Updated WHO Classification of Hematologic Malignancies

Answers to Hematology Expert Review Questions


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Question 1: Which statement about the classification of tumors of hematopoietic and lymphoid tissues is true?

Correct Answer: A. The revised WHO classification defines distant disease entities that can be reliably diagnosed using proposed criteria.

Expert Perspective

WHO last updated its classification of tumors of hematopoietic and lymphoid tissues with a fourth edition of its WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, in 2008.1 This year, WHO is updating that edition with new data from the past 8 years that will have important diagnostic, prognostic, and therapeutic implications.2

The revised WHO classification, as reviewed in a recent issue of Blood,3,4 adopts a multiparameter approach to defining diseases that uses all available pathologic, genetic, and clinical information. In addition, the classification relies on consensus in areas of uncertainties among experts (hematopathologists, hematologists, and geneticists) on the definition and nomenclature of hematologic malignancies.

Question 2: Which statement about the 2016 revised WHO classification of myeloid neoplasms and acute leukemia is correct?

Correct Answer: B. A section about germline predisposition to myeloid neoplasms has been added to the revised WHO classification.

Expert Perspective

Atypical chronic myeloid leukemia (CML), a rare subtype of myelodysplastic syndromes/myeloproliferative neoplasms, is now better characterized molecularly and can be more easily separated from chronic neutrophilic leukemia, a rare subtype of myeloproliferative neoplasms similarly characterized by neutrophilia. CSF3R mutations appear to be very rare in atypical CML (< 10%) but are strongly associated with chronic neutrophilic leukemia.5 A major change to the 2016 revision of the classification of myeloid malignancies is the addition of a section on myeloid neoplasms with germline predisposition, including those with germline mutation in CEBPA, DDX41, RUNX1, ANKRD26, ETV6, or GATA.

In the revised classification of myelodysplastic syndromes, a diagnosis of refractory anemia with ring sideroblasts can be made if ring sideroblasts comprise as few as 5% of nucleated erythroid cells in the presence of SF3B1 mutation. In addition, in patients with isolated del(5q) myelodysplastic syndromes, the prognostic and predictive significance of the TP53 mutation is added. Now, mutation analysis of TP53 is recommended to help identify an adverse prognostic subgroup in patients with del(5q) myelodysplastic syndromes.6

Question 3: Which statement about the 2016 revision of the WHO classification of lymphoid neoplasms specific for monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) is correct?

Correct Answer: C. The revised WHO classification added “proliferation centers” as a significant and independent adverse prognostic indicator in CLL/SLL.

Expert Perspective

The new revision eliminates the option of diagnosing CLL with < 5 × 109/L peripheral blood CLL cells in the absence of extramedullary disease, even if there are cytopenias or disease-related symptoms.4 The updated WHO classification will retain the current criteria for monoclonal B-cell lymphocytosis but will emphasize that “low-count” monoclonal B-cell lymphocytosis, defined as peripheral blood CLL count < 0.5 × 109/L, must be distinguished from “high-count” monoclonal B-cell lymphocytosis.7 This is because low-count monoclonal B-cell lymphocytosis is significantly different from CLL, has an extremely limited (if any) chance of progression, and, until new evidence is provided, requires no follow-up outside of standard medical care.8,9

In contrast, high-count monoclonal B-cell lymphocytosis requires routine/yearly follow-up and has phenotypic and genetic/molecular features that are very similar to Rai stage 0 CLL. Nevertheless, immunoglobulin heavy chain variable region (IGHV)-mutated cases are more frequent in monoclonal B-cell lymphocytosis.10

Histologic criteria for proliferation centers include lymph nodes with either proliferation centers broader than a 20× high-powered field or an increased proliferation rate within the proliferation centers as assessed by a mitotic count greater than 2.4 per proliferation center and/or a Ki67 index greater than 40% per proliferation center.10

Question 4: Which statement about the 2016 revision of the World Health Organization classification of lymphoid neoplasms is correct?

Answer: B. BRAF V600E mutations are found in almost all cases of hairy cell leukemia.

Expert Perspective

Classical mantle cell lymphoma is usually composed of IGHV-unmutated or minimally mutated B cells that usually are SOX11-positive and typically involve lymph nodes and other extranodal sites.11 Other mantle cell lymphomas develop from IGHV-mutated SOX11-negative B cells, which leads to leukemic non-nodal mantle cell lymphoma, usually involving the peripheral blood, bone marrow, and often the spleen. These cases are frequently clinically indolent; however, secondary abnormalities, often involving TP53, may occur and lead to very aggressive disease.

BRAF V600E mutations are found in almost all cases of hairy cell leukemia but not in hairy cell leukemia–variant or other small B-cell lymphoid neoplasms.12 About 90% of lymphoplasmacytic lymphomas or Waldenström macroglobulinemias have MYD88 L265P mutations and, therefore, are not specific for these diagnoses.13

Disclosure: Dr. Abutalib reported no potential conflicts of interest.

References

1. Swerdlow SH, Campo E, Harris NL, et al (eds): WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: International Agency for Research on Cancer, 2008.

2. Swerdlow SH, et al (eds): WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, in World Health Organization Classification of Tumours. Lyon, France: International Agency for Research on Cancer. In press.

3. Arber DA, Orazi A, Hasserjian R, et al: The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 127:2391-2405, 2016.

4. Swerdlow SH, Campo E, Pileri SA, et al: The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 127:2375-2390, 2016; published ahead of print March 15, 2016.

5. Maxson JE, Gotlib J, Pollyea DA, et al: Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML. N Engl J Med 368:1781-1790, 2013.

6. Jädersten M, Saft L, Smith A, et al: TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict disease progression. J Clin Oncol 29:1971-1979, 2011.

7. Rawstron AC, Shanafelt T, Lanasa MC, et al: Different biology and clinical outcome according to the absolute numbers of clonal B-cells in monoclonal B-cell lymphocytosis (MBL). Cytometry B Clin Cytom 78(suppl 1):S19-S23, 2010.

8. Vardi A, Dagklis A, Scarfò L, et al: Immunogenetics shows that not all MBL are equal: The larger the clone, the more similar to CLL. Blood 121:4521-4528, 2013.

9. Morabito F, Mosca L, Cutrona G, et al: Clinical monoclonal B lymphocytosis versus Rai 0 chronic lymphocytic leukemia: A comparison of cellular, cytogenetic, molecular, and clinical features. Clin Cancer Res 19:5890-5900, 2013.

10. Giné E, Martinez A, Villamor N, et al: Expanded and highly active proliferation centers identify a histological subtype of chronic lymphocytic leukemia (“accelerated” chronic lymphocytic leukemia) with aggressive clinical behavior. Haematologica 95:1526-1533, 2010.

11. Jares P, Colomer D, Campo E: Molecular pathogenesis of mantle cell lymphoma. J Clin Invest 122:3416-3423, 2012.

12. Tiacci E, Trifonov V, Schiavoni G, et al: BRAF mutations in hairy-cell leukemia. N Engl J Med 364:2305-2315, 2011.

13. Treon SP, Xu L, Yang G, et al: MYD88 L265P somatic mutation in Waldenström’s macroglobulinemia. N Engl J Med 367:826-833, 2012.


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Updated WHO Classification of Hematologic Malignancies

The ASCO Post is pleased to present Hematology Expert Review, an ongoing feature that quizzes readers on issues in hematology. In this installment, Dr. Abutalib tests your knowledge of the 2016 revisions to the World Health Organization (WHO) classification of hematologic malignancies.

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