Non-Hodgkin’s lymphoma (NHL)

5% of all new cancers in males and 4% in females.

The seventh most common cancer in developed countries.

Heterogeneous group of malignancies, mature and immature phenotypes of B, T cell or natural killer cell lineage.

Most NHL‘s originate in the germinal centers of lymph nodes.

Heterogenous group of lymphoproliferative disorders.

Typically cells infiltrate both lymphoid and hematopoetic tissues and can extend to other organs.

The vast majority of NHL‘s are derived from B cells.

There are more than 80 subtypes of B cell NHL and they are categorized according to their clinical course: indolent or aggressive.

Approximately 80,000 cases per year in the US.

Estimated 544,000 cases of NHL diagnosed worldwide in 2020.

Accounts for the sixth most common cancer in adult men and the 50 most common in adult women.

Overall five your survival rates are 73% for whites and 63% for African-Americans.

More frequent in Western countries then in Asian populations.

Classified by cell type of origin, B,T, or natural killer cells.

B cell lymphomas make up the majority of cases, accounting for approximately 85% of cases.

Subclassified by whether cells are derived from precursor or mature lymphocytes.

Subclassified by immunophenotypic and genetic markers.

Fifth most common cancer in the U.S.

6th most common cause of cancer-related death in the U.S. in Caucasians.

Worldwide overall incidence is 19.1 per 100,000 people but varies with geographical location.

Incidence rate in the U.S. is 13 per 100,000 population.

Incidence of NHL as increased greater than 80% over the last 3 decades.

American Cancer Society estimate of probability for a male from birth to 39 years to develop a NHL is 0.14%.

4th leading cause of cancer mortality for individuals under the age of 15 years.

Steadily increasing incidence over the last 50 years.

5-year relative survival rate approximately 63%.

Associated with both congenital and iatrogenic immunosuppression.

Aggressive B cell NHLs that are refractory to first line therapy or that relapse  following initial treatment are historically associated with the poor prognosis, despite the use of salvage chemotherapy and autologous stem cell transplant.

Epstein-Barr virus commonly associated with the number of B cell lymphomas including Burkitt lymphoma, Lymphomas arising in the setting of immunosuppression, HIV and other lymphomas in patients with normal immune systems.

B-cell lymphomas associated with increased risk include: occupational and environmental exposure to certain pesticides and herbicide, immunosuppression associated with HIV, auto immune disorders, iatrogenic induced immune suppression in the post transplant in other settings, family history, and a personal history of a prior cancer, including Hodgkin’s lymphoma and prior NHL.

Other infectious agents associated with lymphomas include human T-lymphotropic virus type associated with adult T-cell leukemia/lymphoma, human herpesvirus 8 associated with primary effusion lymphoma, hepatitis B virus infection associated with some types of lymphoma,

Helicobacter pylori associated with gastric mucosal associated lymphoid tissue MALToma’s, hepatitis C virus associated with splenic marginal zone lymphoma, and Chlamydia psittacosis, Borelia burgdorferi associated with extranodal marginal zone lymphoma of the ocular adnexa or the skin.

Additional risk factors for the development of lymphoma include exposure to radiation, chemotherapy and particularly combination therapy.

Increased incidence link to hepatitis B and hepatitis C.

50% increase in incidence in the U.S. from 1970-1990, with slowing of rising incidence in the late 1990’s.

Incidence increases with advancing age, more common in males and whites than blacks.

Annual increase in incidence is 1-2%.

Five-year survival rates are 73% for whites and 63% for African-Americans.

Risk 100-300 times increased in patients with HIV/AIDS.

Associated with family history, genetic instability and chemical exposure.

Classification has shifted from a morphological and immunophenotypic one to one based on molecular findings.

Can be classified according to the cell of origin has B, T, one natural killer cell, as well as mature or immature phenotype.

Classified as indolent (low grade), intermediate or aggressive (high grade).

Diffuse large B cell lymphoma is the most common aggressive lymphoma and follicular lymphoma is the most common indolent lymphoma accounting for 45% and 20% of lymphomas, respectively.

Other aggressive lymphomas include Burkitt’s and mantle cell lymphoma.

CT/PET imaging is the standard modality for staging, restaging, monitoring therapy, and to detect recurrent disease.

CNS involvement at presentation occurs in 2% of patients with systemic non-Hodgkin’s lymphoma.

Non-Hodgkin’s lymphoma (NHL)-T-cell lymphomas make patients less than 10% of lymphomas.

Subtypes include follicular lymphoma, diffuse large B-cell lymphoma, marginal zone lymphoma, mantle cell lymphoma, Burkitt and lymphoblastic lymphoma.

Diffuse large B-cell lymphoma represents 30-35% of all NHL subtypes.

Can start in lymph nodes, spleen, or in lymphatic tissue in organs such as the stomach or skin.

Most patients present with painless lymphadenopathy but some present with constitutional symptoms including night sweats, fevers, and unexplained weight loss.

Diagnosis is established by tissue biopsy.

Classification is based on World Health Organization classification of lymphoid neoplasms.

Gastrointestinal tract is site of 30-70% of all extranodal non-Hodgkin’s lymphomas.

Vascular endothelial growth factor-A (VEGF-A) expression is common in all NHL subtypes, and is particularly highly expressed in PTCL (Peripheral T-cell lymphoma).

Primary pancreatic lymphomas constitute less than 1% of all extranodal lymphomas and 0.76% of all pancreatic malignancies.

Primary ovarian NHL accounts for 0.5% of extranodal NHL and 1.5% of primary ovarian cancers.

Primary pulmonary NHL uncommon accounting for 3.6% of extranodal lymphomas.

Most important risk factor is immunodeficiency with increased risk in ataxia telangiectasia, Wiskott-Aldrich syndrome, acquired immunodeficiency, HIV infection and following solid organ or bone marrow transplantation.

Survival 65-75% for advanced lymphoblastic lymphoma, 75-90% for advanced Burkitt’s lymphoma in children.

B-cell NHL with <20% infiltrating CD4 + T cells have and inferior disease free and overall survival compared with patients with >20% CD 4 + cells.

Peripheral T-cell lymphomas are a heterogeneous group of generally aggressive neoplasms, which constitute less than 15% of NHL’s in adults.

Children with recurrent lymphoma have a 5-year survival of 12%.

Persistent abnormal PET scan after first-line chemotherapy in NHL is highly predictive for residual or recurrent disease.

Approximately 80% of patients with negative PET scans after initial chemotherapy have a progression free survival of 1500 days, while 80% of those with positive PET scans demonstrate progressive disease within 180 days.

Diffuse large B-cell lymphoma treatment comparing CHOP (cyclophosphamide, doxirubicin, vincristine and prednisone) with CHOP-R (Rituximab) reveals the latter with a higher complete response rate, event-free survival and prolonged overall survival.

Lenalidomide in aggressive NHL in refractory or relapsed patients overall response rate of 35%, CR 13%, partial response of 22% and stable disease 21% (ASH 1714).

Patients with B symptoms have a higher incidence of severe leucopoenia, anemia, thrombocytopenia, nausea, vomiting, and diarrhea compared to individuals without B symptoms when given chemotherapy (Sharma).

Patients with B symptoms and treated with chemotherapy had no difference in response rates, or survival compared to patients without B symptoms treated with chemotherapy (Sharma).

Indolent lymphoma may develop into aggressive Non-Hodgkin’s lymphoma and the process is designated as transformation.

Frequency of lymphoma transformation ranges from 10-70% of cases.

Transformation to aggressive lymphoma related to poor outcome and most patients die within 1 year.

Associated with increased risk of many forms of cancers including brain tumors, melanoma, lung cancer, nonmelanoma skin cancers, Hodgkin’s disease, Kaposi’s sarcoma, Merkel cell carcinoma, mycoses fungoides, eruptive multiple piloleiomyomas, and metastatic adnexal tumors.

Pembrolizumab approved for classic HD with relapsed disease-overall response rate of 69%.

Chimeric antigen receptor (CAR) T-cell therapy has change the treatment paradigm for patients who have relapse/refractory aggressive B-cell NHL.

The development of CD19 specific chimeric antigen receptor T cell therapy has revolutionized treatment for patients with relapsed or resistant aggressive B cell NHL with overall response rates from 52 to 82%, 12 month progressive free survival between 44 to 65%, 12 month overall survival rate of 49 to 59%.

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