Histiocytic sarcoma

INTRODUCTION — 

Histiocytic sarcoma (HS) is an extremely rare non-Langerhans histiocyte disorder of unknown cause that most commonly presents with symptoms due to unifocal or multifocal extranodal tumors. HS may occur as a sporadic illness or may be clonally related to a separate synchronous or metachronous hematologic malignancy, such as follicular lymphoma or acute lymphoblastic leukemia.

Histiocytic disorders are thought to be derived from mononuclear phagocytic cells (macrophages and dendritic cells) or histiocytes. This group has generally been divided into Langerhans cell histiocytosis and non-Langerhans histiocytosis. Langerhans cell histiocytosis is so named for its presumed derivation from the Langerhans cells, which are specialized dendritic cells found in the skin and mucosa. In contrast, non-Langerhans histiocytoses are thought to be derived from the monocyte-macrophage lineage.

The epidemiology, clinical manifestations, pathologic features, diagnosis, and management of HS will be presented here. The diagnosis and management of Langerhans cell histiocytosis and other non-Langerhans histiocytic disorders are presented separately. (See "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis" and "Pulmonary Langerhans cell histiocytosis" and "Erdheim-Chester disease".)

EPIDEMIOLOGY — 

HS is an extremely rare disease with only a few hundred cases reported in the literature. HS has been diagnosed in all age groups, but is most common in adults. A study of 159 cases of HS (99 men, 60 women) from the US Surveillance, Epidemiology, and End Results (SEER) database reported a median age at diagnosis of 63 years (range 18 to 96 years) [1]. The incidence was lower in African Americans than in White Americans (incidence ratio 0.27) and higher in men (female:male incidence ratio 0.49). In two other case series, the median ages at diagnosis were 46 and 55 years [2,3].

There are no known environmental or hereditary genetic factors predisposing to the development of HS. HS can occur as an isolated disease or in the context of other hematologic neoplasms, such as follicular lymphoma, myelodysplasia, or acute lymphoblastic leukemia [1,3]. When HS occurs in the context of another hematologic malignancy, the two entities are often clonally related [4,5]. Of importance, tumors with pathologic features consistent with HS occurring in the context of acute monocytic leukemia are not considered HS.

PATHOGENESIS — 

The pathogenesis of HS remains unclear.

HS is not a true sarcoma; instead it is derived from cells of the monocyte/macrophage system. HS has been described in association with a number of hematologic neoplasms, most commonly acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and follicular lymphoma (FL). In addition, cases have been reported in patients with mediastinal germ cell tumors, such as malignant teratomas, suggesting a possible derivation of such tumors from pluripotent germ cells [6].

Some cases of HS harbor the BRAF V600E mutation [7-9], but this is less common than with other histiocyte/dendritic cell neoplasms, such as Langerhans cell histiocytosis and Erdheim-Chester disease [7-9]. Other mutations in the MAP2K1 pathway that may be targeted by MEK inhibitors have also been described [10,11]. Given the potential therapeutic implications and conflicting results from published studies, we test tumors from all patients with HS for BRAF mutation by molecular techniques and/or immunohistochemistry.

Attempts to establish clonality have had varied results, and although occasional cytogenetic aberrations have been identified, none are characteristic:

●In some cases of HS associated with lymphoid neoplasms, the HS has been shown to originate from the same clone that gave rise to the lymphoid neoplasm [4,5,12].

●In a study of eight patients with both FL and HS (seven patients) or interdigitating dendritic cell sarcoma (one patient), all eight possessed the t(14;18) either by fluorescence in situ hybridization (FISH) or by polymerase chain reaction (PCR) [13]. Five HS lesions were metachronous, developing two months to 12 years after the follicular lymphoma, while the FL and HS were synchronous in three cases.

●In one study of sporadic HS, 9 of 23 cases (39 percent) demonstrated clonal immunoglobulin (Ig) heavy chain (with or without Ig kappa) gene rearrangements, while two (9 percent) cases showed only clonal Ig kappa gene rearrangements [14]. One case showed t(14;18) by PCR and FISH analysis showed the resulting IGH/BCL2 fusion in the neoplastic histiocytes. All cases of Ig heavy chain and Ig kappa positive HS were negative for B cell-associated transcription factors such as PAX5 and BOB.1, though four of seven were positive for Oct2.

●Human and mouse HS tumors have demonstrated genetic or epigenetic inactivation of PTEN, INK4A (p16), and ARF (p14), but how or why these changes occur remains unclear [15].

CLINICAL MANIFESTATIONS — 

The clinical presentation of HS varies depending on the organs involved. Most patients present with symptoms due to unifocal or multifocal extranodal disease, most often involving the gastrointestinal tract, skin, and soft tissues [16]. However, there is no characteristic pattern of organ system involvement and any organ may be involved including bone, lymph nodes, skin, liver, spleen, lung, and the central nervous system. Solitary involvement of the lymph nodes is seen in less than 20 percent of cases [3].

Organ involvement may be asymptomatic and discovered at the time of radiographic imaging. More commonly, patients present with a palpable mass lesion, symptoms related to compression of surrounding organs (eg, intestinal obstruction), or systemic complaints (eg, fevers and weight loss). Skin involvement has numerous potential manifestations ranging from rash to tumorous growths [16].

Laboratory abnormalities depend on the organ system affected. Cytopenias are seen in approximately one-third of cases, a minority of which will demonstrate hemophagocytosis on bone marrow biopsy [3,17].

PATHOLOGIC FEATURES — 

Biopsies of involved tissue demonstrate an infiltrative process with a diffuse growth pattern and effacement of the normal architecture [16]. When involved, the lymph nodes, bone marrow, and spleen demonstrate sinusoidal infiltration and parenchymal involvement. Skin biopsies do not demonstrate epidermotropism.

The tumor is primarily comprised of non-cohesive large cells (eg, nuclei at least twice the size of a small lymphocyte and larger than the nucleus of a tissue macrophage) that are polygonal or ovoid with focal spindling (picture 1) [3,18]. The cells have abundant eosinophilic cytoplasm that may contain fine vacuoles. The nuclei are pleomorphic and slightly eccentric with moderately dispersed chromatin and one or more small, but prominent nucleoli. Occasionally, the neoplastic cells have a foamy (xanthomatous) appearance.

Hemophagocytosis, tumor giant cells, or a prominent inflammatory infiltrate may be present [19]. Tissue necrosis is not prominent, but may be seen focally in a minority of cases. Occasionally a prominent inflammatory infiltrate obscures the less abundant tumor cells. Birbeck granules (a seminal finding in Langerhans cell histiocytosis) and cellular junctions are absent on electron microscopy.

On immunohistochemistry, the cells typically express CD68, lysozyme, CD4 and CD163, but do not express specific T and B cell markers, myeloid cell markers (eg, myeloperoxidase, CD33), CD1a, S100 protein or epithelial markers (picture 2) [3,20,21]. Staining for lysozyme is usually granular with accentuation of the Golgi [3].

T cell receptor (TCR) and immunoglobulin genes are usually germline, but clonal rearrangements of antigen receptor genes have been identified in some cases. (See 'Pathogenesis' above.)

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS — 

HS is diagnosed based upon the pathologic evaluation of involved tissue interpreted within the clinical context [18]. HS can be difficult to diagnose since it is a very rare disease that can affect many organ systems. An excisional or incisional biopsy of affected tissue is generally preferred, when possible, over a fine needle aspirate or core needle biopsy.

HS must be distinguished from other histiocytic and dendritic cell disorders, metastatic solid or hematopoietic neoplasms, primary familial lymphohistiocytic disorders, and acquired causes of hemophagocytic macrophage activation syndromes. Of importance, tumors with pathologic features consistent with HS occurring in the context of acute monocytic leukemia are not considered HS.

●Langerhans cell histiocytosis – Langerhans cell histiocytosis (LCH) and HS are both histiocytic diseases that can involve multiple sites. These entities can usually be distinguished by morphologic and immunohistochemical evaluation. Unlike Langerhans cell histiocytosis, HS tumor cells do not express CD1a or S100. Birbeck granules, a seminal finding in Langerhans cell histiocytosis, are absent in HS. (See "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis".)

●Hemophagocytic lymphohistiocytosis – Hemophagocytic lymphohistiocytosis and the related macrophage activation syndrome are systemic disorders that demonstrate tissue infiltration by non-neoplastic histiocytes. While both disorders may demonstrate hemophagocytosis, phagocytic activity is much more common in hemophagocytic lymphohistiocytosis. (See "Treatment and prognosis of hemophagocytic lymphohistiocytosis".)

●Lymphoma – Morphologically, HS resembles diffuse large cell lymphoma or anaplastic large cell lymphoma. However, these entities can usually be easily distinguished from HS by immunohistochemistry. HS does not express B or T cell markers (eg, myeloperoxidase, CD33) and T cell receptor and immunoglobulin genes are usually germline. (See "Diffuse large B cell lymphoma and other large B cell lymphomas: Presentation, diagnosis, and classification" and "Clinical manifestations, pathologic features, and diagnosis of systemic anaplastic large cell lymphoma (sALCL)".)

●Metastatic carcinoma – Morphologically, lymph node involvement with carcinoma may resemble HS in that both tumors are comprised of large, atypical cells. Carcinoma can be readily distinguished from HS by the demonstration of cytokeratin upon staining.

●Metastatic melanoma – Both melanoma and HS have large, atypical cells and can involve multiple organ systems. However, unlike HS, melanoma is positive for S100, HMB-45, and/or Melan A. (See "Pathologic characteristics of melanoma".)

STAGING — 

To best treat patients with HS, the initial evaluation must confirm the histologic diagnosis, the extent and sites of disease, and the performance status of the patient. In addition to a history and physical examination, it is our practice to perform the following pretreatment studies in patients with HS:

●Laboratory studies include a complete blood count, serum electrolytes, and chemistries with liver and renal function.

●Positron emission tomography (PET)/computed tomography (CT) to document organ involvement. HS appears to be PET-avid in small case series [22].

●Bone marrow biopsy for patients with cytopenias or findings suggestive of hemophagocytosis.

MANAGEMENT — 

There is no standardized therapy for HS, and patients should be encouraged to enroll when available.

Management is guided by the extent of disease (ie, unifocal versus multisystem disease). The natural history is variable, and treatment data are primarily derived from small case series and single-case reports. Solitary tumors >3.5 cm and multisystem disease are associated with inferior outcomes [2,23].

Unifocal disease — For patients with unifocal disease, we suggest surgical resection followed by adjuvant radiation therapy, rather than either approach alone or systemic therapy. This suggestion is based on good efficacy and limited adverse effects (AEs).

We generally treat with 45 to 50 gray (Gy) involved field radiation therapy (IFRT). There is no clear role for adjuvant chemotherapy in this setting.

The largest case series included 12 patients with unifocal extranodal HS treated at a single institution who underwent surgery [2]. Six tumors were excised with wide margins, four were excised with minimal margins (one with positive margins), and two were biopsied but not excised. Outcomes included:

●Five patients underwent surgical resection alone. Two patients developed distant spread within three to four months, two were alive with no sign of recurrence at short follow-up, and one developed local recurrence at six months that was treated with further resection and radiation therapy and did not recur after 11 years of follow-up.

●Three patients were treated with surgical resection plus adjuvant radiation therapy. None have recurred locally; one developed distant recurrences at 17 and 26 months that were treated with further resection. All three patients were alive with no evidence of disease at a median follow-up of 22 months.

●Six patients were treated with adjuvant chemotherapy (primarily CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone]). Two patients developed distant spread within weeks (one of whom was successfully treated with further chemotherapy), two were alive with no evidence of disease at a median of 16 months of follow-up, and two did not have adequate follow-up.

Multisystem disease — For patients with multisystem involvement of HS, we suggest chemotherapy, rather than treatment with a targeted agent.

There is limited experience with targeted agents (eg, inhibitors of BRAF or MEK) for advanced HS, and we treat with such agents for frontline therapy only in the context of a clinical study. Otherwise, we reserve targeted agents for patients who relapse after initial chemotherapy and who have a documented targetable mutation. (See 'Relapsed disease' below.)

Surgery is limited to diagnostic biopsies and management of complications such as perforation, obstruction, or intractable bleeding. There is no clear role for adjuvant radiation therapy in this setting.

There is no consensus chemotherapy regimen, but most reports describe multiagent regimens that are used for clinically aggressive lymphomas. The two most common regimens are six cycles of ICE (ifosfamide, carboplatin, and etoposide with mesna) or six to eight cycles of CHOP (table 1), but they have not been directly compared in prospective studies. Both regimens are associated with cytopenias, increased risk for infections, and blood product support, but CHOP is generally better tolerated. (See "Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in patients who are medically fit" and "Initial treatment of advanced-stage diffuse large B cell lymphoma".)

Selected fit patients who achieve a complete response to systemic therapy may favor hematopoietic cell transplantation [24,25] because of the high potential for relapse, as described below. (See 'Relapsed disease' below.)

For patients who are unlikely to tolerate ICE or CHOP, single-agent treatments used for Langerhans histiocytosis (eg, single-agent vinblastine, etoposide, or prednisone) may be beneficial. (See "Treatment of nonpulmonary Langerhans cell histiocytosis", section on 'Multisystem'.)

PATIENT FOLLOW-UP — 

Patients should be clinically assessed a minimum of every three to six months or more frequently as symptoms and organ dysfunction require. The frequency of imaging is dictated by baseline disease status, organ involvement, and requirement for ongoing treatment. Affected organs should be imaged every three to six months until stability is documented.

RELAPSED DISEASE — 

Management of relapsed disease is guided by prior treatment and the extent and sites of involvement.

We encourage enrollment in a clinical trial when available.

●Localized relapse – Patients who experience an isolated recurrence can undergo surgical resection and/or radiation therapy (RT).

●Systemic or multiple sites of relapse – Patients with advanced relapsed or refractory (r/r) disease should have a biopsy with mutation analysis. Management is guided by molecular findings, medical fitness, and prior therapy.

•Medically fit – For fit patients with r/r multisystem HS, we suggest salvage chemotherapy with plans to proceed to allogeneic hematopoietic cell transplantation (HCT) if they respond to treatment.

We favor salvage therapy using a non-cross-resistant regimen, such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), (table 1) for patients who relapse after ICE (ifosfamide, carboplatin, and etoposide with mesna), or vice versa. (See 'Multisystem disease' above.)

•Less fit – For less-fit patients, we treat HS that has a potentially vulnerable mutation using a targeted agent.

For example, patients with a targetable BRAF mutation might be treated with vemurafenib or dabrafenib, while those with a mutation that might respond to an MEK inhibitor (eg, mutation of MAP2K1 or MEK pathway components) could be treated with cobimetinib or trametinib [23,26]. These agents have demonstrated efficacy against Langerhans cell histiocytosis and Erdheim-Chester disease. We generally begin with vemurafenib 480 mg twice daily (rather than 960 mg twice daily used in other settings) and adjust the dose based on response and toxicity. (See "Treatment of nonpulmonary Langerhans cell histiocytosis".)

There are case reports of thalidomide [25,27], alemtuzumab [28], and ALK inhibitors in the rare cases when an ALK mutation was found [29]. HS frequently overexpresses PD-L1, and there are case reports of responses to PD-1 inhibitors [30-33].

Radiation therapy may be used for local palliation.

CLINICAL TRIALS — 

Often there is no better therapy to offer a patient than enrollment in a well-designed, scientifically valid, peer-reviewed clinical trial. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the National Cancer Institute or from the Histiocyte Society.

SUMMARY AND RECOMMENDATIONS

●Description – Histiocytic sarcoma (HS) is a rare histiocyte disorder that can present as unifocal or multifocal disease affecting nearly any organ system.

●Epidemiology – HS is most common in adults, and there is a male predominance. (See 'Epidemiology' above.)

●Clinical presentation – Presentation varies according to sites of involvement. Most patients present with symptoms due to unifocal or multifocal extranodal disease, most commonly involving the intestinal tract, skin, and soft tissues. (See 'Clinical manifestations' above.)

●Diagnosis – HS is diagnosed based upon the pathologic evaluation of involved tissue interpreted within the clinical context. HS can be difficult to diagnose since it is a very rare disease and can affect many organ systems. An excisional or incisional biopsy of an affected organ is generally preferred, when possible. (See 'Pathologic features' above and 'Diagnosis and differential diagnosis' above.)

●Management – There is no standard treatment regimen for patients with HS and patients should be encouraged to enroll in a clinical trial. We use the following approach for the management of patients outside of a clinical trial (see 'Clinical trials' above):

•Unifocal disease – For patients with unifocal disease we suggest surgical excision with adjuvant radiotherapy, if possible, depending on the location and extent of disease (Grade 2C). If radiation is not feasible or would be too toxic, post-operative observation is reasonable. Patients may have serial unifocal recurrences over time and repeat surgical excision and/or radiotherapy is reasonable in these instances. (See 'Unifocal disease' above.)

•Multifocal disease – For patients with multifocal disease, we suggest aggressive multiagent chemotherapy with six cycles of ifosfamide, mesna, carboplatin, and etoposide (ICE) (Grade 2C). Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) is an acceptable alternative for those who cannot tolerate ICE. Glucocorticoids, single-agent vinblastine, and single-agent etoposide are generally reserved for patients who cannot tolerate combination chemotherapy. (See 'Multisystem disease' above.)

Allogeneic hematopoietic cell transplantation (HCT) should be considered for medically eligible patients with advanced-stage disease who achieve remission.

●Relapsed/refractory HS – Patients with relapsed or refractory (r/r) disease should participate in a clinical trial, when available. (See 'Relapsed disease' above.)

•An isolated relapse can be treated with surgical excision and radiation therapy (RT).

•For more extensive relapse or r/r HS after systemic therapy, we favor treatment using a non-cross-resistant chemotherapy regimen followed by allogeneic HCT. Others may be treated with a targeted agent (if a vulnerable mutation is found), other agents, and/or RT for palliation of symptomatic sites.