Haematopathology

Understanding of haematopathology is important in anatomical pathology, as haematologic malignancies are often in the (clinical) differential diagnosis and may mimic small blue round cell tumours or lobular breast carcinoma.

The lymph node is discussed below; however, details are covered in the lymph node article and lymph node pathology article.

Bone marrow

Main article: Bone

Bone marrows are important for understanding haematopathology. They are dealt with in the bone article.

Normal lymph node

Normal (clinical)

• Round.
• "Soft".
• Mobile.

Pathologic (clinical) - associations

• Rubbery = suggestive of lymphoma.
• Fixed (immobile) = suggestive of cancer.
• Tender (hurts when ya touch it) = suggestive of infection.

Radiologic & clinical

• Elongated = may be cancer.
• "Large" = could be cancer or infection.

Malignant - statistical associations

Nodes with metstases tend to be:

• Hard.
• Ellipical (as opposed to circular) on section.
• "Large".
• May be immobile (fixed to a surrounding structure).

Note:

• "Large" depends on the location in the body.

Gross pathologic exam

Normal:

• Firm (relative to adipose tissue).
• Glissening surface when cut.

Pathologic:

• White lesions, espically irregular = suggestive of carcinoma.
• white, glissening, with lobulated surface - "fish flesh" = suggestive of lymphoma.

Microscopic

Main article: Lymph node

The microscopic lymph node architecture in described the lymph node article, along with B cell maturation and lymph node cell types.

The cells of the lymph node:

• Germinal center:
  • Centrocytes - cleaved nucleus.
  • Centroblasts - large dark, mitotically active, medullary aspect of germinal center.
  • Tingible body macrophages.
  • Follicular dendritic cells.
• Paracortex:
  • T lymphocytes.
  • Interdigitating dendritic cells.
• Mantle zone:
  • Immunoblasts (Memory B cells) - small lymphocytes.
• Medulla:
  • B lymphocytes.
  • Plasma cells.

Heparin-induced thrombocytopenia

• Thrombocytopenia due to heparin.

Classification:

• Type 1 - in first two days of exposure - considered non-immune and considered not to be serious.
• Type 2 - in the first 4-10 days - considered serious.

Diagnosis (simplified):

• 50% decline in platelets - within 4-10 days of starting heparin.
• HIT assay - several exist.

Lymphoma classification

Lymphomas can be divided into:

• Hodgkin's lymphoma.
• Non-Hodgkin's lymphoma (NHL).

Other categorizations:

• T cell lymphomas (rare).
• B cell lymphomas (more common).

Two most common NHLs:

• Follicular lymphoma (FL).
• Diffuse large B-cell lymphoma (DLBCL).

Lymphoma as a med student

• Acute lymphoid leukemia (ALL) - predominantly in smALL people, i.e. children.
• Acute myeloid leukemia (AML).
• Chronic myeloid leukemia (CML).
• Chronic lymphoid leukemia (CLL) - relatively good prognosis.

Histology

• Lymphomas = cells look discohesive, may be difficult to differentiate from poor differentiated carcinoma.
• Auer rods = Acute myeloid leukemia.
  • Granular cytoplasmic rod (0.5-1 x4-6 micrometres).
• Reed-Sternberg cells = Hodgkin's lymphoma.
  • Large cell - very large nucleus.
    • Classically binucleated.
• Russell bodies = Plasmacytoma (+others).
  • Eosinophilic, large, homogenous immunoglobulin-containing inclusions.
    • Mott cell is a cell that contains Russell bodies.

IHC

• CD45+.
  • AKA common lymphocyte antigen.
  • Useful to differentiate from carcinomas (e.g. small cell carcinoma).
• CD3 -- T cell marker (all T cells).
  • CD4 -- subset of T cells.
  • CD8 -- subset of T cells.
• CD20 -- B cell marker.
  • CD19 -- B cell marker - used for flow cytometry.
• CD10 -- follicular cell ???
• CD30 -- Hodgkin's lymphoma (most sensitive).

Hodgkin's lymphoma

• Abbreviated HL.

Clinical

Sx:

• Fever, night sweats, weight loss.
• Infections (due to immune dysfunction).

Diagnosis:

• HL cannot be diagnosed with standard flow cytometry (FC) - but has been diagnosed with specialized FC.

Histology

• Reed-Sternberg cell (by definition).
  • Large binucleated cell.
  • Macronucleolus - approximately the size of a RBC.

HL subtypes

Types:

• Classical HL (CHL) - ~95% of HL.
• Nodular lymphocyte-predominant HL (NLPHL) - ~5% of HL.

Classical HL

There are four CHL subtypes:

1. Nodular sclerosis CHL - ~70% of CHL.
   • Mixed cellular background - T cell, plasma cells, eosinophils, neutrophils and histiocytes.
   • Nodular sclerosing fibrosis - thick strands fibrosis.
2. Mixed cellularity CHL - ~20-25% of CHL.
   • Like nodular sclerosis - but no fibrosis.
3. Lymphocyte-rich CHL - rare.
   • T lymphocytes only (no mix of cells).
4. Lymphocyte-depleted CHL - rare.
   • Assoc. with HIV infection.

Memory device:

• The subtypes prevalence is in reverse alphabetical order.

Nodular lymphocyte-predominant HL

• AKA lympho-histiocytic variant.

Features:

• The diagnostic cells in this variant: relatively small, lobulated nucleus, small nucleoli.

Image:

• Popcorn cell (webpathology.com).

IHC

Abbreviated panel:

• CD30 Reed-Sternberg cells (RSCs) +ve ~98%
• CD15 Reed-Sternberg cells +ve ~80%, stains neutrophils.
• CD45 often negative in RSCs.
• CD20 may stain RSCs.
• PAX5 +ve.

Additional - for completeness:

• CD3 (T lymphocytes)

NLPHL IHC differs from the classical HL:

• LCA +ve.
• CD20 +ve.
• CD10 +ve.
• Bcl-6 +ve.
• EMA +ve.
• CD30 -ve
• CD15 -ve.

Follicular lymphoma

• A very common type of lymphoma.
• Express Bcl-2.

Microscopic

Features:

• Abundant abnormal lymphoid follicles.

IHC

Features:

• CD10+/-.
• CD5-.
• CD23-/+.
• CD43-.
• CD11c-.

Molecular

• t(14;18) in 70-95% of cases; involves bcl-2 gene.

Diffuse large B-cell lymphoma

• Abbreviated DLBCL.

Microscopic

Features:

• Large cells -- 4-5 times the diameter of a small lymphocytes.
• Typically have marked cell-to-cell variation in size and shape.
• Cytoplasm usu. basophilic and moderate in abundance.
• +/-Prominent nucleoli, may be peripheral and/or multiple.

Notes:

• Large bizarre cells can occasionally mimic Reed-Sternberg cells, seen in Hodgkin lymphoma.

Burkitt's lymphoma

General

• Abbreviated BL.
• Extremely high proliferative rate & rate of apoptosis.

Subtypes

• Three subtypes recognized:

1. Endemic:
   • Found in Africa.
   • EBV (Epstein-Barr virus) associated.
2. Non-endemic:
   • Typical of the BL seen in the western world; EBV negative.
3. Immunodeficiency associated:
   • Associated with HIV infection.

Pathophysiology

• Origin cell: germinal centre B cells (favoured) vs. memory B cells.
• Common translocation t(8;14).

Cytologic definition

• t(8;14) (q24;q32) translocation + a few variants or c-myc rearrangement.

Histology

• "Starry-sky pattern".
  • The stars in the pattern are: tingible-bodies laden macrophages.
    • Tingible-bodies macrophages = macrophages containing dead body of apoptotic tumor cells.
• Tumour cells:
  • Medium size.
  • Round nuclei.
  • Multiple nucleoli.
  • Relatively abundant cytoplasm.

Image: Starry-sky pattern - Ed Uthman (www.wikipedia.org).

Plasmacytoma

General

• Malignancy derived from the plasma cells.
• Histologic component of multiple myeloma; to diagnose multiple myeloma other (non-pathology) criteria are needed.
• Prognosis: poor.

Microscopic

• Cells with "clock face" nuclei.
• Russell bodies:
  • Eosinophilic, large (10-15 micrometres), homogenous immunoglobulin-containing inclusions.
    • Images: Russell bodies (WC), Russell bodies (healthsystem.virginia.edu), Russell bodies - several in one cell (pathguy.com).
• Dutcher bodies - intranuclear crystalline rods.
  • Image Dutcher bodies (hematologylibrary.org).
• Prominent perinuclear hof - cresent shaped lucency at the nuclear membrane (due to large Golgi apparatus).

Images: Various images (hematologylibrary.org).

DDx:

• Neuroendocrine carcinoma - nucleus often has a plasmacytoid (plasma cell) look.

Acute myeloid leukemia

General

• May afflicits young adult.
• Males>females.

Complications

• Chloroma - soft tissue mass.
• Leukostasis.
  • Occurs - lungs and brain.
• Hyperviscosity syndrome.
• Spontaneous bleeding with low platelet counts.

Classification

There are two classifications:

1. FAB (French-American-British) - based on histologic appearance/maturation.
2. WHO classification.

Histology

• Auer rods - not required to diagnose.
  • Cytoplasmic granular rods in blast cells.
    • Dimensions: approx. 0.5-1 x 4-6 micrometres.
  • Images: Auer rods (WP), Auer rods (virginia.edu).

Anaplastic large cell lymphoma

General

• Abbreviated ALCL.
• May look a lot like a carcinoma.
  • Often subcapsular in LNs.
• Usually T-cell derived.
• Alk IHC:
  • +ve = good prognosis.
  • -ve = bad prognosis.

DDx:

• Hodgkin's lymphoma.

Microscopic

Features:

• Large cells with eosinophilic cytoplasm.
• Usu. appear cohesive.
• May be subcapsular.
• Large multinucleated cell - "wreath cell" - key feature.

IHC

Features:

• Variable CD30 +ve. (???)
• CD45 +ve. (???)

Table of B-cell lymphoma

Name	Location	Size of cells	IHC	Translocations	Clinical	Other
Follicular lymphoma	Follicle	Small, centrocytes, centroblasts	CD10, bcl-6	t(14,18)	Clinical ?	Other ?
Burkitt's lymphoma	Follicle	Large cells	CD10, bcl-6	t(8;14) (q24;q32)	Rapid growth	"Starry sky"
Diffuse large B cell lymphoma	Follicle (?)	Large 4-5X of lymphocyte	MIB-1 >40%	none/like follicular l.	Poor prognosis	Common among lymphomas
Name	Location	Size of cells	IHC	Translocations	Clinical	Other

Population cell marker quantification

Two techniques:

• Flow cytometry.
• Laser scanning cytometry (LSC).

Common markers:

• CD3, CD4, CD8, CD5, CD7.
• CD19, CD20, FMC7.
• Kappa, lambda.

Normal:

• T-cells to B-cells usually 1:1.
• In reactive nodes T-cell predominate.
• Normal thymic tissue has cells that are positive for both CD4 and CD8.
• Kappa (k) and lambda (l) are not expressed by the same cell.
• Rule-of-thumb for normal k:l range is: <6:1 and 1:<3.
  • Lambda dominance is less common.

GS guidelines - non-malignant is:

• CD19 ~= CD20
• CD5 = CD3
• CD2 > CD3 and CD5
• CD4 + CD8 ~= CD3
• CD7 = the smalest number of T-cell

Abnormal:

• CD4>CD8 predominance classically seen in:
  • Sarcoidosis.
  • Hodgkin's lymphoma.
• T cell lymphoma - loss of one of the T-cell markers (CD2, CD3, CD5 or CD7).

Sample report

B-Cell Associated Markers

• CD10.
  • Germinal centre marker.
  • +ve in: follicular l., Burkitt l., precursor lymphoblastic leukemia.
• CD19.
  • B cell marker.
  • Should be ~=CD20.
• CD20.
  • B cell marker.
  • Should be ~=CD20.
• CD23.
  • +ve in CLL/SLL.
• FMC7
  • B cell marker.
• Kappa+CD19/20+.
  • B cell clonality.
• Lambda+CD19/20+
  • B cell clonality.

T-Cell Associated Markers

• CD3.
  • CD3 ~= CD4 + CD8.
  • Usually: CD2 > CD3 > CD7.
• CD5.
  • Usually: CD2 > CD5 > CD7.
• CD4.
  • CD3 ~= CD4 + CD8.
• CD8.
  • CD3 ~= CD4 + CD8.
• CD7.
  • Usually least prevalent T cell marker; < CD2, < CD3, < CD5.
• CD2.
  • Usually most prevalent T cell marker; > CD3, > CD5, > CD7.

NK-Cell Associated Markers

• CD56.
• CD16.

Miscellaneous Markers

• CD11c.
• CD14.

See also

• Stomach.
• Lymph nodes.