Diffuse large B‐cell lymphoma primary of lung

Abstract

Primary lung lymphoma (PLL) and diffuse large B‐cell lymphoma (DLBCL) is a rare entity and the biological features, clinical presentation, prognosis markers and treatment have not been well defined. We present 82 cases of PLL‐DLBCL in a uniform population and treated with conventional chemotherapy: CHOP (cyclophosphamide, doxorubicin vincristine and prednisone). To the best of our knowledge, this is the largest series with long term follow reported. We also performed immunohistochemical studies to determine if the cell of origin [germinal center (GC) and non‐GC] have a prognostic significance. All patients were at an early stage and low‐clinical risk without bulk disease and normal levels of lactic dehydrogenase and beta 2 microglobulin. Complete response was achieved in 77 cases (94%), actuarial curves at 10 years showed that event‐free survival (EFS) was 90% and overall survival was 92%. Fifty‐nine patients were of GC phenotype and 23 of non‐GC phenotype. Complete response (93% versus 91%), EFS (91% versus 80%) and overall survival (89% versus 78%) respectively, were not statistically different. Treatment was well tolerated, and second late events have not been seen. We conclude that PLL‐DLBCL is an extranodal lymphoma with a good prognosis event in patients of non‐GC phenotype.

Keywords:

• Malignant lymphoma
• Lung lymphoma
• Immunohistochemistry
• Prognostic factors

Introduction

Primary lymphoma of lung (PLL) is a rare neoplastic disorder, comprising of 4–11% of extranodal lymphomas and less than 1% of all malignant lymphomas.1 The most common histology is mucosa‐associated lymphoid tissue (MALT) that constitutes about 90%. Diffuse large B‐cell lymphoma (DLBCL) is less frequent and generally has been associated with human immunodeficiency virus, but PLL‐DLBCL has been identified in non‐immunosuppresed patients and does not show any clinical difference to the clinical presentation in the immunosuppressed setting.2^–6 PLL‐DLBCL is defined as a lymphoma that is confined to the lung, with or without regional nodal involvement, but without evidence of concurrent systemic involvement. PLL‐DLBCL has a morphological homogeneity, and has a relatively favorable outcome, when it presents in early stage.1

Recently, the insight into the B‐cell development and lymphoma pathogenesis has increased substantially, due to the increasing availability of well‐defined genetic markers. These include the expression of BCL‐6 and CD10 protein which are considered to germinal center (GC) markers, and MUM1 which denotes the final step of intra‐GC B‐cell differentiation studies in gene expression profile has led to the concept that most DLBCL derive from the GC B cells or from their descendents, i.e. activated B cells or non‐GC B cells.7,8

Genotypic studies in extranodal lymphomas are rare, even though the incidence of extranodal lymphoma has increased over the last 20 years and results have been inconclusive, because some lymphomas (central nervous system, testicular, breast) showed both GC and non‐GC B‐cell phenotype, which has been associated to the worst prognosis9^–11 and others, gastro‐intestinal, bone, oral and nodal12^–15 did no show any difference whether they were of GC or non‐GC phenotype.

PLL‐DLBCL has been reported only in case reports or control series; thus, clinical course, treatment and prognosis have not been clearly delineated. Immunohistochemical have not been reported either. In the current study, immunohistochemical staining for BCL‐6, CD10 and MUM1 was performed in 82 patients with PLL‐DLBCL to define the possible cell of origin of these lymphomas as well their prognostic significance.

Patients and Methods

The database of malignant lymphomas in our institution, a national tertiary center, was reviewed. Data from patients with the diagnosis of PLL‐DLBCL between 1991 and 2006, were considered if they have confirmed pathology of DLBCL, according to the World Health Organization, and have a B‐cell histology according to immunophenotype: CD20⁺, CD26⁺, CD45⁻, CD52⁻, CD3⁻ and CD5⁻. All cases selected were clinicopathologically confirmed by two pathologists.

Of the originally identified group of 208 cases, 126 were excluded because of different diagnosis after review of the histopathological slides: 116 were MALT lymphoma, 6 were T‐cell lymphoma, and 4 were lung cancer. Thus, 82 cases were available for the present study. Clinical studies were available in all cases: complete blood counts, serum chemistry, serum determinations of lactic dehidrogenase and beta 2 microglobulin; viral studies: human immunodeficiency virus, hepatitis B and C, and cytomegalovirus. Computed tomography of thorax, abdomen and pelvis, aspirate and biopsy of bone marrow and additional studies were performed when necessary. In all cases, it was possible to classify the clinical risk, according to the International Prognostic Index. Treatment: all patients were treated with combined chemotherapy: CHOP (cyclophosphamide 750 mg/m², intravenous, day 1; vincristine 1·4 mg/m², intravenous, day 1; doxorubicin 50 mg/m², intravenous, day 1 and prednisone 60 mg/m², oral, days 1 to 5; each cycle was administered every 21 days, by 6 cycles, and at the end of the treatment patients were carefully restaged. No additional treatment was considered. Response to treatment was according to international criteria.16 Clinical follow‐up was assessed in all cases. Median follow‐up was 9·3 years (range 3·9–14·8 years).

Immunohistochemical staining was performed on 4‐μm sections of formalin‐fixed, paraffin‐embedded tissues, using staining procedures as detailed elsewhere with a set of markers relevant to GC/non‐GC phenotype: BCL‐6 (type mouse; Dako, Carpinteria, CA, USA), CD10 (mouse; Neomarkers Fremont, CA, USA), and MUM1 (mouse; Dako). To be considered positive, the malignant cells had to be >50%. Applying the Hans algorithm,17 GC was defined as CD10⁺BCL‐6⁺ and non‐GC phenotype as CD10⁻BCL‐6⁻. In the case of CD10⁻BCL‐6⁺, MUM 1 expression was determined. If MUM 1 was negative, the phenotype was defined as GC, whereas if MUM 1 expression was positive, the case was defined as non‐GC. No phenotype was considered as undetermined.

Overall survival was calculated from the date of diagnosis until death (from any cause). Multivariate Cox method was employed to assess the significance of the parameters analyzed: age, gender, International Prognostic Index (IPI) tumor size, GC or non‐GC phenotype.

This study was approved by the Scientific and Ethical Committee of our Institution. As it was a retrospective analysis, it was considered that patients did not have to provide signed informed consents.

Results

All patients presented with cough or chest pain. No B symptoms were present. Table 1 shows the main clinical and laboratory characteristics. Median age was 61·3 years, early stages II to IV were not found; tumor mass between 5 and 10 cm was the most frequent. No high clinical risk patients according to the IPI were found.

Table 1. Clinical and laboratory characteristics

	No.
Number	82
Age (years)
Range	38–83
Median	61·3
Sex
Male	40
Female	42
Stage
I E	70
II E	12
Tumor size
<5 cm	7
5–10 cm	69
>10 cm	6
IPI
Low	63
Low–intermediate	19
Lactic dehidrogenase (>2 N)	0
Beta 2 microglobulin (>2 N)	0
Smoking history	43
Germinal center cell	59
Non‐germinal center cell	23

Complete response was assessed in 77 cases [94%, 95% confidence interval (CI): 89–99%]. Five cases relapsed between 2·1 and 3·4 years, and a second complete response was achieved in four cases, with conventional salvage chemotherapy. Thus, actuarial curves extend to 10 years, and event‐free survival was 96% (95% CI: 87–99%). Six patients died secondary to tumor progression, actuarial curves at 10 years being 92% (95% CI: 81–97%). Toxicity secondary to chemotherapy was granulocytopenia grade III in 24 cycles (5%), and thrombocytopenia grade II in 2 cycles (<1%). Infection related treatment, most pneumonias, were observed in five patients (6%). No death related to treatment has been observed. No late events, including cardiac toxicity or second malignancy have yet been reported.

Fifty‐nine cases were considered as GC and 23 as non‐GC B‐cell phenotype. Table 2 shows the response type according to the phenotype; no differences were observed in complete response rate, event‐free survival and overall survival.

Table 2. Response type and outcome according to the cell of origin

	No.	CR	Failure	EFS (%)	OS (%)
GC	59	55 (93)	4 (7)	94	89
Non‐GC	23	21 (91)	2 (8)	80	78

Note: CR: complete response; EFS: event‐free survival; OS: overall survival; GC: germinal center.

Univariate analysis did not show any statistical differences in response rate and outcome.

Discussion

PLL is a rare presentation of DLBCL, because most patients present as MALT lymphoma. PLL‐DLBCL has been associated with immunosuppression; however, in some series non‐immunosuppressed patients have been reported. Taking into consideration the low number of cases, it is very difficult to draw definitive conclusions in relation to clinical features and treatment. Recently, the immunohistochemical studies have been considered as necessary in the diagnosis of extranodal lymphoma, to decide the best treatment; however, results are contradictories because in some cases (central nervous system, breast, testicular),9^–11 non‐GC phenotype has been considered as indicating a worse prognosis, but in gastrointestinal, oral, bone and nodal,12^–15 non‐GC phenotype did not show any prognostic significance.

Our study of PPL‐DLBCL, to the best of our knowledge, includes the largest number of patients and also includes the determination of immunophenotype. The patients display homogenous clinical features and low clinical risks according to the IPI. Complete response was achieved in 77 patients (94%). Only five patients have relapsed, and four achieved a second and longer complete remission. Four of the five patients that relapse were of GC phenotype.

In our study, we could not demonstrate a statistical significant influence on prognosis of tumor phenotype, nor did we find a significant effect on prognosis by the individual immunohistochemical markers. We speculate that PLL‐DLBCL may have a different biological behavior to other extranodal lymphomas; thus, response to chemotherapy is excellent with >90% achieving a complete response with conventional chemotherapy. Again at relapse the tumor continues to be sensitive to chemotherapy with four of five (80%) achieving the second response, better than that of other extranodal lymphomas. Patients with PLL‐DLCBL have a strong homogeneity: with low clinical risks, early stage, no bulky tumor mass, normal lactic dehidrogenase and beta 2 microglobulin. Patients with nodal lymphoma and the same clinical features also have an excellent outcome. It appears that extranodal lymphomas have a specific homing factors, and PLL‐DLBCL has different homing to other extranodal lymphomas. We believe it is mandatory in the study of a homogenous group of extranodal lymphomas, to determine if immunohistochemical markers are useful in the design of treatment.

In conclusion, PLL‐DLBCL has a favorable prognosis, independently of the phenotype.

Conflict of Interest Statement

All authors do not disclose any financial and personal relationship with other people or organizations, which could innapropiately influence (bias) their work.

The work was performed with the support of the Mexican Institute of Social Security.