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Understanding the diagnosis: CLL and SLL are one disease, but the label and the node findings matter

3.1 CLL, SLL and MBL under WHO-HAEM5, ICC 2022 and the Swedish guideline

Two classifications are in use at the same time: the WHO 5th edition (WHO-HAEM5) and the International Consensus Classification (ICC), both from 2022. They share the same core criteria for CLL/SLL (Karube 2025, abstract only; Falini 2023). The Swedish guideline cites both and does not say which one governs (VP8.2 §7.1) [E].

Entity Clonal CLL-type B cells in blood Other defining features Sources
CLL ≥5×10⁹/L; iwCLL requires this to be sustained for ≥3 months. Sweden stresses that the clonal B-cell count counts, not total lymphocytes Any count is enough if a cytopenia is caused by typical marrow infiltration iwCLL 2018; VP8.2 §7.1
SLL <5×10⁹/L Lymphadenopathy and/or splenomegaly; typical histology and phenotype; no marrow-failure cytopenia. About 5% of cases. Staged by the Lugano system but risk-assessed and treated by CLL rules VP8.2 §7.3; EHA 2026
MBL (monoclonal B-cell lymphocytosis) <5×10⁹/L No lymphadenopathy, organomegaly, cytopenia or symptoms; stable ≥3 months (Sweden). Low-count MBL (<0.5×10⁹/L) needs no follow-up; higher counts progress at about 1–2% a year. MBL is not reported as cancer in Sweden VP8.2 §7.4; WHO-HAEM5
Tissue-based MBL (ICC only) Usually MBL range CLL-type infiltrate without proliferation centres in someone without significant lymphadenopathy ICC 2022
Prolymphocytic progression (WHO-HAEM5) — >15% prolymphocytes in blood or marrow; worse prognosis; German guidance requires mantle cell lymphoma to be excluded by FISH WHO-HAEM5; S3 v2.0

The two classifications differ in four ways:

  • B-cell prolymphocytic leukaemia: WHO-HAEM5 abolished it; the ICC keeps it as a diagnosis of exclusion.
  • MBL subtypes: they are named differently.
  • Tissue MBL: only the ICC recognises it.
  • Wording on testing: WHO-HAEM5 calls FISH, TP53, IGHV and stereotyped subset #2 "essential for full prognostic evaluation". The ICC says IGHV and TP53/17p "need to be evaluated at the time when patients require treatment" (WHO-HAEM5; ICC 2022).

[I] For CLL/SLL itself these differences are mostly about names and rarely change management.

3.2 Why "KLL found in excised nodes" may mean SLL or CLL with nodal involvement

Sweden diagnoses CLL mainly on blood. It needs histopathology only to diagnose SLL (VP8.2 §7.1, §7.3). iwCLL says a node biopsy "is generally not required, unless … the diagnosis is difficult" or Richter transformation is suspected. German guidance reserves node excision for an unclassifiable immunophenotype or suspected transformation (iwCLL 2018; Onkopedia CLL) [E].

[I] J's excisions therefore happened for one of two reasons, and he should ask which:

  • Enlarged nodes were the first sign. The SVF counts a node of at least 1.5 cm with no other explanation as well-founded suspicion (SVF v3.3).
  • Something needed clarifying.

Whether the label is CLL or SLL depends entirely on the clonal B-cell count in his blood, which we do not know. Nobody should assume either. A rarer third possibility under the ICC is tissue-based MBL. In a small retrospective series of 36 patients with CLL-type cells in tissue but <5×10⁹/L in blood, progression or treatment was predicted by nodes ≥1.5 cm on imaging (P=0.01) and by proliferation centres in the biopsy (P=0.004). The size of the excised node did not predict it (Gibson 2011, abstract only).

The label changes nothing about treatment rules (EHA 2026), but it still matters in three practical ways:

  • Registry: since 1 January 2025, SLL has been recorded in the national KLL registry (KLL registry report 2025, p. 15). VP8.2 still says SLL goes to the lymphoma registry. The registry report is the newer source.
  • Trial eligibility differs (section 17).
  • Pathway: a lymphoma clinic may have run his work-up (section 15).

3.3 Immunophenotype: what flow cytometry and stains should show

Flow-cytometry markers. The ERIC/ESCCA harmonisation set the "required" diagnostic markers as CD19, CD5, CD20, CD23, κ and λ. Its "recommended" markers are CD43, CD79b, CD81, CD200, CD10 and ROR1 (Rawstron 2018). Sweden mandates CD5, CD19, CD20, CD23, κ and λ, and recommends CD10, CD43, CD79b, CD81 and CD200 (VP8.2 §7.1) [E].

The typical CLL cell in Sweden's description is:

  • positive for CD5, CD19, CD23 and CD200;
  • negative for CD10;
  • weakly positive for CD20 and CD22 (or CD79b);
  • weakly positive for surface κ or λ (one light chain only).

Scoring. Scores differ in specificity. A score that includes CD200 kept about the same sensitivity as the older Matutes score (97.1% vs 98.6%) but was far more specific (87.2% vs 53.8%) (Köhnke 2017, abstract only).

Tissue stains:

  • LEF1: in one series, nuclear LEF1 was positive in all 92 CLL/SLL cases and negative in all 53 mantle cell lymphomas (Tandon 2011, abstract only).
  • Cyclin D1 is a known pitfall. In about 20% of CLL/SLL biopsies, cyclin D1 appears in the proliferation centres, with negative SOX11 and no CCND1 rearrangement. This finding "should not lead to the diagnosis of focal mantle cell lymphoma" (Gradowski 2012, abstract only).
  • Swedish requirement: SOX11 and cyclin D1 staining, or t(11;14) FISH, when a case is negative for both CD23 and CD200 (VP8.2 §7.2).

3.4 When expert haematopathology review is warranted

Studies of lymphoma biopsies in general (no CLL-specific study was found) show that expert review changes the diagnosis in a meaningful minority of cases.

Study Setting Diagnosis changed Effect on management
Laurent 2017 French national real-time review, 42,145 samples 19.7% overall (37.8% if sent as a provisional diagnosis, 3.7% if sent as a formal one) 17.4%; 12.3% of discrepancies were among small B-cell lymphoma types
Matasar 2012 US cancer centre referrals 16–18% major revision Authors: expert review "should be considered the standard of care"
Proctor 2011 UK regional network 27.3% (falling from 32% to 13% over 6 years) Major management change 2.1%; treatment delay avoided 9.3%
Bowen 2014 US academic centre referrals 14.8% major 12.9% would have changed therapy; more discrepancies in excisional biopsies (17.9% vs 9.6%) and from non-academic referrers (15.8% vs 8.5%)
LaCasce 2008 NCCN centres, five common B-cell lymphomas 6% About one patient in 20 could have had treatment altered

All five sources were read as abstracts only.

What guidance says. UK guidance (NICE NG47) requires specialist integrated review of every new haematological cancer diagnosis (NICE NG47). Sweden is less prescriptive:

  • CLL multidisciplinary conferences are "sällan nödvändiga" (rarely necessary), and a conference with a haematopathologist is "av värde" when there is doubt (VP8.2 ch. 9).
  • Every unit treating CLL must be able to hold such a conference (VP8.2 ch. 21) [E].

[I] A review is most likely to change an excision-based CLL/SLL diagnosis when:

  • the phenotype is atypical (CD23-negative, CD5-negative, or bright CD20 or surface immunoglobulin);
  • cyclin D1 or SOX11 staining is ambiguous;
  • proliferation centres are expanded or Ki-67 is high;
  • large cells or Hodgkin-like cells are present;
  • no integrated blood flow cytometry was done.

3.5 Findings that should raise concern for Richter transformation or another lymphoma

Three histological pictures carry very different meanings (Giné 2010, abstract only; ICC 2022; EHA 2026).

Accelerated CLL is defined by any of:

  • proliferation centres broader than a 20× microscope field;
  • more than 2.4 mitoses per proliferation centre;
  • Ki-67 above 40% per proliferation centre.

In the original series, from before targeted therapy, median survival from biopsy was 76 months for typical CLL, 34 months for accelerated CLL and 4.3 months for DLBCL transformation. Two 2025 series report a median overall survival of about 6 years in accelerated CLL (Vadasz 2025; Sośnia 2025; both abstract only). In the first of these, TP53 mutations were found in 55% of accelerated cases vs 11.5% of conventional ones. EHA says accelerated CLL "should be treated as CLL".

DLBCL-type Richter transformation requires sheets of large cells; expanded proliferation centres alone are not enough. Hodgkin-type transformation shows Hodgkin/Reed-Sternberg cells, which were EBV-positive in 71% of one series (Xiao 2016, abstract only).

Prolymphocytes:

  • 10% or more in blood suggests more aggressive CLL (iwCLL);
  • more than 15% defines prolymphocytic progression (WHO-HAEM5).

Clinical signs. Sweden says transformation should be suspected with rapidly growing nodes at one or more sites, pronounced general symptoms, and/or a marked LD (lactate dehydrogenase) rise (VP8.2 §17.2) [E].

None of this is known for J. The point is that his report should explicitly exclude these features.

3.6 Should the slides and blocks be reviewed at an academic centre?

[I] Yes, if it has not already happened. It is a low-cost request.

  • Where review happens in Skåne. Region Skåne runs pathology in Lund, Malmö, Helsingborg and Kristianstad, and concentrates genetics and molecular diagnostics in Lund (AnalysPortalen, archived copy). Lund's haematopathologists form the regional academic reference. Mats Ehinger and Anna Porwit both have 2026 Lund affiliations; their current diagnostic workload was not verified.
  • If the second opinion goes to Karolinska or Uppsala, the receiving pathology department can request the material.
  • Who can receive the tissue. Under Biobankslagen, tissue can be made available only to legal persons, not handed to the patient. It can be sent for a specified action such as a review, within Sweden or abroad, under an agreement that it is returned or destroyed. The biobank's responsible person decides, and the applicant can ask for reconsideration (Biobankslag 5 kap.) [E].
  • Do not withdraw consent. Withdrawal forces destruction of the tissue. A patient who wants to limit research use should register a restriction instead (4 kap. 14 §).
  • What the reviewer needs. A reviewing pathologist needs earlier PAD reports, laboratory results and clinical findings (KVAST sampling instruction 2019).

3.7 Pathology checklist: what J should obtain or ask about

[I] This list is built from the criteria cited above; no single document requires every item for CLL.

  1. Final diagnosis, with the classification named (WHO-HAEM5 and/or ICC): CLL, SLL, or a CLL-type infiltrate of uncertain significance.
  2. Blood correlation: the clonal CLL-phenotype B-cell count in blood, and whether any cytopenia reflects marrow infiltration.
  3. Specimens: which nodes were taken, their size, and whether fresh tissue went for flow cytometry and FISH.
  4. Architecture: whether the node is effaced, or the pattern is partial or interfollicular.
  5. Proliferation centres: present or absent; expanded or confluent (wider than a 20× field)?
  6. Ki-67 and mitoses in the proliferation centres, with an explicit statement on whether the criteria for accelerated CLL are met.
  7. Sheets of large B cells: an explicit statement that they are present or absent (DLBCL-type Richter).
  8. Hodgkin/Reed-Sternberg-like cells: present or absent; if present, CD30, CD15 and EBER work-up.
  9. Immunohistochemistry:
  10. CD20 weak; CD5 and CD23 positive; LEF1;
  11. cyclin D1 negative, or positive only in proliferation centres;
  12. SOX11 and CD10 negative;
  13. CD200, if tested.
  14. Flow cytometry: the required and recommended markers, and any atypical features (CD23−, CD5−, bright CD20 or surface immunoglobulin, FMC7+).
  15. Exclusion of other lymphomas:
    • mantle cell lymphoma, by cyclin D1/SOX11 with or without t(11;14) FISH;
    • marginal-zone, lymphoplasmacytic and follicular lymphoma.
  16. Prolymphocyte percentage in blood.
  17. Genetic tests: whether FISH, TP53 and IGHV have been done, are pending, or are deferred until treatment.
  18. Who reported it: a specialist haematopathologist, whether the report is integrated, and whether any tests are pending.
  19. Identifiers: PAD numbers and block identifiers, so a second-opinion pathologist can request the material.