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Immunocytoma: A Retrospective Analysis From St Bartholomew's Hospital—1972 to 1996

From the Imperial Cancer Research Fund (ICRF) Department of Medical Oncology, Departments of Histopathology and Haematology, St Bartholomew's Hospital, West Smithfield, London, and ICRF Medical Statistics Group, Institute of Health Sciences, Headington, Oxford, United Kingdom.

Address reprint requests to A.Z.S. Rohatiner, MD, ICRF Department of Medical Oncology, 45 Little Britain, St Bartholomew's Hospital, London EC1A 7BE, United Kingdom; emaila.rohatiner{at}icrf.icnet.uk

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To analyze the presentation features and outcome for patients with immunocytoma (IMC) managed at St Bartholomew's Hospital (SBH), London, United Kingdom, between 1972 and 1996. Outcome was compared with that of patients with small lymphocytic lymphoma (SLL)/B-cell chronic lymphocytic leukemia (B-CLL) treated at SBH during the same period.

PATIENTS AND METHODS: One hundred twenty-six patients with newly diagnosed IMC were identified. Patients were subclassified (using the Kiel classification) as having lymphoplasmacytoid (n =92), lymphoplasmacytic (n = 24), polymorphous (n = 9), or undetermined (n = 1) IMC. Six patients (5%) had stage I to IIE disease; the rest had advanced disease. Treatment was given according to disease stage. Seven patients were managed expectantly.

RESULTS: Eighty-two (69%) of 119 patients responded to treatment, but complete remission was seen in only 15 (13%) of 119. Treatment failed in 29 (24%) of 119 patients. There were three treatment-related deaths; five patients were not assessable for response. When survival of patients with IMC was compared with that of patients with B-CLL/SLL, a significant difference was found (P < .01); this difference was maintained when only patients in whom the diagnosis was based on lymph node biopsy were considered (P = .01). A comparison of the three IMC subgroups showed that there was a trend (P = .06) toward a difference between B-CLL/SLL and the lymphoplasmacytoid subtype.

CONCLUSION: Patients diagnosed with IMC are generally older and present with advanced disease. Conventional therapies usually result in incomplete responses of short duration. Overall, these results support the proposed World Health Organization reclassification of IMC to include lymphoplasmacytoid lymphoma (Kiel classification) as a variant of B-CLL/SLL.

	INTRODUCTION

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MANAGEMENT OF THE malignant lymphomas is determined by a number of factors, of which the pathologic diagnosis remains the most important. Over the past half century, it has become realistic to subcategorize lymphomas, not only by histopathology but also according to immunologic, cytogenetic, and molecular criteria.^1-3 Therapeutic advances have to some extent obscured the prognostic significance of some of the pathologic differences, in terms of the natural history of the diseases. However, a classification that reflects clinicopathologic entities is essential and allows for the design of more rational and specific therapy. An obvious example of this is the use of monoclonal antibodies, either alone or to target irradiation. The Revised European-American Lymphoma classification proposed by the International Lymphoma Study Group (ILSG)³ is an exciting step in this direction. The Kiel classification was one of the first to incorporate the difference between B- and T-cell lineage and has been widely used in Europe for the past two decades.² Many of its features may be recognized in the new proposals.

This retrospective analysis addresses a relatively rare subtype of lymphoma, the terminology of which has recently been modified. In the Kiel classification, the term lymphoplasmacytoid lymphoma superseded immunocytoma (IMC) as the generic term to describe a predominantly nodal lymphoma of lymphoplasmacytoid origin and differentiation (of which there are two rarer subtypes, the plasmacytic and the polymorphous), the bone marrow counterpart of which is Waldenström's macroglobulinemia (WM).⁴ Patterns of survival for a group of consecutive, newly diagnosed patients, referred to St Bartholomew's Hospital (SBH), London, United Kingdom, over a 25-year period, are presented below. The outcome of these patients is compared with that of patients with small lymphocytic lymphoma (SLL)/B-cell chronic lymphocytic leukemia (B-CLL) who presented within the same time period. According to the ILSG classification, the majority of the SLL/B-CLL diagnoses will become defined as a variant of IMC.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
One hundred twenty-six consecutive patients with newly diagnosed IMC (n = 92) and WM (n = 34) referred to SBH between 1972 and 1996 formed the basis of this analysis. For 105 patients, the diagnosis was made after a lymph node biopsy (or biopsy of an extranodal site). For the remaining patients, the diagnosis was made using bone marrow biopsy alone. For patients with WM, the diagnosis was made on the basis of bone marrow infiltration and the presence of an immunoglobulin (Ig) M paraprotein of more than 20 g/L, in conjunction with the relevant clinical features. On the basis of morphology, using criteria based upon the updated Kiel classification,⁵ there were 92 patients with lymphoplasmacytoid, 24 with lymphoplasmacytic, and nine with polymorphous IMC. For one patient, the histologic subtype could not be determined. Clinical characteristics of all patients are listed in Table 1.

The sera of 116 patients were examined at the time of diagnosis for the presence of a monoclonal paraprotein band. The band was identified in 59 patients (51%), and in 37 (29%) of them it was an IgM paraprotein. Thirteen of 24 patients with lymphoplasmacytic IMC were considered to have WM, compared with only 18 of 92 patients with lymphoplasmacytoid IMC. As mentioned above, for one patient with a raised IgM fitting the criteria for inclusion into the WM group, a histologic subtype could not be allocated.

Histology and Immunophenotyping
All cases from SBH's medical oncology database coded as IMC were reviewed by A.J.N.; bone marrow preparations were reviewed by J.A.L.A. In the IMC cases, the following features were histologically noted: the presence and size of proliferation centers, cytoplasmic and nuclear Ig inclusion bodies (detected by periodic acid–Schiff staining, and where available, immunophenotype (presence or absence of cytoplasmic Ig, and CD5 and CD23 antigen status, found using a sensitive method on paraffin-embedded tissues). Phenotyping data were available for 104 (81%) of 126 patients, as phenotyping was not routinely performed before 1984.

On the basis of morphology, the cases of lymphoplasmacytoid IMC were divided into those with large or small proliferation centers (groups 1 and 2, respectively) and those lacking any evidence of proliferation center formation (group 3). In group 1 (large, distinct proliferation centers), immunostaining for CD5 was positive in 12 of 12 cases, with nine (90%) of 10 cases positive for CD23. In group 2 (small, irregularly shaped, ill-formed proliferation centers), eight (73%) of 11 cases were positive for CD5, with four (57%) of seven cases positive for CD23. In group 3 (no evidence of proliferation center formation), 16 (62%) of 26 cases were CD5-positive, with five (38%) of 13 positive for CD23. Thus, as the morphology steadily deviated from a B-CLL–like appearance, the phenotype drifted from the classical CD5 and CD23 "positivity."

Of the lymphoplasmacytic IMC cases, one of 10 was positive for CD5 and two of 10 cases (other than the CD5-positive case) expressed CD23 antigen. Ig inclusions were most frequent and numerous in the lymphoplasmacytic group (Russell bodies alone, 10 [38%] of 26; Russell + Dutcher bodies, 11 [42%] of 26; Dutcher bodies alone, two [8%] of 26) compared with the lymphoplasmacytoid group (Russell bodies alone, 11 [15%] of 75; Russell + Dutcher bodies, four [5%] of 75; Dutcher bodies alone, 19 [25%] of 75). Cytoplasmic Ig in a major part of the tumor population was seen in all cases so stained (n = 33). Cells in all subtypes showed plasmacytoid differentiation, which was best seen in Giemsa- and/or Unna-Pappenheim–stained slides. Table 2 highlights and contrasts the application of the Kiel and I.L.S.G. schemes to this patient population.

Pretreatment Assessment
Clinical examinations, full blood count and differential analyses, kidney and liver function tests, chest radiography, and unilateral bone marrow aspirate and trephine biopsies were performed on all patients at the time of presentation. Before 1977, lymphography was performed in patients who, after these procedures, were considered to have only localized disease. Subsequently, all patients had computerized tomography (CT) scans of the chest, abdomen, and pelvis. Stage was assessed according to the Ann Arbor criteria.⁶

Initial Treatment
Four patients with localized disease received radiotherapy only (n = 2) or radiotherapy followed by adjuvant chemotherapy (n = 2) with chlorambucil (CB) alone or cyclophosphamide, vincristine, and prednisolone (Table 3).

Between November 1972 and December 1976, systemic treatment consisted of either CB or cyclophosphamide/vincristine/prednisolone as part of a randomized study, which showed no significant difference between the two treatment arms.⁷ Subsequently, therefore, patients received either CB alone or CB with prednisolone as initial therapy. A small number of patients who could not tolerate CB were switched to cyclophosphamide. Thereafter, the vincristine, doxorubicin, prednisolone, etoposide, cyclophosphamide, and bleomycin (VAPEC-B) regimen was used to treat 13 patients,⁸ and six received other doxorubicin-containing treatments. Since 1991, 21 patients have received fludarabine as primary treatment.^9,10 Three patients with WM received "maintenance" therapy with oral cyclophosphamide, and two had plasmapheresis as their initial treatment. Seven patients who were asymptomatic at presentation were managed expectantly throughout (Table 3).

Management at Recurrence or Progression
Whenever possible, patients who had clinical or hematologic evidence of recurrence underwent rebiopsy (either excision biopsy of accessible new nodes or ultrasound/CT-guided biopsy.¹¹ Staging CT scans and bone marrow examinations were also performed. Treatment was recommenced after recurrence, when symptoms developed, or when the disease became bulky. CB (with or without prednisolone) was generally the second therapy, except in patients who had responded poorly to this earlier. After 1990, 16 patients were treated with fludarabine at recurrence.^9,12 If transformation was confirmed, patients were treated with an anthracycline-containing regimen (eg, cyclophosphamide, doxorubicin, vincristine, and prednisolone, VAPEC-B, or methotrexate, doxorubicin, cyclophosphamide, vincristine, and prednisolone); if patients were clinically thought to have more aggressive disease, they were treated with an intermediate-dose cytarabine regimen in combination with etoposide.¹³ Radiotherapy was used to control local symptomatic disease in patients who were unresponsive to chemotherapy. Six patients underwent splenectomy after recurrence.

Management at second and subsequent recurrence was the same as described above, except in four patients who received myeloablative therapy as consolidation of second or subsequent remission. The treatment consisted of cyclophosphamide plus total body irradiation with autologous bone marrow transplantation; the marrow mononuclear cell fraction was treated in vitro with the monoclonal antibody anti-CD20 and complement.¹⁴

Assessment of Response
Response was evaluated 1 month after the completion of therapy. The following criteria were used: Complete remission (CR) was defined as the disappearance of all symptoms and signs of disease, with complete resolution of all previously abnormal investigations. A good partial response (GPR) was defined as CR but with minimal residual radiologic abnormalities (CT scan) or minimal bone marrow infiltration upon completion of treatment. A poor partial response (PPR) was defined as a reduction of tumor bulk by at least 50% but less than GPR. Treatment was considered to have failed if it did not decrease the tumor burden by at least 50%.

For patients with WM, the same criteria were applied, but in addition, CR required the disappearance of the monoclonal paraprotein band and a partial response, a more than 50% reduction in the level of IgM. All patients in whom there was bone marrow involvement before treatment had a follow-up bone marrow analysis upon completion of therapy. Response was assessed on the basis of morphology alone.

Statistical Methods
Survival was calculated as the time between diagnosis and death from any cause. Remission duration was calculated as the period from the date of therapy outcome to the date of definite evidence of disease progression. Event-free survival for all patients was calculated as the time between diagnosis and the occurrence of an event (disease progression or death). Survival curves were constructed according to the method of Kaplan and Meier.¹⁵

In order to compare the survival of patients with IMC with that of patients with B-CLL/SLL,¹⁶ the following pretreatment factors were analyzed by univariate Cox proportional hazards regression¹⁷: age, sex, hemoglobin, albumin, sodium, alkaline phosphatase, AST, B symptoms, stage, involvement of lungs, liver, spleen, gastrointestinal tract or peripheral blood, bone marrow infiltration, presence of peripheral lymphadenopathy, chemotherapy regimen (with or without doxorubicin), and histologic examination. Factors significant at the 10% level were included in a multivariate Cox model. The same process was then repeated for patients in both groups in whom the diagnosis was made on the basis of a lymph node biopsy. A separate analysis of prognostic factors correlating with survival of patients with IMC alone was also undertaken. Factors such as age and lymphocyte count were treated as continuous variables, and linear relationships with survival were assessed; two of the variables (age and AST) had a nonlinear relationship with survival and were considered quadratic terms. Lymphocyte count, AST, and alkaline phosphatase were considered on a log scale. The International Prognostic Index could not be applied to this patient population because lactate dehydrogenase was not available until the later years encompassed by this study.

	RESULTS

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Outcome of Initial Treatment
A response to treatment was seen in 82 (69%) of 119 patients overall, with a CR achieved by 15 (13%) of 119 patients and a partial response (GPR + PPR) achieved by 67 (56%) of 119 patients. Treatment failed in 29 patients (24%). There were three treatment-related deaths; five patients were not assessable for response. The 29 patients in whom treatment failed (as well as the five patients who were not assessable for response) were subsequently treated with an alternative regimen, and a response was achieved in seven of 34 patients. These seven patients were not included in the analysis as responders to initial therapy.

When patients with WM were considered as a separate subgroup, the overall response rate was higher than that for the whole group (23 of 32 patients, or 77%). CR was achieved in two and a partial response in 21 patients. The treatment failed in six patients. One patient was not assessable for response.

Outcome of Treatment at Recurrence
The overall response rate at the first, second, and third recurrence was 35% (20 of 57 patients), 28% (five of 18 patients), and 24% (one of four patients), respectively (Table 3).

Duration of Remission
The median duration of first, second, and third remissions (CR, GPR, PPR) was 20, 9, and 5 months, respectively (Fig 1). Multivariate analysis showed that low albumin levels, high alkaline phosphatase levels, and liver involvement correlated with a shorter duration of remission (Table 4).

View larger version (16K): [in this window] [in a new window]   Fig 1. Duration of first and subsequent remissions.

Survival
Thirty patients were alive at a median follow-up period of 9.5 years. The median survival time for all patients was 6.5 years. (Fig 2). The median survival for patients treated after first, second, and third recurrence was 3 years, 10 months, and 7 months, respectively (Fig 2). There was no significant difference in survival between patients with WM and the rest of the patients with IMC. Overall survival was not significantly different between the lymphoplasmacytoid and lymphoplasmacytic subgroups; there was a trend for worse survival in patients with a high blast content (polymorphous) (data not shown).

View larger version (14K): [in this window] [in a new window]   Fig 2. Overall survival of patients with IMC compared with those with B-CLL/SLL.

Causes of Death
There were 96 deaths, the majority of which were disease-related (72 of 96 deaths). Nine patients developed a second malignancy (three had lung cancer, two had basal cell cancer, two had adenocarcinoma, one had prostatic cancer, and one had endometrial cancer), which was the immediate cause of death in six patients. Eleven patients died in remission from other nonmalignant intercurrent diseases related to the older age of the patient population. In seven patients, the precise cause of death is unknown, although they all had active lymphoma at the time.

Seven patients did not receive treatment at any point, two died from progressive disease, two died from cardiac causes, and one was lost to follow-up. Two of the patients who have never received treatment are alive at 3.5 and 22 years after presentation.

Prognostic Factors for Survival and Comparison with the B-CLL Group
Multivariate analysis showed older age, the presence of B symptoms, low albumin levels, high AST levels, and liver involvement to correlate adversely with survival (Table 4). The survival of patients with IMC was worse than that of patients with B-CLL/SLL, who had a median survival of 8.5 years (P < .01) (Fig 2).¹⁶ Multivariate analysis combining patients with IMC and those with B-CLL/SLL showed an important correlation between Kiel histologic subtype (IMC v B-CLL/SLL) and survival, with the B-CLL/SLL patients having a better overall survival than those with IMC (hazard ratio, 1.62; 95% confidence interval, 1.10 to 2.37; P = .01). When the same model was applied to just patients diagnosed using lymph node biopsy (again, both IMC and B-CLL/SLL), the correlation persisted (hazard ratio, 1.97; 95% confidence interval, 1.15 to 3.39; P = .01). However, when a multivariate analysis for overall survival was conducted comparing the three different IMC subgroups with the B-CLL/SLL group, the correlation between Kiel histologic subtype and survival only held for the polymorphous group (hazard ratio, 6.11; 95% confidence interval, 2.64 to 14.15; P < .001). For the lymphoplasmacytoid group (the majority), the correlation was of borderline significance (hazard ratio, 1.47; 95% confidence interval, 0.99 to 2.18; P = .06); for the lymphoplasmacytic group, it was not statistically significant (hazard ratio, 1.62; 95% confidence interval, 0.82 to 3.22; P = .17). Figure 3 shows survival of patients with B-CLL/SLL in comparison with that of patients with the three different subtypes of IMC.

View larger version (21K): [in this window] [in a new window]   Fig 3. Survival of patients with B-CLL/SLL in comparison with that of patients with the three subtypes of IMC.

Histologic Transformation
Repeat biopsy was performed in 75 patients either at first (n = 47) or subsequent recurrence (n = 28). Eleven patients showed evidence of transformation to a histologic picture similar to that of diffuse large B-cell lymphoma (eight of 47 patients at first and three of 27 at second recurrence). The median survival from the time of transformation was only 1 year (Fig 4).

View larger version (10K): [in this window] [in a new window]   Fig 4. Survival from transformation.

Outcome of Patients Who Received Cyclophosphamide + Total Body Irradiation + Autologous Bone Marrow Transplantation
Two of the four patients who received myeloablative therapy (in second or subsequent remission) were still in remission 2 and 8 years after treatment. The other two died of recurrent lymphoma 5 months and 3.5 years after myeloablative therapy.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
These results confirm that lymphoplasmacytoid lymphoma, as defined in the Kiel classification, is usually disseminated at presentation, occurs predominantly in a middle-aged to elderly population, and is almost invariably fatal over a period of years, during which time there is likely to be repeated but incomplete responsiveness to cytotoxic chemotherapy.^18-21 Patients with WM had the same prognosis as those who did not have an IgM paraprotein.

The patients with IMC whose disease transformed to a histologic pattern similar to that of diffuse large B-cell lymphoma had a much worse prognosis, with a shorter survival time after disease transformation. No risk factors or special characteristics were identified in this study in relation to histologic transformation; however, there was a trend for transformation to occur early in the disease, with transformation at first recurrence in eight of 11 patients. On a number of occasions, transformation was clinically suspected before rebiopsy. The incidence of transformation was relatively low (11 of 46 patients, or 24%), but its implications highlight the importance of rebiopsy at the time of each recurrence or progression during treatment.

Comparison of the overall survival for the whole group of patients with that of the SLL/B-CLL group over the same period showed a significant survival advantage for the latter, arguing in favor of retaining the latter group as a separate entity. When only patients in whom the diagnosis was made on the basis of a lymph node biopsy were considered, the survival advantage still held true. Closer examination, however, indicates that this difference is accounted for by a highly significant difference between SLL/B-CLL and the polymorphous subtype of IMC, a very small group, and only a trend toward significance (P = .06) between SLL/B-CLL and lymphoplasmacytoid lymphoma (a large group) and no difference between SLL/B-CLL and the lymphoplasmacytic subtype (a modest size group). Hence, the recommendation that lymphoplasmacytoid lymphoma (the most common type), as defined above, become a variant of SLL/B-CLL is quite justifiable. However, its biologic features and a difference in survival which almost achieves statistical significance should not allow it to disappear altogether as a separate diagnosis. Indeed, on the basis of the survival data presented, it could be argued that the same applies to the lymphoplasmacytic subtype. Inclusion of this subtype as a variant of SLL/B-CLL should be resisted in light of the pathologic differences that put lymphoplasmacytic lymphoma far enough away in the spectrum of lymphocytic-plasmacytic lymphomas to warrant independent status. The real relevance of the definition of the pleomorphic subtype, which is very small, remains unclear, as it is possible that the diagnosis represents "de novo" transformation.

Overall, therefore, these results support the proposed reclassification of this B lymphoid malignancy. It is up to physicians to translate pathologic advances into therapeutic advantages. Conventional treatment for this illness is clearly unsatisfactory. New approaches, such as fludarabine-containing combinations,^20,21 the chimeric antibody anti-CD20,²² and radioimmunotherapy using ¹³¹I anti-CD20,²³ are currently being investigated in the hope of improving the survival of patients with this relatively uncommon, but important, subgroup of non-Hodgkin's lymphoma.

	ACKNOWLEDGMENTS

 
We acknowledge the contribution of the medical and nursing staff at St Bartholomew's Hospital, together with the staff of the Department of Radiology. We thank Chris Sykes for typing the manuscript.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted December 8, 1998; accepted April 23, 1999.

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