Histiocytic sarcoma (HS) is an exceedingly rare tumor and carries a dismal prognosis when patients present with advanced-stage disease. Because of the poor response rates to conventional chemotherapy and the rarity of the disease, no standard of care exists for patients with HS. The authors report the single-agent use of the anti-CD52 antibody alemtuzumab in 2 patients who had advanced-stage HS.
Two patients with chemotherapy-refractory, metastatic HS with tumors that expressed the CD52 antigen received a prolonged course of treatment with the anti-CD52 monoclonal antibody alemtuzumab.
Resected tumor samples from both patients demonstrated CD52 expression. Both patients had marked responses to single-agent alemtuzumab. One patient had a complete response with no evidence of disease for >5 years. The second patient had a major response to alemtuzumab and also remained alive with no evidence of disease for >4 years.
Histiocytic sarcoma (HS) is an exceedingly rare malignancy in both children and adults. It is characterized by neoplastic cells with specific markers of histiocytic differentiation. The World Health Organization defines HS as a malignant proliferation of cells with features similar to those of mature tissue histiocytes. Immunophenotyping reveals 1 or more histiocyte-related markers, including CD68, lysozyme, CD11c, and CD14.1 More recently, it was demonstrated that CD163 is a specific marker for HS.2 In several previous studies, HS lesions were reclassified as non-Hodgkin lymphomas upon further re-examination, adding to the rarity of the disease.3, 4
Given the low frequency of the disease and the wide spectrum of presentations, no standard-of-care therapy exists for HS. There is a paucity of literature addressing HS, and pediatric cases are limited to case reports.2-11 Resections usually are attempted for surgically accessible tumors, often in conjunction with radiation and/or chemotherapy for more advanced-stage tumors. Various outcomes have been reported by different studies. Vos et al reported on 5 adults patients with HS, including 4 patients who died of disease and 1 patient who died without disease 17 years after the diagnosis. The 1 survivor had stage I disease, which was surgically resected. Two of those patients received chemotherapy, and both died of disease.2 Hornick et al reported on 14 patients, including 13 patients who presented with stage I or II disease and 1 patient who presented with stage IV disease. Seven of those patients received lymphoma-based chemotherapy, and 6 remained alive at the time of publication. However, all but 1 patient presented with low-stage disease, and only 1 patient who developed distant metastasis had a durable response to chemotherapy.9 Pileri et al described 18 adult patients with HS, including 11 patients who presented with stage III or IV disease, 9 of whom received chemotherapy as part of their treatment. Of those 11 patients with high-stage disease, 5 died of disease, 2 remained alive with disease, 2 remained alive in remission, and 2 were not evaluable at the time of publication.5
In this report, we describe 2 children diagnosed with stage IV HS who had disease that was refractory to multiple chemotherapeutic agents. Their tumor cells were positive for the cluster of differentiation 52 (CD52) protein (a glycosylphosphatidylinositol-anchored antigen expressed on all lymphocytes), and they demonstrated significant responses after the administration of single-agent alemtuzumab (an anti-CD52 monoclonal antibody) therapy.
MATERIALS AND METHODS
A girl aged 20 months presented to her pediatrician with a widespread petechial rash that was most pronounced in the groin. A complete blood count at the time revealed a platelet count of 57 K/μL, and she initially was diagnosed with idiopathic thrombocytopenic purpura. She was admitted to an outside hospital and received 3 courses of intravenous immunoglobulin. Improvement of the rash was noted, and the patient was discharged home with a platelet count of 108 K/μL. Over the next 2 weeks, her clinical picture worsened with increased agitation, poor oral intake, and febrile episodes. She was taken to another pediatric hematologist who noted significant tachypnea and tachycardia, hepatosplenomegaly, pallor, and petechiae. A complete blood count at the time revealed a white blood cell count of 24.9 K/μL with a predominance of neutrophils and no blasts, a hemoglobin level of 5 g/dL, and a platelet count of 30 K/μL. Her lactic dehydrogenase level was elevated to 1236 U/L, and her uric acid level was elevated to 9.5mg/dL. She had severe metabolic acidosis with a bicarbonate level of 11 mmol/L. Liver function tests and bilirubin levels were moderately elevated. She was admitted to the pediatric intensive care unit for management.
A computed tomography (CT) scan performed that day revealed multiorgan involvement with heterogeneous masses highly suspicious for malignancy (Fig. 1). Involved sites included 2 large, right hepatic lobe masses and retroperitoneal masses with extension into the pancreas and right kidney. There also was extensive tumor involvement of the anterior mediastinum, pleura, and lungs. Hepatic and omental biopsies were performed by laparotomy.
The patient remained intubated after the surgical procedure. While the pathologic diagnosis was pending in the critically ill child, therapy was initiated with dexamethasone, doxorubicin, and vincristine—agents that would be active in most of the diagnostic possibilities (lymphoma, neuroblastoma, sarcoma, etc). A CT scan performed 3 weeks later did not reveal any significant change in the lesions. Clinically, she remained mechanically ventilated in critical condition, and she was not stable enough to receive more aggressive conventional chemotherapy or radiation therapy.
Histiologic examination of the biopsy specimens revealed syncytial sheets of large, oval-to-round cells with significant pleomorphism, prominent nucleoli, eccentrically placed nuclei, and abundant eosinophilic cytoplasm (Fig. 2). Focally, the cells contained cytoplasmic hemophagocytic debris. Immunohistochemical analysis revealed positivity for CD68, S-100, leukocyte common antigen, and lysozyme (focal). The cells were negative for CD1a, CD21, CD35, CD20, CD3, CD8, myeloperoxidase, CD30, cytokeratin, epithelial membrane antigen, and activin receptor-like kinase 1 (ALK-1). After a considerable delay for multiple consultations, a diagnosis of HS was made.
Because of the histiocytic nature of the tumor, a trial of cladribine (2CDA) was initiated. The patient received daily 2CDA for 3 days without any shrinkage of the tumor.
On the basis of the knowledge that CD52 is expressed on many histiocytic cells, the tumor was tested for CD52 and was positive (Fig. 2). Thereafter, we initiated antibody therapy with alemtuzumab in an effort to give targeted therapy. After 1 week of daily initial dose escalation, she received alemtuzumab 10 mg/m2 per dose 3 days weekly.
After the initiation of alemtuzumab therapy, her clinical status improved. She was extubated successfully 2 weeks after starting alemtuzumab. A CT scan at that time demonstrated a decrease in size of the multiple masses. After 1 month of thrice-weekly therapy, the treatment frequency was decreased to twice weekly doses for another 4 weeks, and then to weekly doses for 2 more months. She received a total of 4.5 months of alemtuzumab treatment.
CT scans during therapy demonstrated gradual decrease in her lesions. Residual, ill-defined, low-attenuation lesions remained in the lung, mediastinum, liver, and pancreas. After she discontinued therapy, the liver lesions were biopsied and revealed focal fibrosis with no viable tumor (Fig. 1).
Serial follow-up CT scans and positron emission tomography (PET) scans have been performed after alemtuzumab therapy. They reveal small, PET-negative areas of scarring in the lungs; calcifications in the mediastinum; and subcentimeter, not metabolically active areas of low attenuation in the liver and right kidney. Currently, she has been off therapy for >5 years with no evidence of recurrent disease.
A previously healthy girl aged 14 years presented with isolated pain in her left calf. After progression of the pain, an ultrasound was obtained, which revealed a mass in the deep tissues. A magnetic resonance image (MRI) confirmed the presence of a soft tissue mass that was suspicious for a possible neural sheath tumor. She underwent a biopsy, and, while the pathology of the biopsy specimen was being debated, significant pain in her left groin associated with lymphadenopathy developed. Staging evaluations with CT, MRI, and PET studies revealed extensive metastatic disease, including multiple pulmonary lesions; lesions throughout the liver, spleen, and kidneys; abnormally enlarged lymph nodes in the left inguinal, left internal iliac, left external iliac, left obturator, and subcarinal regions; as well as a large, presumably primary mass in the posterior compartment of the left calf with invasion into the posterior capsule of the knee joint and enlarged popliteal lymph nodes.
Lymph node biopsies were performed. These demonstrated tumor tissue identical to that observed in the calf lesion. Pathology revealed diffuse, malignant histiocytic proliferation. Evaluation of the calf mass and lymph nodes revealed that the tumor cells were stained positive for vimentin, CD4, CD31, CD43, CD45, and CD45RO. Subsets of the tumor cells were positive for lysozyme and CD68. Frequent cells were positive for the E3 ubiquitin-protein ligaseMIB-1. The tumor cells were negative for CD1a, CD3, CD15, CD21, CD30, CD34, CD35, ALK-1, myeloperoxidase, clusterin, S-100, desmin, actin, myogenin, and keratin. It was believed that these features were consistent with the diagnosis of HS. CD52 staining of the primary tumor was positive. Bilateral bone marrow biopsies were negative for tumor involvement.
The slides were reviewed by pathologists at the Mayo Clinic and at Emory University. The unanimous diagnosis was HS. The patient initially received treatment with ifosfamide and doxorubicin and had no response on follow-up imaging studies after 1 cycle. Then, she received chemotherapy based on Children's Cancer Group Protocol 5941. Induction chemotherapy included vincristine, prednisone, cyclophosphamide, pegaspargase, and etoposide. After induction, a follow-up PET scan demonstrated complete resolution of 2-deoxy-2-(18F)fluoro-D-glucose (FDG) activity in the liver, spleen, and left common iliac and internal iliac lymph node chains and persistent but decreased FDG activity in the subcarinal, left external iliac, and popliteal lymph nodes as well as in the left calf soft tissue mass. She then received consolidation chemotherapy, which included vincristine, pegaspargase, etoposide, cytarabine, 6-thioguanine, and methotrexate. Unfortunately, upon completion of consolidation chemotherapy, a PET scan revealed a significant increase in the size and FDG-avidity in the left calf mass, popliteal lymph nodes, subcarinal lymph nodes, and left external iliac lymph nodes, consistent with progressive disease.
After the experience with Patient 1, a decision was made to administer a trial of alemtuzumab. After a 1-week dose-escalation schedule, she continued on a schedule of alemtuzumab 10 mg 3 times per week. The patient tolerated this dosing schedule quite well with no notable sequelae. A follow-up PET scan obtained after 2 months of alemtuzumab therapy revealed a slight decrease in size and metabolic activity of the primary tumor and metastatic sites, consistent with some response to treatment. The alemtuzumab was continued, and follow-up PET scans were obtained at 2-month to 3-month intervals to assess response. Continued interval decreases in FDG activity were observed over several months.
The patient did not experience any infections or other complications during alemtuzumab therapy. She did develop significant lymphopenia with an absolute lymphocyte count of zero soon after starting alemtuzumab. She received prophylactic voriconazole, acyclovir, and pentamidine during alemtuzumab therapy. She did not require intravenous immunoglobulin supplementation during this time.
After 9 months of alemtuzumab therapy, a PET scan revealed an interval increase in metabolic activity in multiple sites, and the alemtuzumab was discontinued. A biopsy of the left calf revealed viable tumor cells. A trial of thalidomide therapy was initiated. After 8 months of thalidomide therapy, follow-up PET scans began to demonstrate interval improvement with decreased metabolic activity in multiple tumor sites, including the left calf. After 3 years of thalidomide therapy, a follow-up PET scan revealed no evidence of disease. The patient has been receiving thalidomide for 4 years and is doing well with no evidence of disease. She is attending college.
RESULTS AND DISCUSSION
HS is an exceptionally rare disease in children. The presentation can vary greatly, from isolated lymph node or skin involvement to rapidly progressive, disseminated, extranodal disease. Patients with low-stage disease often can be cured with complete surgical resection. However, patients with disseminated disease frequently die of disease despite aggressive therapy with chemotherapy, radiation, and surgery.
Alemtuzumab is a humanized monoclonal anti-CD52 antibody that was developed as an immunosuppressive agent that depletes T cells, and it is a potential therapy against lymphoid disease.12, 13 The therapy has been used successfully in various induction protocols for solid organ transplantation.14-18 Similarly, alemtuzumab has been used as a conditioning agent for stem cell transplantation and also as a prophylactic agent against graft-versus-host disease.19-22
Alemtuzumab is currently approved by the US Food and Drug Administration for monotherapy in chronic lymphocytic leukemia.23 Furthermore, it has been evaluated for a myriad of adult-onset tumors, including non-Hodgkin lymphoma and various T-cell malignancies.13, 23-25 Very little is known about the efficacy of alemtuzumab in pediatric cancers. Williams et al reported the successful treatment of a child with T-cell post-transplantation lymphoproliferative disease using an alemtuzumab containing regimen.26 The Children's Oncology Group recently published results from a phase 2 study of alemtuzumab in relapsed/refractory childhood leukemia. Thirteen children with pre-B or T-cell leukemia were treated: One patient achieved a complete remission, and 4 others had stable disease.27
The CD52 antigen is expressed on a variety of peripheral blood cells, including lymphocytes, monocytes, and eosinophils. Although it was believed previously that it was absent on neutrophils, recent evidence suggests neutrophilic expression of the antigen, albeit at lower levels than in mononuclear cells.28 Peripheral blood dendritic cells express CD52; however, tissue dendritic cells, such as Langerhans cells, lack expression of the antigen.29, 30 CD52 expression has been observed in a wide spectrum of leukemias and lymphomas and has served as the impetus for the numerous studies of alemtuzumab in these disease types.31 CD52 expression also has been observed on tumor cells from specimens of Langerhans cell histiocytosis. Because normal Langerhans cells do not express CD52, alemtuzumab is an attractive therapeutic option for patients with Langerhans cell histiocytosis.29, 30, 32
We report the successful treatment of 2 patients who had widespread HS using single-agent alemtuzumab. Patient 1 had multiorgan involvement, which was nonresponsive to aggressive, conventional chemotherapy. She was critically ill with multiorgan failure, requiring mechanical ventilation. After treatment with single-agent alemtuzumab, she achieved a complete remission. Patient 2 had chemotherapy-resistant, metastatic disease to lymph nodes, liver, lung, kidneys, and spleen. After she progressed on aggressive, conventional chemotherapy, she demonstrated a marked improvement of disease with alemtuzumab. Despite a significant initial response, Patient 2 eventually required further treatment with thalidomide to achieve a complete remission. Neither patient suffered any significant toxicity from the antibody therapy.
In previous observations, it appeared that alemtuzumab was more effective at treating disease in blood and bone marrow and was less effective against lymph node and extranodal masses.33 Both patients in the current report had a significant burden of extramedullary disease, and 1 patient responded to alemtuzumab therapy with long-term disease eradication. Further investigations in a larger cohort of tumors are needed into CD52 expression of HS. However, in light of the efficacy in these patients, along with the lack of significant toxicity, we conclude that frontline use of alemtuzumab should be strongly considered in patients with HS who are unable to achieve complete surgical resection.
No specific funding was disclosed.
We thank Dr. Rabah-Hammad and Ms. Mary Currie from the Department of Pathology at C. S. Mott Children's Hospital for their assistance with the collection of materials.