13. Aggressive non-Hodgkin’s lymphomas

Non-Hodgkin lymphoma

Non-Hodgkin lymphomas (NHL) are all lymphomas (neoplasms of lymphocytes) which are not Hodgkin lymphoma. Lymphomas are classified like this:

The most common is DLBCL, followed by follicular lymphoma.

Diagnosis:

  • Excisional biopsy of lymph node
    • FNAB is not sufficient as the lymph node architecture is destroyed.
  • Immunohistochemistry to confirm that the tumor cells in the lymph node are lymphoid
  • Flow cytometry to differentiate T and B cell
    • CD19, CD20 for B cells
    • CD3, CD4, CD8 for T cells

Staging:

The staging system for lymphomas is called the Lugano staging system, which is a modified version of the Ann Arbor staging. It is similar to the TNM staging system. Stages I and II are referred to as “early stage” while stages III and IV are referred to as “advanced stage”.

Stage

Involvement

Stage I

Involvement of a single lymph node region (e.g., cervical, axillary, inguinal, etc.) or lymphoid structure (e.g., spleen, thymus, etc.)

Stage II

Involvement of two or more lymph node regions or lymphoid structures on the same side of the diaphragm

Stage III

Involvement of lymph node regions or lymphoid structures on both sides of the diaphragm

Stage IV

Diffuse or disseminated involvement of one or more extranodal organs or tissues

From https://www.uptodate.com/contents/image?imageKey=HEME%2F66651

In addition to the stages there are some additional parameters:

Parameter

Involvement

A

Absence of B symptoms

B

Presence of B symptoms

E

Extranodal involvement (less extensive than in stage IV)

Bulky disease (or X)

A mass > 6 – 10 cm in diameter, depending on the exact type of lymphoma

The “B-symptoms” refers to the following:

  • Significant night sweats
    • Significant sweating, so that the patient is “drenched” in sweat during the night
  • Unexplained fever
    • > 38.1°C if measured in the axilla
    • > 38.3°C if measured sublingually
  • Unexplained weight loss
    • Of at least 10% during the last 6 months
    • Without any significant change in diet or exercise level

Staging workup:

The following investigations are important in the staging of NHLs:

  • Laboratory investigations
    • CBC
    • Renal function
    • Liver function
    • LDH
    • Viral serology (HIV, HBV, HCV)
  • Imaging studies
    • CT of neck, chest, abdomen, pelvis
    • Bone marrow biopsy and aspirate
Aggressive non-Hodgkin lymphoma

The aggressive NHLs can be considered “high-grade” lymphomas. The life expectancy for patients with these cancers is measured in weeks if untreated, i.e. they progress rapidly. Unlike indolent NHLs the aggressive ones are potentially curable.

The aggressive NHLs are:

  • B cell neoplasms
    • Diffuse large B-cell lymphoma
    • Burkitt lymphoma
    • Precursor B lymphoblastic leukaemia/lymphoma
  • T cell neoplasms
    • Peripheral T cell lymphoma
    • Adult T-cell lymphoma/leukaemia
    • Precursor T lymphoblastic leukaemia/lymphoma

Presentation:

Aggressive NHLs usually present with a rapidly growing mass, B symptoms and/or elevated serum LDH or uric acid.

Treatment:

Early stage aggressive non-Hodgkin lymphomas are treated with 6-8 cycles of R-CHOP or 3-4 cycles of R-CHOP and radiotherapy.

Advanced stage aggressive non-Hodgkin lymphomas are treated with R-CHOP and possible intrathecal chemotherapy or radiotherapy.

Relapsed aggressive B-cell NHLs are treated with high-dose R-CHOP or R-EPOCH.

R-CHOP is the most commonly used combined chemoimmunotherapy regimen for aggressive haematological malignancies. It includes:

  • R – rituximab
  • C – cyclophosphamide
  • H – hydroxydaunorubicin (an anthracycline)
  • O – vincristine (Oncovin, the brand name of vincristine)
  • P – prednisone

Rituximab is an anti-CD20 antibody. As these are B-cell lymphomas they virtually always express CD20. When rituximab binds to the cancer cells, it causes several anti-neoplastic effects:

  • It activates antibody-dependent cell-mediated cytotoxicity (ADCC)
  • It activates the complement system
  • It induces apoptosis
  • It chemosensitizes the tumor cell, thereby making it more susceptible to chemotherapy
Diffuse large B-cell lymphoma

DLBCL is an aggressive, mature, B-cell non-Hodgkin lymphoma. We distinguish two types:

  • de novo DLBCL – DLBCL which arises without an underlying indolent B cell lymphoma
  • DLBCL which is the result of a transformation from an indolent B cell lymphoma
    • Chronic lymphocytic leukaemia (Richter’s transformation)
    • Follicular lymphoma
    • etc.

Etiology:

Translocations between Bcl-6, Bcl-2, c-Myc and IgH are common in DLBCL.

Epidemiology:

DLBCL is the most common lymphoma in adults, but it’s also seen in children. The median age is 64 years.

DLBCL accounts for 90% of all primary CNS lymphomas.

Pathology:

The tumor is composed of a diffuse infiltrate of large, morphologically diverse lymphoid cells.

Prognosis:

Two thirds of people with DLBCL who are treated can be cured. de novo DLBCL has better prognosis than DLBCLs which are transformed from indolent lymphomas.

The following are poor prognostic factors, according to the international prognostic index:

  • CD10÷
  • Advanced age (> 60 y)
  • High serum LDH
  • Advanced stage disease
  • More than one extranodal sites of involvement
  • Poor physical performance of the patient

In addition to these factors, the origin of the tumor cell is important for the prognosis. Germinal centre B cell type DLBCL has a better prognosis than activated (post-follicular) B cell type DLBCL. Some drugs which can be more effective in activated B cell type DLBCL are now in clinical trial (lenalidomide, ibrutinib, bortezomib).

Burkitt lymphoma

Burkitt lymphoma is an aggressive, mature, B-cell non-Hodgkin lymphoma. We distinguish three different types:

  • Sporadic Burkitt lymphoma
  • Endemic Burkitt lymphoma
  • HIV-associated Burkitt lymphoma

Burkitt lymphoma is one of the most rapidly growing tumours, with a doubling time of less than 24 hours.

Etiology:

Translocation involving c-Myc, found on chromosome 8, is found in all cases of Burkitt lymphoma. These translocations cause over-expression of c-Myc, resulting in continuous cell cycling. Common translocations include:

  • t(2;8)
  • t(8;14) – 75% of cases
  • t(8;22)

Endemic Burkitt is highly associated with EBV infection. < 30% of sporadic Burkitt lymphomas are EBV positive.

HIV-associated Burkitt is associated with HIV or other causes of immunodeficiency.

Epidemiology:

Endemic Burkitt lymphoma is endemic to equatorial Africa and South America. The sporadic and endemic types are more common in children while the HIV-associated type is more common in adults.

Clinical features:

Sporadic Burkitt often presents as an abdominal mass. It can be a cause for ileus. Endemic Burkitt usually presents as a mass in the maxilla or mandibula.

Pathology:

The tumor cells have very high rate of proliferation, and apoptosis is widespread. Tingible body macrophages phagocytose the apoptotic bodies, which causes the “starry sky” pattern on histology.

Treatment:

Burkitt tumours are highly chemosensitive. Patients with large tumours are at increased risk for tumor lysis syndrome.

Adult T cell lymphoma/leukaemia

Etiology:

Adult T cell lymphoma/leukaemia is defined as any T cell neoplasm associated with HTLV-1 infection.

Epidemiology:

Almost exclusively in adults. It’s more common in places where HTLV-1 is more common, like Japan, the Caribbean, western Africa, etc.

Clinical features:

Usually presents wth leukaemia (malignant cells in the blood), lymphadenopathy and organomegaly.

Prognosis:

It is generally a very aggressive disease, with life expectancy measured in months.

Lymphoblastic leukaemia/lymphoma

Lymphoblastic leukaemia/lymphoma can be of T cell origin or of B cell origin. The former is more common.

Epidemiology:

These cancers are most common in adolescents and young adults, especially men.

Clinical features:

This tumor usually presents as a mediastinal mass, as it often originates in the thymus.


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5. Microangiopathic haemolytic anaemias (TTP, HUS)

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14. Indolent non-Hodgkin’s lymphomas

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