Diffuse Large B Cell Lymphoma

BCL-6 : Burkitts lymphoma [Ref: Harrison 17⁶/e p. 696-697; Bobbin’s 8^th/e p. 606, 607, 608, 6121

Diffuse large B cell lymphoma 😕

• It is the most common form of NHL
• It is a tumour of the mature B cells
• Immunophenotype of diffuse large B cell lymphoma

They will demonstrate markers of mature B lymphocytes as well as germinal centre markers

– CD 19

– CD 20 – CD 10

– BCL-6

– slg

– BCL-2 (see in 10% to 20% associated with t(14:18))

Burkitts lymphoma

• It is a tumour of mature B cells
• Immunophenotype of Burkitt’s lymphoma

They express phenotype consistent with mature B lymphocytes and germinal centre B cell origin.

– Surface 1gM

– CD 19 – CD 20

– CD 10 – BCL6

• Unlike other tumours of germinal centre origin Burkitt lymphomas always fail to express the anti-apoptotic

protein BCL2.

Mantle cell lymphoma

• It is an uncommon lymphoid neoplasm that makes up 2.5% of NHL.
• The tumour cells closely resemble the normal mantle zone B cells that surround germinal centres.
• Immunophenotype

– CD 19 – CD 20

– High level of surface 1g (usually IgM and 40 with icor Alight chain

– Cyclin Dl (express high levels of cyclin D1)

– CD 5 (+ve) and CD23 (-^ye) (differentiating feature from CLL)

Follicular lymphoma 😕

• It is the most common form of indolent NHL
• The tumour likely arises from germinal centre B cells and is strongly associated with chromosomal translocations involving BCL2.
• Immunophenotype Immunophenotype expresses mature B lymphocytes from germinal centre

– CD 19 – CD 20 – CD 10

– Surface Ig (sIg)

– BCL2 (expressed in more than 90% cases)

– CD 5 (-ve)

Although the ‘anaplastic’ label is there, it is having the maximum 5 year survival rate ie 77%. 5 year survival rate of other lymphomas are Mantle cell lymphoma 27%, Diffuse large B cell lymphoma 46%, Burkitt’s lymphoma 45 %.

Ref: Harrisons principles of internal medicine, 18th edition, Page: 926

In follicular lymphoma, percentage of affected males is only 42%, ie 58 % are females. Other lymphomas are more common in males.

This is an important topic as it is frequently asked in entrance exams. Please go through it in detail:

Ref: Harrisons Principles of Internal Medicine, 18th Edition: Table 100–1 Paraneoplastic Syndromes Caused by Ectopic Hormone Production.

Ans. is ‘a’ i.e., Non Hodgkins lymphoma commonest variety; ‘b’ i.e., Diagnosis is made by biopsy; `c’ i.e., H-Pylori has direct relationship

Gastric lymphoma

• The stomach is the most common site for extranodal lymphoma.

o Nearly all gastric lymphomas are B-cell lymphomas of mucosa-associated lymphoid tissue (MALT lymphoma) o Majority of cases (80%) are associated with chronic gastritis and H. Pylori infection.

o The most striking evidence linking H. Pylori gastritis to MALToma is that eradication of infection by antibiotics induces durable remission with low rate of recurrence.

o Gastric lymphoma represents 5% of all gastric malignancies.

• It is most prevalent is sixth decade of life.

o Like other tumors of mature B cells, MALTomas express B-cell markers CD 19 and CD 20. They do not express CD 5, CD 10 and CD 23.

o Diagnosis is made by endoscopic biopsy.

o Gastric lymphomas are chemosensitive and chemotherapy alone or along with surgery is used for the treatment of gastric lymphoma.

About option ‘a’

o Most common variety of gastric lymphoma is NHL (MALToma). Very rarely, Hodgkin’s lymphoma may also occur in stomach.

Ans. is ‘c’ i.e., Stomach

o Although extra-nodal lymphomas can arise in virtually any tissue, they do so most commonly in the GI tract, particularly stomach.

Ans. is ‘a’ i.e., Involved in Non Hodgkin’s lymphoma

Intestinal lymphoma

o 60-80% of intestinal lymphomas are B cell lymphomas, mostly diffuse large B cell type of Non Hodgkin’s lymphoma of the distal small intestine and especially in the ileo-cecal region.

o Other types of intestinal lymphomas are MALT lymphoma, peripheral T cell lymphoma, Burkitt’s lymphoma.
Most Common Lymphomas Arising in the Small Intestine (REAL Classification)

Histology                                                                 % of Small Bowel Lymphomas

Diffuse large B-cell lymphoma                                           55%

MALT lymphoma                                                                 20%

Peripheral T cell/EATL                                                         15%

Burkitt’s lymphoma                                                                5%

Dffuse large B cell lymphoma

o It is the most common non Hodgkin’s lymphoma occuring in the small bowel, developing most often in the ileocecal region.

o Morphologically, these tumors are composed of diffuse large B cells with large nuclei that are twice the size of a normal lymphocyte. These tumor cells are CD19+, CD20+, CD22+,CD79a+. They tend to have a high percentage of BCL2 gene mutations.

o These tumors commonly occur in adult males, with a median age of 54 to 61 years. They usually present as focal or segmental lesions in the distal small intestine.

o Treatment of localised disease consists primarily of surgical resection followed by adjuvant radiation or chemotherapy.

Mucosal associated Lymphoid Tissue Lymphoma

o In the REAL classification, MALT is known as the marginal zone B cell lymphoma.

o These lymphomas are characterised by cellular heterogeneity, bearing close resemblance to normal gut associated lymphoid tissue (Peyer’s patch and mesentric nodal tissue).

o Treatment is multimodal, including surgical resection and/or chemoradiation therapy.

Burkitt’s lymphoma

o It accounts for fewer than 5% of all the small intestinal lymphomas. Burkitt’s lymphoma of the small intestine occurs as an endemic, sporadic type and immunodeficeincy associated type, and it is a rapidly growing tumor with short doubling time.

o Treatment consists primarily of chemotherapy, usually vincristine, cyclophosphamide, doxorubicin and methotrexate.

T-Cell Lymphomas of Small Intestine

o This tumor was originally termed malignant histiocytosis of the intestine but has since been shown to be conclusively T cell lymphoma arising in the small intestine.

o Intestinal T – cell lymphoma arises most often in the proximal small bowel, and its overall prognosis is poor. o It accounts for approximately 15% of all lymphomas arising in the small intestine.

Ans. is ‘d’ i.e. In general follicular (nodular) NHL has worse prognosis compared to diffuse NHL

o One of the confusing aspects of the lymphoid neoplasms concern the use of descriptive terms “Lymphocytic

leukemia” and “Lymphoma”

o Leukemia is used for lymphoid neoplasms presenting with widespread involvement of the bone marrow usually accompanied by the presence of large number of tumour cells in the peripheral blood.

o The prognosis of Non Hodgkn’s lymphoma varies markedly with various histological types of Non Hodgkin’s lymphoma, “In general lymphomas with a follicular histological pattern are of lower grade (longer survival than those of diffuse pattern)”

Ans is ‘b’ i.e., REAL Classification

In 1994, a group of hematopathologists, oncologists and molecular biologists came together (International Lymphoma Study Group) and introduced a new classification, called the ‘Revised European – American Classification of Lymphoid Neoplasms (REAL) WHO has now reviewed and updated the real classification resulting in inclusion of additional rare entities.

WHO classification/ Modified ‘REAL’ Classification

L Precursor B – cell Neoplasm

Precursor – B lymphoblastic leukemia / lymphoma II. Peripheral B – Cell Neoplasms

Chronic lymphocytic leukemia/small lymphocytic lymphoma

B – cell prolymphocytic leukemia Lymphoplasmacytic lymphoma

Splenic and nodal marginal zone lymphomas Extranodal marginal zone lymphomas

Mantle cell lymphoma

Follicular lymphoma

Marginal zone lymphoma

Hairy cell leukemia

Plasmacytoma/plasma cell myeloma

Diffuse large B – cell lymphoma

Burkitt lymphoma

HI. Precursor T -Cell neoplasms

Precursor T lymphoblastic leukemia/ lymphoma

Peripheral T – Cell and NK – Cell Neoplasms T-cell prolymphocytic leukemia

Large granular lymphocytic leukemia Mycosis fungoides/Sezary syndrome Peripheral large cell lymphoma, unspecified Anaplastic large cell lymphoma

Enteropathy – associated T – cell lymphoma Hepatosplenic 78T – cell lymphoma

Adult T – cell leukemia /lymphoma

NK / T – cell lymphoma, nasal type

NK cell leukemia

V. Hodgkins Lymphoma

Classical subtypes

– Nodular sclerosis

–   Mixed sclerosis

– Lymphocyte – rich

–  Lymphocyte depletion

Lymphocyte predominance

Ans is b’ i.e., Diffuse, small cleaved cell

Working formulation of NHL for clinical usage is as follows:

Low grade :

1. small lymphocytic
2. Follicular, predominantly small cleaved cell
3. Follicular mixed

Intermediate Grade :

1. Follicular predominantly large cell

2. Diffuse small, mixed , as well as large cell.

High grade :

1. Large cell immunoblastic
2. Lymphoblastic
3. Small non cleaved cell.

Note that all varieties of diffuse fall in the intermediate grade category only.

Ans. is D i.e., Hemoglobin and albumin

The prognosis of patients with NHL is best assigned using the International Prognostic index (IPI). 

This is a powerful predictor of outcome in all subtypes of NHL.

Patients are assigned on IPI score based on the presence or absence of five adverse prognostic factors

i)        Age > 60 years

ii)      Elevated serum LDH

iii)      Performance status 2 (ECOG) or 70 ( Karnofsky)

iv)     > I site of extranodal (extralymphatic ) involvement

v)       Ann Arbor Stage III or IV

Ans. is ‘c’ i.e., Leukocyte common antigen

CD45 (leucocyte common antigen) is a _family of single chain transmembrane glycoproteins.

o CD45 (leucocyte common antigen) is exclusively expressed in hematolymphoid cells.

o Almost all hematolymphoid cells including precursor cells and mature B and T lymphocytes granulocytes, monocytes/ histocytes and interdigitating reticulum cells and follicular dendritic cells express CD45.

o While CD45 is strongly expressed on the lymphocytes membranes, histiocytes only exhibit a weak membrane staining.

o CD45 is lost in maturing erythrocytes, megakaryocytes and plasma cells.

o CD45 is detected in large majority of hematolymphoid neoplasmic e.g. leukemias and malignant lymphomas.

Ans. is ‘c’ i.e., B-cell NHL

Ans is ‘a’ i.e., Follicular

Ans. is ‘a’ i.e., Stomach

Ans. is ‘b’ i.e., Intermediate grade

Ans. is ‘a’ i.e., Stomach

• Two thirds NHLS and virtually all cases of hodgkins lymphoma present with nontender nodal enlargement
• Two thirds of NHLS arise at extranodal sites which are skin, stomach or brain.

Ans. is ‘b’ i.e., Paroxysomal nocturnal hemoglobinurea

Rituximab

o Rituximab is a targeted antibody against cell surface molecule CD-20, i.e. Rituximab is anti CD-20 antibody. o It is used in :

1.  B-cell lymphomas –> Low grade lymphomas, mantle cell lymphomas, relapsed aggressive B cell lymphomas, CLL

2.  SLE

Rheumatoid arthritis

D i.e. Hodgkin’s lymphoma 

• Hodgkin’s lymphoma & T-cell lymphoma are not seen (least common) in orbit Q
• B cell lymphoma, Burkit lymphoma, Non Hodgkin’s lymphomaQ, mantle cell lymphoma are common in orbit.

Ans. is ‘b’ i.e. slow growing 

Lymphoma

• Lymphona is a rare malignancy of thyroid (< 1%).
• Most are of non-Hodgkin’s B-cell type.
• Although the disease can arise as part of a generalized lymphomatous condition, most thyroid lymphomas develop in patients with chronic lymphocytic thyroiditis (Hashimoto’s ds.)
• Presenting symptoms are :

– rapidly enlarging mass (similar to anaplastic ca but is often painless.)

–  acute respiratory distress

– hoarseness

– dysphagia

– fever

• Diagnosis is usually suggested by FNA biopsy, although core needle or open biopsy may be necessary for definitive diagnosis.
• Treatment

–   Thyroid lymphoma responds rapidly to chemotherapy (CHOP – cyclophosphamide, doxorubicin, vincristine and prednisone)

– Combined lit with radiotherapy & chemotherapy is recommended.

– Surgical resection is recommended to alleviate pressure symptoms.

Ans is ‘a’ ie stomach 

“The stomach is the most frequent extranodal site for lymphomas. Microscopically, the vast majority of gastric lymphoid tumors are non-Hodgkins lymphomas of B cell origin, Hodgkins ds involving the stomach is extremely uncommon.” – Harrison

Ans. is ‘b’ i.e., Stomach 

Answer is B (REAL Classification)

In 1994, a group of hematopathologists, oncologists and molecular biologists came together (International Lymphoma Study Group) and introduced a new classification, called the ‘Revised European-American Classification of Lymphoid Neoplasms (REAL).

WHO has now reviewed and updated the real classification resulting in inclusion of additional rare entities.

WHO Classification / Modified ‘REAL’ Classification

I. Precursor B-cell Neoplasm

Precursor-B lymphoblastic leukemia/lymphoma

II. Peripheral B-Cell Neoplasms

Chronic lymphocytic leukemia/small lymphocytic lymphoma

B-cell prolymphocytic leukemia Lymphoplasmacytic lymphoma

Splenic and nodal marginal zone lymphomas Extranodal marginal zone lymphomas

Mantle cell lymphoma

Follicular lymphoma

Marginal zone lymphoma

Hairy cell leukemia

Plasmacytoma/plasma cell myeloma

Diffuse large B-cell lymphoma

Burkitt lymphoma

III. Precursor T-Cell Neoplasms

Precursor-T lymphoblastic leukemia/lymphoma

iv Peripheral T-Cell and NK-Cell Neoplasms 

T-cell prolymphocytic leukemia

Large granular lymphocytic leukemia Mycosis fungoides/Sezary syndrome Peripheral large cell lymphoma, unspecified Anaplastic large cell lymphoma Enteropathy-associated T-cell lymphoma Hepatosplenic y8 T-cell lymphoma

Adult T-cell leukemia/lymphoma

NK/T-cell lymphoma, nasal type

NK cell leukemia

V. Hodgkins LF mphoma 

– Classical subtypes

–   Nodular sclerosis – Mixed cellularity

–   Lymphocyte-rich

–   Lymphocyte depletion Lymphocyte predominance

Answer is D (Hemoglobin and Albumin)

`International prognostic index’ does not include Hemoglobin and Albumin as prognostic factors.

Prognostic Factors according to International Prognostic Index for NHL

 International Prognostic Index for NHL

Five clinical risk factors:

• Age  60 years
• Serum lactate dehydrogenase levels elevated
• PerfOrmance status 2 (ECOG) or 70 (Karnofsky)
• Ann Arbor stage III or IV
• > / site of extratiodal involvement

Answer is B (Diffuse, small cleaved cell):

Working formulation of NHL for clinical usage is as follows:

Low grade

1. Small lymphocytic Q
2. Follicular, predominantly small cleaved cell Q
3. Follicular, mixed, small cleaved and large cell. Q

Intermediate grade

1. Follicular predominantly large cell Q
2. Diffuse small cleaved cell
3. Diffuse mixed small and large cell.
4. Diffuse large cell.

High grade

1. Large cell immunoblastic Q
2. Lymphoblastic Q
3. Small non cleaved cell.

Note that all varieties of diffuse fall in the intermediate grade category only.

Answer is A (Diffuse large cell)

Diffuse large cell lymphoma is the most malignant, amongst the options provided.

Although Follicular large cell and Diffuse varieties are both classified in the intermediate grade of the ‘working formulation of NHL’, in general, ‘lymphomas with a follicular histological pattern are of a lower grade (longer survival times) than those with a diffuse pattern’

Answer is A (Diffuse large B-cell lymphoma)

The most common variant of Non-Hodgkin’s Lymphoma in India is Diffuse Large B cell Lymphoma

Diffuse Large B cell Lymphoma is also the most common variant of Non-Hodgkin’s Lymphoma in the United States (Western Data)

‘The majority of Non-Hodgkin’s Lymphoma (NHL) in India are B-cell Lymphomas (around 80 percent). The distribution of Non-Hodgkin’s Lymphoma (NHL) subtypes in India shows important differences with those from the rest of the world. Diffuse  large B-cell l^ymphoma remains the most common form of NHL as in Western Data. However, Follicular lymphoma and mantle-cell l^ymphoma are less common in India compared to Europe and the USA. T cell Lymphomas account for approximately 16 percent of all NHL. T-cell lvmphohlastic lymphoma and anaplastic large T/null cell lymphoma are more prevalent in India. Peripheral T-cell lymphomas and T/NK-cell lymphomas of nasal and nasal types, which are common in man^y other Asian countries, are less prevalent.’

Taken from : ‘Distribution of various subt^ypes of non-Hodgkin’s lymphoma in India: a study of 2773 lymphomas using R.E.A.L. and WHO Classifications’ (http://www.ncbi.nlm.nih.gov/pubmed/10707782)

Ans. A: Morphology of cells

The 1982 Working formulation is a classification of non-hodgkin lymphoma.

It excluded the Hodgkin lymphomas and divided the remaining lymphomas into four grades (Low, Intermediate, High, and Miscellaneous) related to prognosis, with some further subdivisions based on the size and shape of affected cells. This purely histological classification included no information about cell surface markers, or genetics, and it made no distinction between T-cell lymphomas or B-cell lymphomas.

The working formulation was widely accepted at the time of its publication but is now obsolete.

It was superseded by subsequent classifications but it is still used by cancer agencies for compilation of lymphoma statistics and historical comparisons.

Ans. D: Associated symptoms