True histiocytic lymphoma following B-acute lymphoblastic leukaemia: case report with evidence for a common clonal origin in both neoplasms


Réda Bouabdallah, MD, Department of Haematology, Institut Paoli-Calmettes, 232 Boulevard Sainte-Marguerite, 13273 Marseille cedex 09, France. E-mail:


True histiocytic lymphoma (THL) is a very rare type of non-Hodgkin's lymphoma (NHL) in which neoplastic cells exhibit markers of histiocytic differentiation. Some cases of THL have been reported in patients with previous acute lymphoblastic leukaemia (ALL), especially in children and young adults, in whom the acute leukaemia was of T-cell origin. The relationship between the initial lymphoid tumour and the secondary THL remains unclear, as a common monoclonal origin shared by both neoplasms has never been definitively demonstrated. We report a patient with B-ALL who developed a nodal and extranodal tumour with histological and immunohistochemical features of THL 4 years after the initial diagnosis. Genotypic study showed that both neoplasms contained the same immunoglobulin heavy gene rearrangement, which has not been reported previously.

True histiocytic lymphoma (THL) is a very uncommon non-Hodgkin's lymphoma (< 0·5% of NHLs) with a very poor outcome. It is composed of neoplastic cells exhibiting markers of histiocytic differentiation (Harris et al, 1999). The course of the disease shares the same characteristics as aggressive NHLs. It is preferentially localized but may also present as a disseminated disease. The most common clinical features include weight loss, fever, lymphadenopathy and splenomegaly. The gastrointestinal tract is the most frequent extranodal localization, but atypical sites of involvement such as central nervous system, bone, skin, soft tissues, kidney, bone marrow, liver and lung have been reported. Diagnosis is based on morphological and immunohistochemical features. The tumour exhibits a diffuse pattern of loosely cohesive large cells showing abundant eosinophilic, often vacuolated, cytoplasm. Nuclei may be round or highly irregular, sometimes convoluted or cerebriform with prominent nucleoli. Multinucleated giant cells are common and sarcomatoid areas can be seen. In the lymph nodes, the neoplastic cells tend to involve the sinuses. Neoplastic cells usually show reactivity with CD45 and one or more histiocytic markers, but no reactivity for B- or T cell-associated markers, or with CD30. In current practice, histiocytic-associated markers that can be used on paraffin sections are CD68 (KP1 and PGM1), lysozyme and alpha-1 anti-trypsin. PS100 and CD45RO can also be positive. When these strict criterias are applied, THL appears to be very rare and it is generally accepted that the majority of ‘THL’ diagnosed before the early 1980s are, in fact, high-grade B or T NHLs (especially CD30-positive anaplastic large cell lymphomas). The contribution of gene rearrangement studies to the diagnosis of THL is unclear, but both T-cell receptor (TCR) and immunoglobulin gene rearrangements have already been reported (Kamel et al, 1995; Elghetany, 1997; Copie-Bergman et al, 1998).

Although second neoplasms occur at a relatively high frequency in cancer patients who previously received chemotherapy and/or radiotherapy, only a few cases of THL in patients previously treated for lymphoid neoplasms have been reported in the literature.

We report a patient with B-acute lymphoblastic leukaemia (ALL) who developed a nodal and extranodal tumour with histological and immunohistochemical features of THL 4 years after the initial diagnosis. Genotypic study showed that both neoplasms contained the same immunoglobulin gene rearrangement, a result which has not been reported previously.

Patient and methods

In February 1996, a 19-year-old man was admitted to our hospital with peripheral disseminated lymph nodes and fever. Blood tests revealed leucocytosis (4·8 × 109/l) with 60% circulating blast cells, anaemia (9·3 gd/l) and thrombocytopenia (38 × 109/l). The bone marrow aspiration revealed ALL (Fig 1A) and immunological B markers were positive (CD10 and CD19). The phenotype of blast marrow cells indicated a precursor B-cell leukaemia (CD10+, CD20, CD34+, cytoplasmic μ chain, membrane light chains κ and λ). No monocytic marker was positive (CD13, CD33). Karyotype performed on leukaemic cells showed a translocation t(9;9)(p13;q13). The patient was considered as standard-risk group and was treated with the French multicentre trial LALA-94 protocol. This chemotherapy regimen included three phases. An initial induction sequence with daunorubicin, cyclophosphamide, vincristine and prednisolone which led to a complete response (CR) and normal karyotype. Subsequently, the patient underwent consolidation therapy, consisting of chemotherapy (cyclophosphamide, cytosine-arabinoside, 6-mercaptopurine) and cranial prophylactic irradiation. Finally, maintenance treatment was initiated with alternative cycles of either cytosine-arabinoside and cyclophosphamide or methotrexate and asparaginase. The treatment ended on June 1998, after a total duration of 29 months. The patient was then seen monthly and remained in CR.

Figure 1.

(A) B-ALL. Bone marrow smears were stained with May–Grünwald–Giemsa and registered at a 1000-fold magnification on a Leica-ICG system database. (B) Poorly cohesive sheets of pleomorphic cells exhibiting irregular nuclei and abundant eosinophilic cytoplasms. A great number of multinucleated elements was seen (HES ×400). (C) Immunohistochemical reactions showing strong cytoplasmic positivity for CD68 (KP1) (left), and positivity for CD45 and Protein S100 (centre and right respectively).

In March 2000, he presented with abdominal pain and fever. No infection could be assessed and blood tests were normal. The bone marrow aspirate was repeated and showed no evidence of relapse of previous ALL. Computerized tomography (CT) scan showed an agglomerate of enlarged lymph nodes in the mesenteric area. Laparotomy was performed and five mesenteric lymph nodes were resected as well as the adjacent bowel segment. A diagnosis of a malignant neoplasm with morphological and immunophenotypic features of true histiocytic lymphoma was given. The patient was treated with daunorubicin, cyclophosphamide and dacarbazine, and was alive in CR at the last follow-up in November 2000.


Results of morphology and immunostains are shown in Fig 1B and C. Histopathological analysis showed lymph node and intestinal involvement by sheets of malignant cells with a diffuse architecture. Neoplastic cells were large, pleomorphic, with abundant cytoplasm and irregular nuclei exhibiting conspicuous nucleoli. Multinucleated giant cells were numerous (Fig 1B). Immunohistochemichal markers (Fig 1C) were evocative of monocyte-macrophage lineage because of cytoplasmic positivity for CD68 (KP1 and PGM1) and lysozyme. Vimentin, CD45, UHCL1 (CD45RO) and Protein S100 were also positive. B lineage-associated markers (CD10, CD20, CD79a), T lineage-associated markers (CD3 and CD43) and anaplastic lymphomas markers (EMA, CD30) were negative. CD34 and Tdt were also negative on the relapse biopsy specimen. Overall, the histological and immunological pattern was consistent with the diagnosis of true histiocytic lymphoma. Immunoglobulin and TCR gene rearrangement studies were performed on both leukaemic cells and THL cells as previously described (Dubus et al, 1994). Results showed an immunoglobulin heavy chain gene rearrangement on both samples with a band of identical size (Fig 2).

Figure 2.

Analysis of the rearrangement of the Ig heavy chain (IgH) and T-cell receptor (TCR) genes using polymerase chain reaction. A band of identical size was detected in B-ALL cells (lane 1) and THL cells (lane 2), which indicated that neoplastic cells in both neoplasms contain the same Ig gene rearrangement, and thus originate from the same B-cell clone. Lanes 3, 4, 5 contain the negative control, the polyclonal positive control and the clonal positive control respectively.


The relationship between THL and previously treated lymphoid neoplasms remains questionable. Wetzler et al (1995) reported 10 cases (one personal case and nine cases from the literature) of transformation from chronic lymphocytic leukaemia (CLL) to lymphoma of true histiocytic type. The authors clearly separated these observations from the classical Richter's syndrome which is well characterized in the natural history of CLL. They concluded that THL represents an additional form of transformation in CLL, but no molecular markers could be identified to explain the transition from lymphocytic to histiocytic morphology (Wetzler et al, 1995). More recently, Rodilla et al (1997) reported a patient who developed a THL 16 years after the initial diagnosis of follicular lymphoma. They considered it as a second neoplasm in the evolutionary course of the indolent lymphoma. In fact, the patient received many courses of alkylating agents for the treatment of follicular lymphoma and the development of the second cancer could have been related to the mutagenic effects of such drugs. In these two reports, the oncogenic properties of chemotherapy may be implicated in the development of the second neoplasms, as well as the frequent iatrogenic immunodeficiency observed in these patients.

THL may also occur in patients with previous acute lymphoproliferative diseases. Soslow et al (1996) reported two cases of THL arising after therapy for B-ALL or lymphoblastic lymphoma (LyL). Van der Kwast et al (1991) reported a 19-year-old man who developed THL following therapy for T-lymphoblastic lymphoma. In all previously reported cases, a common monoclonal origin shared by both neoplasms has not been demonstrated and, thus, the relationship between the initial lymphoid tumour and the secondary THL remains unclear. In the present case, the genotypic study showed that both neoplasms arose from the same B-cell clone, as tumoral cells from both ALL and THL showed the identical immunoglobulin gene rearrangement.

It is possible that chemotherapy plays a role in the transformation of lymphoblastic immature cells into mature histiocytic ones, in a way similar to the phenomenon of maturation observed in other malignancies such as neuroblastomas or teratomas under treatment (Raaf et al, 1982). Our observation suggests that B-ALL cells could behave like progenitors which can undergo maturation but also differentiate into another lineage. A better prognosis is usually observed in malignant tumours undergoing maturation. In contrast, THL following treatment of a lymphoid neoplasm is usually considered to be of poor prognosis.

If THLs are morphologically and immunophenotypically well recognized, their development still remains controversial. This review of the literature suggests that it could be that there are various forms of THL with different pathways. On the one hand, we can isolate THLs occurring after chronic lymphoproliferative diseases as CLLs or indolent lymphomas, which could represent a second and distinct neoplasm in the natural history of the initial lymphoid disease. On the other hand, THLs occurring after successful treatment of acute lymphoid neoplasms such as LyL or ALL seem to develop otherwise. As the two neoplasms may express an identical gene rearrangement, the frontier between them is unclear. However, as such cases are exceptional, additional observations are still needed to draw a final conclusion.