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Lymphoid Malignancies developing non-Hodgkin lymphoma is 2.1%, whereas the life- time risk of developing Hodgkin lymphoma is considerably ¢ Lymphadenopathy is the most common sign of lymphoma. less. Although incidence has only slightly declined recently, e Diagnosis of lymphoma is generally established by exci- death rates have decreased significantly owing to improve- ments in treatment. The incidence of non-Hodgkin lymphoma sion or core needle biopsy, with excision often preferred rises with increased age, whereas the incidence of Hodgkin to better determine nodal architecture.

developing non-Hodgkin lymphoma is 2.1%, whereas the life- time risk of developing Hodgkin lymphoma is considerably ¢ Lymphadenopathy is the most common sign of lymphoma. less. Although incidence has only slightly declined recently, e Diagnosis of lymphoma is generally established by exci- death rates have decreased significantly owing to improve- ments in treatment. The incidence of non-Hodgkin lymphoma sion or core needle biopsy, with excision often preferred rises with increased age, whereas the incidence of Hodgkin to better determine nodal architecture. lymphoma shows a bimodal age distribution, with an early peak in the second and third decades of life, then a decline, followed by a sustained increase with older age. Classifications, Staging, and Although most of these cases seem sporadic, familial Prognosis of Malignant Lymphoma clustering can be seen, with an increased relative risk in first- Diagnosis and classification of lymphoma are established not degree relatives. Patients with both congenital and acquired just on standard cell type and nodal architecture but also on immunosuppression (such as HIV infection, organ transplan- flow cytometry, immunohistochemical stains, and cytogenetic tation, or inherited immunodeficiencies) are at greater risk. and molecular genetic features. Experienced hematopatholo- Various viral infections are also associated with increased gists are essential to obtaining proper classification. However, risk. Epstein-Barr virus is associated with Burkitt lymphoma, there can be disagreement among experts and some overlap seen in African pediatric patients, as well as some cases of among tumor types. Hodgkin lymphoma. Human T-cell lymphotropic virus Staging the anatomical extent of spread can be simplified type 1 is associated with T-cell leukemias and lymphomas, through the Ann Arbor staging system (Figure 3). endemic in Japan, West Africa, Central America, the Lymphomas are staged I to IV based on the number of Southeastern United States, and the Caribbean. Hepatitis C disease sites and the presence of extranodal involvement. virus is associated with an increased risk of lymphoma, par- Staging involves physical examination, CT scans, and PET ticularly splenic marginal zone lymphoma. HIV infection is scans in most patients. However, PET scans tend to be less associated with an increased risk of principally B-cell lym- sensitive for some very indolent lymphomas (such as small phomas, typically with aggressive histology, more advanced lymphocytic lymphoma and marginal zone lymphomas). stage, more B symptoms, and a higher risk of extranodal and The use of PET scans has obviated the need for bone marrow central nervous system involvement. Kaposi sarcoma herpes- biopsies in many patients with Hodgkin lymphoma and virus (human herpesvirus 8) is associated with primary effu- large cell lymphoma, as marrow involvement is rarely found sion lymphoma. if it is not suggested by PET and abnormal complete blood Patients with autoimmune rheumatic disorders, such as count. Sjégren syndrome, systemic lupus erythematosus, and rheu- Lymphoma stages are also designated A or B; A indicates matoid arthritis, have an increased risk of non-Hodgkin no systemic symptoms are present, and B indicates the pres- lymphoma. ence of one or more of the following: fever >38.0 °C (>100.4 °F), drenching night sweats, or a weight loss of >10% of body weight over the past 6 months. Evaluation and Diagnosis The prognosis of the lymphoma varies greatly depending Lymphadenopathy is the most common sign of lymphoma. on the subtype, stage, and comorbidities. Imnmunophenotypic, There are many causes of lymphadenopathy, and in most cytogenetic, and molecular genetic classifications also com- patients, it is of benign origin (infectious or inflammatory). monly inform the prognosis. Prognostic indices have been Palpable small cervical and inguinal lymph nodes may be reported and validated for most common types, including the noted in otherwise healthy adults and need not be evaluated International Prognostic Index for large cell lymphoma, the further. Increase in size, distribution, and persistence, along Follicular Lymphoma International Prognostic Index, and the with systemic symptoms, raises the concern for lymphoma. Mantle Cell International Prognostic Index. CT scan of the chest, abdomen, and pelvis can assess lymph nodes not amenable to physical examination but generally should not be done in asymptomatic patients before estab- e A negative PET scan may obviate the need for bone HVC lishing the lymphoma diagnosis. An excisional biopsy is marrow biopsies in many patients with Hodgkin and often preferable to a core needle biopsy, as it may better large cell lymphoma, but PET scans are less sensitive in determine nodal architecture. Fine-needle aspiration cytol- the very indolent lymphomas. ogy is generally inadequate to make a specific diagnosis. Flow cytometry can suggest monoclonality and demonstrate B-cell

lymphoma shows a bimodal age distribution, with an early peak in the second and third decades of life, then a decline, followed by a sustained increase with older age. Classifications, Staging, and Although most of these cases seem sporadic, familial Prognosis of Malignant Lymphoma clustering can be seen, with an increased relative risk in first- Diagnosis and classification of lymphoma are established not degree relatives. Patients with both congenital and acquired just on standard cell type and nodal architecture but also on immunosuppression (such as HIV infection, organ transplan- flow cytometry, immunohistochemical stains, and cytogenetic tation, or inherited immunodeficiencies) are at greater risk. and molecular genetic features. Experienced hematopatholo- Various viral infections are also associated with increased gists are essential to obtaining proper classification. However, risk. Epstein-Barr virus is associated with Burkitt lymphoma, there can be disagreement among experts and some overlap seen in African pediatric patients, as well as some cases of among tumor types. Hodgkin lymphoma. Human T-cell lymphotropic virus Staging the anatomical extent of spread can be simplified type 1 is associated with T-cell leukemias and lymphomas, through the Ann Arbor staging system (Figure 3). endemic in Japan, West Africa, Central America, the Lymphomas are staged I to IV based on the number of Southeastern United States, and the Caribbean. Hepatitis C disease sites and the presence of extranodal involvement. virus is associated with an increased risk of lymphoma, par- Staging involves physical examination, CT scans, and PET ticularly splenic marginal zone lymphoma. HIV infection is scans in most patients. However, PET scans tend to be less associated with an increased risk of principally B-cell lym- sensitive for some very indolent lymphomas (such as small phomas, typically with aggressive histology, more advanced lymphocytic lymphoma and marginal zone lymphomas). stage, more B symptoms, and a higher risk of extranodal and The use of PET scans has obviated the need for bone marrow central nervous system involvement. Kaposi sarcoma herpes- biopsies in many patients with Hodgkin lymphoma and virus (human herpesvirus 8) is associated with primary effu- large cell lymphoma, as marrow involvement is rarely found sion lymphoma. if it is not suggested by PET and abnormal complete blood Patients with autoimmune rheumatic disorders, such as count. Sjégren syndrome, systemic lupus erythematosus, and rheu- Lymphoma stages are also designated A or B; A indicates matoid arthritis, have an increased risk of non-Hodgkin no systemic symptoms are present, and B indicates the pres- lymphoma. ence of one or more of the following: fever >38.0 °C (>100.4 °F), drenching night sweats, or a weight loss of >10% of body weight over the past 6 months. Evaluation and Diagnosis The prognosis of the lymphoma varies greatly depending Lymphadenopathy is the most common sign of lymphoma. on the subtype, stage, and comorbidities. Imnmunophenotypic, There are many causes of lymphadenopathy, and in most cytogenetic, and molecular genetic classifications also com- patients, it is of benign origin (infectious or inflammatory). monly inform the prognosis. Prognostic indices have been Palpable small cervical and inguinal lymph nodes may be reported and validated for most common types, including the noted in otherwise healthy adults and need not be evaluated International Prognostic Index for large cell lymphoma, the further. Increase in size, distribution, and persistence, along Follicular Lymphoma International Prognostic Index, and the with systemic symptoms, raises the concern for lymphoma. Mantle Cell International Prognostic Index. CT scan of the chest, abdomen, and pelvis can assess lymph nodes not amenable to physical examination but generally should not be done in asymptomatic patients before estab- e A negative PET scan may obviate the need for bone HVC lishing the lymphoma diagnosis. An excisional biopsy is marrow biopsies in many patients with Hodgkin and often preferable to a core needle biopsy, as it may better large cell lymphoma, but PET scans are less sensitive in determine nodal architecture. Fine-needle aspiration cytol- the very indolent lymphomas. ogy is generally inadequate to make a specific diagnosis. Flow cytometry can suggest monoclonality and demonstrate B-cell or T-cell markers. Non-Hodgkin Lymphomas Although most patients with lymphoma present with Approximately 85% of non-Hodgkin lymphomas are B-cell lymph node involvement, presentation in extranodal sites is derived and express surface immunoglobulin and B-cell mark- not uncommon. ers, whereas 15% are T-cell derived.

or T-cell markers. Non-Hodgkin Lymphomas Although most patients with lymphoma present with Approximately 85% of non-Hodgkin lymphomas are B-cell lymph node involvement, presentation in extranodal sites is derived and express surface immunoglobulin and B-cell mark- not uncommon. ers, whereas 15% are T-cell derived. 32

Lymphoid Malignancies Stage | Stage Il Stage Ill Stage IV * Involvement of single = Involvement of =2 lymph * Involvement of lymph = Disseminated (multifocal) lymph node region; or node regions on same node regions on both extralymphatic disease side of diaphragm sides of diaphragm involving one or more Involvement of single organs (e.g., liver, bone, extralymphatic site " May include localized » May include involvement marrow, lung, skin), (stage IE) extralymphatic of spleen (stage IIIS) +/— associated lymph involvement on same or localized extranodal node involvement; or side of diaphragm disease (stage IIIE) or (stage IIE) both (IIIE+S) = Isolated extralymphatic disease with distant For Hodgkin lymphoma: (nonregional) lymph 111 node involvement

* Involvement of single = Involvement of =2 lymph * Involvement of lymph = Disseminated (multifocal) lymph node region; or node regions on same node regions on both extralymphatic disease side of diaphragm sides of diaphragm involving one or more Involvement of single organs (e.g., liver, bone, extralymphatic site " May include localized » May include involvement marrow, lung, skin), (stage IE) extralymphatic of spleen (stage IIIS) +/— associated lymph involvement on same or localized extranodal node involvement; or side of diaphragm disease (stage IIIE) or (stage IIE) both (IIIE+S) = Isolated extralymphatic disease with distant For Hodgkin lymphoma: (nonregional) lymph 111 node involvement Disease limited to upper abdomen-spleen, splenic hilar, celiac, or portahepatic nodes

Disease limited to upper abdomen-spleen, splenic hilar, celiac, or portahepatic nodes WN Disease limited to lower abdomen-periaortic, pelvic or inguinal nodes FIGURE 3. Ann Arbor Staging System for Hodgkin and non-Hodgkin lymphoma. Reprinted with permission from Skarkin, A. The Atlas of Diagnostic Oncology, 3rd Edition. Mosby. Copyright Elsevier, 2002. Indolent B-Cell Lymphomas without bulky disease are usually observed. Some patients The indolent lymphomas may be present for many years with- may undergo spontaneous, although generally transient, dis- out symptoms and typically have a favorable response to vari- ease regression. ous sequential therapies when needed, but all have a tendency Most patients with follicular lymphoma will present with for continued relapse. stage III or IV disease. When therapy is indicated, single-agent rituximab is associated with high response rates and durable

ous sequential therapies when needed, but all have a tendency Most patients with follicular lymphoma will present with for continued relapse. stage III or IV disease. When therapy is indicated, single-agent rituximab is associated with high response rates and durable Follicular Lymphoma remissions. Combining rituximab with chemotherapy (such as Follicular lymphomas demonstrate lymph node architecture the alkylating agent bendamustine or the immune modulator with a follicular morphology. They arise from the germinal lenalidomide) leads to remission in more than 90% of patients. center B cells of the lymph node and are characterized by the The use of maintenance rituximab after induction of an initial presence of a t(14;18) translocation that causes an overexpres- remission is associated with prolonged duration of remission, sion of the BCL2 oncogene. Follicular lymphomas are classi- but no clear improvement in overall survival. Patients with fied based on their dominant cell type: predominantly smaller relapsing or refractory cases can be treated with other cells (grade 1), a mixture of smaller and larger cells (grade 2), approaches, including alternate chemotherapy regimens as and predominantly large cells (grade 3). For prognostic and well as autologous or allogeneic hematopoietic stem cell trans- treatment purposes, grades 1 and 2 are commonly combined. plantation (HSCT). Grade 3 follicular lymphoma can be divided into 3A and 3B. A minority of patients present with localized disease and Grade 3A follicular lymphoma is more akin in behavior and can be approached with radiation therapy and/or systemic treatment to grades 1 and 2, whereas 3B is usually treated more rituximab-based therapy with curative intent.

Follicular Lymphoma remissions. Combining rituximab with chemotherapy (such as Follicular lymphomas demonstrate lymph node architecture the alkylating agent bendamustine or the immune modulator with a follicular morphology. They arise from the germinal lenalidomide) leads to remission in more than 90% of patients. center B cells of the lymph node and are characterized by the The use of maintenance rituximab after induction of an initial presence of a t(14;18) translocation that causes an overexpres- remission is associated with prolonged duration of remission, sion of the BCL2 oncogene. Follicular lymphomas are classi- but no clear improvement in overall survival. Patients with fied based on their dominant cell type: predominantly smaller relapsing or refractory cases can be treated with other cells (grade 1), a mixture of smaller and larger cells (grade 2), approaches, including alternate chemotherapy regimens as and predominantly large cells (grade 3). For prognostic and well as autologous or allogeneic hematopoietic stem cell trans- treatment purposes, grades 1 and 2 are commonly combined. plantation (HSCT). Grade 3 follicular lymphoma can be divided into 3A and 3B. A minority of patients present with localized disease and Grade 3A follicular lymphoma is more akin in behavior and can be approached with radiation therapy and/or systemic treatment to grades 1 and 2, whereas 3B is usually treated more rituximab-based therapy with curative intent. like diffuse large B-cell lymphoma. Histologic transformation, most typically to a diffuse Follicular lymphoma is the most common indolent B-cell large B-cell lymphoma, occurs in approximately 30% of lymphoma and accounts for approximately 30% of non-Hodgkin patients with follicular lymphomas and is associated with an lymphomas. Many patients are not symptomatic at diagnosis aggressive course and poor prognosis. Transformation may be and may not require therapy for many years. Early treatment suggested by a change in the clinical pattern of disease with does not improve outcomes, so asymptomatic patients new systemic symptoms or rapid progression of a localized

like diffuse large B-cell lymphoma. Histologic transformation, most typically to a diffuse Follicular lymphoma is the most common indolent B-cell large B-cell lymphoma, occurs in approximately 30% of lymphoma and accounts for approximately 30% of non-Hodgkin patients with follicular lymphomas and is associated with an lymphomas. Many patients are not symptomatic at diagnosis aggressive course and poor prognosis. Transformation may be and may not require therapy for many years. Early treatment suggested by a change in the clinical pattern of disease with does not improve outcomes, so asymptomatic patients new systemic symptoms or rapid progression of a localized 33

Lymphoid Malignancies « 3,98 area of disease, a rise in serum lactate dehydrogenase, or G 4 —— ww markedly higher areas of standardized uptake values on PET o< heal scans. A new biopsy is required to establish that transforma- 006 tion has occurred. ¢ Many patients with follicular lymphoma are not symp- | 90’ 9o.6lCP tomatic at diagnosis and may not require therapy for ,0 many years. e In advanced-stage follicular lymphoma, rituximab plus chemotherapy or with lenalidomide leads to remission '@90 “Wai in more than 90% of patients, although the disease will recur in most individuals. e Histologic transformation of follicular lymphoma to a FIGURE 4. The key to suspecting the diagnosis of chronic lymphocytic diffuse large B-cell lymphoma, which should be con- leukemia is the recognition of an increased blood leukocyte count due to increased firmed by obtaining another lymph node biopsy, is numbers of mature lymphocytes and “smudge’ cells (lymphocytes that appear associated with a poor prognosis. flattened or distorted) during the process of preparing the peripheral smear.

e Histologic transformation of follicular lymphoma to a FIGURE 4. The key to suspecting the diagnosis of chronic lymphocytic diffuse large B-cell lymphoma, which should be con- leukemia is the recognition of an increased blood leukocyte count due to increased firmed by obtaining another lymph node biopsy, is numbers of mature lymphocytes and “smudge’ cells (lymphocytes that appear associated with a poor prognosis. flattened or distorted) during the process of preparing the peripheral smear. Although less common, other lymphomas may appear Mucosa-Associated Lymphoid Tissue Lymphoma similar to CLL in peripheral blood smears and must be distin- Mucosa-associated lymphoid tissue (MALT) lymphoma is an guished by morphology, flow cytometry, and genetic studies. extranodal marginal zone lymphoma. Gastric MALT lym- These other disorders include hairy cell leukemia, marginal phoma is associated with Helicobacter pylori infection. and mantle zone lymphomas, T-cell lymphoma, and prolym- However, MALT lymphomas can arise in other sites of the phocytic leukemia. gastrointestinal tract as well as in the thyroid, orbits, skin, and CLL and small lymphocytic lymphoma represent the lung. They generally demonstrate indolent behavior and a low same disease, with the designation as leukemia or lymphoma propensity for transformation. Repetitive immune stimula- based on the dominant clinical manifestation in either periph- tion, from underlying chronic infection or an autoimmune eral blood and marrow or nodal involvement, respectively. process, likely plays a role in the pathogenesis of this tumor. Both CLL and small lymphocytic lymphoma are treated the H. pylori-associated gastric MALT lymphoma should be same. CLL is now grouped more with the lymphomas than initially treated with antibiotics and proton pump inhibitors, with the leukemias in treatment centers. as this treatment may lead to remission. Other localized MALT CLL is typically an indolent disease, and many patients lymphomas may be treated with irradiation, to which they are require no therapy for many years. Prognosis can relate to the quite sensitive. When systemic therapy is required, rituximab extent of cytopenias, organomegaly, and degree of nodal alone or in combination with chemotherapy is associated with involvement but also on cytogenetic and molecular genetic high response rates. characteristics.

Although less common, other lymphomas may appear Mucosa-Associated Lymphoid Tissue Lymphoma similar to CLL in peripheral blood smears and must be distin- Mucosa-associated lymphoid tissue (MALT) lymphoma is an guished by morphology, flow cytometry, and genetic studies. extranodal marginal zone lymphoma. Gastric MALT lym- These other disorders include hairy cell leukemia, marginal phoma is associated with Helicobacter pylori infection. and mantle zone lymphomas, T-cell lymphoma, and prolym- However, MALT lymphomas can arise in other sites of the phocytic leukemia. gastrointestinal tract as well as in the thyroid, orbits, skin, and CLL and small lymphocytic lymphoma represent the lung. They generally demonstrate indolent behavior and a low same disease, with the designation as leukemia or lymphoma propensity for transformation. Repetitive immune stimula- based on the dominant clinical manifestation in either periph- tion, from underlying chronic infection or an autoimmune eral blood and marrow or nodal involvement, respectively. process, likely plays a role in the pathogenesis of this tumor. Both CLL and small lymphocytic lymphoma are treated the H. pylori-associated gastric MALT lymphoma should be same. CLL is now grouped more with the lymphomas than initially treated with antibiotics and proton pump inhibitors, with the leukemias in treatment centers. as this treatment may lead to remission. Other localized MALT CLL is typically an indolent disease, and many patients lymphomas may be treated with irradiation, to which they are require no therapy for many years. Prognosis can relate to the quite sensitive. When systemic therapy is required, rituximab extent of cytopenias, organomegaly, and degree of nodal alone or in combination with chemotherapy is associated with involvement but also on cytogenetic and molecular genetic high response rates. characteristics. There have been rapid advances in the number and effi- cacy of active agents for CLL. Although these therapies are not ¢ Helicobacter pylori-associated gastric mucosa-associated curative, most patients can now achieve durable remissions lymphoid tissue (MALT) lymphoma should be treated once treatment is required. Treatment options include alkylat- with antibiotics and proton pump inhibitors initially; ing agents (chlorambucil, cyclophosphamide, bendamustine), other localized MALT lymphomas may be treated with purine nucleoside analogues (fludarabine, cladribine, pento- irradiation. statin), monoclonal antibodies (rituximab, alemtuzumab, ofa- tumumab, obinutuzumab), and the phosphoinositide-3 kinase Chronic Lymphocytic Leukemia inhibitors idelalisib and duvelisib. The Bruton kinase inhibitor Chronic lymphocytic leukemia (CLL) is generally readily diag- ibrutinib is now approved for first-line therapy and active in a nosed as an increase in absolute lymphocytes on complete blood broad spectrum of patients, including those with 17p deletion, count. The lymphocytes are predominantly small and mature an indicator of poor prognosis and resistance to older treat- appearing, although they may be fragile and form “smudge cells” ments. Venetoclax, an oral BCL2 inhibitor, is active in first-line on the peripheral smear (Figure 4). Flow cytometry using and in refractory cases, induces brisk apoptosis, and can peripheral blood is essential in establishing the diagnosis and induce tumor lysis syndrome. Allogeneic HSCT is rarely per- will reveal B-cell antigens (CD19, 20, and 23), co-expression of formed in those with CLL but has been used in refractory cases CD5 (normally a T-cell marker), and low levels of a monoclonal in selected, younger patients. Anti-CD19 chimeric antigen surface immunoglobulin. Bone marrow aspiration and biopsy receptor T-cell therapy has also been shown to be active in are not necessary to diagnose and stage most patients with CLL. refractory cases.

There have been rapid advances in the number and effi- cacy of active agents for CLL. Although these therapies are not ¢ Helicobacter pylori-associated gastric mucosa-associated curative, most patients can now achieve durable remissions lymphoid tissue (MALT) lymphoma should be treated once treatment is required. Treatment options include alkylat- with antibiotics and proton pump inhibitors initially; ing agents (chlorambucil, cyclophosphamide, bendamustine), other localized MALT lymphomas may be treated with purine nucleoside analogues (fludarabine, cladribine, pento- irradiation. statin), monoclonal antibodies (rituximab, alemtuzumab, ofa- tumumab, obinutuzumab), and the phosphoinositide-3 kinase Chronic Lymphocytic Leukemia inhibitors idelalisib and duvelisib. The Bruton kinase inhibitor Chronic lymphocytic leukemia (CLL) is generally readily diag- ibrutinib is now approved for first-line therapy and active in a nosed as an increase in absolute lymphocytes on complete blood broad spectrum of patients, including those with 17p deletion, count. The lymphocytes are predominantly small and mature an indicator of poor prognosis and resistance to older treat- appearing, although they may be fragile and form “smudge cells” ments. Venetoclax, an oral BCL2 inhibitor, is active in first-line on the peripheral smear (Figure 4). Flow cytometry using and in refractory cases, induces brisk apoptosis, and can peripheral blood is essential in establishing the diagnosis and induce tumor lysis syndrome. Allogeneic HSCT is rarely per- will reveal B-cell antigens (CD19, 20, and 23), co-expression of formed in those with CLL but has been used in refractory cases CD5 (normally a T-cell marker), and low levels of a monoclonal in selected, younger patients. Anti-CD19 chimeric antigen surface immunoglobulin. Bone marrow aspiration and biopsy receptor T-cell therapy has also been shown to be active in are not necessary to diagnose and stage most patients with CLL. refractory cases. 34

Lymphoid Malignancies Patients with CLL are prone to infection, in part related to a lacunar appearance. Classically, the bone marrow aspirate is commonly associated hypogammaglobulinemia. In patients a dry tap due to some degree of marrow fibrosis. Flow cytom- with repeated infections and hypogammaglobulinemia, regu- etry is positive for characteristic surface markers. In addition, lar treatment with intravenous gamma globulin reduces infec- The BRAF V600E mutation has been associated with hairy cell tious events. The infection risk increases in more advanced leukemia in most patients and represents not only a diagnostic disease, a result of both impaired T-cell-mediated and B-cell- marker but also a therapeutic target. mediated immune response along with treatment-induced As with CLL and other low-grade lymphomas, some immunosuppression. Patients with CLL and small lympho- patients with hairy cell leukemia do not require immediate cytic lymphoma may also develop autoimmune cytopenias treatment if not symptomatic. However, the front-line therapy such as immune thrombocytopenic purpura and autoimmune remains purine nucleoside agents, typically pentostatin or hemolytic anemias. Transformation to a large cell lymphoma cladribine. These agents are highly active, and almost all (Richter transformation) occurs in about 5% of patients with patients respond, many with durable responses, with only one CLL and small lymphocytic lymphoma and is generally associ- course of treatment. Relapses can be treated with the alternate ated with a poor prognosis and refractory disease. purine nucleoside agent, rituximab and the anti-CD22 immu- noconjugate moxetumomab pasudotox-tdfk. The selective BRAF inhibitor vemurafenib has also shown activity in e Chronic lymphocytic leukemia and small lymphocytic patients experiencing relapse. lymphoma are the same disease, but the former pre- The hairy cell leukemia variant is a distinct entity that dominates in peripheral blood and bone marrow, typically presents with a high circulating leukocyte count, as whereas the latter predominates in lymph nodes. opposed to the leukopenia seen in the classic form. These e The diagnosis of chronic lymphocytic leukemia mani- patients respond less well to cladribine and have shorter dura- fests as an increase in absolute lymphocytes on com- tions of response. plete blood count; the lymphocytes are predominantly small and mature appearing and may form “smudge cells” on the peripheral smear. e Patients with hairy cell leukemia typically present with circulating lymphocytes with cytoplasmic projections, e Patients with low-stage, asymptomatic chronic lympho- termed “hairy cells”; cytopenias; and splenomegaly but cytic leukemia can often be observed without therapy no lymphadenopathy. for many years. e Durable remissions of hairy cell leukemia can often be achieved with one course of a purine nucleoside agent Hairy Cell Leukemia such as pentostatin or cladribine. Like CLL, hairy cell leukemia is a low-grade B-cell disorder with characteristic clinical, pathologic, immunophenotypic, and genetic changes. Patients typically present with cytope- Aggressive B-Cell Lymphomas nias and splenomegaly; lymphadenopathy is typically absent. The more aggressive lymphomas, such as diffuse large B-cell Circulating “hairy cells,” characterized by cytoplasmic projec- and Burkitt lymphoma, are more likely to present with sys- tions, are often identified in the peripheral blood smear temic symptoms or signs of rapid tumor progression. These (Figure 5); when seen on bone marrow biopsy, these cells have patients have a greater potential for cure with therapy.

commonly associated hypogammaglobulinemia. In patients a dry tap due to some degree of marrow fibrosis. Flow cytom- with repeated infections and hypogammaglobulinemia, regu- etry is positive for characteristic surface markers. In addition, lar treatment with intravenous gamma globulin reduces infec- The BRAF V600E mutation has been associated with hairy cell tious events. The infection risk increases in more advanced leukemia in most patients and represents not only a diagnostic disease, a result of both impaired T-cell-mediated and B-cell- marker but also a therapeutic target. mediated immune response along with treatment-induced As with CLL and other low-grade lymphomas, some immunosuppression. Patients with CLL and small lympho- patients with hairy cell leukemia do not require immediate cytic lymphoma may also develop autoimmune cytopenias treatment if not symptomatic. However, the front-line therapy such as immune thrombocytopenic purpura and autoimmune remains purine nucleoside agents, typically pentostatin or hemolytic anemias. Transformation to a large cell lymphoma cladribine. These agents are highly active, and almost all (Richter transformation) occurs in about 5% of patients with patients respond, many with durable responses, with only one CLL and small lymphocytic lymphoma and is generally associ- course of treatment. Relapses can be treated with the alternate ated with a poor prognosis and refractory disease. purine nucleoside agent, rituximab and the anti-CD22 immu- noconjugate moxetumomab pasudotox-tdfk. The selective BRAF inhibitor vemurafenib has also shown activity in e Chronic lymphocytic leukemia and small lymphocytic patients experiencing relapse. lymphoma are the same disease, but the former pre- The hairy cell leukemia variant is a distinct entity that dominates in peripheral blood and bone marrow, typically presents with a high circulating leukocyte count, as whereas the latter predominates in lymph nodes. opposed to the leukopenia seen in the classic form. These e The diagnosis of chronic lymphocytic leukemia mani- patients respond less well to cladribine and have shorter dura- fests as an increase in absolute lymphocytes on com- tions of response. plete blood count; the lymphocytes are predominantly small and mature appearing and may form “smudge cells” on the peripheral smear. e Patients with hairy cell leukemia typically present with circulating lymphocytes with cytoplasmic projections, e Patients with low-stage, asymptomatic chronic lympho- termed “hairy cells”; cytopenias; and splenomegaly but cytic leukemia can often be observed without therapy no lymphadenopathy. for many years. e Durable remissions of hairy cell leukemia can often be achieved with one course of a purine nucleoside agent Hairy Cell Leukemia such as pentostatin or cladribine. Like CLL, hairy cell leukemia is a low-grade B-cell disorder with characteristic clinical, pathologic, immunophenotypic, and genetic changes. Patients typically present with cytope- Aggressive B-Cell Lymphomas nias and splenomegaly; lymphadenopathy is typically absent. The more aggressive lymphomas, such as diffuse large B-cell Circulating “hairy cells,” characterized by cytoplasmic projec- and Burkitt lymphoma, are more likely to present with sys- tions, are often identified in the peripheral blood smear temic symptoms or signs of rapid tumor progression. These (Figure 5); when seen on bone marrow biopsy, these cells have patients have a greater potential for cure with therapy. Diffuse Large B-Cell Lymphoma Diffuse large B-cell lymphoma represents approximately 30% of non-Hodgkin lymphomas. These patients often present with symptomatic enlarging lymphadenopathy. Approximately 40% may have symptoms or signs of extranodal disease, and one third have systemic B symptoms. Biopsy specimens show diffuse effacement of normal nodal architecture by large, atyp- ical lymphoid cells with prominent nucleoli and basophilic cytoplasm. Flow cytometry reveals B-cell antigens, and most patients have monoclonal surface immunoglobulin. The B-cell lymphoma 6 (BCL6) gene shows rearrangement or other mutations that lead to overexpression in most patients. Sixty percent of patients have advanced (stage III or IV) disease at diagnosis, and standard therapy is rituximab plus

Diffuse Large B-Cell Lymphoma Diffuse large B-cell lymphoma represents approximately 30% of non-Hodgkin lymphomas. These patients often present with symptomatic enlarging lymphadenopathy. Approximately 40% may have symptoms or signs of extranodal disease, and one third have systemic B symptoms. Biopsy specimens show diffuse effacement of normal nodal architecture by large, atyp- ical lymphoid cells with prominent nucleoli and basophilic cytoplasm. Flow cytometry reveals B-cell antigens, and most patients have monoclonal surface immunoglobulin. The B-cell lymphoma 6 (BCL6) gene shows rearrangement or other mutations that lead to overexpression in most patients. Sixty percent of patients have advanced (stage III or IV) disease at diagnosis, and standard therapy is rituximab plus FIGURE 5. Hairy cell leukemia depicted by a peripheral blood smear showing cyclophosphamide, doxorubicin, vincristine, and prednisone atypical lymphocytes with thread-like cytoplasmic projections from the cell surface. (R-CHOP). Consolidative radiation therapy may be given to 35

Lymphoid Malignancies sites of bulky disease. Residual masses, which are often benign, Burkitt Lymphoma may remain after treatment. PET may help determine if these A relatively rare lymphoma, Burkitt lymphoma, is remarkable represent active disease or just scarring. Patients should also for its extremely rapid growth. The endemic form occurs pri- have molecular studies performed to assess for double-hit marily in Africa, is a common cause of childhood cancer, and lymphoma (showing gene rearrangements of MYC in addition is associated with Epstein-Barr virus infection. Patients may to either BCL2 or BCL6), which is associated with worse prog- present with a large jaw mass. The sporadic form is more typi- nosis. Double-hit lymphoma is usually treated with aggressive cally seen in the United States, occurs at a somewhat later age, chemotherapeutic regimens and up-front autologous HSCT. and is more likely to present with abdominal or pelvic involve- Patients with poor prognostic features, such as elevated ment. A third variety of Burkitt lymphoma is the immunode- serum lactate dehydrogenase level, extensive tumor burden, ficiency-associated form and occurs in HIV-infected patients. and poor performance status, may receive more aggressive MYC gene activation is characteristic of this lymphoma. initial therapy, although superiority over standard R-CHOP is Early signs of the tumor lysis syndrome (TLS) are often unproven. Patients who present with localized disease can be present in patients with Burkitt lymphoma even before treat- treated with a shorter course of chemotherapy with consoli- ment is initiated and should be anticipated during treatment dative radiation therapy. In addition to further standard because the tumor is quite chemosensitive. Prophylaxis for chemotherapy, autologous HSCT and anti-CD19 chimeric TLS should be started before initiation of chemotherapy (for a antigen receptor T-cell therapy may be used in patients who more complete discussion of TLS, see Oncologic Emergencies relapse. and Urgencies). Various aggressive multiagent chemotherapy Primary mediastinal large cell lymphoma is a distinct regimens with rituximab have been associated with high cure clinical, morphologic, and genetic lymphoma, often present- rates. These regimens are more intensive than standard lym- ing in younger patients. It putatively arises from thymic B cells. phoma therapy and are associated with some risk of treatment- It has a female predilection, a tendency to present with bulky related mortality. Treatment of occult central nervous system but localized disease, and a relatively high cure rate. It may involvement is included in initial treatment regimens because have significant overlap histologically and genetically with of the risk for leptomeningeal involvement. nodular sclerosing Hodgkin lymphoma, and some cases may be difficult to classify as one or the other; these are called mediastinal gray-zone lymphomas. e Prophylaxis to manage tumor lysis syndrome should be instituted before initiation of chemotherapy for patients with Burkitt lymphoma. ¢ Aggressive B-cell lymphomas, such as diffuse large B-cell lymphoma, progress more quickly than indolent T-Cell Lymphomas lymphomas but have a greater potential for cure. T-cell lymphomas, a heterogeneous group of disorders with ¢ Standard therapy for most patients with advanced-stage distinct clinical features and morphology, represent approxi- diffuse large B-cell lymphoma is rituximab plus cyclo- mately 10% to 15% of lymphomas in Western countries but are phosphamide, doxorubicin, vincristine, and prednisone. more common in Asia. Diagnosis relies on routine pathology flow cytometry and immunohistochemistry. Monoclonality

sites of bulky disease. Residual masses, which are often benign, Burkitt Lymphoma may remain after treatment. PET may help determine if these A relatively rare lymphoma, Burkitt lymphoma, is remarkable represent active disease or just scarring. Patients should also for its extremely rapid growth. The endemic form occurs pri- have molecular studies performed to assess for double-hit marily in Africa, is a common cause of childhood cancer, and lymphoma (showing gene rearrangements of MYC in addition is associated with Epstein-Barr virus infection. Patients may to either BCL2 or BCL6), which is associated with worse prog- present with a large jaw mass. The sporadic form is more typi- nosis. Double-hit lymphoma is usually treated with aggressive cally seen in the United States, occurs at a somewhat later age, chemotherapeutic regimens and up-front autologous HSCT. and is more likely to present with abdominal or pelvic involve- Patients with poor prognostic features, such as elevated ment. A third variety of Burkitt lymphoma is the immunode- serum lactate dehydrogenase level, extensive tumor burden, ficiency-associated form and occurs in HIV-infected patients. and poor performance status, may receive more aggressive MYC gene activation is characteristic of this lymphoma. initial therapy, although superiority over standard R-CHOP is Early signs of the tumor lysis syndrome (TLS) are often unproven. Patients who present with localized disease can be present in patients with Burkitt lymphoma even before treat- treated with a shorter course of chemotherapy with consoli- ment is initiated and should be anticipated during treatment dative radiation therapy. In addition to further standard because the tumor is quite chemosensitive. Prophylaxis for chemotherapy, autologous HSCT and anti-CD19 chimeric TLS should be started before initiation of chemotherapy (for a antigen receptor T-cell therapy may be used in patients who more complete discussion of TLS, see Oncologic Emergencies relapse. and Urgencies). Various aggressive multiagent chemotherapy Primary mediastinal large cell lymphoma is a distinct regimens with rituximab have been associated with high cure clinical, morphologic, and genetic lymphoma, often present- rates. These regimens are more intensive than standard lym- ing in younger patients. It putatively arises from thymic B cells. phoma therapy and are associated with some risk of treatment- It has a female predilection, a tendency to present with bulky related mortality. Treatment of occult central nervous system but localized disease, and a relatively high cure rate. It may involvement is included in initial treatment regimens because have significant overlap histologically and genetically with of the risk for leptomeningeal involvement. nodular sclerosing Hodgkin lymphoma, and some cases may be difficult to classify as one or the other; these are called mediastinal gray-zone lymphomas. e Prophylaxis to manage tumor lysis syndrome should be instituted before initiation of chemotherapy for patients with Burkitt lymphoma. ¢ Aggressive B-cell lymphomas, such as diffuse large B-cell lymphoma, progress more quickly than indolent T-Cell Lymphomas lymphomas but have a greater potential for cure. T-cell lymphomas, a heterogeneous group of disorders with ¢ Standard therapy for most patients with advanced-stage distinct clinical features and morphology, represent approxi- diffuse large B-cell lymphoma is rituximab plus cyclo- mately 10% to 15% of lymphomas in Western countries but are phosphamide, doxorubicin, vincristine, and prednisone. more common in Asia. Diagnosis relies on routine pathology flow cytometry and immunohistochemistry. Monoclonality can be confirmed by findings of clonal rearrangements of the Mantle Cell Lymphoma T-cell receptor genes detected by polymerase chain reaction. Mantle cell lymphomas represent approximately 3% to 6% of In general, T-cell lymphomas are more refractory and relapse non-Hodgkin lymphomas. Median age at diagnosis is 68 years, more quickly in response to therapy than B-cell lymphomas. and there is a 3:1 male predominance. It is defined by a t(11;14) translocation, which leads to constitutive overexpression of Cutaneous T-Cell Lymphoma cyclin D1, a cell-cycle gene regulator. Patients can present with Mycosis fungoides and Sézary syndrome are the two major nodal or extranodal disease, and the disease is usually widely subtypes of cutaneous T-cell lymphoma. The skin findings in disseminated at diagnosis. Gastrointestinal involvement with mycosis fungoides range from nonspecific macular-papular lymphomatoid polyposis is well described, as is involvement eruptions or plaques, to more defined skin tumors with ulcer- of the peripheral blood and bone marrow. ation, to diffuse erythroderma (Figure 6). There is often a Although mantle cell lymphoma is responsive to various preceding prodromal illness, or “premycotic” period, with conventional chemotherapy regimens and newer agents, it milder skin disease that waxes and wanes or that may progress will often relapse. There is no clear consensus on the optimal for months or even years with nondiagnostic skin biopsies. therapeutic approach, with treatments spanning a spectrum Pruritus is common and can be debilitating. Ultimately, as skin of least aggressive (lenalidomide or bendamustine plus rituxi- involvement becomes more extensive, the disease often pro- mab) to more aggressive (R-CHOP or other aggressive combi- gresses to involve extracutaneous sites, including lymph nodes nation regimens with or without HSCT). A subset of patients and organs, such as the lung, liver, and gastrointestinal tract. with indolent disease may not require therapy for many years. Infections are more common as a function of underlying

can be confirmed by findings of clonal rearrangements of the Mantle Cell Lymphoma T-cell receptor genes detected by polymerase chain reaction. Mantle cell lymphomas represent approximately 3% to 6% of In general, T-cell lymphomas are more refractory and relapse non-Hodgkin lymphomas. Median age at diagnosis is 68 years, more quickly in response to therapy than B-cell lymphomas. and there is a 3:1 male predominance. It is defined by a t(11;14) translocation, which leads to constitutive overexpression of Cutaneous T-Cell Lymphoma cyclin D1, a cell-cycle gene regulator. Patients can present with Mycosis fungoides and Sézary syndrome are the two major nodal or extranodal disease, and the disease is usually widely subtypes of cutaneous T-cell lymphoma. The skin findings in disseminated at diagnosis. Gastrointestinal involvement with mycosis fungoides range from nonspecific macular-papular lymphomatoid polyposis is well described, as is involvement eruptions or plaques, to more defined skin tumors with ulcer- of the peripheral blood and bone marrow. ation, to diffuse erythroderma (Figure 6). There is often a Although mantle cell lymphoma is responsive to various preceding prodromal illness, or “premycotic” period, with conventional chemotherapy regimens and newer agents, it milder skin disease that waxes and wanes or that may progress will often relapse. There is no clear consensus on the optimal for months or even years with nondiagnostic skin biopsies. therapeutic approach, with treatments spanning a spectrum Pruritus is common and can be debilitating. Ultimately, as skin of least aggressive (lenalidomide or bendamustine plus rituxi- involvement becomes more extensive, the disease often pro- mab) to more aggressive (R-CHOP or other aggressive combi- gresses to involve extracutaneous sites, including lymph nodes nation regimens with or without HSCT). A subset of patients and organs, such as the lung, liver, and gastrointestinal tract. with indolent disease may not require therapy for many years. Infections are more common as a function of underlying 36

Lymphoid Malignancies Anaplastic Large Cell Lymphoma Anaplastic large cell lymphoma can present with nodal as well as extranodal disease, including skin, bone marrow, and bone. Patients commonly have B symptoms. Tumor cells are typi- cally CD30 positive. An important prognostic and potentially therapeutic distinction is the presence or absence of a t(2;5) or variant ALK gene translocation and protein expression. Patients diagnosed with ALK-positive disease are younger and have a much more favorable prognosis with conventional chemotherapy and may also respond to treatment with crizotinib. Although still rare, there are increasing reports of ana- plastic large cell lymphoma associated with textured breast implants; patients most commonly present with a peripros- FIGURE 6. Cutaneous T-cell lymphoma (mycosis fungoides) has various thetic fluid collection best detected on ultrasound. presentations, including large patches, plaques, tumors, papules, and generalized erythroderma. The most common presentation consists of large, often pruritic, scaly Angioimmunoblastic T-Cell Lymphoma patches or plaques that vary in size, shape, and color. Angioimmunoblastic T-cell lymphoma, initially termed angio- immunoblastic lymphadenopathy, was thought to be a disease immunodeficiency and disruption of the protective barrier of impaired immune regulation rather than a true malignancy; provided by healthy skin. Sézary syndrome is a more aggres- however, patients with this disease are now recognized to have sive form of cutaneous T-cell lymphoma in which diffuse clonal rearrangement of T-cell receptors consistent with a erythroderma characterizes the skin involvement and malig- T-cell neoplasm. Patients with angioimmunoblastic T-cell lym- nant T cells circulate in the blood. phoma often present with systemic B symptoms, generalized The staging of cutaneous T-cell lymphoma depends on lymphadenopathy, hepatosplenomegaly, and a skin rash. They the extent of skin disease and involvement of lymph nodes and commonly show polyclonal hypergammaglobulinemia and extranodal sites. Early stages of cutaneous T-cell lymphoma elevated erythrocyte sedimentation rate and C-reactive protein are confined to the skin and managed with topical therapy, level. Autoimmune manifestations (such as autoimmune such as glucocorticoids, retinoids, or ultraviolet light therapy, hemolytic anemia) may be present. Although the lymphoma in that may be combined with interferon. Survival is greater than some patients is responsive to glucocorticoids and conventional 10 years. More advanced disease is associated with a survival of chemotherapy, it typically has a moderately aggressive clinical less than 4 years and requires more aggressive skin treatment course and median survival of less than 2 years. with electron beam irradiation and systemic chemotherapy. Patients with Sézary syndrome require systemic chemother- apy. Extracorporeal photopheresis uses psoralens, compounds e The skin findings in mycosis fungoides, a subtype of that enter Sézary cells and sensitize them to injury after activa- cutaneous T-cell lymphoma, range from nonspecific

Anaplastic Large Cell Lymphoma Anaplastic large cell lymphoma can present with nodal as well as extranodal disease, including skin, bone marrow, and bone. Patients commonly have B symptoms. Tumor cells are typi- cally CD30 positive. An important prognostic and potentially therapeutic distinction is the presence or absence of a t(2;5) or variant ALK gene translocation and protein expression. Patients diagnosed with ALK-positive disease are younger and have a much more favorable prognosis with conventional chemotherapy and may also respond to treatment with crizotinib. Although still rare, there are increasing reports of ana- plastic large cell lymphoma associated with textured breast implants; patients most commonly present with a peripros- FIGURE 6. Cutaneous T-cell lymphoma (mycosis fungoides) has various thetic fluid collection best detected on ultrasound. presentations, including large patches, plaques, tumors, papules, and generalized erythroderma. The most common presentation consists of large, often pruritic, scaly Angioimmunoblastic T-Cell Lymphoma patches or plaques that vary in size, shape, and color. Angioimmunoblastic T-cell lymphoma, initially termed angio- immunoblastic lymphadenopathy, was thought to be a disease immunodeficiency and disruption of the protective barrier of impaired immune regulation rather than a true malignancy; provided by healthy skin. Sézary syndrome is a more aggres- however, patients with this disease are now recognized to have sive form of cutaneous T-cell lymphoma in which diffuse clonal rearrangement of T-cell receptors consistent with a erythroderma characterizes the skin involvement and malig- T-cell neoplasm. Patients with angioimmunoblastic T-cell lym- nant T cells circulate in the blood. phoma often present with systemic B symptoms, generalized The staging of cutaneous T-cell lymphoma depends on lymphadenopathy, hepatosplenomegaly, and a skin rash. They the extent of skin disease and involvement of lymph nodes and commonly show polyclonal hypergammaglobulinemia and extranodal sites. Early stages of cutaneous T-cell lymphoma elevated erythrocyte sedimentation rate and C-reactive protein are confined to the skin and managed with topical therapy, level. Autoimmune manifestations (such as autoimmune such as glucocorticoids, retinoids, or ultraviolet light therapy, hemolytic anemia) may be present. Although the lymphoma in that may be combined with interferon. Survival is greater than some patients is responsive to glucocorticoids and conventional 10 years. More advanced disease is associated with a survival of chemotherapy, it typically has a moderately aggressive clinical less than 4 years and requires more aggressive skin treatment course and median survival of less than 2 years. with electron beam irradiation and systemic chemotherapy. Patients with Sézary syndrome require systemic chemother- apy. Extracorporeal photopheresis uses psoralens, compounds e The skin findings in mycosis fungoides, a subtype of that enter Sézary cells and sensitize them to injury after activa- cutaneous T-cell lymphoma, range from nonspecific tion with ultraviolet light. macular-papular eruptions or plaques, to more defined skin tumors with ulceration, to diffuse erythroderma. Peripheral T-Cell Lymphoma, e Sézary syndrome is a more aggressive subtype of cuta- Not Otherwise Specified neous T-cell lymphoma in which diffuse erythroderma Peripheral T-cell lymphoma, not otherwise specified, is the characterizes the skin involvement and malignant T cells most commonly diagnosed subtype of peripheral T-cell lym- circulate in the blood. phoma. It typically presents in older adults at an advanced stage, has a male predominance, and has a generally poor Lymphoblastic Lymphoma clinical outcome compared with B-cell lymphomas. Lymphoblastic lymphoma is an aggressive lymphoma that can Various combination chemotherapy regimens have been be of T- or B-cell origin. It is akin to and treated with protocols used. The addition of etoposide or brentuximab vedotin (in for acute lymphoblastic leukemia. Presentation with a medi- patients with CD30-positive tumor cells) to standard combina- astinal mass, blood or bone marrow, and central nervous sys- tion chemotherapy may provide some benefit as part of initial tem involvement is typical. therapy. The use of chemotherapy designed for acute lympho- blastic leukemia or management with HSCT, both autologous and allogeneic, may benefit some patients, although there is Hodgkin Lymphoma controversy as to when and in whom these are best used. Newer Hodgkin lymphoma represents approximately 10% of lympho- chemotherapy agents such as pralatrexate and romidepsin yield mas and is curable in most patients. It most commonly pre- responses in some patients with relapsed disease. sents in young adults. Presentation with mediastinal, cervical,

tion with ultraviolet light. macular-papular eruptions or plaques, to more defined skin tumors with ulceration, to diffuse erythroderma. Peripheral T-Cell Lymphoma, e Sézary syndrome is a more aggressive subtype of cuta- Not Otherwise Specified neous T-cell lymphoma in which diffuse erythroderma Peripheral T-cell lymphoma, not otherwise specified, is the characterizes the skin involvement and malignant T cells most commonly diagnosed subtype of peripheral T-cell lym- circulate in the blood. phoma. It typically presents in older adults at an advanced stage, has a male predominance, and has a generally poor Lymphoblastic Lymphoma clinical outcome compared with B-cell lymphomas. Lymphoblastic lymphoma is an aggressive lymphoma that can Various combination chemotherapy regimens have been be of T- or B-cell origin. It is akin to and treated with protocols used. The addition of etoposide or brentuximab vedotin (in for acute lymphoblastic leukemia. Presentation with a medi- patients with CD30-positive tumor cells) to standard combina- astinal mass, blood or bone marrow, and central nervous sys- tion chemotherapy may provide some benefit as part of initial tem involvement is typical. therapy. The use of chemotherapy designed for acute lympho- blastic leukemia or management with HSCT, both autologous and allogeneic, may benefit some patients, although there is Hodgkin Lymphoma controversy as to when and in whom these are best used. Newer Hodgkin lymphoma represents approximately 10% of lympho- chemotherapy agents such as pralatrexate and romidepsin yield mas and is curable in most patients. It most commonly pre- responses in some patients with relapsed disease. sents in young adults. Presentation with mediastinal, cervical, 37

Lymphoid Malignancies FIGURE 7. Hodgkin lymphoma is the most common lymphoma to involve the mediastinum, shown in this chest radiograph (left) as a mass that originates from the mediastinum, given the convex angles resulting from the mass impinging on the pleura. The lateral film (right) localizes the mass to the anterior mediastinum. Hodgkin lymphoma is the most common cause of anterior mediastinal masses in patients aged 20 to 30 years. _— FIGURE 9. Reed-Sternberg cells are large and either are multinucleated or and supraclavicular involvement is particularly common for have a bilobed nucleus (“owl's eye” appearance) with prominent eosinophilic the nodular sclerosing subtype (Figure 7 and Figure 8). Patients inclusion-like nucleoli. They can be seen with light microscopy in biopsies from may also present with B symptoms, although that is more individuals with Hodgkin lymphoma. They are usually derived from B lymphocytes. When seen against a sea of B cells, they give the tissue a “starry sky” or “moth- commonly seen in elderly patients with more advanced dis- eaten” appearance. The absence of Reed-Sternberg cells has very high negative ease. Pruritus may also be a presenting symptom. predictive value for Hodgkin disease. Lymph node biopsy specimen shows Reed-Sternberg cells (Figure 9), malignant cells that originate from germinal center diagnostic splenectomy, are no longer done. Routine bone B cells and are seen in an inflammatory infiltrate. The number marrow biopsy, in the absence of unexplained blood abnor- of Reed-Sternberg cells and variability in the composition of malities, is not indicated. the infiltrate lead to pathologic subtypes, including nodular More than 90% of patients present with classic Hodgkin sclerosis, mixed cellularity, lymphocyte predominant, and lymphoma pathology and, even with early-stage disease, lymphocyte depleted. Patients are staged by physical examina- receive chemotherapy because this has been shown to result in tion and PET/CT scan. Staging laparotomies, including higher cure rates. The doxorubicin, bleomycin, vinblastine, and dacarbazine regimen has been the most commonly used in the United States. Fertility is better preserved and secondary

FIGURE 7. Hodgkin lymphoma is the most common lymphoma to involve the mediastinum, shown in this chest radiograph (left) as a mass that originates from the mediastinum, given the convex angles resulting from the mass impinging on the pleura. The lateral film (right) localizes the mass to the anterior mediastinum. Hodgkin lymphoma is the most common cause of anterior mediastinal masses in patients aged 20 to 30 years. _— FIGURE 9. Reed-Sternberg cells are large and either are multinucleated or and supraclavicular involvement is particularly common for have a bilobed nucleus (“owl's eye” appearance) with prominent eosinophilic the nodular sclerosing subtype (Figure 7 and Figure 8). Patients inclusion-like nucleoli. They can be seen with light microscopy in biopsies from may also present with B symptoms, although that is more individuals with Hodgkin lymphoma. They are usually derived from B lymphocytes. When seen against a sea of B cells, they give the tissue a “starry sky” or “moth- commonly seen in elderly patients with more advanced dis- eaten” appearance. The absence of Reed-Sternberg cells has very high negative ease. Pruritus may also be a presenting symptom. predictive value for Hodgkin disease. Lymph node biopsy specimen shows Reed-Sternberg cells (Figure 9), malignant cells that originate from germinal center diagnostic splenectomy, are no longer done. Routine bone B cells and are seen in an inflammatory infiltrate. The number marrow biopsy, in the absence of unexplained blood abnor- of Reed-Sternberg cells and variability in the composition of malities, is not indicated. the infiltrate lead to pathologic subtypes, including nodular More than 90% of patients present with classic Hodgkin sclerosis, mixed cellularity, lymphocyte predominant, and lymphoma pathology and, even with early-stage disease, lymphocyte depleted. Patients are staged by physical examina- receive chemotherapy because this has been shown to result in tion and PET/CT scan. Staging laparotomies, including higher cure rates. The doxorubicin, bleomycin, vinblastine, and dacarbazine regimen has been the most commonly used in the United States. Fertility is better preserved and secondary acute leukemia is less common than with prior regimens. For patients with early-stage, favorable disease, treatment can

FIGURE 7. Hodgkin lymphoma is the most common lymphoma to involve the mediastinum, shown in this chest radiograph (left) as a mass that originates from the mediastinum, given the convex angles resulting from the mass impinging on the pleura. The lateral film (right) localizes the mass to the anterior mediastinum. Hodgkin lymphoma is the most common cause of anterior mediastinal masses in patients aged 20 to 30 years. _— FIGURE 9. Reed-Sternberg cells are large and either are multinucleated or and supraclavicular involvement is particularly common for have a bilobed nucleus (“owl's eye” appearance) with prominent eosinophilic the nodular sclerosing subtype (Figure 7 and Figure 8). Patients inclusion-like nucleoli. They can be seen with light microscopy in biopsies from may also present with B symptoms, although that is more individuals with Hodgkin lymphoma. They are usually derived from B lymphocytes. When seen against a sea of B cells, they give the tissue a “starry sky” or “moth- commonly seen in elderly patients with more advanced dis- eaten” appearance. The absence of Reed-Sternberg cells has very high negative ease. Pruritus may also be a presenting symptom. predictive value for Hodgkin disease. Lymph node biopsy specimen shows Reed-Sternberg cells (Figure 9), malignant cells that originate from germinal center diagnostic splenectomy, are no longer done. Routine bone B cells and are seen in an inflammatory infiltrate. The number marrow biopsy, in the absence of unexplained blood abnor- of Reed-Sternberg cells and variability in the composition of malities, is not indicated. the infiltrate lead to pathologic subtypes, including nodular More than 90% of patients present with classic Hodgkin sclerosis, mixed cellularity, lymphocyte predominant, and lymphoma pathology and, even with early-stage disease, lymphocyte depleted. Patients are staged by physical examina- receive chemotherapy because this has been shown to result in tion and PET/CT scan. Staging laparotomies, including higher cure rates. The doxorubicin, bleomycin, vinblastine, and dacarbazine regimen has been the most commonly used in the United States. Fertility is better preserved and secondary acute leukemia is less common than with prior regimens. For patients with early-stage, favorable disease, treatment can consist of just two courses of chemotherapy and involved site irradiation. Chemotherapy alone for four to six cycles in patients with good response is also an option. For more advanced disease, chemotherapy alone is used. Although the regimen is usually well tolerated, up to 25% of patients may develop bleomycin-induced lung injury during treatment or within 6 months of its conclusion. A newer regimen eliminat- ing bleomycin and substituting brentuximab vedotin (an anti- CD30 monoclonal antibody linked to the anti-tubulin agent monomethyl auristatin E) is associated with less pulmonary toxicity and slightly improved outcomes for patients with advanced disease. Complete response indicated by PET scan after two to three cycles of chemotherapy is a reliable prognostic indica- tor. Early repeat PET scan is an appropriate response- adapted strategy in Hodgkin lymphoma and may allow some patients with early-stage disease to forgo radiation FIGURE 8, This image depicts an anterior view of the head and neck region revealing greatly enlarged cervical lymph nodes, due to Hodgkin lymphoma. therapy and thereby reduce the risks of late irradiation Reproduced from CDC Public Image Health Library; image ID 12630. adverse effects.

consist of just two courses of chemotherapy and involved site irradiation. Chemotherapy alone for four to six cycles in patients with good response is also an option. For more advanced disease, chemotherapy alone is used. Although the regimen is usually well tolerated, up to 25% of patients may develop bleomycin-induced lung injury during treatment or within 6 months of its conclusion. A newer regimen eliminat- ing bleomycin and substituting brentuximab vedotin (an anti- CD30 monoclonal antibody linked to the anti-tubulin agent monomethyl auristatin E) is associated with less pulmonary toxicity and slightly improved outcomes for patients with advanced disease. Complete response indicated by PET scan after two to three cycles of chemotherapy is a reliable prognostic indica- tor. Early repeat PET scan is an appropriate response- adapted strategy in Hodgkin lymphoma and may allow some patients with early-stage disease to forgo radiation FIGURE 8, This image depicts an anterior view of the head and neck region revealing greatly enlarged cervical lymph nodes, due to Hodgkin lymphoma. therapy and thereby reduce the risks of late irradiation Reproduced from CDC Public Image Health Library; image ID 12630. adverse effects. 38

Cancer of Unknown Primary Site For patients with relapsed or refractory disease, salvage symptom- or presentation-related evaluations may be pur- chemotherapy and autologous or allogeneic HSCT may pro- sued, such as upper endoscopy and colonoscopy in patients vide curative options. Brentuximab vedotin is active in refrac- with gastrointestinal symptoms or evidence of gastrointesti- tory disease and has also been used for consolidation after nal bleeding. Patients with regional lymphadenopathy autologous HSCT. The programmed death 1 antibodies (pem- require focused evaluation, such as pan-endoscopic evalua- brolizumab and nivolumab) are highly active in relapsed or tion of the head and neck for patients with isolated or domi- refractory disease. nant cervical lymphadenopathy or anoscopy for those with Nodular lymphocyte-predominant Hodgkin lym- isolated inguinal lymphadenopathy. In female patients, breast phoma is distinct clinically and pathologically from classic examination and mammography should be done to search Hodgkin lymphoma (nodular sclerosis, mixed cellularity, for a breast primary cancer, and a gynecologic evaluation and lymphocyte depleted). It represents approximately 10% should be performed to look for an ovarian primary. Male of Hodgkin lymphomas and is more likely to present with patients require a testicular examination and, in those with localized disease but is associated with a high rate of late bone metastases, a prostate examination and serum prostate- relapse. Early-stage disease may be treated with radiation specific antigen level measurement to evaluate for prostate therapy alone. Single-agent rituximab or combined with cancer. Nonspecific tumor markers, such as serum carci- chemotherapy may be used for more advanced or relapsed noembryonic antigen, CA-19-9, CA-15-3, or CA-125, are not disease. routinely recommended because they are not definitive for identifying a specific primary site. In some patients, PET scans may suggest the possible primary location, but false- HVC ¢ Physical examination and PET/CT are used to stage positive results are significant, and PET scan findings are not patients with Hodgkin lymphoma; laparotomy and apt to change the treatment plan. Gene expression arrays splenectomy are no longer performed. have been commercially promoted, but the clinical utility of ¢ All patients with classic Hodgkin lymphoma, regardless these tests to identify more effective therapy has not been of stage, receive chemotherapy. established, and they should not be used.

For patients with relapsed or refractory disease, salvage symptom- or presentation-related evaluations may be pur- chemotherapy and autologous or allogeneic HSCT may pro- sued, such as upper endoscopy and colonoscopy in patients vide curative options. Brentuximab vedotin is active in refrac- with gastrointestinal symptoms or evidence of gastrointesti- tory disease and has also been used for consolidation after nal bleeding. Patients with regional lymphadenopathy autologous HSCT. The programmed death 1 antibodies (pem- require focused evaluation, such as pan-endoscopic evalua- brolizumab and nivolumab) are highly active in relapsed or tion of the head and neck for patients with isolated or domi- refractory disease. nant cervical lymphadenopathy or anoscopy for those with Nodular lymphocyte-predominant Hodgkin lym- isolated inguinal lymphadenopathy. In female patients, breast phoma is distinct clinically and pathologically from classic examination and mammography should be done to search Hodgkin lymphoma (nodular sclerosis, mixed cellularity, for a breast primary cancer, and a gynecologic evaluation and lymphocyte depleted). It represents approximately 10% should be performed to look for an ovarian primary. Male of Hodgkin lymphomas and is more likely to present with patients require a testicular examination and, in those with localized disease but is associated with a high rate of late bone metastases, a prostate examination and serum prostate- relapse. Early-stage disease may be treated with radiation specific antigen level measurement to evaluate for prostate therapy alone. Single-agent rituximab or combined with cancer. Nonspecific tumor markers, such as serum carci- chemotherapy may be used for more advanced or relapsed noembryonic antigen, CA-19-9, CA-15-3, or CA-125, are not disease. routinely recommended because they are not definitive for identifying a specific primary site. In some patients, PET scans may suggest the possible primary location, but false- HVC ¢ Physical examination and PET/CT are used to stage positive results are significant, and PET scan findings are not patients with Hodgkin lymphoma; laparotomy and apt to change the treatment plan. Gene expression arrays splenectomy are no longer performed. have been commercially promoted, but the clinical utility of ¢ All patients with classic Hodgkin lymphoma, regardless these tests to identify more effective therapy has not been of stage, receive chemotherapy. established, and they should not be used. ¢ Complete response indicated by PET scan after two to Ultimately, CUP is a diagnosis of exclusion after a reason-

For patients with relapsed or refractory disease, salvage symptom- or presentation-related evaluations may be pur- chemotherapy and autologous or allogeneic HSCT may pro- sued, such as upper endoscopy and colonoscopy in patients vide curative options. Brentuximab vedotin is active in refrac- with gastrointestinal symptoms or evidence of gastrointesti- tory disease and has also been used for consolidation after nal bleeding. Patients with regional lymphadenopathy autologous HSCT. The programmed death 1 antibodies (pem- require focused evaluation, such as pan-endoscopic evalua- brolizumab and nivolumab) are highly active in relapsed or tion of the head and neck for patients with isolated or domi- refractory disease. nant cervical lymphadenopathy or anoscopy for those with Nodular lymphocyte-predominant Hodgkin lym- isolated inguinal lymphadenopathy. In female patients, breast phoma is distinct clinically and pathologically from classic examination and mammography should be done to search Hodgkin lymphoma (nodular sclerosis, mixed cellularity, for a breast primary cancer, and a gynecologic evaluation and lymphocyte depleted). It represents approximately 10% should be performed to look for an ovarian primary. Male of Hodgkin lymphomas and is more likely to present with patients require a testicular examination and, in those with localized disease but is associated with a high rate of late bone metastases, a prostate examination and serum prostate- relapse. Early-stage disease may be treated with radiation specific antigen level measurement to evaluate for prostate therapy alone. Single-agent rituximab or combined with cancer. Nonspecific tumor markers, such as serum carci- chemotherapy may be used for more advanced or relapsed noembryonic antigen, CA-19-9, CA-15-3, or CA-125, are not disease. routinely recommended because they are not definitive for identifying a specific primary site. In some patients, PET scans may suggest the possible primary location, but false- HVC ¢ Physical examination and PET/CT are used to stage positive results are significant, and PET scan findings are not patients with Hodgkin lymphoma; laparotomy and apt to change the treatment plan. Gene expression arrays splenectomy are no longer performed. have been commercially promoted, but the clinical utility of ¢ All patients with classic Hodgkin lymphoma, regardless these tests to identify more effective therapy has not been of stage, receive chemotherapy. established, and they should not be used. ¢ Complete response indicated by PET scan after two to Ultimately, CUP is a diagnosis of exclusion after a reason- three cycles of chemotherapy can allow some patients able evaluation has failed to identify the primary tumor, which

For patients with relapsed or refractory disease, salvage symptom- or presentation-related evaluations may be pur- chemotherapy and autologous or allogeneic HSCT may pro- sued, such as upper endoscopy and colonoscopy in patients vide curative options. Brentuximab vedotin is active in refrac- with gastrointestinal symptoms or evidence of gastrointesti- tory disease and has also been used for consolidation after nal bleeding. Patients with regional lymphadenopathy autologous HSCT. The programmed death 1 antibodies (pem- require focused evaluation, such as pan-endoscopic evalua- brolizumab and nivolumab) are highly active in relapsed or tion of the head and neck for patients with isolated or domi- refractory disease. nant cervical lymphadenopathy or anoscopy for those with Nodular lymphocyte-predominant Hodgkin lym- isolated inguinal lymphadenopathy. In female patients, breast phoma is distinct clinically and pathologically from classic examination and mammography should be done to search Hodgkin lymphoma (nodular sclerosis, mixed cellularity, for a breast primary cancer, and a gynecologic evaluation and lymphocyte depleted). It represents approximately 10% should be performed to look for an ovarian primary. Male of Hodgkin lymphomas and is more likely to present with patients require a testicular examination and, in those with localized disease but is associated with a high rate of late bone metastases, a prostate examination and serum prostate- relapse. Early-stage disease may be treated with radiation specific antigen level measurement to evaluate for prostate therapy alone. Single-agent rituximab or combined with cancer. Nonspecific tumor markers, such as serum carci- chemotherapy may be used for more advanced or relapsed noembryonic antigen, CA-19-9, CA-15-3, or CA-125, are not disease. routinely recommended because they are not definitive for identifying a specific primary site. In some patients, PET scans may suggest the possible primary location, but false- HVC ¢ Physical examination and PET/CT are used to stage positive results are significant, and PET scan findings are not patients with Hodgkin lymphoma; laparotomy and apt to change the treatment plan. Gene expression arrays splenectomy are no longer performed. have been commercially promoted, but the clinical utility of ¢ All patients with classic Hodgkin lymphoma, regardless these tests to identify more effective therapy has not been of stage, receive chemotherapy. established, and they should not be used. ¢ Complete response indicated by PET scan after two to Ultimately, CUP is a diagnosis of exclusion after a reason- three cycles of chemotherapy can allow some patients able evaluation has failed to identify the primary tumor, which with early-stage classical Hodgkin lymphoma to forgo either may be too small to be detected or may have been

¢ Complete response indicated by PET scan after two to Ultimately, CUP is a diagnosis of exclusion after a reason- three cycles of chemotherapy can allow some patients able evaluation has failed to identify the primary tumor, which with early-stage classical Hodgkin lymphoma to forgo either may be too small to be detected or may have been radiation therapy. destroyed immunologically and is no longer present. Once the more treatable possibilities have been excluded, specific iden- tification of the site of origin is very unlikely to improve treat- Cancer of Unknown ment options or clinical outcome. At that point, it should be Primary Site determined whether the metastatic cancer has a favorable or unfavorable prognosis and if there is a specific, efficacious Introduction therapy for that patient. Less than 5% of patients with metastatic cancer do not have an identified primary site, with improvements in imaging and e In patients with a metastatic cancer of unknown pri- HVC other diagnostic techniques steadily decreasing that number. mary site, CT and histologic, endoscopic, and gender- This heterogeneous group of patients is classified as having specific cancer evaluations are reasonable; however, cancer of unknown primary (CUP). nonspecific tumor markers, PET, and gene expression arrays should not be done.

identified primary site, with improvements in imaging and e In patients with a metastatic cancer of unknown pri- HVC other diagnostic techniques steadily decreasing that number. mary site, CT and histologic, endoscopic, and gender- This heterogeneous group of patients is classified as having specific cancer evaluations are reasonable; however, cancer of unknown primary (CUP). nonspecific tumor markers, PET, and gene expression arrays should not be done. e Ifreasonable attempts to identify primary cancer have Diagnosis and Evaluation failed, management should shift focus, treating the On identification of metastatic cancer without a known pri- metastasis based on histology and prognostic factors, as mary site, a full medical history, physical examination, and a finding the primary site is unlikely to improve treatment contrast-enhanced CT of the chest, abdomen, and pelvis options or clinical outcome. should be obtained. The most accessible tumor mass should be biopsied, and a limited number of immunohistochemical stains are warranted to assess the nature of the tumor and identify or exclude the most treatable histologies (such as Favorable Prognostic Subgroups lymphoma or germ cell tumor). Mismatch repair-deficiency, of Cancer of Unknown Primary Site or microsatellite instability, although very rare in CUP, would For patients with CUP, the identification of a favorable prognos- warrant treatment with immune checkpoint inhibitors. tic subgroup allows selection of specific surgical, irradiation, or Workup should be focused to diagnose more treatable prima- chemotherapy to which patients are more likely to respond and ries, histologies, or subtypes of CUP. In addition, specific on occasion achieves long-term remission and cure. 39