Clinical presentation
Non-Hodgkin lymphoma (NHL) consists of a heterogeneous group of tumors, which are classified based on immunologic origin, clinical features, and treatment options. Most commonly non-Hodgkin lymphomas are manifesting as a painless swallowing of superficial lymph nodes stations (neck, axillary, inguinal), but sometimes can also rise in other areas (gastrointestinal, nervous, skin, bone marrow).
Two main types are known, which can be distinguished only on histopathologic features on biopsy:
(1) B-cell lymphomas (about 90% of the cases)
(2) T-cell lymphomas
Causes
The factors known to have the most impact on non-Hodgkin lymphoma (NHL) incidence at the population level are older age and, for most subtypes, male sex. Like many cancers, there appears to be a genetic component to NHL risk, though the extent and variability by NHL subtype remains unclear. Several reports about large pedigrees with recurrent cases of non-Hodgkin lymphoma across multiple generations have been reported. Familial association has been described also between non-Hodgkin lymphoma and other different types of lymphoproliferative malignancies (Altieri et al, 2005). However, with the exception of PRF1 mutations, only somatic mutations in few genes have been reported so far, indicating that the susceptibility to the disease is not transmitted as a pure Mendelian trait. Therefore it is likely that other genetic/epigenetic components and/or environmental factors are pivotal in the development of the disease. So far, somatic mutations in non-Hodgkin lymphoma have been detected in the following genes: CASP10, ATM, RAD54L, BRAF, CARD11, TNFAIP3, TRAF2, EZH2, CREBBP, EP300, MLL2, and MEF2B (see OMIM 605027). However, it is important to stress once again that mutations in these gene might be a contributory cause or even a consequence of the development of non-Hodgkin lymphoma, thus that genetic testing for the aforementioned genes is not indicated as a diagnostic step. An exception is represented by PRF1 mutations. Four patients with non-Hodgkin lymphoma and apparently pure autosomal recessive inheritance have been found to carry mutations in the PRF1 gene. However, these patients also had features of hemophagocytic lymphohistiocytosis, a genetic disorder caused by PRF1 mutations (Clementi et al. 2005).
As an interesting genetic aspect, it has been reported that anticipation (a phenomenon by which the severity of the disease increases from a generation to the next one) has been described as being a trait of familial susceptibility to non-Hodgkin lymphoma (Wiernik PH, 2000, Jønsson V, 2010). In general, it seems that anticipation can be a characteristic of all familial B-cell malignancies (non-Hodgkin lymphoma and Hodgkin’s disease) and can correlate with the parental age at conception (Alexandrescu DT, 2007). However, it is of note that not all authors agree on anticipation concepts in familial B-cell malignancies (Daugherty SE et al, 2005, PMID: 15894680).
In regards to other genetic factors, but with emphasis on the differential diagnosis, it is important to highlight that non-Hodgkin lymphomas may also be part of the clinical spectrum of features of X-linked lymphoproliferative disease (XLP). XLP is caused by mutations in SH2D1A (XLP1) and XIAP (XLP2). XLP is inherited in an X-linked manner (that means females are carriers and males are affected). XLP1 (the subtype caused by SH2D1A mutations can actually show up with three different phenotypes: (1) severe infectious mononucleosis or hemophagocytic lymphohistiocytosis (HLH), (2) dysgammaglobulinemia or (3) B-cell origin lymphoproliferative disorders like non-Hodgkin lymphoma. XLP1 presents marked clinical variability (even within the same family), with some males being even asymptomatic. XLP1 lymphomas often develop in childhood and may occur prior to EBV exposure. By contrast, no lymphoproliferative disease has been reported in males with XLP2 (caused by XIAP mutation). Also some males with XLP2 can be asymptomatic.
In general, in suspected familial non-Hodgkin lymphoma, epidemiological evidence is just limited to self-reported family history. There is also some evidence that relatives may develop the same NHL subtype, and that other cancers in first-degree relatives may also be associated with an increased risk of NHL.
Diagnosis
The diagnosis of non-Hodgkin lymphoma is based on clinical examination (anamnesis, palpation of lymph nodes, spleen and liver), imaging techniques (ultrasound, magnetic resonance, tomography) and lump biopsy. No genetic test is available to date, as familial non-Hodgkin lymphoma is better identified as a complex trait of susceptibility where genes may play an important but no exclusive role. The patients so far described as having an apparently pure Mendelian form of autosomal recessive non-Hodgkin lymphoma also had features of hemophagocytic lymphohistiocytosis (PRF1 gene mutations).
Patients with known or suspected lymphoma will be examined by routine blood test, which includes complete blood cell count. Anemia may be present, as well as lactate dehydrogenase (LDH) levels and erythrocyte sedimentation rate (ESR) are often increased.
What to do in cases of positive familial history
Unfortunately there is little to do to prevent the occurrence of non-Hodgkin lymphoma. However, in case of positive family history, the referring physician should be informed. Even considering that familial susceptibility to non-Hodgkin lymphoma does not appear to segregate as a pure Mendelian trait, it could be recommended considering regular follow-ups by routine blood tests and clinical examination.
References:
cancerresearchuk.org
OMIM 605027
Filipovich, 2011, PMID: 20301580
Altieri, 2005 PMID: 15811955
Wiernik, 2000, PMID: 10651726
Jønsson, 2010, PMID: 21576419
Alexandrescu, 2007, PMID: 17673812
Clementi, 2005, PMID: 15728124
Two main types are known, which can be distinguished only on histopathologic features on biopsy:
(1) B-cell lymphomas (about 90% of the cases)
(2) T-cell lymphomas
Causes
The factors known to have the most impact on non-Hodgkin lymphoma (NHL) incidence at the population level are older age and, for most subtypes, male sex. Like many cancers, there appears to be a genetic component to NHL risk, though the extent and variability by NHL subtype remains unclear. Several reports about large pedigrees with recurrent cases of non-Hodgkin lymphoma across multiple generations have been reported. Familial association has been described also between non-Hodgkin lymphoma and other different types of lymphoproliferative malignancies (Altieri et al, 2005). However, with the exception of PRF1 mutations, only somatic mutations in few genes have been reported so far, indicating that the susceptibility to the disease is not transmitted as a pure Mendelian trait. Therefore it is likely that other genetic/epigenetic components and/or environmental factors are pivotal in the development of the disease. So far, somatic mutations in non-Hodgkin lymphoma have been detected in the following genes: CASP10, ATM, RAD54L, BRAF, CARD11, TNFAIP3, TRAF2, EZH2, CREBBP, EP300, MLL2, and MEF2B (see OMIM 605027). However, it is important to stress once again that mutations in these gene might be a contributory cause or even a consequence of the development of non-Hodgkin lymphoma, thus that genetic testing for the aforementioned genes is not indicated as a diagnostic step. An exception is represented by PRF1 mutations. Four patients with non-Hodgkin lymphoma and apparently pure autosomal recessive inheritance have been found to carry mutations in the PRF1 gene. However, these patients also had features of hemophagocytic lymphohistiocytosis, a genetic disorder caused by PRF1 mutations (Clementi et al. 2005).
As an interesting genetic aspect, it has been reported that anticipation (a phenomenon by which the severity of the disease increases from a generation to the next one) has been described as being a trait of familial susceptibility to non-Hodgkin lymphoma (Wiernik PH, 2000, Jønsson V, 2010). In general, it seems that anticipation can be a characteristic of all familial B-cell malignancies (non-Hodgkin lymphoma and Hodgkin’s disease) and can correlate with the parental age at conception (Alexandrescu DT, 2007). However, it is of note that not all authors agree on anticipation concepts in familial B-cell malignancies (Daugherty SE et al, 2005, PMID: 15894680).
In regards to other genetic factors, but with emphasis on the differential diagnosis, it is important to highlight that non-Hodgkin lymphomas may also be part of the clinical spectrum of features of X-linked lymphoproliferative disease (XLP). XLP is caused by mutations in SH2D1A (XLP1) and XIAP (XLP2). XLP is inherited in an X-linked manner (that means females are carriers and males are affected). XLP1 (the subtype caused by SH2D1A mutations can actually show up with three different phenotypes: (1) severe infectious mononucleosis or hemophagocytic lymphohistiocytosis (HLH), (2) dysgammaglobulinemia or (3) B-cell origin lymphoproliferative disorders like non-Hodgkin lymphoma. XLP1 presents marked clinical variability (even within the same family), with some males being even asymptomatic. XLP1 lymphomas often develop in childhood and may occur prior to EBV exposure. By contrast, no lymphoproliferative disease has been reported in males with XLP2 (caused by XIAP mutation). Also some males with XLP2 can be asymptomatic.
In general, in suspected familial non-Hodgkin lymphoma, epidemiological evidence is just limited to self-reported family history. There is also some evidence that relatives may develop the same NHL subtype, and that other cancers in first-degree relatives may also be associated with an increased risk of NHL.
Diagnosis
The diagnosis of non-Hodgkin lymphoma is based on clinical examination (anamnesis, palpation of lymph nodes, spleen and liver), imaging techniques (ultrasound, magnetic resonance, tomography) and lump biopsy. No genetic test is available to date, as familial non-Hodgkin lymphoma is better identified as a complex trait of susceptibility where genes may play an important but no exclusive role. The patients so far described as having an apparently pure Mendelian form of autosomal recessive non-Hodgkin lymphoma also had features of hemophagocytic lymphohistiocytosis (PRF1 gene mutations).
Patients with known or suspected lymphoma will be examined by routine blood test, which includes complete blood cell count. Anemia may be present, as well as lactate dehydrogenase (LDH) levels and erythrocyte sedimentation rate (ESR) are often increased.
What to do in cases of positive familial history
Unfortunately there is little to do to prevent the occurrence of non-Hodgkin lymphoma. However, in case of positive family history, the referring physician should be informed. Even considering that familial susceptibility to non-Hodgkin lymphoma does not appear to segregate as a pure Mendelian trait, it could be recommended considering regular follow-ups by routine blood tests and clinical examination.
References:
cancerresearchuk.org
OMIM 605027
Filipovich, 2011, PMID: 20301580
Altieri, 2005 PMID: 15811955
Wiernik, 2000, PMID: 10651726
Jønsson, 2010, PMID: 21576419
Alexandrescu, 2007, PMID: 17673812
Clementi, 2005, PMID: 15728124
