MBL versus SLL

One of the questions that I have been asked is how one distinguishes between MBL and SLL. To recap on the problem, monoclonal B cell lymphocytosis (MBL) is the appearance in the blood of monoclonal B cells with the morphological and immunophenotypic characteristics of CLL cells but at numbers lower than 5 x 10e9 per liter. SLL or small lymphocytic lymphoma is a form of CLL in which the tumor does not appear in the blood but is present in the lymph nodes.

The question to be asked is whether there is a form of SLL that is really equivalent to MBL in that the amount of disease present in the lymph nodes is so small that it should not really be called or treated as a CLL equivalent.

An attempt at an answer has come from Philadelphia and Boston and has been published on line in Haematologica

The 2008 WHO Classification definition of CLL requires ≥5 x 10e9/L peripheral blood monoclonal B-cells with a CLL-phenotype. The 2008 IWCLL paper allows the diagnosis also to be made with lower MBC counts if the patient has cytopenias or symptoms attributable to the CLL. Patients who in the past would have been diagnosed with CLL but who no longer fulfil these new criteria are now classified as MBL with a CLL phenotype. Using highly sensitive flow cytometry techniques, MBL has been identified in up to 12% of adults with normal blood counts. While the vast majority of MBL patients maintain stable counts over time, a small proportion progress to CLL at a rate of approximately 1-2% per year. This figure is very dependent on the height of the B-cell count and the progression rate is very much smaller for those whose B-cell counts can only be detected by the most sensitive flow cytometry tests. Various studies have placed the B-cell thresholds that best predict the risk of progression, treatment-free survival and overall survival at from 1.2x10e9/L to 11x10e9/L.

The IWCLL report states that in CLL lymphocytes typically comprise more than 30% of nucleated cells in the bone marrow trephine of normal celluarity. However, bone marrow examination is not recommended at the time of the diagnosis of CLL, and the guidelines do not specify a level of bone marrow involvement that would discriminate between MBL and CLL. Neither the WHO nor IWCLL provide guidelines defining the minimal level of tissue involvement that would qualify for a diagnosis of SLL.

While palpable lymphadenopathy and/or splenomegaly are considered exclusion criteria for MBL, these criteria are not part of the WHO or IWCLL definitions of SLL and the diagnosis of SLL can therefore be made without regard to the extent of nodal involvement.

The authors have studied the clinicopathologic features of 36 extramedullary tissue biopsies (34 lymph nodes and 2 extranodal sites) containing monoclonal B cells with a CLL phenotype, but with less than 5 x 10e9/L monoclonal B cells in the peripheral blood, in order to determine if a subset of these cases might represent a more indolent disorder than SLL (i.e. a tissue equivalent of MBL).

In 16 patients, the tissue was biopsied for reasons other than to evaluate palpable lymphadenopathy. These tissues included 9 lymph nodes removed during staging for carcinoma or melanoma, 4 removed during surgery for benign diseases, and 1 removed when lymphadenopathy was detected on imaging studies performed to evaluate another process, as well as 2 extranodal tissue biopsies (one nasal biopsy in a patient with nasal obstruction without a mass and one breast biopsy performed to evaluate breast calcification without a mass). After the tissue diagnosis was made the doctors went on to find palpable lymphadenopathy on physical examination in 8 of these 16 patients. Twenty other patients underwent lymph node biopsies because they had disease that could be felt. It was localized in 14 cases and more extensive in 6 cases.

On CT scanning lymph nodes enlarged to >1 cm were detected in 32/36 (90%) patients and involved 3 or more lymph node regions in 22/36 patients (61%). In comparison, only 2/10 (20%) clinical MBL patients diagnosed on peripheral blood flow cytometry had any enlarged lymph nodes detected on CT scans. Combining physical exam and CT studies, 34/36 patients (94%) had detectable lymphadenopathy. Three patients had splenomegaly, while hepatomegaly was not identified in any patients. Bone marrow involvement was identified in 10/10 patients who underwent a bone marrow biopsy. The extent of bone marrow involvement varied from less than 5% to over 50% (median 30%) of the biopsy cellularity.

Among the 28 patients with palpable lymphadenopathy, 23 were Rai Stage I, 2 were Stage II, and 3 were Stage III (5 patients were anemic with hemoglobin <11 gm/dL, but in two cases the anemia was attributable to causes other than CLL/SLL). Twenty-five patients were Binet stage A and 3 patients Binet stage B. Rai and Binet staging was not applicable in the 8 patients lacking palpable lymphadenopathy. Among these 8 (22%) patients, all 4 examined by PB flow cytometry would have been classified as clinical MBL according to IWCLL (because lymphadenopathy or splenomegaly were absent or only detectable on imaging studies), while flow cytometry was not performed in the other 4 patients.

Thus the patients studied would mainly have been diagnosed as SLL rather than MBL, though a fifth would probably have been called MBL.

Five patients were treated for CLL/SLL. These included 2 patients treated within one month of diagnosis due to symptomatic disease (progressive myopathy attributed to CLL cell infiltration in one patient and bulky lymphadenopathy in the other) and 3 patients treated for disease progression at 5, 19, and 19 months following diagnosis. After a median follow up time of 26 months, an additional 7 patients developed progression (new or increasing lymphadenopathy on physical exam and/or CT studies) but were not treated during the follow-up period. The median time to lymph node progression in these 7 patients and the 3 patients treated for progression was 22 months (range 4 – 53 months). At last follow-up, 24 patients had no evidence of progressive lymphadenopathy and remained untreated. No patients died due to CLL/SLL.

Over the follow-up period, the peripheral blood ALC remained <5.0x109/L in 25/36 patients (69%), all of whom had CBC results available at the latest follow up. Eight of the remaining 11 patients at least doubled their ALC at a median of 27 months after diagnosis (range 3-104 months).

The following indicators showed no association with progression/treatment: age; sex; Rai or Binet stage; number of involved lymph node sites; palpable lymphadenopathy on physical exam; splenomegaly; or IPI score. There was no association between any hematologic measurements, including ALC and absolute monoclonal B cell count at diagnosis, and progression/treatment. There were no statistically significant differences in the size of the biopsied lymph node, nor were maximal lymph node diameters of greater than 1 cm, 1.5 cm, or 3 cm associated with progression or treatment. However, detection of any lymph node ≥ 1.5 cm in diameter on CT staging studies was associated with progression/treatment and the largest lymph node size measured on CT at diagnosis was greater in patients who subsequently experienced progression or were treated. The degree of histological or flow cytometric involvement of the biopsied tissue by CLL/SLL was not associated with progression/treatment.

The only histological parameter that was associated with rogression/treatment was the presence of proliferation centers, which were found in all 12 patients who progressed or required therapy but in only 9/18 (50%) of patients who did not progress. There was no significant difference in CD38 or ZAP-70 expression between those who did or did not progress or require therapy.

So, what they are saying is that there is less likely to be progression in SLL if there is no lymphadenopathy on CT scanning and there are no proliferation centers in the lymph node biopsy. Though, of course, CT scanning is not recommended. One recent study found that CT-detected abdominal lymphadenopathy in Rai Stage 0 CLL predicted
progression and earlier treatment requirement, so perhaps this question will have to be revisited in the future. Exactly who should have an abdominal CT scan. The authors suggest that CT staging of patients with CLL/SLL cells identified
in tissue biopsies may help in identifying patients more likely to progress. Rossi and colleagues identified 19 patients (15%) with clinical MBL who progressed to SLL after a median of 42.7 months (Br J Haematol. 2009;146:64-75).