Haematopathology: an introduction to lymphoid neoplasms

Haematopathology

THE LYMPHOID NEOPLASMSDr Brian Mitchelson

Qatar Cardiovascular Research Centre

Definition

Lymphoid Neoplasms:

Lymphoid neoplasms are derived from the clonal expansion and proliferation of B- and T-lymphocytes.

They encompass a heterogeneous group of lymphomas and leukemias including B-cell, T-cell, and natural killer (NK)-cell disorders.

Classification

In 2008 the WHO classified 8 separate categories of lymphoid neoplasms:

1. Chronic lymphocytic leukemia2. Lymphoplasmacytic lymphoma and Waldenström macroglobulinemia3. Plasma cell neoplasms4. Immunoglobulin deposition diseases.5. Follicular lymphoma: 6. Diffuse large B-cell lymphomas7. Enteropathy-associated T-cell lymphoma8. ALK-positive anaplastic large cell lymphoma

Chronic Lymphocytic Leukemia CLL

Chronic lymphocytic leukemia (CLL) is a type of cancer that starts from the B lymphocytes in the bone marrow.

It then invades the blood.

Leukemia cells tend to build up over time, and many people don't have any symptoms for at least a few years.

In time, it can also invade other parts of the body, including the lymph nodes, liver, and spleen.

Compared with other types of leukemia, CLL usually grows slowly.

Chronic Lymphocytic Leukemia CLL

Chronic lymphocytic leukemia is a monoclonal disorder characterized by a progressive accumulation of functionally incompetent lymphocytes.

It is the most common form of leukemia found in adults in Western countries.

Some patients die rapidly, within 2-3 years of diagnosis, because of complications from CLL, but most patients live 5-10 years.

Diagnosis

Patients with CLL have a higher-than-normal white blood cell count, which is determined by complete blood count (CBC).

Peripheral blood flow cytometry is the most valuable test to confirm a diagnosis of CLL.

Other tests that may be helpful for diagnosis include bone marrow biopsy and ultrasonography of the liver and spleen.

Immunoglobulin testing may be indicated for patients developing repeated infections.

Peripheral smear from a patient with chronic lymphocytic leukemia, small lymphocytic variety.

The cells of origin in most patients with CLL are clonal B cells arrested in the B-cell differentiation pathway, intermediate between pre-B cells and mature B cells.

Morphologically, in the peripheral blood, these cells resemble mature lymphocytes.

CLL Images

Circulating CLL cells may be recognized as mature lymphocytes by the high nuclear cytoplasmic ratio and the characteristic "cobblestone" pattern of the nuclear chromatin.

CLL Images

Bone marrow smear of CLLBeginning in the bone marrow, CLL is typically due to changes to the DNA of stem cells in the bone marrow.This leads to the growth and development of mutated cells that are called leukemic cells. These do not mature into normal white cells. The mutations confer a survival advantage over regular cells that over time, take over the bone marrow and crowd out the normal blood cells.

CLL Images

Rarer forms of Lymphocytic Leukemia

The common form of CLL starts in B lymphocytes, but there are some rare types of leukemia that share some features with CLL.

1.Prolymphocytic leukemia (PLL): In this type of leukemia the cancer cells are similar to normal cells called prolymphocytes - immature forms of B lymphocytes (B-PLL) or T lymphocytes (T-PLL). Both B-PLL and T-PLL tend to be more aggressive than the usual type of CLL. Most people will respond to some form of treatment, but over time they tend to relapse. PLL may develop in someone who already has CLL (in which case it tends to be more aggressive), but it can also occur in people who have never had CLL.

Approximately 20% of the lymphocytes had the morphologic features of prolymphocytes with finely dispersed chromatin and central nucleoli (arrows).

Prolymphocytic leukemia (PLL)

Prolymphocytic leukemia (PLL)

2. Large granular lymphocyte (LGL) leukemia:

This is another rare form of chronic leukemia.

The cancer cells are large and have features of either T lymphocytes or natural killer (NK) cells.

Most LGL leukemias are slow-growing, but a small number are more aggressive.

Drugs that suppress the immune system may be helpful, but aggressive cases are very hard to treat.

Large granular lymphocyte (LGL) leukemia

Large granular lymphocyte (LGL) leukemia

Peripheral blood: medium/large lymphocytes with abundant cytoplasm containing coarse azurophilic granules

Hairy cell leukemia (HCL): This is another cancer of lymphocytes that tends to progress slowly.

It accounts for about 2% of all leukemias.

The cancer cells are a type of B lymphocyte but are different from those seen in CLL.

There are also important differences in symptoms and treatment.

This type of leukemia gets its name from the way the cells look under the microscope -- they have fine projections on their surface that make them look "hairy."

Treatment for HCL by splenectomy can be very effective.

Hairy cell leukemia (HCL):


Hairy cells are characterized by their fine, irregular pseudopods and immature nuclear features. They are seen only in hairy cell leukemia.

This is a scanning electron micrograph which illustrates the multiple cytoplasmic pseudopodia-like projections which gives rise to the descriptive name.


Lymphoplasmacytic lymphoma and Waldenström macroglobulinemia

Lymphoplasmacytic lymphoma is a rare type of non-Hodgkin lymphoma.

Nearly all lymphoplasmacytic lymphomas are a type known as ‘Waldenström’s macroglobulinaemia’ (WM).

This disease has a wide range of clinical presentations with symptoms attributable either to tissue infiltration by neoplastic cells or to the quantity and immunological properties of the monoclonal IgM produced.


Lymphoplasmacytic lymphoma (LPL) is a rare type of non-Hodgkin lymphoma that develops from B cells.

Biopsy samples show a mixture of cancerous lymphocytes and plasma cells .

This is why it is described as 'lymphoplasmacytic'.

LPL is a low-grade lymphoma that usually develops slowly over a period of months or even years.

There are a few different types of LPL but Waldenström’s macroglobulinaemia or WM is by far the most common kind.

In LPL cancerous B cells build up in the bone marrow, the spleen and the lymph nodes

The bone marrow aspirate shows increased lymphoplasmacytoid lymphocytes with scattered plasma cells.


Imprint preparation of lymphoplasmacytic lymphoma demonstrating small lymphocytes and cells with plasmacytoid features (eccentric nuclei and bluish cytoplasm).


Bone marrow biopsy:The yellow arrow shows the presence of Dutcher bodies, intranuclear inclusions in the plasma cells


Bone Marrow aspirate:The marrow was infiltrated by lymphoplasmacytoid cells on aspiration.


Plasma cell neoplasms

• Plasma cell myeloma • Asymptomatic (smoldering) myeloma • Nonsecretory myeloma • Plasma cell leukemia

• Plasmacytoma • Solitary plasmacytoma of bone • Extraosseous (extramedullary) plasmacytoma

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

• Osteosclerotic myeloma (POEMS syndrome)

Plasma cell myeloma

In plasma cell myeloma, collections of abnormal plasma cells accumulate in the bone marrow, where they interfere with the production of normal blood cells.

Most cases of plasma cell myeloma also feature the production of a paraprotein —an abnormal antibody which can cause kidney problems.

Bone lesions and hypercalcemia (high blood calcium levels) are also often encountered.

Diagnosis

Symptomatic myeloma:Clonal plasma cells >10% on bone marrow biopsy or in a biopsy from other tissues (plasmacytoma)

A monoclonal paraprotein in either serum or urine (except in cases of true non-secretory myeloma)

Evidence of end-organ damage related to the plasma cell disorder.

HyperCalcemia (corrected calcium >2.75 mmol/L)Renal insufficiency attributable to myelomaAnaemia (haemoglobin <10 g/dL)Bone lesions

Diagnosis

Asymptomatic (smoldering) myeloma:Serum paraprotein >30 g/L AND/ORClonal plasma cells >10% on bone marrow biopsy NO myeloma-related organ or tissue impairment

Plasma Cell LeukaemiaThe WHO criterion for diagnosis of PCL is that

plasma cells constitute more than 20% of cells in the peripheral blood with an absolute plasma cell count of more than 2 × 109/L.

A classical blood film picture from a case of “multiple myeloma”.

Multiple Myeloma is the most common malignant plasma cell dyscrasia.

There are many other malignant and secondary plasma cell disorders

Plasma cell myeloma

The plasma cells seen in the marrow can be mature - with classic PC features or immature - with prominent nucleoli.

Binucleate and multinucleate PCs can be seen. Masses of immunoglobulin may form intracytoplasmic globules or Russell bodies.

Plasma cell myeloma

Cells containing multiple immunoglobulin globules are known as Mott cells

Plasma cell myeloma

Myeloma cells may also contain crystalline inclusions of immunoglobulin

Plasma cell myeloma

Plasma cell myeloma

The excessive production of an abnormal immunoglobulin is the second major characteristic of myeloma.

The abnormal Ig is most often IgG (50%) and sometimes IgA (25%), but rarely (<1%) IgM ,IgD, or IgE.

Production of excess light chain is frequent and is excreted in the urine as Bence- Jones proteins.

About 20-25% of cases produce only light chains which are often detectable only in the urine.

Fewer than 5% of myelomas are nonsecretory.

Immunoglobulin filled cytoplasm may invaginate into the nucleus creating the appearance of an intranuclear inclusion (a Dutcher body).

Plasmacytoma

Plasmacytoma refers to a malignant plasma cell tumor growing within soft tissue or within the axial skeleton. There are three distinct groups of plasmacytoma defined by the International Myeloma Working Group:

Solitary Plasmacytoma of Bone (SPB) Extramedullary Plasmacytoma (EP) and multiple plasmacytomas that are either primary or recurrent.

The most common of these is SPB, accounting for 3–5% of all plasma cell malignancies. SPBs occur as lytic lesions within the axial skeleton and EPs most often occur in the upper respiratory tract (85%), but can occur in any soft tissue.

Plasmacytoma

Approximately half of all cases produce paraproteinaemia.

The skeletal forms frequently progress to multiple myeloma over the course of 2–4 years. Due to their cellular similarity, plasmacytomas have to be differentiated from multiple myeloma. For SPB and EP the distinction is the presence of only one lesion (either in bone or soft tissue), normal bone marrow (<5% plasma cells), normal skeletal survey, absent or low paraprotein and no end organ damage.

Low power photomicrograph shows classic histological features of a plasmacytoma.

This is an example of an SPB found in the pelvis.

Plasmacytoma - SPB

Vertebral plasmacytoma which caused compression of the spinal cord.

Plasmacytoma - SPB

An example of EP from a biopsy of the mouth.Histopathologic features showed oral mucosa lined by nonkeratinizing stratified squamous epithelium. Areas of ulceration were seen. The underlying connective tissue was infiltrated by closely packed plasma cells arranged in sheets and islands with varying degrees of differentiation, some with perinuclear halo, occasionally 2 nuclei within a single cell. Russell bodies were seen.

Plasmacytoma - EP

Plasmacytoma - EP

Low power view of lesion demonstrating plasma cells

High power view demonstrating typical plasma cell cytoplasm and clock face chromatin. Some pleomorphic atypical forms also present

Plasma Cell Leukaemia

Plasma cell leukemia (PCL) is a rare cancer involving the plasma cells.

Plasma cell leukemia is one of the most aggressive human neoplasms and constitutes 2% to 4% of all cases of plasma cell disorders.

The WHO criterion for diagnosis of PCL is that plasma cells constitute more than 20% of cells in the peripheral blood with an absolute plasma cell count of more than 2 × 109/L.


Pathologic diagnosis of PCL is based on histologic, immunophenotypic, and cytogenetic findings in addition to circulating high plasma cell counts.

Bone marrow biopsy typically reveals aggregates or sheets of neoplastic plasma cells that displace normal marrow elements.


Peripheral blood plasma cells range from mature forms with characteristic "clock-face" chromatin and perinuclear halo, to immature blast forms.

These have loose reticular chromatin, high nuclear/cytoplasmic ratio, and prominent nucleoli.

Immature neoplastic cells may be indistinguishable from myeloblasts.

In some instances, plasma cells display lymphoid morphology.

At routine ante-natal screening a review of the peripheral blood film displayed 90% plasma cells, a bluish background, rouleaux, occasional nucleated red blood, and low platelets.

A bone marrow examination showed replacement by plasma cells.


Multiple abnormal cells with clefted nuclei and basophilic cytoplasm suggestive of plasma cells, in peripheral blood


Bone marrow aspiration showed markedly increased cellularity with infiltration by atypical plasma cells comprising more than 90% of all nucleated cells


Immunoglobulin Deposition Diseases

Light and heavy-chain immunoglobulin deposition diseases belong to a family of diseases that include:

Light-chain (AL)-amyloid.

Nonamyloid fibrillary and immunotactoid glomerulonephritis, and cryoglobulinemic glomerulonephritis, in which monoclonal Ig or their subunits become deposited in kidney.

It is a rare disease characterized by deposition of nonamyloid immunoglobulin light chains, and they do not stain with Congo red and do not exhibit a fibrillar structure when examined ultrastructurally.


It is categorized as a “monoclonal deposition disease” in the World Health Organization (WHO) classification of tumors of haematopoietic and lymphoid tissues.A single clone of plasma cells is responsible for overproduction of kappa chains and, very rarely, lambda chains. A monoclonal population of plasma cells can be detected in the bone marrow, and an altered serum-free light chain ratio is present.In 25% of patients, an abnormal serum free light chain ratio is noted, even without an abnormal finding with serum and or urine electrophoresis with immunofixation.


Amyloid Disease:

Primary amyloidosis arise from a disease with disordered immune cell function, such as multiple myeloma or other immunocyte dyscrasias.

Secondary (reactive) amyloidosis occurs as a complication of some other chronic inflammatory or tissue-destroying disease. Examples are reactive systemic amyloidosis and secondary cutaneous amyloidosis.

Here amyloid deposits in the kidney are seen as dense amorphous pink areas in glomeruli at the left and in arteries at the right.

Primary Amyloidosis

Cardiac AmyloidA Congo red stain has been performed on the myocardium in a case of amyloidosis. The amyloid stains orange-red, but with polarized light, the amyloid has an "apple-green" birefringence as seen here

Primary Amyloidosis

This electron micrograph shows the typical ultrastructure of amyloid:randomly-oriented, non-branching fibrils, 7.5-10 nm in diameter, of indeterminate length. Electron microscopy is usually reserved for cases in which the stains at the light microscopic level are non-diagnostic or for cases with minimal deposits, as in the kidney. All amyloids have a similar ultrastructure.

Primary Amyloidosis

In this image of Cardiac amyloid disease, the dense amyloid protein is seen adjacent to a blood vessel.

This disease was secondary to chronic rheumatic heart disease

Secondary Amyloidosis

This is a section from a skin biopsy stained with Congo Red and shows the amorphous deposits surrounding the blood vessels.

The final histologic diagnosis was AA (secondary) amyloidosis, associated to psoriasis.


This is the same section as the previous slide but was viewed under polarized light and shows the Amyloid deposits as an “apple green” bi-refringence.


Nonamyloid fibrillary GN: This rare disorder comprises less than 1% in renal biopsy series and usually presents with renal insufficiency, nephrotic range proteinuria, and microhaematuria.

It is characterized pathologically by the deposition in glomeruli of fibrillar deposits that generally range from 16 to 24 nm in diameter.

These fibrils usually stain for immunoglobulin G (IgG) and C3, with more variable and weaker positivity for other immunoglobulins2. By definition, the glomerular deposits are Congo red–negative, allowing their differentiation from amyloid.

Nonamyloid Fibrillary and Immunotactoid Glomerulonephritis

Nonamyloid Fibrillary and Immunotactoid Glomerulonephritis

There is considerable debate about the relationship of Fibrillary Glomerular Nephritis (FGN) to immunotactoid glomerulonephritis (IT).

IT is an entity with larger microtubular deposits, usually>30 nm in diameter, which are often hollow and arranged in parallel or stacked arrays.

An electron microscopy example of FGN displays intramembranous, randomly oriented fibrils of a mean 20 nm diameter that infiltrate and thicken the glomerular basement membrane.

The fibrils lack hollow centers and parallel stacking.

Nonamyloid FGN

B is also an electron micrograph from a case of IT and exhibits subendothelial accumulations of microtubules of 35 nm diameter with hollow centers arranged in parallel stacks. The microtubules do not infiltrate the glomerular basement membrane.

Immunotactoid GN

Cryoglobulinaemic GN (CGN)

CGN can be differentiated from idiopathic MPGN, especially in the acute stage,, by the following findings: (1) the presence of large deposits filling the capillary lumen that sometimes are shown to have a characteristic fibrillar or crystalloid structure by electron microscopy;

(2) the extent of the exudative component consequent to the frequently massive infiltration of monocytes;

(3) a more diffuse and evident thickening of the glomerular basement membrane, which has a double-contoured appearance that is mainly due to the peripheral interposition of monocytes, with less evident mesangial expansion;

The most common morphological picture is a membranoproliferative exudative glomerulonephritis, characterized by variable degrees of mesangial proliferation and massive intracapillary leukocyte (mainly monocyte-macrophage) accumulation.


Immunocytochemistry shows a massive accumulation of monocyte-macrophages (CD68 positive cells) is evident. This type of glomerular infiltration is rather specific of Cryoglobulinaemic nephritis,


Electron microscopy shows that monocyte-macrophages are likely involved in the degradation of immune deposits. In fact they are found in close proximity to the subendothelial deposits and their cytoplasm contains electron dense material.


Follicular Lymphoma NHL

Follicular lymphoma (FL) is a B-cell lymphoma and is the most common indolent (slow-growing) form of NHL, accounting for approximately 20 percent to 30 percent of all Non- Hodgkins Lymphomas (NHLs).

Common signs of disease include enlargement of the lymph nodes in the neck, underarm, stomach, or groin, as well as fatigue, shortness of breath, night sweats, and weight loss.

Often, people with FL have no obvious symptoms of the disease at diagnosis.

Follicular Lymphoma-NHL

The average age for people with this lymphoma is about 60. It’s rare in very young people. Most of the time, this lymphoma occurs in many lymph node sites in the body, as well as in the bone marrow.Follicular lymphomas are often slow-growing and respond well to treatment, but they are hard to cure. These lymphomas may not require treatment when they are first diagnosed. Instead, treatment may be delayed until the lymphoma is causing problems. Over time, about 1 in 3 follicular lymphomas turns into a fast-growing diffuse B-cell lymphoma.

Follicular Lymphoma- NHL

FOLLICULAR LYMPHOMA DIAGNOSIS AND STAGING

The diagnosis of follicular lymphoma is confirmed by removing all or part of an enlarged lymph node to examine its cells under a microscope, a procedure known as a biopsy.

Once the diagnosis is confirmed, additional tests are performed to obtain more information about the extent to which the disease has spread in the body. This process is called staging. The results of these tests will help determine the most effective course of treatment.

History and physical exam — A careful interview and physical examination will help determine the extent of the disease. The physical exam may reveal swollen lymph nodes in various locations.

Staging tests — A number of tests are available to help determine which areas of the body have been affected by follicular lymphoma. Tests that may be done include:●Blood tests●Bone marrow biopsy ●Computed tomography (CT) scan●Positron emission tomography (PET) scan

Follicular lymphoma.

Nodular aggregates, not effacement as in CLL/SLL.


Many small lymphoid cells with condensed chromatin and irregular nuclear outlines (centrocytes)

along with larger cells with multiple nucleoli (centroblasts).


ImmunocytochemistryA.Normally, B lymphocyte mantle cells in the lymph node express the BCL-2 antibody (blue arrows) and follicular B-cells don't.

B.In the malignant follicle on the right, the follicular B-cells (red arrow) are overexpressing BCL-2.


Hodgkins Lymphoma

The cause of Hodgkin lymphoma is not known. Hodgkin lymphoma is most common among people ages 15 to 35 and 50 to 70. Past infection with the Epstein-Barr virus (EBV) is thought to contribute to some cases. Persons with HIV infection are at increased risk compared to the general population.

Symptoms may include any of the following:FatigueFever and chills that come and goItching all over the body that cannot be explainedLoss of appetiteSoaking night sweatsPainless swelling of the lymph nodes in the neck, armpits, or groin Weight loss that cannot be explained

Hodgkins Lymphoma

Hodgkins Lymphoma is divided into 4 classes

A.Nodular Sclerosing HL : Is the most common subtype and is composed of large tumor nodules showing scattered lacunar

classical RS cells set in a background of reactive lymphocytes, eosinophils and plasma cells with varying degrees of collagen fibrosis/sclerosis.

B. Mixed-cellularity subtype:Is a common subtype and is composed of numerous classic RS cells admixed with numerous

inflammatory cells including lymphocytes, histiocytes, eosinophils, and plasma cells without sclerosis. This type is most often associated with EBV infection and may be confused with the early, so-called ‘cellular' phase of nodular sclerosing CHL.

C. Lymphocyte-rich or Lymphocytic predominance:Is a rare subtype, show many features which may cause diagnostic confusion with nodular lymphocyte predominant B-cell Non-Hodgkin's Lymphoma (B-NHL). This form also has the most favorable

prognosis.

D. Lymphocyte depleted:Is a rare subtype, composed of large numbers of often pleomorphic RS cells with only few reactive lymphocytes which may easily be confused with diffuse large cell lymphoma. Many cases previously classified within this category would now be reclassified under anaplastic large cell lymphoma.

Hodgkins Lymphoma

Hodgkins lymphoma may be treated with radiation therapy, chemotherapy, or hematopoietic stem cell transplantation, with the choice of treatment depending on the age and sex of the patient and the stage, bulk, and histological subtype of the disease. The five-year survival rate is currently approximately 85%.

Tumour Staging

Stage I: is involvement of a single lymph node region (mostly the cervical region) or single extralymphatic site.

Stage II: is involvement of two or more lymph node regions on the same side of the diaphragm or of one lymph node region and a contiguous extralymphatic site.

Stage III: is involvement of lymph node regions on both sides of the diaphragm, which may include the spleen and/or limited contiguous extralymphatic organ or site.

Stage IV: is disseminated involvement of one or more extralymphatic organs.

Lymph node section showing the characteristic Reed-Sternberg (RS cell) giant cells which are frequently multinuclear and often found in clumps in the tumour.

RS cell

Two additional features distinguish the nodular sclerosing type of Hodgkin disease.

Fibrosis: dense bands of collagenous fibrous tissue separate the cellular areas producing a lobular appearance.

Hodgkins LymphomaNodular Sclerosing

The lymph node architecture is diffusely replaced by a polymorphous population of small lymphocytes, histiocytes, plasma cells, and eosinophils in varying proportions. Among this mixed inflammatory cell infiltrate are present scattered mononucleate and multinucleate large Reed-Sternberg cells (arrow).

Hodgkins LymphomaMixed-cellularity subtype

Nodular lymphocyte predominant –

The popcorn cells that characterize this form of the disease invariably express B lymphocyte markers such as CD20 (thus making NLPHL an unusual form of B cell lymphoma), and that, unlike classic HL, NLPHL these tumours may progress to diffuse large B cell lymphoma.

Hodgkins LymphomaNodular lymphocyte predominant

Lymphocyte-depleted, comprises less than 5% of all Hodgkin lymphomas. In the diffuse fibrosis subtype, there is progressive sclerosis over time and the number of lymphocytes decreases.

Hodgkins LymphomaLymphocyte-depleted

A Reed-Sternberg cell occupies the centre, surrounded by a few lymphocytes and fibrosis that might be described as disorganized. When viewed through polarized light, it is not birefringent, unlike the fibrous bands of nodular sclerosis.

Hodgkins LymphomaLymphocyte Depletion Type

Diffuse large B-cell lymphomasDLBCL

Diffuse large B-cell lymphoma (DLBCL) is the most common form of Non-Hodgkins Lymphoma (NHL), accounting for up to 30 percent of newly diagnosed cases in the United States.

It can arise in lymph nodes or outside of the lymphatic system, in the gastrointestinal tract, testes, thyroid, skin, breast, bone, or brain.DLBCL is a fast-growing, aggressive form of NHL. DLBCL is fatal if left untreated, but with timely and appropriate treatment, approximately 60 percent of all patients can be cured.

Diffuse Large B-cell LymphomasDLBCL

Age, gender, and ethnicity affect a person's likelihood of developing DLBCL.

Although DLBCL has been found in people of all age groups, it is found most commonly in people who are middle-aged or elderly.

The average age at the time of diagnosis is 64 years. Men are slightly more likely to develop DLBCL than women.

In the United States, white people are more likely to develop this type of lymphoma than are Asians or Blacks.

DLBCL is not an inherited disease. Siblings and children of patients with DLBCL do not have a substantially increased risk of developing DLBCL.


DIFFUSE LARGE B CELL LYMPHOMA SYMPTOMS

The first sign of DLBCL is often a quickly growing, non-painful mass that is typically an enlarged lymph node in the neck, groin, or abdomen. Patients may also experience fever, weight loss, drenching night sweats, or other symptoms.

Extranodal disease — In about 40 percent of cases, the cancer does not begin in the lymph nodes, but instead develops elsewhere. This is called extranodal disease. The most common site of extranodal involvement is the stomach or gastrointestinal tract, but the disease can arise in virtually any normal organ.

Advanced versus localized disease — Most patients (about 60 percent) are not diagnosed with DLBCL until the disease is advanced (stage III or IV). In the remaining 40 percent of patients, the disease is confined to one side of the diaphragm (above or below the diaphragm). This is called localized disease

The normal architecture of this lymph node from the mediastinum has been destroyed by the B-Cell infiltrate


Close-up from the previous tumour.The neoplastic lymphocytes are large, with a large irregular nucleus and coarse chromatin. Mitotic figures are easily found. This type of lymphoma may occur de novo, or as an advanced phase of a pre-existing B-cell lymphoma such as follicular or monocytoid types.


The malignant lymphocytes here are very large with a moderately abundant cytoplasm, and the nuclei are round to ovoid with prominent nucleoli and occasional mitoses. The diagnosis is diffuse large B cell lymphoma (also known as immunoblastic lymphoma).


Enteropathy-associated T-cell lymphoma (EATL)

Enteropathy-associated T-cell lymphoma is a very rare type of T-cell lymphoma. It usually occurs in the small intestine, most often the middle part (jejunum) or lower part closest to the large intestine (ileum). It may also be called enteropathy-type T-cell lymphoma or intestinal T-cell lymphoma. EATL is associated with gluten sensitive enteropathy (GSE). People with this disease cannot tolerate gluten, a protein found in many grains, such as wheat, rye and barley (gluten sensitivity). A gluten-free diet helps prevent EATL from developing, so this type of lymphoma does not commonly occur in people diagnosed with GSE at a young age. Most adults are diagnosed with the disease at the same time as their lymphoma or shortly before their lymphoma is diagnosed.

Enteropathy-associated T-cell lymphoma (EATL)

People with EATL often have ulcers in the small intestine, an obstruction or a perforation in the wall of the intestine.

All of these can cause abdominal pain. EATL may spread to the liver, spleen, lymph nodes, gallbladder, stomach, colon or skin. EATL is usually a fast-growing (aggressive) lymphoma. The prognosis for people with EATL is often not very good.

Enteropathy-associated T-cell lymphoma.

The tumour is seen deeply infiltrating into adjacent enteropathic mucosa.

Enteropathy-associated T-cell lymphoma

Enteropathy-associated T-cell lymphoma. There is a heavy infiltrate of eosinophils between the tumour cells.


This is a common picture of EATL with large tumour cells with round or angulated vesicular nuclei with prominent nucleoli, and moderate to abundant, pale-staining cytoplasm. A heavy eosinophil infiltrate is evident between the tumour cells.


ALK-positive anaplastic large cell lymphoma (ALCL)

Anaplastic large cell lymphoma (ALCL) is a rare type of T-cell lymphoma. It accounts for about 1–2% of all cases of non-Hodgkin lymphoma (NHL) in adults. ALCL usually starts in T cells but, in some cases, it is hard to tell what type of cell the cancer started in. This is called null-cell type. ALCL can occur in any age group, but is more common in children and young adults. It makes up about 14% of childhood NHL cases. It affects more males than females.

ALK-positive anaplastic large cell lymphoma

Types of ALCLThere are 2 types of ALCL. ALCL can appear only in the skin (primary cutaneous ALCL) or in organs throughout the body (primary systemic ALCL). A high number of ALCLs are associated with translocations involving the ALK (anaplastic lymphoma receptor tyrosine kinase) gene.

ALK-positive tumours (sometimes referred to as ALKomas) have a better outcome than ALK-negative ALCLs.

People whose lymphomas express ALK are usually younger.

ALK-negative ALCL is more common in older adults and often has an aggressive course.


CharacteristicsThe lymphoma cells involved in ALCL have a certain marker on their surface called the CD30 antigen. They also express the anaplastic lymphoma kinase (ALK). People with ALK-positive disease respond to chemotherapy and have a more favourable outcome than people with ALK-negative lymphoma. Many people with ALK-negative ALCL will relapse and may need more aggressive chemotherapy. Primary cutaneous ALCL is usually ALK negative, whereas primary systemic ALCL can be ALK positive or negative.

Fatal ALK-negative systemic anaplastic large cell lymphoma presenting with disseminated cutaneous dome-shaped papules and nodules


Infiltrate is composed of large transformed lymphocytes, including hallmark cells with kidney-shaped nuclei.The morphology of ALCL, systemic type, consists of large lymphoid cells with pleomorphic or multiple prominent nuclei and abundant cytoplasm.Tumor cells grow in a cohesive pattern, and there is often sinusoidal spread in the lymph nodes. Tumor cells express CD30 and either T cell or no specific lineage antigens (null cell).


The EndThank you for your attention.

I would like to thank the following for the use of several images and data:Lichtman’s Atlas of HematologyThe American Society of HematologyWeill Cornel UniversityHematopathology for medical education – WebPathAtlas of Hematopathology | 978-0-12-385183-3 | Elsevier

Health & Medicine

Haematopathology: an introduction to lymphoid neoplasms