis. etic precursors through the conversion of Langerhans In patients with extensive disease, Saygin et al10 cells as they travel to the lymph node.10,34,39-41 Malignant reported that 23 patients treated with combined che- IDCs result in IDCS and are usually positive for S100 motherapy and radiotherapy had excellent survival and vimentin and negative for CD1a and .1 rates, with only 2 deaths due to disease. These data Unlike FDCS, they do not express CD21 or CD35. suggest the importance of combined modality in ad- IDCS have been reported in association with vanced FDCS, although no prospective randomized other hematological and solid tumor malignancies, trial data exist. Regimens designed to manage ag- including B-cell neoplasms, mycosis fungoides, and gressive lymphomas, such as cyclophosphamide/vin- neoplasms of the skin, liver, stomach, colon, breast, cristine/doxorubicin/prednisone (CHOP), ifosfamide/ and brain.10 A clonal relationship between IDCS and carboplatin/etoposide (ICE), and doxorubicin/bleomy- low-grade B-cell lymphomas has been reported and cin/vincristine/dacarbazine (ABVD), have been used may be due to the transdifferentiation of the lympho- with variable success.5,10,32,33 Currently, lymphoma-type ma clones.2-4 In one series of 7 patients with chronic chemotherapy remains the mainstay of treatment for lymphocytic /small lymphocytic leukemia, disseminated FDCS. The role of allogeneic transplan- 4 patients had features suggestive of IDCS. In these

Table 2. — Clinical and Pathological Findings of Dendritic Cell Sarcomas

FDCS IDCS INDCS HS FRCT JXG

Clinical Findings Slow growing Asymptomatic Papules, nodules, Solitary mass Asymptomatic Small solitary (usual presentation) mass, usually a solitary lymph or plaques on the with systemic mass papule lymph node node mass skin symptoms Can have skin le- sions (rash-like)

Cytomorphology Spindle to Spindle to Resembles Large and round Spindle to Small and oval ovoid cells ovoid cells Langerhans cells to oval shape ovoid cells with a bland with whorls with whorls with irregular with focal areas with whorls round to oval nuclear grooves of spindling in paracortical nucleus without and clefts areas grooves

Immunophenotypical CD4 (+) CD4 (+) CD1a (–) CD163 (+) Vimentin (+) Vimentin (+) Markers CD21 (+) CD45 (+/–) CD4 (+) CD68 (+) Desmin (+) sCD14(+) CD34 (–) CD68 (+) Fascin (+) Lysozyme (+) CD68 (+) CD35 (+) Fascin (+) S100 (+) CD1a (–) actin (+) Stabilin-1 (+) CD68 (+/–) S100 (+) CD68 (+/–) CD21 (–) Factor XIIIa (+) CD163 (+) Fascin (+) Birbeck granules (–) CD35 (–) CD21 (–) Factor XIIIa (+) CD33(–) CD35 (–) CD1a (–) S100 (–) CD1a (–)

Treatment for Surgical resec- Surgical Surgical excision Surgical Surgical None needed Limited Disease tion ± adjuvant resection resection resection for localized chemotherapy or RT ± RT ± RT asymptomatic or RT lesion

Treatment for Lymphoma-type Lymphoma-type Multimodality Lymphoma-type Participation Langerhans Disseminated chemotherapy chemotherapy chemotherapy in a clinical trial histiocytosis– Disease based treatment

FDCS = follicular dendritic cell sarcoma, FRCT = fibroblastic reticular cell tumor, HS = histiocytic sarcoma, IDCS = interdigitating dendritic cell sarcoma, INDCS = indeterminate dendritic cell sarcoma, JXG = juvenile xanthogranuloma, RT = radiation therapy.

October 2014, Vol. 21, No. 4 Cancer Control 293 cases, identical clonal IGH or IGK was found, along Pathology with 17p deletion by fluorescence in situ Cytomorphology typically reveals large spindle to hybridization, suggesting a common clonal origin.2 ovoid cells with the formation of whorls. Cells may Another series of 3 cases showed an identical V-J have coarse nuclear chromatin with moderate to abun- junction sequences and trisomy 12 in both chronic dant cytoplasm resembling .28 The presence lymphocytic leukemia and IDCS tumors, suggesting of small lymphocytes intermingling with the large transdifferentiation of the lymphoma clones.4 histiocytic cell population is a key diagnostic feature Unlike FDCS, a viral etiology for IDCS has not less typical of carcinomas and sarcomas (Fig 2A).28 been demonstrated. Most cases of IDCS are negative Immunophenotype will show cells negative for for EBV and the human herpesvirus 8 genome.10 IDCS CD1a, positive for S100 and CD45, and have variable has also been reported following the use of calci- positivity for CD68 (Fig 2B).24,45 Some cases of IDCS are neurin inhibitors, which may be due to their effect positive for vimentin, HLA-DR, and fascin.35 Lysozyme by dampening the responses of T cells to which IDCs can also be positive, although this is uncommon.45 present antigens.10,42,43 The differential diagnosis for B-cell markers such as CD20 and T-cell markers such IDCS is presented in Table 1. With advances in immu- as CD3 and CD5 are usually negative. Cytokeratin, nohistochemistry and molecular diagnosis, IDCS has myeloperoxidase, CD1a, CD21, CD23, CD30, CD35, become less difficult to diagnose; however, a recent clusterin, langerin, CD34, CD79a, BCL2, and BCL6 are report reclassified malignant fibrous histiocytoma as negative.1,24,45,46 A distinguishing feature of IDCS is the IDCS, highlighting the importance of accurate diag- absence of Birbeck granules on electron microsco- nosis in these rare neoplasms.44 py.24,45 Immunoglobulin and T-cell receptor genes are in a germline configuration.48 Table 2 illustrates the Clinical Features clinical and pathological findings associated with IDCS. IDCS is an extremely rare disease with a pooled analysis of 462 cases of dendritic cell sarcomas, of Treatment which 100 were cases of IDCS. Another Surveillance, Historically, the mainstay of treatment of IDCS has been Epidemiology, and End Results database study of surgical resection. One report suggests that surgical 74 DCS cases included 20 IDCS cases.10,26 Median age at resection is associated with improved overall survival diagnosis is 56.5 years (range, 21 months to 88 years), rates (P = .04).26 Conversely, another study reported no and the disease has a male:female ratio of 1.38:1.10 difference in overall survival rates between surgery and Prognosis varies in patients with IDCS, from a benign nonsurgical modalities of treatment such as radiation course to rapidly progressive lethal disease in patients treatment for localized IDCS.10 Until further conclu- with disseminated disease. Patients who are younger sive evidence is available, either surgical resection or and those who have a higher stage as well as intra-ab- radiation therapy is recommended as initial therapy dominal involvement have a worse prognosis than their for localized IDCS. In disseminated disease, chemo- counterparts.10,26 Median survival rates for patients with therapy such as CHOP, ICE, and ABVD has been used disseminated disease are between 9 and 10 months; with variable success.10,43,46 Although chemotherapy is according to 2 reported series, those with localized dis- usually considered for patients with disseminated IDCS, ease did not reach median survival.10,26 Saygin et al10 re- surgical resection may still play a role, with 1 study ported 1- and 2-year survival rates of 84.8% and 68.1%, reporting a trend toward improved overall survival respectively, while patients with metastatic disease had in patients who underwent surgery followed by che- 1- and 2-year survival rates that dropped to 38.5% and motherapy.10 Currently, no consensus exists on opti- 15.8%, respectively. mal treatment in patients with disseminated disease; Patients normally present with a solitary lymph participation in a clinical trial or referral to a tertiary node mass, but cases with skin and soft-tissue involve- care center is optimal. No data have been published ment have been described.1,28,35,45-47 Patients are usually on hematopoietic stem-cell transplantation in IDCS; asymptomatic, but fatigue, fever, and night sweats may therefore, the procedure cannot be recommended. be present. Similar to FDCS, staging includes CT scans with contrast from the neck to the pelvis to evaluate Indeterminate Dendritic Cell Sarcoma other sites of disease, complete blood counts, bone Tumor Biology marrow aspiration, and biopsy. Because viral etiology INDCS, also known as indeterminate cell histiocytosis, has not been implicated in patients with IDCS, test- is a rare neoplastic proliferation of normal dendritic ing for HIV infection and hepatitis is not indicated accessory cells, which are usually found in the der- in most cases. Core needle biopsy or excisional bi- mis. Because indeterminate cells share morphological opsy (preferred) of the tumor mass is necessary for and immunophenotypical features with Langerhans an accurate diagnosis; fine needle aspiration biopsy cells (except the presence of Birbeck granules on should be avoided. electron microscopy), some authors speculate that

294 Cancer Control October 2014, Vol. 21, No. 4 A B S100 CD21

Clusterin Langerin

Fig 2. — Interdigitating dendritic cell sarcoma. (A) Paracortical infiltrate by large neoplastic cells with oval to elongated nuclei, abundant eosinophilic cyto- plasm, and indistinct cell border. (B) Neoplastic cells positive for S100 and negative for CD21, clusterin, and langerin. Note the positive stain for CD21 and cluster on follicular dendritic cells in the residual germinal centers. indeterminate cells may represent a mature form of and CD34 are both negative, unlike xanthogranulo- Langerhans cells.49-52 Neoplasms of indeterminate cells mas and dermatofibrosarcoma protuberance, respec- are extremely rare and little is known of the natural tively.59,61 Variable positivity is seen for CD45, CD68, history of INDCS. Associations between the prolif- lysozyme, and CD4.62 One case report indicates that eration of indeterminate cells and nodular scabies, INDCS may be clonal by the human androgen receptor pityriasis rosea, and low-grade B-cell lymphomas have gene assay.62 The clinical and pathological character- been reported.53-57 Immunophenotypical markers are istics for INDCS are summarized in Table 2. similar to IDCS, which show cells positive for S100 and CD1a; on an ultrastructural examination, Birbeck Treatment granules will be absent. The differential diagnosis for Due to the rarity of INDCS, little is known about the INDCS is presented in Table 1. natural history or treatment of this disease. Most le- sions are indolent or self-limited.58 New lesions may Clinical Features develop, and the spontaneous regression of lesions INDCS has been reported in case reports alone; thus, has been reported.53 Currently, the resection of le- no data exist on median age, sex, or race predilection sions, if present, remains the therapy of choice. The among those with INDCS. Most patients present with roles of chemotherapy and radiation therapy remain 1 or more papules, nodules, or plaques on the trunk, unclear in INDCS. In rare cases of disseminated dis- face, neck, or extremities.58,59 Generalized distribu- ease, multimodality treatment can be considered. tion has rarely been reported.60 Diagnosis is usually made by skin biopsy and systemic workup, including Histiocytic Sarcoma CT scans and bone marrow biopsy. Other testing is Tumor Biology typically not indicated in localized cases. HS is a rare non-Langerhans disorder of ma- ture tissue histiocytes. The etiology of this disorder Pathology remains unknown, but some cases have occurred in Microscopy evaluation shows that these dermal le- patients with mediastinal germ cell tumor, suggesting sions are diffusely infiltrating and are composed of that HS may arise from pluripotential germ cells.63 As- cells with irregular nuclear grooves and clefts that sociations between HS and , myel- resemble Langerhans cells.59 Cytoplasm is abundant, odysplastic syndrome, and acute lymphoblastic leuke- pale, and eosinophilic. Multinucleated giant cells may mia have also been made.2,24,64,65 A study has reported be seen and the spindling or dendritic formation of transdifferentiation in patients with HS and follicular some cells may be present (Fig 3A, B). These cells lymphoma and reported the presence of t(14;18) and lack Birbeck granules on electron microscopy and IGH gene rearrangements in all of the patients, suggest- desmosomes are lacking; however, interdigitating cell ing a common clonal origin of follicular lymphoma and processes may be present.1,58 HS.3 Another study reported that 2 patients with HS had Immunophenotype shows that INDCS cells are a clonal immunoglobulin rearrangement, suggesting a positive for S100 and CD1a (Fig 3C–E).58 These cells clonal evolution of HS from chronic lymphocytic leu- are negative for specific B- and T-cell markers, CD30, kemia/small lymphocytic leukemia.2 Further research CD163, CD21, CD23, CD35, and langerin. Factor XIIIa is needed to confirm these findings.

October 2014, Vol. 21, No. 4 Cancer Control 295 Expert morphology review and immunohisto- nucleoli (Fig 4A). On occasion, the cells may have a chemistry remain important in the diagnosis of HS. xanthomatous appearance.1,24,64 Immunohistochemical markers in patients with HS Immunochemistry is positive for histiocytic mark- include positivity for CD163, CD68, and lysozyme. The ers, including CD163, CD68, and lysozyme. CD1a, differential diagnosis for HS is presented in Table 1. CD21, CD35, and CD33 markers are all negative. S100 can be positive but is usually weak or focal (Fig 4B). Clinical Features Ki67 is variable (see Table 2).24,64 HS has been reported in all age groups but is more commonly seen in adults (median age, Treatment 46–55 years).24,64,66 Male predilection has been found The rarity of HS makes it difficult to assess the ben- in 2 reports but has not been confirmed in others.24,64,66 efits of multimodality treatment in these patients. In The disease usually presents with single or multifocal unifocal extranodal disease, a study of 14 patients extranodal tumors, most commonly in the intestines, gave insights into different treatment modalities.64 skin, or .24,64 Rarely, cases have been de- In this series, 5 patients were treated with surgical scribed with diffuse lymphadenopathy and multiple resection alone, 3 patients with surgical resection sites of involvement, and those with multifocal disease and adjuvant radiation therapy, and 6 patients were have a worse outcome.64,66,67 Systemic symptoms such treated with surgical resection followed by adjuvant as fever and weight loss are common, and symptoms chemotherapy. The 2 patients treated with surgery from the compression of a vital organ (eg, small bowel alone went on to develop distant disease within obstruction) can occur. Skin involvement can include 6 months, while 1 recurred at 6 months and was rash to innumerable tumors in multiple areas of the alive 11 years after repeat resection and adjuvant body.1 Cytopenias are seen in 30% of cases.24 Because radiation therapy. Two patients treated with surgery patients with unifocal disease have better outcomes, alone did not have evidence of recurrence. In the we recommend that patients receive full staging, in- 3 patients initially treated with surgical resection cluding CT scans and bone marrow biopsy, to rule out and adjuvant radiation therapy, no local recurrences multifocal disease. Excisional biopsy is the preferred were seen; however, 1 patient had distal recurrence diagnostic method in these cases. and was treated with repeat resection. The most common chemotherapy regimen in the 6 patients Pathology receiving adjuvant chemotherapy was CHOP. Two Microscopic evaluation can show a noncohesive pro- patients had distant spread within weeks and re- liferation of large cells twice the size of small lym- ceived salvage chemotherapy, and 2 patients were phocytes that may have focal spindling.24 The eosin- alive and disease free at a median follow-up of ophilic cytoplasm can contain vacuoles. Nuclei are 16 months.64 From this series we can conclude that pleomorphic and can be eccentric and have 1 or more the mainstay of treatment in patients with HS re-

A B C

D E

Fig 3. — Indeterminate dendritic cell sarcoma presenting as a rapidly growing scalp nodule. (A) Low power view showing a deep tumor nodule extending to the subcutis. (B) High power view shows the dermal histiocytic infiltrate with spindly to dendritic to polygonal histiocytic cells with oval nuclei, abundant pink cytoplasm with distinct cell borders, and grooved nuclei. (C) These cells are diffusely positive for CD1a. (D) High power oil magnification view of CD68 histiocytic marker highlights the grooved or clefted nuclear folds. (E) These are typically S100 positive, similar to Langerhans cells, but are also character- istically negative for factor XIIIa, a dermal dendrocyte marker. Birbeck granules are not present on electron microscopy.

296 Cancer Control October 2014, Vol. 21, No. 4 A mains surgical resection. Adjuvant radiation thera- py may help reduce local recurrence rates, but the role of adjuvant chemotherapy remains unclear and should only be used in cases of disseminated dis- ease in which surgical resection is not possible. The optimal chemotherapy regimen remains unclear, and patients should be referred for clinical trials or treat- ment at tertiary care centers.

Fibroblastic Reticular Cell Tumor Tumor Biology FRCT is a rare neoplasm of fibroblastic reticular cells. Fibroblastic reticular cells are stromal support cells located in the parafollicular areas and the deep cortex of lymph nodes where they are associated B CD68 with the nodal reticular network.68,69 These cells are also thought to be crucial to the interaction between IDCs and T cells in the primary immune response.68 The entity previously reported as cytokeratin-pos- itive interstitial reticulum cell tumor is likely the same as FRCT, and both entities usually present together in a series.1,10 In general, FRCT presents in the lymph nodes but can occur in the spleen, lung, liver, and soft tissue.10,70 Although smoking, drug abuse, and viral illnesses have been reported with FRCT, these associations are controversial.10,70 FRCT is differentiated from IDCS and FDCS based on immunohistochemistry. FRCTs are immunoreactive CD163 with vimentin, smooth-muscle actin, factor XIIIa, and desmin, but they are negative for CD21, CD35, and CD1a. The differential diagnosis for FRCT is presented in Table 1.

Clinical Features Clinical information about FRCT generally comes from a pooled analysis of 19 cases.10 In this analysis, Say- gin et al10 reported the median age of patients to be 61 years with a male predominance. Sixteen of the 19 patients presented with nodal disease, with the cervical and mediastinal lymph nodes being the most commonly involved. Extranodal sites included the liv- S100 er, spleen, lung, kidney, adrenal, bone, and soft tissue. Univariate analysis of the prognostic variable did not show a statistically significant prognostic marker in patients with FRCT but did show that patients with higher-stage disease have a significantly shorter sur- vival rate than their counterparts. Patients with local disease had a 2-year survival rate of 85.7%; median survival was not reached.10 Patients with distant dis- ease died in 2 years and had a median survival rate of 13 months.10 Most patients present with a newly diagnosed asymptomatic mass that is surgically excised.10,70 The value of CT scans, bone marrow biopsy, and other Fig 4. — Histiocytic sarcoma. (A) Diffuse infiltrate by large atypical neo- plastic cells with pleomorphic nuclei and moderate to abundant cytoplasm. staging work in single nodal disease is unknown and (B) Neoplastic cells positive for CD68 and CD163 and negative for S100. should be considered in patients with multiple en-

October 2014, Vol. 21, No. 4 Cancer Control 297 larged lymph nodes. Excisional biopsy is the preferred These disorders have been associated with type 1 diagnostic method for FRCT. neurofibromatosis and juvenile myelomonocytic leu- kemia.1,72 Patients with both LCH and JXG have also Pathology been reported, suggesting a clonal relationship of Morphologically, FBRC presents as spindle to ovoid these disorders.1 The differential diagnosis for DJX is cells with whorls in the paracortical areas associated presented in Table 1. with abundant reticulin staining fibers. Immunohis- tochemistry is positive for vimentin, desmin factor Clinical Features XIIIa, and smooth muscle actin. CD45RB, CD21, DJX usually occurs by 10 years of age, with one-half CD35, S100, CD65, and CD1a are negative.1,68 Ul- of reported cases occurring in the first year of life.72 trastructural evaluation reveals peripherally located Skin and soft-tissue presentations are the most com- fusiform densities, long cytoplasmic extensions, and mon sites of involvement and can include the muco- desmosomal-like intercellular attachments. sal surfaces of the upper airway. These lesions are commonly solitary, papular, and small, and multiple Treatment lesions can be present. Although rare, the central Surgery is the treatment of choice for patients with nervous system, eyes, liver, lungs, lymph nodes, and localized disease. Limited data exist on the role of bone marrow can all be involved.72 Lesions of the adjuvant radiation therapy, and chemotherapy has no central nervous system can cause diabetes insipidus, role in localized disease.10,70 Not enough data exist seizures, hydrocephalus, and changes in mental sta- to offer treatment recommendations for distal FRCT. tus.72 The workup in patients with suspected DJX Patients should be encouraged to participate in clin- should include excisional biopsy of the lesion with ical trials, referred to tertiary care centers for treat- an immunopathological review. The role of staging ment recommendations, or both. CT scans and bone marrow biopsy remains unclear.

Disseminated Juvenile Xanthogranuloma Pathology Tumor Biology Morphologically, the JXG cell is small and oval with DJX is a proliferation of histiocytes similar to that a bland, round to oval nucleus and pink cytoplasm seen in dermal juvenile xanthogranuloma (JXG). (Fig 5A). Touton cells are seen at dermal sites but are Solitary dermal JXG is common and does not progress less common in nondermal sites. The cells become to more disseminated forms. Skin lesions normally xanthomatous and inflammatory components can regress, but lesions have been reported in the brain, be seen.1 Immunohistochemistry reveals cells that soft tissue, or, rarely, with disseminated disease.71,72 express vimentin, lysozyme, CD14, CD68, CD163,

A B C

D E

Fig 5. — Disseminated juvenile xanthogranuloma presenting as a recently growing yellowish nodule in the lower leg associated with a spinal compressive mass. (A) Dermal histiocytic infiltrate by xanthomatous and spindle to scalloped histiocytic cells with oval to elongated nuclei and abundant foamy cytoplasm with an indistinct cell border. (B) These cells are diffusely positive for factor XIIIa and (C) CD68 in a coarse granular pattern as well as (D) lysozyme. (E) These cells are typically negative for S100 with focal variable staining (usually < 10%) and characteristically negative for CD1a. Vascular and myofibro- blastic markers for dermatofibrosarcoma, such as CD34, are negative. Note the inflammatory component of , lymphocytes, and few plasma cells. Touton giant cells are usually transient and not present in all cases.

298 Cancer Control October 2014, Vol. 21, No. 4 stabilin-1, and factor XIIIa (Fig 5B–D). CD1a is nega- and accessory activity in initiation of memory IgG responses in vitro. J Immunol. 1996;157(8):3404-3411. tive and S100 is usually negative but can be variably 8. Chan JK, Fletcher CD, Nayler SJ, et al. Follicular dendritic cell sarcoma. weak and focally positive in some cases (Fig 5E; Clinicopathologic analysis of 17 cases suggesting a malignant potential higher 1,72 than currently recognized. Cancer. 1997;79(2):294-313. see Table 2). Despite this multifocal presentation, 9. Lee IJ, Kim SC, Kim HS, et al. Paraneoplastic pemphigus associated which simulates lymphoma in some cases, immuno- with follicular dendritic cell sarcoma arising from Castleman’s tumor. J Am Acad Dermatol. 1999;40(2 pt 2):294-297. globulin and T-cell receptor genes are present in a 10. Saygin C, Uzunaslan D, Ozguroglu M, et al. 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