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Secondary Malignant Histiocytosis (SMH) is a distinct entity and forms part of a spectrum of disorders of the monocyte-phagocytic lineage, categorised into five main groups in the current WHO classification. It includes conditions such as Langerhans Cell Histiocytosis (LCH), Hemophagocytic Lymphohistiocytosis (HLH), Rosai-Dorfman disease, cutaneous and mucocutaneous manifestations of these disorders and primary and secondary malignant histiocytosis , , . It can occur either as a sporadic illness or secondary to clonally-related hematological malignancies. Pathogenesis of SMH remains unclear but it is derived from cells of the Macrophage/Dendritic Cell (DC) system and is most commonly associated with Acute Lymphoblastic Leukemia (ALL) and Follicular Lymphomas, as well as myeloid disorders like Chronic Myelomonocytic Leukemia (CMML) and Acute Myeloid Leukemia (AML). SMH is diagnosed based on anaplastic morphology, expression of macrophage and DC markers, a definite temporal and a probable clonal relationship with the primary hematologic neoplasm . The marked hyperferritinemia, triglyceridemia and hemophagocytosis in the bone marrow, typical of HLH, are generally not seen in SMH.
A 40-year-old male, with no past medical history of significance other than smoking, attended the general practitioner's clinic with three weeks’ history of feeling generally unwell and one-week history of night sweats. At presentation, the patient did not manifest any signs or symptoms of marrow failure. He also did not have pallor, jaundice, lymphadenopathy, or hepatosplenomegaly. Initial full blood count (FBC) showed a hemoglobin of 14.4 g/dL, platelets of 59 × 109/L, white cell count of 38.8 × 109/L and neutrophils of 4.11 × 109/L. Liver function tests, lactate dehydrogenase (LDH), creatinine, electrolytes and coagulation screen were normal. A peripheral blood film revealed lymphoblasts.
Bone marrow aspirate and trephine showed a hypercellular marrow with decreased tri-lineage hematopoiesis and 90% blasts [Fig. 1(a)]. Flow cytometry confirmed Pre-B-Cell Acute Lymphoblastic Leukemia (Pre-B-ALL) and karyotyping met the criteria for complex cytogenetics . Molecular analyses were negative for a bcr-abl1 transcript (both p190 and p210 variants).
The patient was enrolled in the UKALL14 trial (09/H0711/90) in May 2016 and was randomized to receive 4 doses of rituximab in phase-1 induction. Bone marrow assessment after phase-1 of 4-drug induction chemotherapy revealed the persistence of 13% blasts by flow cytometry and 15% on trephine [Fig. 1(b)]. As per protocol, it was decided that he should continue with phase-2 of induction therapy (cyclophosphamide, cytosine arabinoside and 6-mercaptopurine). He then developed persistently high fevers and was treated with broad-spectrum antibiotics for neutropenic fever. Anti-viral and anti-fungal prophylaxis was continued during this time. Microbiological investigations for viral, fungal and bacterial pathogens were repeatedly negative. Imaging studies including a CT and PET scans did not show lymphadenopathy, hepatosplenomegaly, or other organ involvement. In view of his persistent fever, a mid-cycle bone marrow aspirate and trephine were performed which showed a reduction in lymphoblasts to 5% by flow cytometry and an extensive infiltration of malignant histiocytes, amounting to nearly 80%, with no associated hemophagocytosis [Figs. 2(a) & (b); (b);3(a)3(a) & (b)]. This ‘secondary malignant histiocytosis’ (SMH) was considered to be the cause of his persistent fevers, based on flow cytometric analysis. Karyotyping was not performed on the marrow at this stage. There was mild hepatomegaly, no splenomegaly, ferritin levels were 1197 microgram/L (normal 10–400 mcg/L), whereas LDH and triglyceride levels were normal. Other differential diagnoses which were ruled out included: Anaplastic large cell lymphoma (negative staining for CD30 and ALK1), carcinoma (negative staining for cytokeratin) and dendritic cell neoplasms (negative staining for CD23 and S100 as well as morphology). Phase-2 induction chemotherapy was discontinued.
His secondary malignant histiocytosis was treated with alemtuzumab (Campath) 2.4 mg/kg over 5 days , intravenous immunoglobulins (IVIG) 1 gm/kg for 2 days and methylprednisolone 2 mg/kg for 5 days. He defervesce after 48 h and became well and ambulant. Assessment of bone marrow on day 15, 2 weeks after receiving alemtuzumab, showed a decrease in histiocytes to less than 15% and lymphoblasts to 0.1% by flow cytometry.
With an excellent performance status, normalization of blood counts and a partial response of his SMH, it was decided to proceed to T-cell replete allogeneic stem transplantation from his sibling with fludarabine (40 mg/m2/day) on days − 7 to − 3 and IV busulfan (130 mg/m2/day) conditioning on days − 6 to − 3 . His bone marrow examination, 70 days’ post-allogeneic stem cell transplantation, showed a complete morphological [Fig. 4], flow cytometric and cytogenetic remission. He developed features of mild skin graft versus host disease (GVHD), 2 months’ post-transplant, which was treated with topical steroids. The patient maintained complete remission for 8 months’ post-allogeneic stem cell transplant but has relapsed with ALL in thigh muscles, the middle ear and the leptomeninges. Biopsies from two sites reveal no evidence of SMH.
Histiocytoses encompass a rare, heterogeneous group of disorders characterized by the aggregation of cells of mononuclear-phagocytic lineage and occur more commonly in children. Histiocytes, a morphological term for tissue-dweller macrophages, perform the phagocytic function whereas dendritic cells (DC) are involved in antigen presentation and T-cell activation. Nomenclature for this rare entity has evolved since 1987 and most recent classification group >100 subtypes into 5 categories , .
Secondary Malignant Histiocytosis (SMH) is a neoplastic disorder occurring simultaneously or after another hematologic malignancy and is classified under “M group (MH: Malignant Histiocytoses)” according to the revised classification of histiocytic disorders. SMH is diagnosed based on anaplastic morphology, expression of macrophage and DC markers, a definite temporal and a probable clonal relationship with the primary hematologic neoplasm , .
Differential diagnosis mainly includes high-grade lymphoma, metastatic carcinoma, malignant melanoma, primary malignant histiocytosis and requires the establishment of anaplastic morphology and staining markers of macrophages/DCs, without synchronous hematological malignancy, via negative staining pattern and hence the exclusion of other tumors.
SMH evolves through transdifferentiation, a series of processes where one differentiated somatic cell line transforms into another, without going through a pluripotent cell phase . Recent studies have highlighted the important role transcription factors play in the transdifferentiation of somatic and malignant cell lines, to specialized and pluripotent stem cells, as well as across different hematopoietic lineages. Transcription factor C/EBPα, in particular, appears to play an important role in relation to the pre-B cell to macrophage transdifferentiation , .
We report a case of SMH developing synchronously with pre-B ALL in a 40-year-old male. There is no standard of care treatment for SMH currently and prognosis remains poor, especially in patients with multisystem involvement. Data regarding treatment is derived from other related histiocytic disorders, commonly HLH, and includes etoposide-based combination chemotherapy , , . There are reports in the literature of the use of Alemtuzumab in LCH and HLH ,  but seldom for its use in the treatment regimens for SMH, likely because of the rarity of SMH itself. Albeit malignant histiocytes were not examined for CD52 expression in this case, evidence from response of other biologically and clinically similar conditions to alemtuzumab was extrapolated and led to the clinical decision of utilizing this monoclonal antibody in the setting of SMH and this patient responded well to alemtuzumab, intravenous immunoglobulin and methylprednisolone.
This report is the first to highlight the role of alemtuzumab, an anti-CD52 monoclonal antibody, in clonal disorders originating from transdifferentiation. However, the alemtuzumab-based regimen should be reserved only for carefully selected allogeneic transplant patients, given its considerably long lympholytic half-life and established roles in T-cell depletion and GVHD. Further studies are needed to better understand the transdifferentiation phenomenon involved in SMH so that specific molecular targets can be identified in order to improve the dismal outlook associated with SMH.
Informed consent was obtained from the patient prior to publication.
The authors declare no conflict of interest.
MBA conceived of the study and wrote the manuscript. JP and KW helped in the preparation of the manuscript. JP provided the histopathology images. JMB and DIM rendered patient care and performed a critical review of the manuscript. All authors read and approved the final manuscript.