Abstract
Follicular lymphoma FL) is a prevalent subtype of non-Hodgkin lymphoma in the United States and Europe. Although, FL typically presents with nodal involvement, extranodal involvement has been rarely described. There is mounting evidence that leukemic presentation portends a worse prognosis in patients with FL. We describe 7 patients with a pathological diagnosis of FL who presented with a leukemic component. We also present data on patients with leukemic FL reported in the literature. Based on our results, leukemic FL seems to be associated with a worse prognosis. However, larger prospective studies are needed to confirm our findings.
Keywords: Follicular lymphoma, leukemic phase
Introduction
Follicular lymphoma (FL) is a lymphoproliferative neoplasm of follicle center B-cells, which have at least a partially identifiable follicular pattern. FL is the second most frequent type of B-cell lymphoma seen in United States (US) and Europe, and accounts for approximately 25–30% of all the cases of non-Hodgkin lymphomas (NHL) among adults [1]; however, FL is less common in Asia and Latin America. In a comparative study, the incidence of FL in Hong Kong was 8% compared to 32% in the Omaha, NE and 28% in London, UK [2]. Similarly, a recent report shows an incidence of 17% in Latin American countries, which was lower than the 34% seen in North America [3].
FL tends to present with generalized lymph node involvement at diagnosis and is usually asymptomatic or oligosymptomatic, although it can also present with B symptoms, such as fever, drenching night sweats and unintentional weight loss, and autoimmune cytopenias. FL often involves spleen and bone marrow, but a leukemic phase of FL at the time of diagnosis is rare [4]. In a previous study, there was an indication that although FL is rare in Asia, the rates of leukemic presentation of FL might be higher than in the US and Europe [5].
We present the clinical, pathological and cytogenetic characteristics of seven cases of FL who presented with a leukemic phase at diagnosis, and a brief review of the literature.
Patients and methods
Medical records from three institutions (Hospital Nacional Edgardo Rebagliati Martins in Lima, Peru; Rhode Island Hospital in Providence, RI, USA, and the Moffitt Cancer Center in Tampa, FL, USA) were reviewed between 2008 and 2010 looking for patients with a pathological diagnosis of FL and evidence of FL cells in the peripheral blood identified by flow cytometry. Clinical data from all cases were collected from retrospective chart review, and included age, sex, race, absolute lymphocyte count at presentation, FL International Prognostic Index (FLIPI) score, therapeutic regimens received, outcome and overall survival (OS). Cases were reviewed by at least two hematopathologists at the respective center of diagnosis. All cases were then evaluated by a third hematopathologist (RNM). Pathological characteristics evaluated were grade, expression of CD20, bcl2, bcl6 and CD10, and cytogenetic and fluorescent in situ hybridization (FISH) studies looking for t(14;18).
For the literature review, a literature search was performed independently by two authors (BGB, JJC) using Pubmed from January 1990 through December 2011 looking for case reports and series providing data on patients with FL with a leukemic component. Inclusion criteria were age <18 years, pathological diagnosis of FL and absolute lymphocyte count <4,000/uL. Patients with primary cutaneous FL were excluded. Two authors independently gathered pertinent clinical and pathological data (BGB, JJC).
Characteristics will be presented using descriptive statistics. OS was calculated as the time elapsed from diagnosis to death or last follow-up. All graphs and calculations were obtained using Medcalc (Mariakereke, Belgium).
Results
Clinical characteristics
We identified seven cases of leukemic FL. The median age at presentation was 57 years (range: 39–76 years). All cases were men. Six cases (86%) presented with concurrent lymphadenopathy and one case (14%) had pure leukemic FL. The median absolute lymphocyte count was 81,260/uL (range 5,000–226,950/uL). All cases presented with high-risk FLIPI score; 4 cases (67%) had a score of 4 and 2 cases (33%) had a score of 5. All cases were treated with rituximab-containing therapies. Three patients (43%) have died, 2 (29%) are alive with disease and 2 (29%) are alive without disease. Clinical characteristics are shown in Table 1.
Table 1.
Clinical characteristics of 7 patients with leukemic follicular lymphoma
| Case | Age | Sex | Race | Stage | Tumors or LAD? |
Lymphocyte count (cells/mm3) |
Therapy | Survival (months) |
Outcome |
|---|---|---|---|---|---|---|---|---|---|
| 1 | 39 | M | White | IVB | Yes | 36,600 | R-bendamustine×1 R-cyclophosphamide×5 Maintenance R |
20 | AWD |
| 2 | 60 | M | White | IVB | Yes | 226,950 | R-CVP×6 R-fludarabine×6 R-bendamustine×9 |
33 | Dead |
| 3 | 56 | M | Hispanic | IVB | Yes | 5,000 | R-CHOP×6 R-ICE R-GEMOX |
17 | Dead |
| 4 | 76 | M | Hispanic | IVB | Yes | 11,430 | R-CHOP | 3 | Dead |
| 5 | 40 | M | Hispanic | IVB | Yes | 51,840 | R-CHOP R-ICE R-ESHAP |
15 | AWD |
| 6 | 61 | M | White | IVB | No | 200,000 | R-CHOP ASCT |
34 | AWOD |
| 7 | 64 | M | Hispanic | IVA | Yes | 37,000 | R-CHOP | 4 | AWD |
M: male; LAD: lymphadenopathy; CVP: cyclophosphamide, vincristine, prednisone; CHOP: cyclophosphamide, doxorubicin, vincristine, prednisone; ICE: ifosfamide, carboplatin, etoposide; GEMOX: gemcitabine, oxaliplatin; ESHAP: etoposide, methylprednisolone, cytarabine, cisplatin; ASCT: autologous stem cell transplant; AWD: alive with disease; AWOD: alive without evidence of disease
Pathological characteristics
Pathological characteristics are shown in Table 2.
Table 2.
Pathological characteristics of 7 patients with leukemic follicular lymphoma
| Case | Grade | CD20 | CD10 | BCL2 | BCL6 | KI67 | Cytogenetics | FISH t(14;18) |
|---|---|---|---|---|---|---|---|---|
| 1 | 2 | + | + | + | + | ND | inv(3)(q12q27), del(10)(q24q26), t(14;18)(q32;q21) | ND |
| 2 | 1 | + | + | + | ND | ND | 4p+, 5q−, 6q+, 14q+, 18−, 22p+ | + |
| 3 | 2 | + | + | + | + | 40% | ND | + |
| 4 | 1 | + | + | + | + | 20% | ND | + |
| 5 | 1 | + | + | + | + | 60% | ND | ND |
| 6 | 1 | + | + | + | + | 20% | ND | + |
| 7 | 3a | + | + | + | + | 20% | ND | ND |
ND: not done; FISH: fluorescent in situ hybridization
Literature review
We identified 9 studies [5–13] reporting data on 24 cases with leukemic FL for a total of 31 cases, including ours. The median age at presentation was 60 years (range: 30–89 years). There was a male predominance (ratio 2.4:1). The median WBC count was 37,000/uL (range: 4,800–560,000/uL). Complete characteristics are shown in Table 3.
Table 3.
Characteristics of 31 patients with leukemic follicular lymphoma from the literature
| Characteristic | Number | Percentage |
|---|---|---|
| Age >60 years | 15/31 | 48.4% |
| Male sex | 22/31 | 71.0% |
| Region | ||
| Europe | 15/31 | 48.4% |
| America | 8/31 | 25.8% |
| Asia | 8/31 | 25.8% |
| Concurrent tumors | 21/26 | 80.8% |
| Blood only | 5/26 | 19.2% |
| B symptoms | 6/15 | 40.0% |
| FLIPI | ||
| Low (0–2 points) | 8/17 | 47.1% |
| High (3–5 points) | 9/17 | 52.9% |
| WBC count >100/uL | 8/27 | 29.6% |
| CD10 expression | 27/29 | 93.1% |
| CD20 expression | 31/31 | 100% |
| BCL2/IgH gene rearrangement* | 19/22 | 86.4% |
| Therapy | ||
| R-chemotherapy | 17/24 | 70.8% |
| Chemotherapy | 6/24 | 25.0% |
| None | 1/24 | 4.2 |
| Outcome | ||
| Alive | 22/26 | 84.6% |
| Dead | 4/26 | 15.4% |
FLIPI: follicular lymphoma international prognostic index; WBC: white blood cell; IgH: immuhoglobulin heavy chain
By FISH or PCR
Discussion
FL is the second most common type of lymphoma in the United States and Europe, accounting for approximately 20% of all NHL the cases [1]. However, the distribution of FL in other regions of the world appears different. Recent studies have shown that the proportion of FL in Asian and Latin American countries varies between 10–15% [3, 14, 15]. Based on this, it is also likely that the clinical presentation of FL would vary according to race and/or ethnicity. However, additional research is needed to clarify this point.
Although the presentation of FL is typically nodal, cases of extranodal presentation have been reported [16–19]. FL may evolve to or present with a leukemic component. In the leukemic form of FL, a variable proportion of the peripheral blood lymphocytes exhibit a distinct appearance that has been previously described as "notched-nucleus cell" [20]. The lymphocyte count varies from moderately to severely elevated; in the present study, it ranged between 5,000 and <500,000 cells/mm3. The true incidence of such an event is unknown but varies in different series, ranging between 4–23%. A Japanese group reported leukemic phase at presentation in FL patients as high as 45% [5]. However, circulating FL cells can also be identified in patients without lymphocytosis [21], as FL cells are frequently detected in peripheral blood by molecular methods (11a ).
Published studies described FL with leukemic phase that could occur in conjunction with other areas of disease (i.e. lymph nodes) or without concurrent tumors or lymphadenopathy. Al-Nawakil et al. described ten patients with FL and leukemic phase at diagnosis [6]. Six of them had concomitant lymph node involvement and four patients had pure FL cell leukemia, which was associated with a more indolent clinical outcome. In our report, the only patient that presented with pure leukemic FL is alive and in a complete remission after receiving chemoimmunotherapy followed by autologous stem cell transplantation. All the other patients have died or are alive with evidence of disease.
Given the indolent nature of FL, it is difficult to establish the true aggressiveness of leukemic presentations and its potential prognostic value. There are mounting data, however, associating a leukemic presentation with an adverse outcome in patients with FL. In a recent report from Japan, Kodaira and colleagues showed that a leukemic presentation, which accounted for 21% of the cases, portends a worse progression-free survival (PFS) in patients with FL treated with chemoimmunotherapy [22]. More recently, Sarkozy and colleagues identified a leukemic phase in 7% of patients with FL, which was associated with a shorter PFS, independent of the FL international prognostic index (FLIPI) score and beta-2-microglobulin levels [23]. Of note, both studies have been presented solely in abstract form. Therefore, leukemic FL might be considered to have a distinct biological behavior and could influence the prognosis of these patients.
Currently, the FLIPI score is arguably the most commonly used prognostic tool in patients with FL [24], and has shown to be applicable across a range of clinical settings [25, 26]. In such study, patients with a leukemic component were categorized as having extranodal disease, and were not analyzed separately. More recently, the FLIPI-2 score has been developed [27], which specifically considers bone marrow involvement as an adverse factor. However, leukemic presentation was not evaluated as a prognostic factor.
The introduction of anti-CD20 monoclonal antibodies has resulted in better response and survival rates in patients with FL [28, 29]. However, based on the available data, patients with leukemic phase still have an unsatisfactory prognosis. Several unanswered questions remain: Should leukemic FL be diagnosed based on the solely presence of circulating FL cells? Or should a diagnosis of leukemic FL be rendered based on an actual number of circulating FL cells? Should all patients with a clinical diagnosis of FL undergo flow cytometry to detect a leukemic component? What is the best regimen to treat patients with leukemic FL? Should we recur to ASCT in specific cases? Future prospective studies are necessary to evaluate the role of leukemic phase in the prognosis of FL, and to improve our current therapies in these patients.
References
- 1.Morton LM, Wang SS, Devesa SS, et al. Lymphoma incidence patterns by WHO subtype in the United States, 1992–2001. Blood. 2006;107(1):265–276. doi: 10.1182/blood-2005-06-2508. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Anderson JR, Armitage JO, Weisenburger DD. Epidemiology of the non-Hodgkin's lymphomas: distributions of the major subtypes differ by geographic locations. Non-Hodgkin's Lymphoma Classification Project. Ann Oncol. 1998;9(7):717–720. doi: 10.1023/a:1008265532487. [DOI] [PubMed] [Google Scholar]
- 3.Laurini JA, Perry AM, Boilesen E, et al. Classification of non-Hodgkin lymphoma in Central and South America: a review of 1028 cases. Blood. 2012;120(24):4795–4801. doi: 10.1182/blood-2012-07-440073. [DOI] [PubMed] [Google Scholar]
- 4.Medeiros LJ, Jaffe ES. Pathology of non-Hodgkin’s lymphomas and Hodgkin’s disease. In: Wiernik PH, et al., editors. Neoplastic diseases of the blood. New York: Churchil Livingstone; 1996. pp. 753–805. [Google Scholar]
- 5.Chubachi A, Miura I, Hashimoto K, et al. High incidence of leukemic phase in follicular lymphoma in Akita, Japan: clinicopathologic, immunological and cytogenetic studies. Eur J Haematol. 1993;50(2):103–109. doi: 10.1111/j.1600-0609.1993.tb00149.x. [DOI] [PubMed] [Google Scholar]
- 6.Al-Nawakil C, Kosmider O, Stern MH, et al. Leukemic phase of follicular lymphomas: an atypical presentation. Leuk Lymphoma. 2011;52(8):1504–1508. doi: 10.3109/10428194.2011.574753. [DOI] [PubMed] [Google Scholar]
- 7.Ganguly S. Leukemic phase of follicular lymphoma after treatment with etanercept in a patient with psoriasis. Am J Clin Dermatol. 2009;10(2):125–126. doi: 10.1007/BF03256596. [DOI] [PubMed] [Google Scholar]
- 8.Hsieh YC, Lee LP, Chuang SS. Follicular lymphoma with many circulating buttock cells: a leukemic presentation mimicking mantle cell leukemia. Am J Hematol. 2006;81(4):294–295. doi: 10.1002/ajh.20555. [DOI] [PubMed] [Google Scholar]
- 9.Inaba T, Okamoto A, Tatsumi T, et al. Hyperleukocytosis in patients with leukemic follicular lymphoma. Ann Hematol. 2007;86(4):299–300. doi: 10.1007/s00277-006-0232-z. [DOI] [PubMed] [Google Scholar]
- 10.Khokhar MT, Brito-Babapulle V, Matutes E, et al. Cytogenetic abnormalities in the leukemic phase of non-Hodgkin lymphoma. Cancer Genet Cytogenet. 1995;83(1):18–24. doi: 10.1016/s0165-4608(94)00308-4. [DOI] [PubMed] [Google Scholar]
- 11.Ono Y, Aoki K, Kato A, et al. Systemic follicular lymphoma with massive intestinal involvement with leukemic manifestation. J Clin Exp Hematop. 2011;51(2):135–140. doi: 10.3960/jslrt.51.135. [DOI] [PubMed] [Google Scholar]
- 12.Rymkiewicz G, Paszkiewicz-Kozik E, Blachnio K, et al. Unusual IgD+/CD38-follicular lymphoma with leukemic presentation. Med Oncol. 2006;23(1):131–135. doi: 10.1385/MO:23:1:131. [DOI] [PubMed] [Google Scholar]
- 13.Sole F, Woessner S, Florensa L, et al. A new case of t(14;19) (q32;q13) in a patient with follicular lymphoma in leukemic phase. Cancer Genet Cytogenet. 1994;75(1):72–73. doi: 10.1016/0165-4608(94)90219-4. [DOI] [PubMed] [Google Scholar]
- 14.Aoki R, Karube K, Sugita Y, et al. Distribution of malignant lymphoma in Japan: analysis of 2260 cases, 2001–2006. Pathol Int. 2008;58(3):174–182. doi: 10.1111/j.1440-1827.2007.02207.x. [DOI] [PubMed] [Google Scholar]
- 15.Yang QP, Zhang WY, Yu JB, et al. Subtype distribution of lymphomas in Southwest China: analysis of 6,382 cases using WHO classification in a single institution. Diagn Pathol. 2011;6:77. doi: 10.1186/1746-1596-6-77. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Chim CS, Loong F, Leung AY, et al. Primary follicular lymphoma of the small intestine. Leuk Lymphoma. 2004;45(7):1463–1466. doi: 10.1080/10428190310001645906. [DOI] [PubMed] [Google Scholar]
- 17.Fernandez de Larrea C, Martinez-Pozo A, Mercadal S, et al. Initial features and outcome of cutaneous and non-cutaneous primary extranodal follicular lymphoma. Br J Haematol. 2011;153(3):334–340. doi: 10.1111/j.1365-2141.2011.08596.x. [DOI] [PubMed] [Google Scholar]
- 18.Goodlad JR, MacPherson S, Jackson R, et al. Extranodal follicular lymphoma: a clinicopathological and genetic analysis of 15 cases arising at non-cutaneous extranodal sites. Histopathology. 2004;44(3):268–276. doi: 10.1111/j.1365-2559.2004.01804.x. [DOI] [PubMed] [Google Scholar]
- 19.Martinelli G, Ryan G, Seymour JF, et al. Primary follicular and marginal-zone lymphoma of the breast: clinical features, prognostic factors and outcome: a study by the International Extranodal Lymphoma Study Group. Ann Oncol. 2009;20(12):1993–1999. doi: 10.1093/annonc/mdp238. [DOI] [PubMed] [Google Scholar]
- 20.Anday GJ, Schmitz HL. Follicular lymphoma with transient leukemic phase; brief review of literature and report of a case. AMA Arch Intern Med. 1952;89(4):621–634. doi: 10.1001/archinte.1952.00240040100012. [DOI] [PubMed] [Google Scholar]
- 21.Rohatiner A, Lister A. The non-Hodgkin’s lymphomas. Arnold: London; 1997. Follicular lymphoma; pp. 867–895. [Google Scholar]
- 22.Kodaira M, Takeuchi K, Nara E, et al. Leukemic Presentation Is Predictive Indicator for Relapse for Patients with Follicular Lymphoma Treated with Rituximab Containing Initial Therapy. ASH Annual Meeting Abstracts. 2009;114(22):4763. [Google Scholar]
- 23.Sarkozy C, Baseggio L, Callet-Bauchu E, et al. Detection of Leukemic Phase in Patients with Follicular Lymphoma At Diagnosis: A Rare Event Associated with Poor Prognosis. ASH Annual Meeting Abstracts. 2012;120(21):1594. [Google Scholar]
- 24.Solal-Celigny P, Roy P, Colombat P, et al. Follicular lymphoma international prognostic index. Blood. 2004;104(5):1258–1265. doi: 10.1182/blood-2003-12-4434. [DOI] [PubMed] [Google Scholar]
- 25.Gine E, Montoto S, Bosch F, et al. The Follicular Lymphoma International Prognostic Index (FLIPI) and the histological subtype are the most important factors to predict histological transformation in follicular lymphoma. Ann Oncol. 2006;17(10):1539–1545. doi: 10.1093/annonc/mdl162. [DOI] [PubMed] [Google Scholar]
- 26.Montoto S, Lopez-Guillermo A, Altes A, et al. Predictive value of Follicular Lymphoma International Prognostic Index (FLIPI) in patients with follicular lymphoma at first progression. Ann Oncol. 2004;15(10):1484–1489. doi: 10.1093/annonc/mdh406. [DOI] [PubMed] [Google Scholar]
- 27.Federico M, Bellei M, Marcheselli L, et al. Follicular lymphoma international prognostic index 2: a new prognostic index for follicular lymphoma developed by the international follicular lymphoma prognostic factor project. J Clin Oncol. 2009;27(27):4555–4562. doi: 10.1200/JCO.2008.21.3991. [DOI] [PubMed] [Google Scholar]
- 28.Hiddemann W, Kneba M, Dreyling M, et al. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 2005;106(12):3725–3732. doi: 10.1182/blood-2005-01-0016. [DOI] [PubMed] [Google Scholar]
- 29.Marcus R, Imrie K, Solal-Celigny P, et al. Phase III study of R-CVP compared with cyclophosphamide, vincristine, and prednisone alone in patients with previously untreated advanced follicular lymphoma. J Clin Oncol. 2008;26(28):4579–4586. doi: 10.1200/JCO.2007.13.5376. [DOI] [PubMed] [Google Scholar]