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Hematopathology, 2nd edition by Jaffe, Arber, Campo, Harris, and Quintanilla-Martinez

Hematologic malignancies by incidence

Lymphoid malignancies

  • 19.3 NHL DLBCL ~ .624*.31 ~19.3%
  • 16.0 Plasma cell disorders (multiple myeloma) ~16%
  • 13.7 NHL Follicular lymphoma ~ .624*.22 ~13.7%
  • 09.0 CLL ~9%
  • 08.2 HL ~8.2%
  • 04.7 NHL MALT lymphoma .624*.076 ~4.7%
  • 04.7 NHL Mature T-cell lymphoma .624*.076 ~4.7%
  • 04.2 NHL Small lymphocytic lymphoma .624*.067 ~4.2%
  • 03.8 ALL ~3.8%
  • 03.7 Mantle cell lymphoma 0.624*.06 ~ 3.7%

Plasma cell dyscrasias

  • Multiple myeloma * 139,000

Lymphomas

  • NHL * 461,000
  • Hodgkin lymphoma * 73,000

Leukemias

  • Other leukemias * 150,000
  • CLL * 105,000
  • AML * 103,000
  • ALL * 76,000
  • CML * 32,000

I. Technical aspects

1. Processing of the lymph node biopsy specimen

  • Instructions for the surgeon

  • Gross processing of the lymph node biopsy by the pathologist

    • Gross examination
    • Frozen sections
    • Cytologic preparations
    • Sectioning
    • Fixation
    • Contribution of the histotechnologist
  • Routine histologic, histochemical, and special stains
  • Choice of ancillary studies
  • Reporting the lymph node biopsy

2. Fine needle aspiration of lymph nodes

3. Collection, processing, and examination of bone marrow specimens

4. Immunohistochemistry for the hematopathology laboratory

5. flow cytometry

6. Molecular diagnosis in hematopathology

7. Important chromosomal aberrations in hematologic neoplasms and key techniques to diagnose them

II. Normal and reactive conditions of hematopoietic tissues

8. Normal lymphoid organs and tissues

9. Reactive lymphadenopathies

  • Follicular and nodular patterns
  • Predominantly sinus pattern

  • Interfollicular or mixed patterns

    • Paracortical hyperplasia and dermatopathic reaction
    • Granulomatous lymphadenitis
    • Immunoglobulin G4-related lymphadenopathy
    • Kimura’s disease
    • Toxoplasmic lymphadenitis
    • Systemic lupus erythematosus

    • Kikuchi’s lymphadenitis (histiocytic necrotizing lymphadenitis)

      • Epidemiology

        • First described in Japan in 1972
        • Predominantly affects young adults
        • Young women of Asian descent are commonly affected

      • Clinical presentation

        • cervical lymphadenopathy
        • sometimes with fever and leukopenia

      • Stages

        • Proliferative stage

          • numerous immunoblasts
          • large mononuclear cells including histiocytes with curved nuclei

          • aggregates of plasmacytoid dendritic cells with interspersed Karyorrhectic bodies

            • necrosis may appear to have begun within these aggregates or nests

        • Necrotizing stage

          • neutrophil-depleted patchy areas of necrosis within the paracortex containing abundant karyrrhectic nuclear debris and surrounded by a mixture of mononuclear cells (as in the proliferative type)
          • karyorrhectic debris is both extracellular and phagocytized by histiocytes

        • Xanthomatous stage

          • foamy histiocytes and fewer immunoblasts
          • necrosis may be absent
          • thought to represent the healing phase

      • Diagnostic criteria

        • Histologic features

          • paracortical clusters of plasmacytoid dendritic cells
          • karyorrhectic bodies
          • crescentic histiocytes
          • immunoblasts scattered among small lymphocytes
          • proliferation of high endothelial venules

        • Immunophenotype

          • CD8+ T cells outnumber CD4+ T cells
          • CD123/68/4/43+ plasmacytoid dendritic cells
          • CD68+ and MPO+ histiocytes
          • rare B cells

      • Differential diagnosis

        • Lupus lymphadenitis

          • Extensive necrosis, hematoxylin bodies, and plasma cells or neutrophils favor SLE
          • Kikuchi’s patients usually lack ANA
        • Non-Hodgkin’s lymphoma
    • Kawasaki’s disease (mucocutaneous lymph node syndrome)
    • Inflammatory pseudotumor
    • Bacillary angiomatosis
  • Diffuse pattern

10. Normal bone marrow

  • Hematopoiesis

    • Erythropoiesis
    • Granulopoiesis
    • Megakaryocytes and thrombopoiesis
    • Other myeloid cells
    • Cytologic abnormalities in myeloid cells in hematologically normal subjects
  • Bone marrow lymphoid cells

  • Other cells present in normal bone marrow

    • Normal bone marrow components
    • Extraneous cells and tissues

  • Cytochemistry and histochemistry

    • Cytochemistry
    • Histochemistry
    • Immunophenotyping including immunohistochemistry
  • Conclusion

11. Evaluation of anemia, leukopenia, and thrombocytopenia

12. Bone marrow findings in inflammatory, infectious, and metabolic disorders

III. Lymphoid neoplasms

13. Principles of classification of lymphoid neoplasms

  • Historical background
  • Early events in lymphoid neoplasia: borderlands of malignancy
  • Small B-cell neoplasms
  • Aggressive B-cell lymphomas and borderline malignancies
  • Peripheral T-cell lymphomas
  • Histiocytic and dendritic cell neoplasms
  • Conclusion

S1. Mature B-cell neoplasms

    1. B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma, Monoclonal B-cell lymphocytosis, and B-cell prolymphocytic leukemia
    1. Lymphoplasmacytic lymphoma and Waldenstrom macroglobulinemia

    • Definition of disease

      • LPL: small B-cell neoplasm composed of lymphocytes, plasma cells, and plasmacytoid lymphocytes, which does not meet criteria for any of the other small B-cell lymphomas that exhibits plasmacytic differentiation
    • Epidemiology and incidence
    • Clinical features

    • Morphology

      • Peripheral blood and bone marrow
      • Lymph nodes
      • Spleen and other tissues
    • Immunophenotype

    • Genetic features

      • MYD88 L265P mutation
      • Other somatic mutations
      • Cytogenetic abnormalities
    • Postulated normal counterpart and pathogenesis
    • Clinical course, treatment and prognosis

    • Differential diagnosis

      • Neoplastic conditions
      • IgM-secreting disorders
      • Other conditions
    1. Hairy cell leukemia
    1. Splenic marginal-zone lymphoma and other small B-cell neoplasms in the spleen
    1. Follicular lymphoma (~13.7% of lymphomas)
    1. Extranodal marginal zone lymphoma: MALT lymphoma
    1. Primary cutaneous B-cell lymphomas
    1. Nodal marginal zone lymphoma
    1. Mantle cell lymphoma
    1. Diffuse large B-cell lymphoma (~19.3% of lymphomas, 414-444)

    • Overview

      • Agressive
      • Curable in a large portion of patients who achieve remission
      • Previously there were two subtypes that were merged due to low intra* and inter-observer reproducibility

    • Definition

      • Diffuse proliferation of large or medium-sized neoplastic B cells with a nuclear size greater than or equal to that of a histiocyte nucleus, or more than twice the size of a small lymphocyte

    • Epidemiology

      • Most common type of NHL (~31%)

      • No clear ethnic bias

        • Appears to be more DLBCL than Follicular lymphoma in Asians
      • Median age is 64 years
      • Slight male predominance 1.2:1

    • Etiology

      • Unclear in most patients

      • Minority occurs in setting of congenital immunodeficiency or acquired immunodeficiency such as HIV, transplant, history of methotrexate treatment for rheumatoid arthritis, fludarabine treatment for low-grade B-cell lymphoma

        • Commonly associated with Epstein-Barr virus (EBC) positivity
      • Angioimmunoblastic T-cell lymphoma
      • Rare extranodal cases association with chronic inflammation or irritation
      • Transformation from underlying low-grade lymphoma

    • Clinical features

      • Rapidly enlarging lymph nodes or tumor masses in extranodal sites

      • Extranodal involvement

        • 71% have extranodal involvement during course of disease
        • 30% present with extranodal involvement
        • Common sites include the GI tract (esp stomach) and Waldeyer’s ring
      • Half with stage I or II (early); III (13%); IV(33%)
      • One-third have B symptoms
      • 16% have bone marrow involvement, which includes cases with concordant and discordant bone marrow histology

    • Morphology

    • Immunophenotype

      • Pan B-cell markers (CD20, CD22, CD79a, PAX5)
      • Positive for surface or cytoplasmic immunoglobulin
      • BCL6+ in about 60%

    • Genetics

      • Clonally rearranged immunoglobulin heavy-chain and light-chain genes (IGH, IGK, and IGL) and germline T-cell receptor genes.
      • Hypermutated IGHV

      • Transformation pathway

        • 20% of cases show t(14; 18)(q32; q21) BCL2 rearrangement, which is considered a hallmark of follicular lymphoma
        • Such cases may have transformed from a known or occult follicular lymphoma

      • De novo pathway

        • 30% show BCL6 3q27 rearrangement, but is also found in some follicular lymphomas

          • Most commonly the translocation partner involves the immunoglobulin genes via t(3;14)(q27; q32)

        • 73% show BCL6 somatic mutation and is unrelated to the presence or absence of BCL6 rearrangement

          • This is a marker for cells that have been through the germinal center and is thereby also observed in

      • Myc 8q24 rearrangement occurs in about 10% of DLBCLs being more common in HIV infected patients, pediatric patients, and extranodal lymphomas

        • 40-60% of cases with Myc rearrangment represent double or triple-hit lymphoma with co-existing BCL2 and/or BCL6 rearrangement and such cases are reclassified as high-grade B-cell lymphoma with BCL2 and/or BCL6 and Myc rearrangement in the 2016 WHO classification
        • Double-hit

    • Molecular subtypes

      • Germinal-center B-cell type
      • Activated B-cell type
    • Postulated cell of origin
    • Clinical course
    • Prognostic factors
    • Differential diagnosis

    • Other lymphomas of large B-cells

      • T-cell/Histiocyte-rich large B-cell lymphoma
      • Primary mediastinal (thymic) large B-cell lymphoma
      • Intravascular large B-cell lymphoma
    1. Burkitt’s lymphoma and its mimics
    1. Plasmablastic neoplasms other than plasma cell myeloma
    1. Plasma cell neoplasms

    • Plasma cell neoplasms

      • Definition

        • Clonal proliferations of Ig-producing plasma cells or lymphocytes that make and secrete a single class of Ig or a polypeptide subunit of a single Ig detectable as a so-called monoclonal protein (M-protein) on serum or urine protein electrophoresis
      • Classification

    • Plasma cell myeloma

      • Definition

        • Bone marrow-based, multifocal plasma cell neoplasm associated with an M-protein in serum or urine. Other organs may be secondarily involved.
      • Diagnostic criteria
      • Epidemiology
      • Etiology and pathogenesis
      • Clinical features
      • Laboratory findings
      • Radiographic studies
      • Blood smear and bone marrow findings
      • Histopathology
      • Plasma cell myeloma clinical variants
      • Non-secretory plasma cell myeloma
      • Smoldering plasma cell myeloma (asymptomatic myeloma)
      • Plasma cell leukemia
      • Immunophenotypic features of normal and neoplastic plasma cells
      • Technical issues
      • Diagnostic issues
      • Unusual morphologic variants of myeloma
      • Florid reactive plasmacytosis
      • Non-Hodgkin’s lymphomas with extreme plasma cell differentiation
      • Prediction of genetic abnormalities
      • Prognostic issues
      • Quantitative issues at diagnosis
      • Minimal residual disease
      • Circulation plasma cells
      • Immunophenotype
      • Genetics
      • Genetic testing for plasma cell myeloma
      • Differential diagnosis
      • Treatment and prognosis

    • Monoclonal gammopathy of undetermined significance

      • Definition
      • Epidemiology and etiology
      • Clinical and laboratory features
      • Blood and bone marrow findings
      • Immunophenotype
      • Genetics
      • Differential diagnosis
      • Clinical course, treatment, and prognostic factors

    • Plasmacytoma

      • Solitary plasmacytoma of bone
      • Extraosseous plasmacytoma

    • Immunoglobulin deposition diseases

      • Primary amyloidosis
      • Systemic light chain and heavy chain deposition diseases

    • Plasma cell neoplasms with associated paraneoplastic syndrome

      • POEMS syndrome (osteosclerotic myeloma)
      • TEMPI syndrome
    1. Nodular lymphocyte–predominant Hodgkin’s
    1. Classical Hodgkin’s lymphoma and related lesions
    1. Virally associated B-cell lymphoproliferative disease

S2. Mature T-cell and NK-cell neoplasms

    1. Virally associated T-cell and NK-cell neoplasms
    1. T-cell and NK-cell large granular lymphocyte proliferations
    1. T-cell prolymphocytic leukemia
    1. Adult T-cell leukemia/lymphoma
    1. Hepatosplenic T-cell lymphoma
    1. Peripheral T-cell lymphoma, not otherwise specified (NOS)
    1. Angioimmunoblastic T-cell lymphoma
    1. Anaplastic large cell lymphoma, ALK positive and ALK negative
    1. Enteropathy-associated T-cell lymphoma and other primary intestinal T-cell lymphomas
    1. Mycosis fungoides and Sezary syndrome
    1. Primary cutaneous CD30-Positive T-cell lymphoproliferative disorders
    1. Primary cutaneous T-cell lymphomas: rare subtypes

S3. Precursor B* and T-cell neoplasms

    1. Precursor B* and T-cell neoplasms

    • 42.1 Classification of precursor lymphoid neoplasms

      • The majority of ALLs are derived from precursor B cells
      • The majority of LBLs possess a precursor T-cell phenotype

    • 42.2 B-cell lymhoblastic leukemia/lymhoblastic lymphoma

      • Definition

        • Clonal disorder of hematopoietic precursors with evidence of early B-cell differentiation
        • More than 95% express CD19, HLA-DR, and rearrangement of IgH locus

      • Epidemiology

        • ALL is most common malignancy of children (80% of childhood leukemias) in children <6 years old
        • 20% of adult leukemias

      • Etiology

      • Clinical features
      • Morphology
      • Immunophenotype
      • Genetics and molecular findings
      • Normal counterpart
      • Clinical course
      • Differential diagnosis

    • 42.3 T-cell lymphoblastic leukemia/lymhoblastic lymphoma

      • Definition
      • Epidemiology
      • Etiology
      • Clinical features
      • Morphology
      • Immunophenotype
      • Genetics and molecular findings
      • Normal counterpart
      • Clinical course
      • Differential diagnosis
    1. Acute leukemias of ambiguous lineage

IV. Myeloid neoplasms

44. Principles of classification of myeloid neoplasms

45. Myelodysplastic syndromes

46. Acute myeloid leukemia

47. Myeloproliferative neoplasms

48. Myelodysplastic/Myeloproliferative neoplasms

49. Mastocytosis

50. Eosinophilia and chronic eosinophilic leukemia, including myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, FGFR1, or JAK2

51. Blastic plasmacytoid dendritic cell neoplasm

V. Histiocytic proliferations

52. Non-neoplastic histiocytic proliferations of lymph nodes and bone marrow

53. Histiocytic and dendritic cell neoplasms including Langerhans cell histiocytosis and Langerhans cell sarcoma

VI. Immunodeficiency disorders

54. The pathology of primary immunodeficiencies

55. Iatrogenic immunodeficiency-associated lymphoproliferative disorders

VII. Site-specific issues in the diagnosis of lymphoma and leukemia

56. Bone marrow evaluation for lymphoma

57. Evaluation of the bone marrow after therapy

58. Non-hematopoietic neoplasms of the bone marrow

59. Non-lymphoid lesions of the lymph nodes

60. Spleen: normal architecture and neoplastic and non-neoplastic lesions

61. Diagnosis of lymphoma in extranodal sites other than skin