National Health Commission of the People’s Republic of China

Contents

1.Overview

2.Diagnosis of lymphoma

2.1 Clinical manifestations

2.2 Physical examination

2.3 Laboratory examination

2.4 Imaging examination

2.4.1 CT

2.4.2 MRI

2.4.3 PET-CT

2.4.4 Ultrasound

2.4.5 Isotope bone scan

2.4.6 Endoscopy

2.5 Pathological examination

2.5.1 Morphology

2.5.2 IHC

2.5.3 Fluorescencein situhybridization (FISH)

2.5.4 Antigen receptor gene rearrangement of lymphocytes

2.5.5 Others

3.Staging of lymphoma

4.Radiotherapy of lymphoma

5.Comprehensive treatment of lymphoma

6.Treatment of lymphoma with Traditional Chinese Medicine(TCM)

7.Clinical manifestations,diagnosis and treatment of common lymphoma pathological types

7.1 HL

7.1.1 Clinical manifestations

7.1.2 Pathological classification and diagnosis

7.1.3 Treatment principles

7.1.4 Prognostic factors of HL

7.2 NHL

7.2.1 DLBCL

7.2.2 FL

7.2.3 MZL

7.2.4 CLL/SLL

7.2.5 MCL

7.2.6 Burkitt’s lymphoma (BL)

7.2.7 Lymphoblastic lymphoma (LBL)

7.2.8 Peripheral T-cell lymphoma,not otherwise specified(PTCL-NOS)

7.2.9 Mycosis fungoides/Sézary syndrome (MF/SS)

7.2.10 Extranodal NK/T-cell lymphoma,nasal type(ENKTL)

1.Overview

Lymphoma is one of the most common malignancies in China.According to the report from the World Health Organization (WHO) GLOBOCAN 2020,there were 6,829 new cases of Hodgkin lymphoma (HL) in China in 2020,including 4,506 males and 2,323 females;and 2,807 deaths,including 1,865 males and 942 females.In 2020,92,834 cases of non-Hodgkin lymphoma (NHL) were reported in China,including 50,125 cases in males and 42,709 cases in females;54,351 cases of death were reported,including 29,721 cases in males and 24,630 cases in females.The incidence and mortality rate of NHL in males are the 10th highest among all malignant tumors;while those in females are not in the top 10 of all malignant tumors.The pathological classification in lymphoma is complex,and related principles of treatment are various(Appendix 1).In order to improve the standardized implementation of diagnosis and therapy in lymphoma,to cooperate with the policy adjustment of the supply of antitumor medicine,and to guarantee medical quality and safety,here we are updating and revising Chinese guidelines for diagnosis and treatment of malignant lymphoma.

2.Diagnosis of lymphoma

The diagnosis of lymphoma should integrate clinical manifestations with physical,laboratory,imaging and pathological examinations.

2.1 Clinical manifestations

The manifestation of lymphoma includes systemic and local symptoms.Systemic symptoms include fever of unknown origin,night sweating,weight loss,skin itching and fatigue.Local symptoms depend on the primary and invaded sites of lesions.Lymphoma may originate from any organ or tissue of the body,and it is usually divided into two categories — from lymph node and extra lymph node.The most common manifestation is painless progressive lymphadenectasis.

2.2 Physical examination

Special attention should be paid to the enlargement of lymph nodes in different regions,the size of liver and spleen,accompanying signs and general state,and so on.

2.3 Laboratory examination

Laboratory tests include complete blood count,liver and kidney function,lactate dehydrogenase (LDH),β2 microglobulin,erythrocyte sedimentation rate,and infection screening of human immunodeficiency virus(HIV),hepatitis B virus (HBV) and hepatitis C virus(HCV).If necessary,bone marrow aspirate cytology and/or biopsy should be performed.For patients with risk of central nervous system involvement,lumbar puncture,and routine,cytological and biochemical examinations of cerebrospinal fluid should be performed.For patients with NK/T cell lymphoma,and other Epstein-Barr virus (EBV)-related lymphomas,including EBV-positive diffuse large Bcell lymphoma,lymphomatoid granulomatosis,etc.EBV DNA titer in peripheral blood should be detected.For primary gastric mucosa-associated marginal zone B-cell lymphoma,Helicobacter pylori(Hp) test should be routinely performed.

2.4 Imaging examination

Common methods of image examination: computed tomography (CT),magnetic resonance imaging (MRI),positron emission tomography-CT (PET-CT),ultrasound and endoscopy.

2.4.1 CT

It is still the most commonly used imaging method for staging,re-staging,efficacy evaluation and follow-up of lymphoma.For patients without contraindications for iodine contrast agent,enhanced CT scan should be used as far as possible

2.4.2 MRI

MR imaging should be preferred for lesions in the central nervous system,bone marrow and muscles.For lesions in liver,spleen,kidney,uterus and other parenchymal organs,MR imaging could be selected or preferred,especially for those who are not suitable for enhanced CT scan,or as a further examination for suspicious lesions found by CT.

2.4.3 PET-CT

It is the best method for staging and re-staging,efficacy evaluation and prognosis prediction of most lymphomas.However,PET-CT is not recommended for follow-up after disease remission.

2.4.4 Ultrasound

Ultrasound is a routine examination for diagnosis and follow-up of lesions in superficial lymph nodes and organs(testis,thyroid,breast,etc.),but not for staging.It is optional for abdominal and pelvic lymph node examination and is a supplement to CT and MRI for examination of liver,spleen,kidney,uterus and other abdominal and pelvic parenchymal organs,especially when enhanced CT scan is not applicable.For excision biopsy of superficial lymph nodes,it is helpful to improve the accuracy of biopsy to select lymph nodes with abnormal sonogram.Ultrasoundguided puncture biopsy should also be used for pathological diagnosis of deep lymph nodes,liver and mediastinum.

2.4.5 Isotope bone scan

Lymphoma patients with bone invasion lack characteristic changes of systemic bone imaging.Therefore,it is difficult to distinguish it from bone metastases,multiple myeloma,bone tuberculosis,fibrous dysplasia,hyperparathyroidism and infections.Medical history,laboratory examinations and other imaging examinations are required for such cases.Conventional bone scan (99mTc-MDP) has limited value in the evaluation of primary Hodgkin lymphoma (HL)patients,but it should be combined with CT examination in the follow-up and prognosis evaluation of primary bone lymphoma after treatment.

2.4.6 Endoscopy

It is suitable for patients with suspected gastrointestinal tract involvement,and biopsy can be completed at the same time to confirm the pathology.

2.5 Pathological examination

Pathological examination is the principal means of diagnosis of lymphoma.For lymph node lesions,the whole lymph node should be excised as far as possible.If lymph node lesions are superficial,neck,supraclavicular and axillary lymph nodes are the first choices.Core needle puncture is only used for patients who cannot effectively and safely obtain excision of the whole or partial lesion.For the primary diagnosis,excision of the whole or partial lesion should be the first choice.For relapsed patients,pathological diagnosis can be made by core needle puncture if excision of the lesion is not applicable.

Pathological diagnosis of lymphoma requires comprehensive application of morphology,immunohistochemistry (IHC),genetic and molecular biological technologies,and flow cytometry etc.At the same time,clinical characteristics are also very important.

2.5.1 Morphology

It is very important in pathological diagnosis of lymphoma.Different types of lymphoma have characteristic and diagnostic morphological features.

2.5.2 IHC

It can be used to distinguish the immunophenotype of lymphoma cells,such as B or T cell,or NK/T cell,differentiation and maturation of lymphoma cells.Differential diagnosis of different pathological subtypes was made through combination of related IHC markers.

2.5.3 Fluorescence in situ hybridization (FISH)

FISH can help identify specific chromosome breaks,translocations,deletions,or amplifications,and guide auxiliary diagnosis of lymphoma with specific chromosome abnormality,such as Burkitt lymphoma (BL)-related t (8;14) translocation,t (2;8) or t (8;22) translocation,follicular lymphoma (FL)-related t (14;18) translocation,extranodal mucosa associated lymphoid marginal zone lymphoma(MZL)-related t (11;18) translocation,mantle cell lymphoma (MCL)-related t (11;14) translocation,and double or triple hit high-grade B-cell lymphoma-related MYC (8q24),BCL-2 (18q21) and BCL-6 (3q27)rearrangement,etc.

2.5.4 Antigen receptor gene rearrangement of lymphocytes

Monoclonal rearrangement of lymphocyte receptor gene is the main feature of lymphoma cells.It could be used as evidence to identify monoclonal or polyclonal proliferation of lymphocytes,and lymphoma that cannot be diagnosed by IHC.It is an important supplement to morphology and IHC assays.

2.5.5 Others

Others including next-generation sequencing (NGS),flow cytometry etc.,are significant supplements to routine pathological diagnosis.

3.Staging of lymphoma

Ann-Arbor staging (revised at the Cotswolds meeting),a current universal staging system for describing HL and NHL,is applicable to HL and primary nodal NHL.However,it is difficult to apply to some primary extranodal NHL,such as chronic lymphocytic leukemia,cutaneous Tcell lymphoma and primary gastrointestinal and central nervous system lymphoma,which originated from special extranodal organs and sites and usually have their own staging system.In addition,based on the data from patients with extranodal nasal type NK/T-cell lymphoma in Asia and China,a staging system for extranodal nasal type NK/T-cell lymphoma was established and named the Chinese Southwest Oncology Group (CSWOG) and the Asian Lymphoma Study Group (ALSG) staging system.The system is referred to as CA staging (Appendix 2).

4.Radiotherapy of lymphoma

Radiotherapy is an important component of comprehensive treatment of lymphoma.How to choose the radiation beam,radiation field and dosage during the process depends on the purpose of treatment and related conditions for each case.Photon,electron and proton beams can be used to achieve reasonable coverage of the target area and maximum protection of normal tissues. Advanced radiotherapy technologies,such as intensity modulated radiation therapy (IMRT),breath holding and breathing gating,image guidance and proton therapy,could significantly reduce damage to normal tissue on the premise of ensuring tumor control.

According to the purpose and function,indications for radiotherapy of lymphoma are classified as 1) radical treatment;2) consolidation radiotherapy after chemotherapy;3) salvage therapy for intolerance of chemotherapy,resistant or residual lesions;and 4) palliative treatment.

Radiotherapy field settings consist of total lymphoid irradiation (TLI) and sub-total lymphoid irradiation(STLI).TLI usually includes mantle field+hoe field +pelvic field (splenic irradiation is also needed in patients without splenectomy).STLI may omit part of field.Involved field radiotherapy (IFRT) only includes the entire lymph node region of the involved lymph node before chemotherapy.With the development of imaging diagnosis and conformal radiotherapy technique,IFRT is replaced by more accurate involved-node radiotherapy (INRT) or involved-site radiotherapy (ISRT) in HL and aggressive lymphoma.

ISRT target definition and delineation:

ISRT intranodal lesions: ISRT is currently a standard radiation field setting scheme for HL and NHL sensitive to chemotherapy.The radiation range needs to be based on CT simulation and combined with other modern imaging methods such as PET-CT and MRI.The target sites of ISRT mainly include lymph nodes involved in the initial diagnosis and all suspected tumor involved areas before chemotherapy or biopsy,but the adjacent uninvolved normal tissues,including lung,bone,muscle,kidney,etc.,should be excluded.The gross tumor volume before chemotherapy or biopsy is the basis for delineation of clinical target volume (CTV).Considering the uncertainty of subclinical lesions and the possible lack of accuracy of the original tumor image,the boundary can be appropriately expanded based on clinical judgment when setting CTV.Radiotherapy for indolent lymphoma tends to use a larger radiation field.For example,the radiation field of FL should be larger than that of diffuse large B-cell lymphoma after chemotherapy.In the chest and abdomen areas,organ movement should be considered to determine the internal target volume,and then expand outward to form the planning target volume.

ISRT extranodal lesions: the radiation field setting principle of extranodal lesions is similar to that of intranodal lesions.However,in some primary lesions of extranodal organs,CTV needs to include the whole organ,such as stomach,salivary gland and thyroid gland.In other extranodal organs,including eyes,mammary glands,lungs,bones,skin,etc.,partial organ irradiation can be considered.In most cases,prophylactic radiation of uninvolved lymph nodes is not required.

Radiation dose: Radiation dose for HL is 20-30 Gy when complete response (CR) is achieved after chemotherapy,and 36-40 Gy when partial response (PR) is achieved after chemotherapy.The radical dose for indolent lymphoma is 24-30 Gy.The dose for consolidation radiotherapy of diffuse large B-cell lymphoma (DLBCL)after CR with chemotherapy is 30-46 Gy.According to individual factors such as risk stratification,response to chemotherapy and radiotherapy,the radiation dose after PR is 36-50 Gy.The radical dose for extranodal nasal type NK/T-cell lymphoma is 50-56 Gy.

5.Comprehensive treatment of lymphoma

Multidisciplinary treatment (MDT) is the principle of lymphoma treatment.Lymphoma is a group of malignant tumors with different clinical features,diagnostic criteria and therapies.Lymphoma diagnoses require identification of pathological subtypes and molecular markers for prognosis.Stage of patients is defined with imaging diagnostic techniques.Prognosis evaluation is based on the integration of clinical manifestations,laboratory examinations,and related criteria for prognostic risk.Optional comprehensive treatment including medical treatment,radiotherapy and necessary surgical treatment.

6.Treatment of lymphoma with Traditional Chinese Medicine (TCM)

In TCM,lymphoma belongs to the category of hard nodule,nucleus of pathogen,haggard weakness and nucleus of phlegm.Its treatment is the combination of disease differentiation and syndrome differentiation. Mostly,composite syndromes composed of two or more syndrome elements,including phlegm-heat accumulation type,Qi stagnation phlegm-blocking type,spleen deficiency phlegm-dampness type,Qi and blood deficiency type,liver and kidney Yin deficiency type,etc.TCM treatment is based on the principle of comprehensive concept and clinical manifestation differentiation,which not only considers the balance of Yin and Yang in the body,but also considers the reduction of tumor and elimination of pathogen,which is the anti-tumor “balance blocking” based on the classical prescription. The combination of chemotherapy and radiotherapy with TCM can reduce toxicity and improve efficacy,reduce gastrointestinal reactions,bone marrow suppression,peripheral neuritis and other adverse events of our treatment,and increase efficacy. For the patients after chemotherapy and radiotherapy,TCM can adjust the balance of Yin and Yang of the patient’s body,so as to improve the constitution,improve the immune function and promote the rehabilitation of the patient.

Suitable patients: During chemotherapy and radiotherapy,recovery period after antitumor therapy and palliative care of terminal-stage patients.

Methods:Oral decoction,Chinese patent medicine and other TCM measures (external application,acupuncture,etc).

7. Clinical manifestations,diagnosis and treatment of common lymphoma pathological types

7.1 HL

HL is an uncommon malignancy involving lymph nodes and lymphatic system,mainly in males,with the ratio of males to females being 1.3:1-1.4:1.The onset age of this disease shows a typical bimodal distribution in developed countries in Europe and America,ranging from 15 to 39 years old and over 50 years old,respectively.In East Asian region including China,the age of onset is mainly in early adulthood (aged 30-40 years),showing a unimodal distribution.

7.1.1 Clinical manifestations

Lymphadenopathy is the initial symptom in 90% of HL patients,mostly starting from a group of involved lymph nodes in cervical and inguinal area.As the disease progresses,it can gradually spread to other lymph node regions,and in advanced stage,spleen,liver and bone marrow can also be involved.Most patients have no obvious systemic symptoms at first diagnosis,and 20%-30% of patients can be accompanied by B symptoms,including unexplained fever,drenching and recurrent night sweats,weight loss as well as pruritus,fatigue and other symptoms.

7.1.2 Pathological classification and diagnosis

According to the revised edition (2017) of WHO classification of lymphoma (Appendix 1),HL is divided into classical HL (cHL) and nodular lymphocyte-predominant HL (NLPHL),which is less common accounting for 10%of cases.The cHL can be divided into four histological subtypes,which are nodular sclerosis type,lymphocyte-rich type,mixed cellularity type and lymphocyte-depleted type.HL originates from germinal center B lymphocytes,and its morphological features are defined by destruction of normal tissue structure and heteromorphic large cells like Reed-Sternberg (R-S) cells scattering in the inflammatory cellular background.Classical R-S cell features binucleated or multinucleated giant cell with abundant cytoplasm and large prominent and eosinophilic nucleoli.When the cell appears as a symmetrical dual nucleus,it is called mirror image cell.Malignant cells in nodular lymphocytepredominant HL is called lymphocyte predominant (LP)cell which in the past was named lymphocytic-histocytic(L-H) cells or popcorn cells as the nuclei are large,folded and “popcorn-like”.LP is surrounded by programmed death-1 (PD-1) positive T cells.Increasing evidence has suggested the overlap between NLPHL with complete diffuse growth pattern and T-cell/ histocytic cell-rich large B-cell lymphoma.

The routinely tested IHC markers for HL diagnosis include CD45 (LCA),CD20,CD15,CD30,PAX5,CD3,MUM1,Ki-67 and EBV-EBER.cHL often appears as CD30 (+),CD15 (+) or (-),PAX5 weak (+),MUM1 (+),CD45 (-),CD20 (-) or weak (+),CD3 (-),EBER (+) in some cases.NLPHL shows CD20 (+),CD79α (+),BCL-6 (+),CD45 (+),CD3 (-),CD15 (-),CD30 (-),BOB1 (+),OCT2 (+),EBV-EBER (-).For differential diagnosis,appropriate markers should be added to identify anaplastic large cell lymphoma (ALCL) or DLBCL,etc.

Marrow cytology inspection shows that nuclear cells proliferate actively,eosinophil increase in partial cases.If tumor cells infiltrate bone marrow,HL-specific R-S cells can be found there.The positive rate of R-S cell is rather low by detection of bone marrow puncture cytology smear with only about 3%,while bone marrow biopsy can reach to 9%-22%.

7.1.3 Treatment principles

(1) NLPHL:It is not cHL,with indolent course and late recurrence occasionally,which is different from cHL in natural course and treatment efficacy.Most patients are in the early stage without B symptoms,mediastinal or bulky extra nodal involvement disease.It is characterized by potential transform to large B-cell lymphoma.Early-stage patients had a favorable prognosis,while late stage,age ≥45 years,low hemoglobin,and B symptoms were associated with unfavorable prognosis.Because CD20 antigen is expressed on the surface of tumor,rituximab is an effective treatment option.

(a) Principles of treatment for newly diagnosed patients:For I/II stage,non-bulky disease and without B symptoms,radiotherapy is the main treatment.For I/II stage,bulky disease or with B symptoms,combine immunochemotherapy with radiotherapy is the option.For III/IV stage,immunochemotherapy is the main measure.Due to the indolent course of disease,some advanced stage patients can choose to observe.IA/limited IIA stage (non-bulky disease): preferred ISRT,complete surgical removal of isolated lymphadenopathy,observation is an option.IA with bulky disease,IIA with extensive lesions or bulky disease and IB/IIB stage: preferred chemotherapy +rituximab+ISRT.III/IV stage: Based on the different clinical characteristics of patients,chemotherapy +rituximab ± ISRT,rituximab alone,palliative radiotherapy for symptomatic local lesions,or observation and follow-up for asymptomatic patients can be selected.

(b) Treatment regimen: Primary treatment regimen:ABVD regimen (doxorubicin+bleomycin+vinblastine +dacarbazine) +rituximab,CHOP regimen(cyclophosphamide +doxorubicin +vincristine +prednisone)+rituximab,CVP regimen (cyclophosphamide +vinblastine+prednisone)+rituximab or rituximab alone.Second-line therapy regimen for relapsed or refractory disease: R+DHAP (dexamethasone,high-dose cytarabine,cisplatin),R+ICE (ifosfamide,carboplatin,etoposide),R+IGEV (ifosfamide,gemcitabine,vinorelbine),R+bendamustine,R-CHOP,R-ABVD,R-CVP are also optional if not used before.

(2) cHL

(a) Principles of treatment for newly diagnosed patients:Early-stage patients were treated with combined modality therapy (chemoradiotherapy),while advanced-stage patients were treated with chemotherapy.Depending on following factors: favorable disease,unfavorable disease,bulky disease and interim PET-CT scan efficacy assessment,early-stage patients could decide the cycle of chemotherapy,whether to receive radiotherapy and radiotherapy dose,While,advanced-stage patients could decide whether to change the chemotherapy regimen or reduce the intensity of chemotherapy according to the results of the interim PET-CT efficacy evaluation.

I/IIA stage,favorable and non-bulky disease: the recommended treatment strategy is 3-4 cycles of ABVD chemotherapy ± ISRT 20-30 Gy.If PET-CT is selected for early efficacy evaluation,and the PET-CT efficacy evaluation result is Deauville score 1-3 after 2 cycles of chemotherapy,it is recommended to continue the treatment with ABVD regimen for 1-2 cycles ± ISRT 20-30 Gy.If Deauville score was 4,patients could continue 2 cycles ABVD and the involved field radiotherapy dose was 30 Gy.If Deauville score was 5,biopsy should be recommended.Patients with negative biopsy results should be treated according to the Deauville score of 4,and those with positive results should be treated according to the treatment strategy for patients with relapsed and refractory cHL.The PET-CT Deauville five-point scale is shown inAppendix 3.1.The treatment effect evaluation criteria of Lugano 2014 lymphoma are detailed inAppendix 3.2.

I/IIB stage,unfavorable or bulky disease: the general recommended treatment strategy is 4-6 cycles of ABVD chemotherapy ± ISRT 30 Gy.If patients choose PET-CT to early efficacy evaluation,and the efficacy evaluation result is Deauville score 1-3 after 2 cycles of chemotherapy,it is recommended to continue ABVD regimen for 2 cycles plus ISRT 30 Gy,or adjust to AVD regimen(doxorubicin,vinblastine,dacarbazine) for 4 cycles without radiotherapy.If Deauville score is 4-5,it is recommended to change to escalated BEACOPP regimen (bleomycin,etoposide,doxorubicin,cyclophosphamide,vinblastine,methylbenzyl hydrazine,prednisone) for 2-4 cycles ± ISRT 30 Gy.

III/IV stage: The overall recommended treatment strategy is 6 cycles of ABVD chemotherapy.If PET-CT is selected for early efficacy evaluation,after 2 cycles of chemotherapy,if the interim PET-CT efficacy evaluation result is Deauville score 1-3,it is recommended to adjust to AVD regimen for 4 cycles.If the Deauville score is 4-5,it is recommended to change to the escBEACOPP regimen for 3 cycles of chemotherapy,and evaluate again.If the Deauville score is still 4-5,biopsy is required.Patients with negative biopsy continued to complete BEACOPP chemotherapy for 1 cycle.Patients with positive biopsy were treated according to the treatment strategy of relapsed and refractory cHL patients.

(b) First-line treatment: Preferred regimens including ABVD regimen,escalated BEACOPP regimen (age ＜60 years,interim PET-CT evaluation did not reach CR after 2 cycles of,high HL international prognostic score (IPS≥4).(c) Therapeutic strategies and rescue therapy for relapsed and refractory patients: The general treatment strategy for R/R patients is to select an appropriate second-line regimen for rescue chemotherapy.After remission of chemotherapy,it is suitable for high-dose chemotherapy combined with autologous stem cell transplantation(HDT/ASCT) patients were treated with HDT/ASCT consolidation therapy ± radiotherapy.Patients who are not candidate for transplantation can choose to change the treatment regimen,radiotherapy or observation according to the efficacy of rescue chemotherapy.

Options for second and subsequent treatment regimen include DHAP,ESHAP (etoposide,methylprednisolone,high-dose cytarabine,cisplatin),and GVD (gemcitabine,vinorelbine,liposomal doxorubicin),ICE,IGEV,MINE(etoposide,ifosfamide,mesosodium,mitoxantrone),etc.

The National Medical Products Administration (NMPA)approved brentuximab vedotin for the treatment of relapsed/refractory CD30-positive HL on May 14,2020.NMPA approved sintilimab,camrelizumab and tislelizumab for the treatment of relapsed/refractory cHL after second-line systemic chemotherapy on December 27,2018,May 29,2019,and December 27,2019,respectively.

7.1.4 Prognostic factors of HL

Prognostic factors of HL are shown inAppendix 4.1.

(1) Unfavorable prognosis factors of early-stage HL: The prognostic factors of early HL were slightly different in different groups.

(2) Unfavorable prognosis factors of advanced-stage HL:IPS: a) albumin level ＜40 g/L;b) hemoglobin level ＜105 g/L;c) male gender;d) aged 45 years or older;e) stage IV disease;f) leukocytosis (white blood cell count ＞15×109/L);and g) lymphocytopenia (lymphocyte count ＜8% of the white blood count and/or lymphocyte count ＜0.6×109/L).(3) Early PEI-CT evaluation results: PET negativity at the end of 2-3 cycles treatment has been shown to be a significant favorable factor in patients with no matter earlystage or advanced-stage disease at the time of diagnosis.

7.2 NHL

7.2.1 DLBCL

DLBCL is the most common lymphoid neoplasm in adults,accounting for 30%-40% of NHLs in Western countries,and 35%-50% in China.The median age at diagnosis of DLBCL was 50-70 years,with males are slightly more than females.

(1) Clinical manifestations

The clinical manifestations of DLBCL vary according to the involved tissues,organs and tumor load.Most of DLBCL patients appear as painless lymphadenopathy at the beginning.However,the proportion of lesions outside the lymph nodes could reach 40%-60%,which can be originated from any extranodal tissues and organs.The pathogenesis of DLBCL is invasive and presents as a rapidly increasing mass.About 1/3 of DLBCL patients have B symptoms,and more than 50% of DLBCL patients have elevated LDH.

(2) Pathological diagnosis and classification

The main pathological feature of DLBCL is the diffuse growth of abnormal lymphoid cells,which destroys the normal structure of lymph nodes.DLBCL includes a variety of variants,subgroups and subtypes (Appendix 1).

The regular IHC markers to diagnose DLBCL include CD19,CD20,PAX5,CD3,CD5,CD79α,CyclinD1 and Ki-67.The typical immunophenotype exhibits as CD19 (+),CD20 (+),PAX5 (+) and CD3 (-).Furthermore,in order to explore the origin of cell [germinal center B-cell (GCB) or non-GCB],Han’s classification (CD10,BCL-6 and MUM-1) or Choi classification (GCET1,FOXP1,CD10,BCL-6 and MUM-1) can be selected,several markers,such as CD30,CD138 and ALK also can be added for differential diagnosis.Moreover,it is recommended that all DLBCL patients routinely detect EBER to identify EBV-positive DLBCL (non-specific).In addition,all DLBCL patients are also suggested to routinely detect BCL-2 and C-MYC immunohistochemistry.Patients especially with GCB-like immunophenotype along with the positive rate of C-MYC(≥40%) and BCL-2 (≥50%) by IHC and the Ki-67 index＞80% positive should undergo FISH testing to identify high-grade B-cell lymphoma withC-MYC,BCL-2and/orBCL-6genes rearrangements,which is known as “doublehit” or “triple-hit” lymphoma,which indicates a poor prognosis.If there is no condition for FISH testing and gene translocation of MYC,BCL-2 and BCL-6 cannot be evaluated,MYC protein (cut-off value is 40%) and BCL-2 protein (cut-off value is ＞50%) is known as double expression (DE) lymphoma,which indicates a poor prognosis.

Bone marrow hemocytology: When DLBCL cells infiltrate to bone marrow,it can be seen that the volume of tumor cell is large,the chromatin is rough,the nucleolus is multiple,but not obvious,and the cytoplasm presents grayish blue with a few vacuoles.

(3) Principle of treatment

The principle of treatment of DLBCL is multidisciplinary treatment based on medical treatment. Treatment strategies should be stratified based on different factors such as age,general status,international prognostic index(IPI) score,clinical stage,presence of large mass and subtypes.For patients with high tumor burden,a low dose of induction therapy can be given before the start of regular chemotherapy.The drugs of induction therapy could include prednisone ± vincrinstine to avoid the occurrence of tumor lysis syndrome.For patients with or infected with HBV,peripheral blood HBV-DNA titer should be closely monitored and appropriate antiviral therapy,such as entecavir,should be selected.

(a) First-line treatment of stage I and II: For patients with no large masses in stage I and II,R-CHOP regimen chemotherapy can be selected for 3-4 cycles+ISRT,or RCHOP regimen for 6 cycles ± ISRT.For patients with IPI score=0,4 cycles of R-CHOP regimen or 4 cycles of RCHOP regimen followed by 2 cycles of rituximab monotherapy can be selected.For patients with large lumps in stage I and II,R-CHOP regimen can be chosen for 6 cycles ± ISRT.

(b) First-line treatment of stage III and IV: Patients in stage III and IV are firstly recommended to select to participate in a clinical trial,or receive 6-8 cycles of R-CHOP regimen thermotherapy.Treatment strategies can be developed and adjusted according to the results of PETCT examinations,which could be performed before the start of treatment,during treatment or at the end of treatment.In order to avoid false positive result of PETCT,especially the influence of PET-CT results in the midtreatment on the judgment of curative effect,re-biopsy is recommended to perform before changing the treatment regimen.

(c) For patients over 80 years old or frail,the first-line treatment could select R-miniCHOP regimen,R-CDOP regimen (rituximab,cyclophosphamide,liposomal doxorubicin,vincristine,prednisone),R-GemOx regimen(rituximab,gemcitabine,oxaliplatin) or R-GCVP regimen(rituximab,gemcitabine,cyclophosphamide,vincristine,prednisone).For patients with left ventricular dysfunction,R-CDOP,DA-EPOCH-R (etoposide,prednisone,vincristine,cyclophosphamide,doxorubicin,rituximab),RCEOP (rituximab,cyclophosphamide,etoposide,vincristine,prednisone) and R-GCVP regimens could be selected.

(d) For patients with central nervous system invasion,highdose methotrexate (HdMTX) (≥3 g/m2,administered on d 15 of a 21-d cycle R-CHOP regimen) is recommended if the brain parenchyma is involved. Intrathecal administration of methotrexate/cytarabine is recommended for patients with meningeal involved.HdMTX (3.0-3.5 g/m2) can be administered cyclically with R-CHOP or selected as consolidation therapy after R-CHOP regimen combined with intrathecal injection.

(e) First-line consolidation therapy (elective): Lenalidomide may be considered as consolidation therapy for patients aged 60-80 years.

(f) Rescue treatment: For patients suitable for HDC/ASCT,the available rescue chemotherapy regimens include ICE±R,DHAP,(dexamethasone,cisplatin,cytarabine) ±R,ESHAP±R,GDP±R,DHAX(dexamethasone,cytarabine,oxaliplatin)±R,GemOx(Gemcitabine,Oxaliplatin)±R,MINER±R.For patients who are not suitable for HDC/ASCT,the rescue treatment options include: GemOx±R,DA-EPOCH±R,GDP±R,gemcitabine+vinorelbine ±R,and rituximab monotherapy.Palliative radiotherapy is also a treatment option.A portion of patients can only receive the best supportive care.Allogenic hematopoietic stem cell transplantation may also be considered for appropriate patients. Anti-CD19 chimeric antigen receptor T cells (CAR-T) can be selected for patients who have failed ≥second-line rescue therapy.

(4) Prognostic indicators

The IPI is currently identified as the most common and useful scoring system to predict the prognosis of DLBCL.IPI scores are based on five independent adverse prognostic factors,including age ＞60 years,stage III-IV disease,extranodal involvement ＞1,Eastern Cooperative Oncology Group performance status (ECOG PS) score ≥2,serum LDH level more than upper limit of normal,each poor prognostic factor is 1 point.0-1 point is divided into lowrisk group,2 points is divided into low-medium risk group,3 points is divided into high-medium risk group,4-5 points is divided into high-risk group.For patients treated with rituximab,a revised IPI could be used.For patients ≤60 years of age,an age-adjusted IPI could be used (Appendix 4.2).

In addition to clinical factors,with the progress of molecular genetics research in recent years,“double-hit” or“triple-hit” lymphoma with gene rearrangements of MYC,BCL-2 or/and BCL-6,and mutation of TP53 are also associated with poor prognosis of DLBCL.

(5) DLBCL of specific primary site and pathological type

(a) Primary central nervous system DLBCL: It is one of the subtypes of DLBCL,which refers to the primary intracranial or intraocular DLBCL,excluding dural lymphoma,intravascular large B-cell lymphoma,lymphoma secondary to central nervous system invasion and immune deficiency lymphoma.The primary central nervous system DLBCL is less than 1% of NHL,accounting for 2%-3% of primary brain tumors.The medium age of this disease is about 60 years old,and males are slightly more than females.

Clinical manifestations: There are 50%-80% of patients have focal symptoms,generally accompanied by changes in mental and reactional levels.Patients also have nausea,vomiting,headache and other symptoms due to the elevated intracranial pressure.In addition,pia mater lesions could cause headaches and asymmetrical cranial nerve dysfunction.Intraocular lymphoma manifests as blurred vision,visual field defects,etc.

Diagnosis: Imaging findings present the central nervous system nodules or masses.MRI is the preferred method of examination.It can be seen that the lesions exhibit a low signal or equal signal in the T1-weighted image,and the T2-weighted image shows a high signal,usually accompanied by edema.The pathological samples can be obtained by stereotactic needle biopsy or craniotomy.Cerebrospinal fluid cytology is also acceptable when tumor biopsy is not available,and cerebrospinal fluid flowcytometry can be used as an auxiliary diagnostic tool.Diseases that need to be identified with DLBCL include demyelinating disease,subacute infarction,intracranial space-occupying lesions caused by infection,gliomas and metastases.In particular,it should pay attention to the identification of disease with similar imaging findings and hormonal therapies,such as multiple sclerosis and neurological sarcoidosis.

The perivascular infiltration of the primary central nervous system DLBCL is significantly obvious.The morphology of the tumor cells is similar to that of the centroblast or immunoblast,which basically originate from the non-GCB,and the proportion of Ki-67 positive cells often exceeds 90%.The markers of IHC are identical to DLBCL.

Principle of treatment: Comprehensive treatment mainly based on medical treatment.Corticosteroids can quickly relieve patients’ symptoms;however,diseases often recur in the short term without chemotherapy or radiotherapy.Moreover,corticosteroids are not recommended prior to biopsy,except when intracranial hypertension is lifethreatening.Chemotherapy is the most important treatment,and the principle of using drug is to penetrate the blood-brain barrier.The preferred treatment regimen is HdMTX,high-dose cytarabine,temozolomide,rituximab can be combined to improve the curative effect.Moreover,consolidation therapy can be performed in patients who have achieved CR/unconfirmed complete response (CRu) after first-line treatment,including HDT/ASCT,high-dose cytarabine CTetoposide or whole brain radiotherapy.Relapse or refractory patients can select HdMTX,HdAra-c and monotherapy or combination regimens including temozolomide,topotecan,pemetrexed,ibrutinib,lenalidomide (temozolomide,topotecan,pemetrexed,ibrutinib,lenalidomide and other single-drug or combined regimens).For patients who are effective to rescue treatment could consider HDC/ASCT.For primary central nervous system lymphoma,a combination regimen containing thiotepa is recommended as conditioning regimen for autologous hematopoietic stem cell transplantation.

Chemotherapy combined with whole brain radiotherapy can prolong progression-free survival (PFS).However,the neurotoxicity of whole brain radiotherapy is more obvious in patients over 60 years of age.So it is recommended that patients over 60 years of age should delay radiotherapy after chemotherapy remission.In addition,the role of surgery is limited to biopsy,and complete tumor resection is not beneficial.

Prognosis: The disease has a high degree of malignancy.The median survival time of different treatment strategies is 2-3 months for supportive therapy,3-5 months for surgery alone,12-16 months for radiotherapy alone,and 25-84 months for chemotherapy regime contained high dose of methotrexate,respectively.The most important prognostic factors are age and physical status.

(b) Primary testicular DLBCL: The primary testicular DLBCL accounts for 3%-9% of testicular tumors,and accounts for 1%-2% of NHL.Moreover,DLBCL is the most common pathological type of primary testicular lymphoma with the rate of 80%-90%.In addition,the disease is the most common testicular malignancy in males over 50 years old,with a median age at diagnosis of 65 years old.

Clinical manifestations: Most patients present testicular painless mass or swelling,while a few of patients appear as scrotal pain.About 20% of patients have both tests affected,and 35% of patients are involved with the contralateral testis during the course of disease.Patients with retroperitoneal lymphadenopathy may present with abdominal pain and ascites.B symptoms are usually seen only in patients with advanced disease.The disease is prone to extranodal organs involvement,including the central nervous system,skin,subcutaneous tissue,lung,pleura,etc.The main presentations of ultrasound is increased testicular volume,smooth appearance,localized testicular or diffuse hypoechoic area,clear or unclear borders.Additionally,color ultrasound shows abundant blood supply,and normal testicular blood vessels can pass through the lesion.

Principle of treatment: Primary testicular DLBCL should receive comprehensive treatment,including surgery,radiotherapy and immunochemotherapy.Moreover,patients with this disease should be performed orchiectomy and high spermatic ligation.Then patients should receive immunochemotherapy after operation.Prophylactic radiotherapy to the contralateral testicular and central nervous system prophylaxis with HdMTX is recommended due to the high rate of contralateral testicular and central nervous system invasion.Patients with II disease could also receive ISRT.

Prognosis: Poor prognositic factors of primary testicular DLBCL include advanced age,advanced stage,elevated LDH,B symptoms,high IPI score,and without surgery or radiotherapy.

(c) Primary mediastinal large B-cell lymphoma (PMBL): It is common in young adults with the median age at diagnosis of 35 years old,and females are slightly more than males.Tumor cells of this disease originate from thymic B cells,and the gene expression profiles are unique and similar to cHL.Unlike most DLBCL,most PMBL express CD23,CD30 and PD-L1.

Clinical manifestations: The clinical symptoms and signs are associated with a rapidly increasing mediastinal mass,which could cause superior vena cava compression syndrome,hydropericardium,pleural effusion,etc.At the initial treatment,the lesions are usually limited,mainly located in the anterior superior mediastinum,which might be associated with supracondylar,cervical and hilar lymph nodes.After recurrence,lesions often involved with extensive extranodal organs or tissues.

Principle of treatment: The option of first-line chemotherapy strategies is still controversial.The alternative options include DA-EPOCH-R,R-CHOP or R-CHOP continuous R-ICE,etc.Consolidation radiotherapy is feasible after chemical therapy,in addition to those with negative PET-CT evaluation.Owing to the application of CT for evaluation,residual mass lesions are usually existing,however,it is impossible to identify whether the tumor remains.Therefore,it is suggested to use PET-CT for evaluation at the end of chemotherapy.However,the false positive rate of PET-CT is high so it is recommended that re-biopsy should be done before changing the chemotherapy regimen based on PET-CT results.Additionally,treatment of relapsed or refractory primary mediastinal DLBCL patients is based on relapsed or refractory DLBCL.

Prognosis: The prognosis of this disease is better than that of non-specific DLBCL,and the 5-year PFS can achieve 80%-95%.Poor prognostic factors can be referred to DLBCL.

(d) High-grade B-cell lymphoma,withMYCandBCL-2and/orBCL-6rearrangements (double/triple-hit lymphoma): The definition is high-grade B-cell lymphoma,withMYCandBCL-2and/orBCL-6gene translocation detected by FISH.Patients withMYCandBCL-2orBCL-6translocation are double-hit lymphoma,while patients with all three genes translocation are triple-hit lymphoma.It accounts for about 2%-11% of DLBCL,and most of them originate from GCB.

Clinical manifestations: It has highly invasive features.High LDH,bone marrow invasion,central nervous system invasion and high IPI score are common.

Principle of treatment: There is no standard treatment,and participation in clinical trials is recommended first.The efficacy of R-CHOP is poor,and the high-intensity regimen may improve the efficacy.The recommended treatment regimen includes DA-EPOCH-R,RHyperCVAD/HdMA (rituximab,cyclophosphamide,vincristine,doxorubicin,dexamethasone alternating with HdMTX and HdAra-C) and R-CODOX-M/IVAC(rituximab,cyclophosphamide,vincristine,doxorubicin and methotrexate,ifosfamide,etoposide,cytarabine).Consolidation radiation is recommended for patients of limited stage.Central nervous system prophylaxis is recommended due to the high rate of central nervous system invasion.

Prognosis: The prognosis is poor.In a retrospective study with a long follow-up,the R-CHOP regimen treatment achieved low 5-year PFS and OS,which were 18% and 27%,respectively.Another meta-study compared the efficacy of R-CHOP,R-HyperCVAD or R-CODOXM/IVAC and DA-EPOCH-R as the first-line therapy.The median PFS of the three groups were 12,19 and 22 months,respectively.Compared with the R-CHOP regimen,the DA-EPOCH-R regimen prolongs the PFS of these patients significantly.

7.2.2 FL

FL is the most common indolent lymphoma in Europe and America,accounting for 20%-30% of NHL. The incidence of FL in Asia,including China,is low,less than 10% of NHL.The median age of onset was about 60 years old.

(1) Clinical manifestations

The main manifestations were multiple lymph node enlargement,which also involved bone marrow,peripheral blood,spleen,Waldeyer’s ring,gastrointestinal tract and soft tissues.Primary extranodal cases were rare.Advancedstage patients are more frequently observed,accounting for about 70%.

(2) Pathological diagnosis

Morphological manifestations were the proliferation of follicular central cells and centroblasts,most of which were follicular nodular growth.According to the number of centroblasts,FL was divided into three grades: 0-5 centroblasts in each view of highly magnifying lens of microscopes were grade 1,6-15 centroblasts were grade 2,15 or more were grade 3.Grade 3 could be further divided into grade 3a and grade 3b,of which grade 3b showed that centroblasts were patchy distribution or lacked of centroblasts.IHC markers for FL diagnosis included CD19,CD20,PAX5,CD3,CD10,BCL-2,BCL-6,LMO2,CD21 and Ki-67,also included the markers for differential diagnosis,such as chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL),and mantle cell lymphoma (MCL),such as CD23,CD5 and cyclin D1.FL often has t (14;18) translocation and Bcl-2 protein overexpression,which makes it difficult to diagnose.FISH can be used to detect BCL-2 expression when necessary.

Paediatric-type follicular lymphoma (PTFL) is a follicular lymphoma of lymph node origin that occurs mainly in children and young adults.PTFL is commonly involved of head and neck lymph nodes,and of early stage.The phenotype of tumor cells is CD10+/CD20+/CD79a+/PAX5+/BCL6+,and mostly BCL-2 is negative.This type of FL has a good prognosis,and most patients can be cured by surgical resection alone without radiation or chemotherapy.

A new classification of duodenal-type follicular lymphoma (DTFL) was proposed in the revised WHO classification in 2017,which has a good prognosis and needs to be differentiated from FL in other gastrointestinal anatomical sites.The newly proposed large B-cell lymphoma withIRF4gene rearrangement often occurs in Waldeyer’s ring and cervical lymph nodes,which is common in children and young people.Histological manifestations are consistent with classical high-grade FL.The prognosis is relatively good when epidemic histochemistry showed that IRF4+/CD10+/BCL-6+and molecular detection showed thatIRF4gene rearrangement.In addition,the formerin situFL was replaced byin situfollicular neoplasms.

Bone marrow cytology: When tumor cells involve bone marrow,the proliferation of nucleated cells can be obviously active.FL cells were mainly increased with larger lymphocytes than normal cells.The nucleus is round or irregular,the nuclear chromatin is finer,the nucleolus is obscure,the cytoplasm is rich,pale blue,and some of the FL cells are vacuolar degeneration.The diagnosis of FL is mainly based on histopathology.When FL leukemia occurs,a certain number of FL cells can be seen in bone marrow or peripheral blood.

(3) Treatment

Grade 1-2 FL belongs to indolent lymphoma,and the treatment strategies are as follows.The treatment of grade 3 FL is equivalent to DLBCL.

(a) Stage I/II FL: Stage I/II patients may be potentially cured by radiotherapy.Radiotherapy is the main treatment strategy for stage I and limited non-bulky stage II patients.ISRT,or ISRT+CD20 monoclonal antibody ±chemotherapy is recommended;in certain circumstances where radiotherapy is impossible,CD20 monoclonal antibody ± chemotherapy can be selected.Stage I patients with bulky masses or stage II patients with non-contiguous lesions should be managed as stage III or IV disease,and medical treatment is the main method.CD20 monoclonal antibody ± chemotherapy ± palliative ISRT is recommended.Patients without indications for treatment may choose to follow up with observation.

(b) Stage III/IV FL: Stage III/IV FL is considered as an incurable disease.For FL patients with advanced stage but low tumor burden,there is no difference in OS time between immediate treatment after diagnosis and administrate treatment after observation the therapeutic indications.

During observation periods for patients without treatment indications,physical examinations or laboratory tests may be performed every 3-6 months for 5 years,and once a year after 5 years;CT is performed ≥6 months over 2 years and 1 CT scan ≥1 year after 2 years.

The indications for the treatment of advanced FL are as follows: appropriate clinical trials,high-tumor burden,threatened end-organ function,cytopenia secondary to lymphoma,bulky disease and continuous progression of lesions.

The recommended first-line treatment for FL included:R-B (rituximab,bendamustine),R-CHOP or G-CHOP(obinutuzumab,cyclophosphamide,doxorubicin,vincristine,prednisone),R-CVP (rituximab,cyclophosphamide,vincristine,prednisone) or G-CVP(obinutuzumab,cyclophosphamide,vincristine,prednisone)and R-R (rituximab,lenalidomide).For some patients with low tumor burden,rituximab monotherapy can be selected.For elderly and frail patients,single-drug rituximab or single-drug alkylating agents (such as nitrogen mustard phenylbutyrate,cyclophosphamide) ± rituximab can also be used.For patients with initial treatment and high tumor burden,CR or PR can be achieved after induction chemotherapy,and rituximab maintenance therapy may prolong PFS.

(c) Treatments of relapsed and refractory FL: For relapsed FL,observation and waiting can be preferred,and rescue treatments can be started when treatment indications appear. For FL with rapid progress,histological transformation should be excluded first.Especially in the following cases: elevated LDH,uncontrolled rapid growth in an affected area,extranodal lesions or newly emerged B symptoms.If PET-CT examination showed a significant increase in the standard uptake value of an invaded site,we should be highly suspicious of the occurrence of histological transformation.

If the relapse or progression is more than 6 months after the last application of rituximab,it can also be treated with rituximab.According to the first-line regimens,the recommended second-line regimens included: R-B,RCHOP,R-CVP,or R-R.Patients with progression of disease (POD) ≤24 months after first-line therapy with RCHOP or R-CVP regimens should be considered for treatment with lenalidomide-based regimens,participation in clinical trials or HDT/ASCT as consolidation therapy are recommended.After remission with second-line induction chemotherapy,rituximab maintenance therapy can also be selected.CAR-T therapy is an option for patients who have failed after ≥2 prior therapies.

Histologic transformation of FL to DLBCL occurs in approximately 15% of patients with an estimated annual rate of 2%-3%.Risk factors associated with histological transformation include advanced stage FL,high follicular lymphoma international prognostic index (FLIPI),elevated LDH,and B symptoms.Immediate treatment and observation had no significant influence on histologic transformation rates.Transformed FL (TFL) usually has a poor prognosis,and factors such as staging at the time of transformation,whether they received chemotherapy or rituximab before transformation,and whether they transformed to double-or triple-hit DLBCL are associated with prognosis.Treatment of TFL refers to DLBCL.

(d) Prognosis: FLIPI has two scoring systems,FLIPI1 and FLIPI2,which contain five independent adverse prognostic factors.All patients are divided into three risk groups.In the FLIPI1 scoring system,0-1 into low-risk group,2 into medium-risk group,and ≥3 into high-risk group,and in the FLIPI2 scoring system,0 into low-risk group,1-2 into medium-risk group,and ≥3 into high-risk group (Appendix 4.3).POD24 or event-free survival ≤12 months after firstline immunochemotherapy is associated with poor prognosis.Results of a study showed that after first-line treatment with R-CHOP,the 5-year survival rate of POD24 and non-POD24 patients overall survival rates were 50% and 90%,respectively.

7.2.3 MZL

MZL is a type of indolent lymphoma that originates from the marginal zone and comprises of 3 distinct subtypes:extranodal MZL (EMZL),nodal MZL (NMZL) and splenic MZL (SMZL),among which EMZL,also known as mucosa-associated lymphoid tissue (MALT) lymphoma,is the most common subtype.

The cause of MZL is associated with persistent immune stimulation due to chronic infection or inflammation [e.g.gastric MALT lymphoma is associated with Hp infection;thyroid MALT lymphoma is associated with Hashimoto’s thyroiditis;parotid MALT lymphoma is associated with Sj?gren’s syndrome (SS);NMZL and SMZL are associated with hepatitis C viral infection].

Due to the lack of specific immunological markers,exclusion method is mainly used for the pathological diagnosis of MZL and the main exclusion subtypes are other types of small B-cell lymphoma.CD21 and CD23 are often used to reflect an expanded follicular dendritic cell network.Pathological morphology often appears as small lymphocytic clonal hyperplasia,causing the widening of marginal zone,atrophy of the germinal center,visible follicular implantation phenomenon and lymphatic epithelial lesions.

(1) MALT lymphoma

The most common primary site of MALT lymphoma is the gastrointestinal tract,of which gastric accounts for approximately 80%-85%.About 2/3 of the patients have a limited-stage,while the other patients have an extensivestage,and bone marrow invasion is 10%-15%.

1) Primary gastric MALT lymphoma

(a) Clinical manifestations: The common symptoms include indigestion,acid reflux,abdominal pain,weight loss,etc.,while B symptom is uncommon.The proportion of gastric bleeding and perforation are 20%-30% and 5%-10%,respectively.Stage I and II patients account for 80%-90%,and 90% patients are Hp positive.Endoscopic appearance can vary from erythema,erosion to ulceration,etc.

(b) Pathological diagnosis: Gastroscopic biopsy is an essential examination and routine Hp staining is required.The typical morphology of MALT lymphoma is small lymphocyte dense proliferation,and in most cases,infiltration and destruction of mucosal epithelium,leading to the formation of lymphatic epithelial lesions.The common IHC markers include CD3,CD5,CD10,BCL-2,CD19,CD20,CD21,CD23,CD43 and PAX5.Patients excluded as FL,CLL/SLL and MCL,can be diagnosed as MALT lymphoma by the combination of morphology and B cell phenotype.A small number of cases require polymerase chain reaction-immunoglobulin (PCR-Ig)testing to obtain monoclonal evidence for definitive diagnosis (for monoclonal evidence to confirm the diagnosis).Detection of t (11;18) translocation by FISH or PCR can be used to determine whether the gastric MALT lymphoma is Hp-dependent,and the patients with t (11;18)translocation are predicted to have poor response to anti-HP therapy (predict poor efficacy of anti-Hp treatment).DLBCL accompanied with MALT lymphoma should be diagnosed if large transformed lymphocytes show solid or flaky hyperplasia.

(c) Principle of treatment: Stages I and II patients: For Hp positive patients,anti-Hp therapy is recommended as the first choice in t (11;18) negative or unknown patients.Anti-Hp therapy combined with ISRT is preferred for t (11;18)positive patients;if radiotherapy is contraindicated,anti-HP combined with rituximab is also an option (can also be selected).For Hp negative patients or Hp positive patients with failed anti-Hp therapy,ISRT is preferred.Patients who are not suitable for radiation therapy may consider single-agent rituximab treatment.After anti-Hp treatment,the first endoscopy can be performed 3 months later.If the gastroscopy indicates remission of lesions,the endoscopy can be performed once every 3-6 months thereafter.Stages IIE,III/IV patients: Patients with no treatment indications can choose “watch and wait”,while patients with indications for treatment can refer to the treatment principle of advanced FL [7.2.2 (3) Treatment].Surgical treatment is limited to special cases such as bleeding,perforation,etc.

2) Non-gastric MALT lymphoma

(a) Clinical manifestations: Non-gastric MALT lymphoma presents an inert process with a similar prognosis to primary gastric MALT lymphoma.The common involved sites include salivary glands,lungs,head and neck,eye appendages,skin,thyroid,breast,etc.

(b) Principle of treatment: For stage I and II patients,ISRT or surgery is preferred,but those suffering serious complications due to these therapy may consider “watch and wait” or single-agent rituximab treatment.Stages III and IV patients refer to the treatment principle of advanced FL [7.2.2 (3) Treatment].

(2) NMZL

(a) Clinical manifestations: NMZL,accounting for 1.5%-1.8% in all lymphomas,distributing similarly in males and females,with a median age of onset of 60 years.Late lesions are common,mainly involving the lymph nodes and even the bone marrow and peripheral blood.Most patients present with painless multiple lymphadenopathy,but patients with MALT lymphoma or SMZL,accompanied by lymph node involvement,should be noted.

(b) Pathological diagnosis: The structural features are similar to the SMZL,and the immunophenotype is not specific,similar to other MZL subtypes.

(c) Principle of treatment: Refer to treatment principle of FL [7.2.2 (3) Treatment].

(d) Prognosis: The 5-year OS is 60%-80%,and the prognosis refer to FLIPI in details [7.2.2 (3) Treatment].

(3) SMZL

(a) Clinical manifestations: SMZL,accounting for 2% in all lymphomas,distributing similarly in males and females,with a median age of onset of 50 years.The common involved sites include spleen,splenic hilar lymph nodes and even bone marrow,peripheral blood and liver.The most common symptom is splenomegaly,occasionally accompanied by autoimmune thrombocytopenia,anemia,visible hair cells in the peripheral blood.HCV should be included in laboratory tests.

(b) Pathological diagnosis: The tissue structure is similar to NMZL,but the immunophenotype is not specific.Patients who are excluded as FL,CLL/SLL,MCL,may be diagnosed as SMZL if abnormal small lymphocytes involve in the bone marrow or peripheral blood,accompanied by splenomegaly.

(c) Principle of treatment: For patients with no symptoms,progressive hematopenia,or splenomegaly,“watch and wait” is preferred.For patients with splenomegaly and positive HCV infection,anti-hepatitis C treatment is recommended if there are no contraindications.For patients with splenomegaly,but negative for HCV,clinical symptoms should be considered when choosing a treatment plan.For those without symptoms,“watch and wait” is recommended,while for those with symptoms,single-agent rituximab treatment is preferred. Splenectomy is recommended for patients who do not respond to rituximab therapy.Patients who have progressed after the above treatments,could refer to the principles of treatment of advanced FL [7.2.2 (3) Treatment].

(d) Prognosis: The prognosis of FL is assessed [Refer to the prognostic evaluation of FL in 7.2.2 (3) (d) Prognosis].

7.2.4 CLL/SLL

CLL and SLL are indolent B-cell malignancies that are often considered to be different clinical presentations of one disease,and the treatment methods are the same.The major difference is that in CLL,a significant number of abnormal lymphocytes are found in peripheral blood;whereas in SLL,the bulk of disease is in lymph nodes.The International Workshop on Chronic Lymphocytic Leukemia (IWCLL) defines SLL as having lymphadenopathy and/or splenomegaly,no hemocytopenia due to bone marrow invasion,and clonal B cell count in peripheral blood less than 5×109/L.SLL needs to be confirmed by histopathology of lymph node biopsy,while flow cytometry is usually sufficient to diagnose CLL,and lymph node biopsy and bone marrow biopsy are required for difficult diagnoses.The diagnosis of CLL should meet the following criteria: the presence of monoclonal B cell lymphocytes in peripheral blood ≥5×109/L;clonal B-cell phenotype confirmed by flow cytometry;the typical immunophenotypes were CD19 (+),CD5 (+),CD23 (+),CD200 (+),CD20 weak (+),CD79b weak (+),FMC7 (-),CD10 (-) and CyclinD1 (-).If there is hemocytopenia due to bone marrow invasion,even the clonal B cell count in peripheral blood does not reach 5×109/L,CLL is still diagnosed.

CLL/SLL,in Europe and the United States,is one of the most common type of leukemia,accounting for 7%-10% of NHL.In comparison,Asian populations have a significantly lower incidence of disease.The incidence of CLL/SLL accounts for about 1%-3% of NHL in China.The median age of onset was 65 years old,and the ratio of male to female was 1.5:1-2:1.

(1) Clinical manifestations

Lesions usually involve peripheral blood,bone marrow,lymph nodes and liver and spleen.Clinical manifestations are diverse,most patients can be asymptomatic,and some may have fatigue,autoimmune anemia,infection,hepatosplenomegaly and lymphadenopathy.

(2) Pathological diagnosis

Typical CLL/SLL cells are singular,diffuse infiltration,with pseudo-follicle formation (proliferative foci),and nuclear chromatin granules are characteristics,showing the proliferation center.IHC phenotype: CD5 (+),CD23 (+),CD43 (+/-),CD10 (-),CD19 (+),CD20 weak (+) and LEF1 (+).Other markers such as Cyclin D1 and SOX11 can be added when MCL needs to be differentiated.The appearance of proliferative foci could be easily misdiagnosed as reactive hyperplasia,all have a monoclonal B-cell lymphocytosis in early stage.

Routine blood test: The number of white blood cells and lymphocytes continuously increases,and mainly consists of differentiated CLL lymphocytes,often more than 50%,up to 80%-90%.Its morphology is similar to normal lymphocyte,but the nucleus is irregular,presenting as deep incision or nuclear fissure;the nuclear chromatin irregularly aggregated,with small cytoplasm,grayish blue and no particles.Broken cells (e.g.,basket cells) are more common;a small number of young lymphocytes increase,usually less than 2%.B-CLL/prolymphocytic leukemia can be diagnosed when the young lymphocytes are more than 55%.Thrombocytopenia can be seen in late stage.

Bone marrow cytology: Bone marrow nucleated cells are significantly or extremely active.Lymphocytes are highly proliferative,mainly composed of abnormal mature small lymphocytes,accounting for more than 40%,and even up to 90%.The size and shape of the cells are basically as same as those in peripheral blood.The morphological abnormalities are not obvious.The nucleus shows deep incisions or fissures,and the nuclear chromatin irregularly aggregated,with nucleolus absence or not obvious.There was a small amount of cytoplasm and no particles.It can also be mixed with some medium to large lymphocytes.Primary and young lymphocytes are generally less than 5%.Increased numbers of young lymphocytes are associated with disease progression.The granulocyte,erythroid and megakaryocytic cells were significantly reduced.When the patient is accompanied by hemolysis,nucleated red blood cells may significantly proliferate.

(3) Staging

The Lugano staging system is utilized for patients with SLL;CLL refers to the Rai and Binet staging systems(Appendix 2.2).

(4) Treatment

1) SLL: Phase I patients use local radiotherapy;patients with stage II-IV can wait for treatment if there is no indication for treatment,and refer to the treatment principles of CLL [7.2.4 (4) Treatment] when there are indications for treatment.

2) CLL: Low-risk and intermediate-risk patients with stage 0-II of Rai can “watch and wait” if there is no indication for treatment;when there are indications for treatment in patients with stage 0-II of Rai,or patients with stage III-IV of Rai and with continuous hemocytopenia,select the corresponding treatment programs according to del(17p) and/or TP53 mutation detected by FISH,mutation status of immunoglobulin heavy chain variable region(IGHV),general state of patients and comorbidities.Attention should be paid to the supportive treatment of CLL,such as tumor lysis syndrome,infection and autoimmune cytopenia.

3) Treatment indications: Suitable for clinical trials;obvious disease-related symptoms such as severe fatigue,night sweats,weight loss and non-infectious fever;threatening organ function;continuously enlarged masses,such as splenomegaly beyond the left costal margin 6 cm,lymph node diameter ＞10 cm;progressive anemia and progressive thrombocytopenia; autoimmune diseases associated with CLL with ineffective hormone therapy.4) First-line treatment options:

(a) Patients withoutdel(17p)/TP53mutation: Ibrutinib is recommended first for frail patients with severe comorbidities (intolerant to purine analogs),and patients≥65 years old or ＜65 years old but those with serious concomitant diseases (creatinine clearance rate ＜70 mL/min). Other recommended regimens include:bendamustine +CD20 monoclonal antibody (not recommended for frail patients),high-dose methylprednisolone+rituximab,chlorambucil,rituximab.

For patients ＜65 years old without severe comorbidities,the recommended options include: ibrutinib,bendamustine +CD20 monoclonal antibody,FCR (fludarabine,cyclophosphamide,rituximab) (preferred in CLL patients with IGHV mutations),FR (fludarabine,rituximab),highdose methylprednisolone+rituximab,ibrutinib +rituximab.

Maintenance therapy after first-line treatment: For highrisk patients (peripheral blood minimal residual disease≥10-2or unmutated IGHV peripheral blood minimal residual disease ≥10-4and ＜10-2),lenalidomide maintenance therapy can be considered.

(b) Patients withdel(17p)/TP53mutations: Ibrutinib is preferred;Other recommended regimens include highdose methylprednisolone+rituximab.

5) Treatment options for patients with relapse and resistance:

(a) Patients withoutdel(17p)/TP53mutation: For frail patients with severe comorbidities (intolerant to purine analogs),and patients ≥65 years old or ＜65 years old but those with serious concomitant diseases (creatinine clearance rate ＜70 mL/min),brutton tyrosine kinase inhibitors (ibrutinib,zanubrutinib,orelabrutinib),venetoclax+rituximab is preferred.Other recommended regimens include: bendamustine+rituximab,reduced dose FCR,high-dose methylprednisolone +rituximab,lenalidomide ± rituximab,venetoclax,increased dose rituximab,bendamustine+rituximab+ibrutinib.

For patients ＜65 years old without severe comorbidities,it is preferred to treat with brutton tyrosine kinase inhibitors (ibrutinib,zanubrutinib,orelabrutinib).Other recommended regimens include: bendamustine +rituximab,FCR,high-dose methylprednisolone +rituximab,lenalidomide ± rituximab,venetoclax,bendamustine+rituximab+ibrutinib.

Maintenance therapy after second-line therapy: For patients who achieve CR or PR after second-line therapy,lenalidomide maintenance therapy may be considered.

b) Patients withdel(17p)/TP53mutations: Preferred treatment regimens recommended above second line:Bruton tyrosine kinase inhibitors (ibrutinib,zanubrutinib,orelabrutinib),venetoclax+rituximab,venetoclax.Other recommended regimens include:high-dose methylprednisolone+rituximab,lenalidomide ± rituximab.

(5) Prognosis

The factors associated with poor prognosis include:Unmutated IGHV,del(17p)/TP53mutations,del(11q),complex karyotype (≥3 chromosomal abnormalities),tumor cells CD38 positive ≥30%,ZAP70 positive cells ratio≥20%,CD49d ≥30% detected by flow cytometry,increased β2-microglobulin and late stage.

7.2.5 MCL

MCL accounts for approximately 3%-10% of NHL.MCL predominates in males over females with a ratio of around 2:1-3:1,the median age at diagnosis is around 65 years old.The natural course of this disease can be divided into aggressive and indolent MCL,but most MCL characterized with aggressive behaviors.MCL resembles indolent lymphoma in sensitivity to therapy,thus this disease is considered incurable with traditional chemotherapy.The overall survival of MCL patients with prior combined chemotherapy is about 3-5 years.But in recent years,with the introduction of HDC/ASCT,cytarabine and targeted agents,the survival has improved significantly.A small proportion of patients with indolent MCL,so called leukemic non-nodal MCL,with less molecular genetic variations,nodel(17p)/TP53mutation,have no mutation or lack ofp53gene and appear nonexpression or low expression of SXO11.Similarly,to the course of indolent lymphoma,this disease presents with a good prognosis.

(1) Clinical features of MCL: Frequently involving lymph nodes,bone marrow,gastrointestinal tract,spleen and Waldeyer’s ring.About 70% of patients present with stages IV disease at diagnosis.The invasion rate of bone marrow can reach 50% to 100%.The invasion rate of lower gastrointestinal tract is high,and it often shows digestive tract involvement under endoscope presents with multiple polypoid lesions.

(2) Pathological diagnosis: Tumor cells of MCL are small,medium or large size lymphocytes with similar morphological characteristics and irregular nuclear surface.The main architectural patterns of these cells are mantle zone,nodular and diffuse.Given its poor prognosis,it is,therefore,of significance to conduct differential diagnosis,distinguishing from CLL/SLL,FL and MZL. The commonly used IHC markers are CD20,PAX5,CD3,Cyclin D1,CD10,CD23,MUM-1,CyclinD1,SOX11 and CD138. The typical immunophenotype of MCL is CD19 (+),CD5 (+),CD23 (-),CD200 (weak +),CD20 (+),CD79b (+),FMC-7,CD10 (+) (-) and CyclinD1 (+).Cyclin D1+and CD5+expression can be observed in most patients.While when Cyclin D1-,FISH detection of CCND2 and CCND3 and IHC detection of SOX11 can be applied for comprehensive diagnosis.When diagnosis of MCL is difficult,other available evidence is essential,detection of t (11;14) using FISH presents with great sensitivity and specificity in the diagnosis of MCL.Furthermore,according to the revised version of WHO Hematopoietic and Lymphoid Tumor Classification(2017),MCL can be divided into two types: the classic variant of MCL with SOX11 positive and no IGHV mutation.This type of MCL shows high invasiveness and has poor prognosis,or appears blastoid variants and pleomorphic cells with greater invasiveness and p53 mutation.The other type,leukemic non-nodal MCL,frequently involving peripheral blood,bone marrow and spleen,presents with SOX11 negative expression and IGHV mutation,with an indolent clinical traits and good prognosis.

Bone marrow cytology: With bone marrow infiltration,various amounts of abnormal lymphocytes increasing can be observed in bone marrow smear.These tumor cells vary in size,and mainly have a circular or mild irregular nucleus frequently with a big and abnormal nucleolus.The chromatin is finely dispersed.Rich and pale blue cytoplasm can be observed in these cells.

(3) Treatment: Overall detections and accurate staging are needed for the patients with MCL to guide treatment options.The patients with blastoid variants and symptoms of central nervous system should conduct cerebrospinal fluid examination and brain MRI.For patients diagnosed with stages I-II MCL,endoscopy examination is necessary to exclude gastrointestinal involvement.

(a) Treatment options: Patients with stage I or localized stage II without masses,ISRT or routine dose intensity immunochemotherapy ± ISRT is recommended.

Routine dose intensity immunochemotherapy is recommended for patients with extensive stage II without masses.Some patients with indolent clinical features,such as leukemia like non-lymph node MCL with splenomegaly,SOX11 negative (IGHV mutant),no TP53 mutation or deletion,low tumor burden,Ki-67 proliferation index＜10%,can be observed and followed up.

For patients in stage II accompanying masses and in stage III/IV with invasive clinical features,if HDT/ASCT is suitable,sequential HDT/ASCT after high-dose intensive induction chemotherapy is recommended;Patients who are not suitable for HDT/ASCT are recommended to participate in clinical trials or conventional dose intensity treatment.Patients with indolent clinical characteristics,such as no symptoms or treatment indications can be observed and followed up.Those with symptoms or treatment indications should choose the corresponding treatment according to whether there is TP53 mutation.

(b) First-line treatment: High-dose intensity therapy: RDHA (rituximab,dexamethasone,cytarabine)+platinum(carboplatin,cisplatin or oxaliplatin),R-CHOP/R-DHAP alternative therapy,NORDIC [intensive dose of R-CHOP(maxi-CHOP) and rituximab+high dose cytarabine alternative] therapy,HyperCVAD,rituximab,bendamustine sequential rituximab and high dose cytarabine;Other recommended regimens: bendamustine +rituximab.

Routine dose intensity therapy: bendamustine +rituximab,VR-CAP (bortezomib,rituximab,cyclophosphamide,adriamycin and prednisone),R-CHOP or lenalidomide+rituximab are recommended;Other recommended regimens: modified R-HyperCVAD regimen (for patients ＜60 years old),RBAC500 (rituximab,bendamustine,cytarabine).

Consolidation treatment: HDT/ASCT can be considered.

Maintenance therapy: Rituximab.(c) Second-line treatment: Choosing a regimen or agent that is not applied to the first-line regimen. The recommended preferred regimen includes: BTK inhibitors(ibrutinib,zanubrutinib,orelabrutinib);Lenalidomide +rituximab; Other recommended regimens include:bendamustine+rituximab,bendamustine+rituximab +cytarabine,bortezomib ± rituximab;R-DHAP,R-DHAX(dexamethasone,cytarabine,oxaliplatin),R-GemOx,Btk inhibitor+lenalidomide+rituximab,Btk inhibitor +Venetoclax,Venetoclax ± rituximab,etc.

Consolidation therapy after second-line treatment:Allogeneic hematopoietic stem cell transplantation.

(4) Prognosis: IPI for aggressive lymphomas,identified from the survival data of aggressive lymphomas,can be used as a prognostic indication of MCL,although with poor efficiency.Simplified version of the international prognostic index for mantle cell lymphoma (MIPI),which can better stratify the prognosis of MCL,is widely used.Other bad-prognostic factors include Ki-67,TP53 and blastoid variant.Ki-67 is the most important biological prognostic factor independent of MIPI.By including Ki-67 and MIPI,the so-called MIPI-c can better stratify the prognosis of MCL,which is also recommended (Appendix 4.4).Patients with TP53 mutations have poor response to traditional regimens and HDT/ASCT therapy.TP53 mutations are related to Ki-67 ＞30% and blast-like cell morphology.

7.2.6 Burkitt’s lymphoma (BL)

BL is a highly invasive NHL,which can be divided into three variants: local epidemic,sporadic and immune deficiency correlation.BL accounts for about 3%-5% of NHL and about 40% of children’s NHL.

(1) Clinical characteristics

Epidemic BL mainly occurs in equatorial Africa and Northeastern Brazil,with the peak onset age of 4-7 years old,male to female ratio of 2:1,more involved jaw bones,and EBV positive rate of ＞95%.Sporadic BL is scattered all over the world,mainly in children and young people,with a male to female ratio of 2:1 to 3:1.The abdominal involvement is more common in BL,and the positive rate of EBV is less than 30%.Most of the immune deficiencyrelated types occur in acquired immune deficiency syndrome (AIDS) patients,often involving lymph nodes and bone marrow.BL is a tumor with the shortest cell multiplication cycle which grows rapidly.Extranodular invasion of BL is common,of which head and neck,abdomen,bone marrow and central nervous system are the most commonly affected sites.

(2) Pathological diagnosis

Typical BL morphology shows diffuse proliferation of medium size neoplastic B cells,obvious mitosis and apoptosis,and common starry sky phenomenon.Tumor cells originate from germinal centers,and IHC immunophenotypes often presents as sIgM+,single light chain+,CD19 (+),CD20 (+),CD22 (+),C-MYC (+),CD10 (+),Bcl-6 (+),Bcl-2 (-/+),CD5 (-),CD23 (-),MUM-1 (-) and TdT (-).The proliferation index is very high,and the positive rate of Ki-67 is nearly 100%.Even if morphological and immunophenotypes all suggest typical BL,FISH should also be applied for MYC detection,of which t (8;14) accounts for about 80%,t (2;8) and t (8;22)for about 15%.The differential diagnosis includes highgrade B-cell lymphoma,NOS which morphology and immunophenotype are typical BL but without MYC abnormality (-).EBV-EBER detection is necessary for BL,but more sporadic patients are found in China,and EBVEBER negative is more common.

Bone marrow cytology: Bone marrow hyperplasia is obviously active or hyperactive.The typical BL cells are medium to large lymphocytes,which tend to be distributed in piles with different sizes,and the nuclei of leukemic cells are large,mostly round or irregular.The nuclear chromatin is coarse granular,and there are one or more obvious nucleoli of different sizes.The number of cytoplasm is uncertain,strongly basophilic and contains a large number of lipid vacuoles of different sizes,and vacuoles can also be seen in the nucleus.The degenerated cells are more common in the smear,and the proliferation of granulocytic and erythroid cells are inhibited.

(3) Treatment

Chemotherapy is the main treatment,but the curative effect of CHOP regimen is not ideal,and high-dose intensive treatment and combined rituximab could improve the efficacy.Prophylactic treatment of central nervous system should be carried out,and fully prevent the occurrence of tumor lysis syndrome.BL chemotherapy regimens may include: CODOX-M+rituximab,CODOXM/IVAC,dose-adjusted EPOCH-R or R-Hyper-CVAD/HD-MA regimens.For the low risk patients with low tumor burden,after 3 cycles of treatment to achieve CR,the treatment can be terminated after another cycle of consolidation therapy.In patients with concomitant brain parenchymal invasion at the time of diagnosis,the first cycle of treatment should begin with a regimen that includes drugs which can penetrate the blood-brain barrier.DA-EPOCH-R regimen should be combined with intrathecal injection of MTX,which is not suitable for patients with brain parenchymal invasion.

There is no clearly recommended second-line rescue regimen,R-ICE,R-GDP,R-IVAC,high-dose cytarabine +rituximab can be considered,HDT/ASCT or allogeneic hematopoietic stem cell transplantation can be considered for patients who achieve CR after rescue therapy.

(4) Prognosis

Age ＞40 years,bad performance status,late staging,high LDH,bone marrow and central nervous system invasion,HIV positive are the adverse prognostic factors of BL.

7.2.7 Lymphoblastic lymphoma (LBL)

LBL accounts for 3%-4% of adult NHL and about 40% of children NHL,which is a highly invasive lymphoma.It can be divided into T-LBL and B-LBL derived from T cells and B cells,respectively.T-LBL accounts for more than 80% of LBL and B-LBL accounts for about 10%-15% of LBL.LBL and acute lymphoblastic leukemia (ALL) are the same disease with different clinical manifestations and different stages of development.The ratio of primitive and immature lymphocytes in bone marrow ≥20% is defined as ALL according to the 2017 edition of WHO hematopoietic and lymphoid tissue tumors.

(1) Clinical manifestations

Typical clinical manifestations of T-LBL are cough and shortness of breath caused by a huge mass in the anterior mediastinum,which can be accompanied by pleural effusion,bone marrow and central nervous system invasion.B-LBL is often characterized by enlarged lymph nodes,with skin or bone invasion.

(2) Pathological diagnosis

In terms of cell morphology,LBL is mainly characterized by diffuse growth of medium-sized tumor cells,round,irregular or twisted nucleus,indistinct nucleolus,few cytoplasm,fine chromatin and easy mitosis.The LBL immunophenotype is characterized by TdT (+),which can also increase the determination of CD99,CD34 and CD10 to assist in the differentiation of mother cells.The immunophenotype of B-LBL is sIg (-),cIg (+),CD10 (+),CD19 (+),CD20 (-) or (+),CD79 (+) and PAX5 (+).The immunophenotypes of T-LBL are CD3ε (+/—),CD2 (+),CD4 (+),CD8 (+),CD1α (+/-) and CD7 (+).CD7 and CD43 cannot be used as markers of T lymphocytes alone.When the cells are immature,it is necessary to increase the detection of CD34,CD117,MPO and Lys in order to distinguish acute myeloid leukemia.Since LBL is derived from immature lymphocytes,tumor cells can simultaneously express markers of B or T lymphocytes,and even express molecular markers of NK or myeloid cells,therefore this situation is not uncommon and should be noted in particular.When the lesion occurs in the mediastinum,additional epithelial-related markers (such as AE1/AE3 and CK19) and clonal rearrangement of T/B cell genes are needed to differentiate and diagnose thymus tumor.B-LBL is often associated with some specific genetic abnormalities,such as BCR-ABL1,ETV6RUNX1 and KMT2A rearrangements. Relevant genetic examination is recommended if conditions permit.

Bone marrow cytology: The proliferation of nucleated cells in bone marrow is usually hyperactive or obviously active,mainly with primary and juvenile lymphocyte hyperplasia,often accompanied by morphological abnormalities.The prolymphocyte is round,elliptic or caudate.The nuclei are mostly round and large,with uneven chromatin thickness and irregular arrangement,and pits,folds,cuts and cracks can be seen in the nuclei.The cell mass is less and the nucleoplasma ratio is high.Granulocyte proliferation is significantly inhibited and granulocytes decreased significantly,or even disappeared.The proliferation of erythroid cells is also significantly suppressed,and juvenile erythrocytes are rare or absent.Most of the megakaryocytes are significantly reduced or not seen,and platelets were rare.The number of degenerating cells increases obviously.Mitotic cells are readily visible.It is found that when there are eosinophils infiltrating around the lymphoma cells in T-LBL,the 8p11.2 cytogenetic abnormalities of eosinophilic granulocytosis and myeloid hyperplasia associated withFGFR1gene should be ruled out.

Routine blood test: Most of the white blood cell count is increased,a few can be as high as 100×109/L.

(3) Treatmemt

Patients with whether I or IV stage should be treated as systemic diseases.LBL patients should adopt the treatment scheme of ALL.For young adult patients,the therapeutic effect of ALL treatment scheme for children is better than that for adults.The treatment process includes induction therapy,consolidation and reinforcement,maintenance therapy and so on.In order to prevent tumor lysis syndrome,glucocorticoid plus cyclophosphamide can be pretreated.According to different age groups,such as children,young adults and adults,a multi-drug combination treatment plan should be selected,the recommended treatment plan includes: Berlin-Farnkfurt-Münster regimen (cyclophosphamide,vincristine,daunorubicin,dexamethasone) methotrexate,cytarabine,methotrexate,pegaspargase and prednisone),Hyper-CVAD/MA,etc.In the case of Ph+B-ALL,a BCR-ABL tyrosinase inhibitor should be combined.All patients should receive central nervous system prophylaxis,which should be started as soon as possible.For patients who achieve CR after induction therapy,further detection of minimal residual disease (MRD) is required.If MRD is positive,allogeneic hematopoietic stem cell transplantation is recommended;if MRD is negative,maintenance therapy is recommended,allogeneic hematopoietic stem cell transplantation is recommended for high-risk patients.

(4) Prognosis

The prognosis of children’s LBL is significantly better than that in adults.Other adverse prognostic factors included high leukocyte count,central nervous system involvement,long time to complete remission and residual lesions after induction chemotherapy.Some gene abnormalities are associated with poor prognosis,such as hypodiploid (＜44 chromosomes),t (9;22)(q34;q11.2): BCR-ABL1,BCRABL1-like (Ph-like),KMT2A rearrangement [t (4;11)],t(v;14q32)/IgH,t (17;19): TCF3-HLF fusion,complex karyotype (≥5 chromosomal abnormalities),IKZF1 mutation,intrachromosomal amplification of chromosome 21 (iAMP21).While patients with t (12;21)(p13;q22):ETV6-RUNX1 and polyploidy (patients with chromosome 4,10 and 17 triploidy showed a better prognosis) was associated with a good prognosis.

7.2.8 Peripheral T-cell lymphoma,not otherwise specified(PTCL-NOS)

PTCL is a group of lymphoid malignancies originating from post-thymic mature T lymphocytes,which has many subtypes,PTCL-NOS is the most common one.PTCLNOS accounts for 7%-10% of all NHL in European and American countries,while the incidence rate in Asian countries accounts for 15%-22% of all NHL,which is significantly higher than that in European and American countries.The diagnosis of PTCL-NOS can only be confirmed after excluding other independent types of Tcell lymphoma,because it is not specific in morphology,immunology,genetics and clinical manifestations.

(1) Clinical manifestations

The median age of onset of PTCL-NOS was 55 years old,which was common in middle-aged and elderly people,with no significant gender difference.Superficial lymph node enlargement was the most common symptom,and half of patients had B symptoms.Outside the knot often involves in skin and the subcutaneous tissue,liver,spleen,digestive tract,thyroid gland and bone marrow,etc.Most patients were diagnosed with III,IV period at their first visit.

(2) Pathological diagnosis

PTCL-NOS is the tumor at the stage of mature(peripheral) T cell development.Histopathology shows a mixed background of abundant small endothelial hyperplasia,epithelioid histiocytosis and inflammatory cell infiltration.Tumor cells are diverse and varied,and are composed of small,medium or large cells,most of which are medium to large cells.The characteristics of PTCLNOS also include pale cytoplasm,pleomorphic and irregular nuclei,abundant or vesicular chromatin,prominent nucleoli,and mitotic appearance.Common immunophenotypes of PTCL-NOS contain CD3 (+),CD4 (+) ＞CD8 (+),CD5 (+),CD45RO (+),CD7 (-) and CD8 (-).Tumor cells often express T cell-related antigens,such as CD3ε and CD2,and lose one or more other mature T cell antigens (CD5 or CD7),which indicates that clonal proliferation of T cells was existed.Meanwhile,TCRgene of PTCL-NOS often presents as clonal rearrangement,which meansTCRgene rearrangement can be used to assist diagnosis when it is difficult to distinguish it from reactive changes in lymphoid tissues.Attention should also be paid to differentiating follicular helper T-cell lymphomas of origin,such as angioimmunoblastic T-cell lymphoma,peripheral T-cell lymphomas of lymph nodes with follicular helper T-cell phenotypes,and lymph node follicular T-cell lymphomas,etc.In addition,they resemble T cells and need to be identified,when the pleomorphism of DLBCL cells is obvious.Therefore,B-cell markers,such as CD20 and PAX5,are indispensable.Note the clonality of plasma cells in the presence of multiple plasma cell proliferation.

Bone marrow cytology: Proliferation of nucleated cells in bone marrow was mostly active,mainly lymphocyte hyperplasia.In most cases,adult T-cell leukemia cells were over 10%,but up to 80%.Granulocytes,erythrocytes and megakaryocytes are often reduced.

(3) Treatment

(a) Treatment principles.PTCL-NOS is a group of heterogeneous diseases,of which optimal treatment plan and strategy are still being explored.Stage I-IV patients are first recommended to participate in an appropriate clinical trial,or 4-6 cycles of chemotherapy ± ISRT.For patients who achieve CR after treatment，appropriate clinical trials,HDT/ASCT,or discontinuation observation may be considered.For patients with recurrent refractory PTCL-NOS,clinical trials are still be recommended first,or posterior therapy and palliative radiotherapy.Patients who achieve CR after second-line treatment can consider HDT/ASCT or allogeneic hematopoietic stem cell transplantation.

(b) First-line treatment scheme.First recommendation:CHOP,CHOEP,DA-EPOCH;Other regimens include CHOP continuous IVE (ifosfamide,etoposide,epirubicin),hyperCVAD/MA.

(c) Second-line treatment scheme.Clinical trials are recommended first. Recommended treatment options include chidamide,brentuximab vedotin (CD30 positive),DHAP,DHAX,ESHAP,GDP,GemOx,ICE,etc.Other regimens include bendamustine,gemcitabine,lenalidomide or GVD (gemcitabine,vinorelbine and Doxil).

(4) Prognosis

Overall prognosis of PTCL-NOS was worse than that of patients with invasive B-cell lymphoma,and the 5-year survival rate of PTCL-NOS was approximately 30%.The prognostic scoring system includes IPI and prognostic index for PTCL-NOS (prognostic index for peripheral Tcell lymphoma，not otherwise specified，PIT),and the PIT includes ＞60 years old,LDH increase,ECOG PS score ≥2 and bone marrow invasion (Appendix 4.5).

7.2.9 Mycosis fungoides/Sézary syndrome (MF/SS)

MF/SS are the most common cutaneous T cell lymphoma(CTCL),accounting for approximately 2%-3% of NHL.While MF accounts for 60% of CTCL,SS only accounts for 5%.MF is a primary cutaneous matural T-cell lymphoma with an indolent course.Most patients present with intermittent,stable or slowly developing skin lesions.The involvement of extra-cutaneous tissues,mainly lymph nodes and peripheral blood,suggests advanced stage.SS is considered as a variant of MF with a characteristic of invasive erythrodermic leukemic.

(1) Clinical features

MF presents clinically with erythematous patches,plaques and tumors.Generally distributed in skins,pruritus can be found frequently in this disease.With a recurring course,the lesion can be limited to the skin,typically months to years,even decades.Lymph node and visceral organ involvement can be found in the later stage.Generalized erythroderma accounts for approximately 10% of MF skin lesions.SS typically features as generalized erythroderma with peripheral blood involvement,and Sézary cells can be detected in lesional tissues,lymph node and peripheral blood.The diagnosis of SS should be based on: absolute Sézary cell counts ≥1×109/L,CD4+/CD8+ratio ≥10,the immunophenotypic analysis of the tumor cells as CD3 (+),CD4 (+),CD5 (+),CD45RO (+),CD7 (-) and CD8 (-),and evidence of T-cell clonal proliferation.

(2) Pathological diagnosis

A definitive diagnosis of MF may need years of observation and several biopsies.Atypical T cells of small regular size with irregular nuclei aggregate in epidermis and dermoepidermal junctions,infiltrating epidermis and forming Pautrier microabscesses as its feature.The main characteristics of SS are considered similarly as MF.Immunophenotype of MF presents with matural memory T cells,CD3ε (+),CD4 (+),CD45RO (+) and CD8 (-).Matural T cells with phenotype of CD4 (-) and CD8 (+),as the evidence of clonal proliferation of T cells,are infrequently detected.This disease should be distinguished from lymphoma originated from helper follicular T cells.Pathological diagnosis at non-tumor stage is difficult,and it should be distinguished from non-atopic dermatitis.Clinical traits should be especially noticed.

(3) Staging

The Staging Criteria of Cutaneous T cell Lymphoma(Appendix 2.3).

(4) Treatment

While present treatment strategies for MF and SS are generally not curative,thus,stage of this disease is considered the main factor to guild therapy.The main purpose of treatment is to control the scope of skin lesions,relieve symptoms and reduce the risk of progression.Durable relief is not achieved with treatment in most cases.For the treatment of initial lesions,methods with low toxicity and low cumulative toxicity should be selected to achieve the purpose of durable or maintenance therapy.When chemotherapy is required,single-agent therapy is recommended as the first choice,since combination therapy does not significantly prolong the remission time.Lesions in different parts,such as skin,lymph nodes or peripheral blood,are not completely consistent in response to treatment,and the relationship between efficacy and prognosis is not clear.The changes of clinical symptoms and signs can be used as the basis for the judgment of efficacy.When the disease progresses again after a period of discontinuation of treatment,the previous treatment or drug may be resumed,which may continue to be effective.Preventing and controlling skin infections and relieving itching are also important treatments.

Intense treatment should not be conducted in the early stage of skin lesions,and topical treatment or the combination of several topical treatments is recommended.Comprehensive treatments with systemic treatment as the main or clinical trials are recommended at the IIB,III and IV stages of the disease or with the refractory lesions.Therapy targeted at skin includes radiotherapy,light therapy,topical corticosteroids,nitrogen mustard or retinoid,etc.Systemic treatment includes brentuximab vedotin,interferon,methotrexate (≤50 mg/week),gemcitabine,liposomal doxorubicin,tretinoin,etc.

(5) Prognosis

Favorable prognosis can be found in most patients with MF,with a 5-year survival rate as nearly 90%.Adverse prognostic factors include stage of T3/T4,involvement besides skin and ages ≥65 years old.Patients with SS frequently present with a poor prognosis,with median survivals of 2-4 years.

7.2.10 Extranodal NK/T-cell lymphoma,nasal type(ENKTL)

The most common type of NK/T-cell lymphoma is extranodal NK/T-cell lymphoma,nasal type,often localized to the upper aerodigestive tract including the nasal cavity,nasopharynx,paranasal sinuses,tonsils,hypopharynx and larynx.NK/T-cell lymphoma can also have an extranasal presentation,with skin,testis and gastrointestinal tract being the most common sites of extranasal involvement or metastatic disease.This type of lymphoma is more common in Asia than in Europe and America,and it is the most common type of peripheral Tcell lymphoma in China,accounting for 40%-50% of peripheral T-cell lymphoma.

(1) Clinical features

Young males are more common patients of NKTL.B symptoms are common.The tumor is usually confined to the nasal cavity or directly invaded the adjacent structures or tissues.Patients diagnosed with early stage account for 70%-90%. Common clinical features include nasal obstruction,nasal bleeding and swollen lymph nodes in the neck.

(2) Pathological diagnosis

Pathological features of ENKTL are diffuse lymphoma cell infiltration with vascular centrality and destructive growth of blood vessels,resulting in tissue ischemia necrosis(common and a major cause of missed diagnosis) and mucosal ulcer.The IHC markers needed for diagnosis include CD3,CD56,CD2,CD4,CD5,CD7,CD8,CD45RO,CD20,PAX5,TIA-1,granzyme B,Ki-67 and EBV-EBER,etc.The typical ENKL immunophenotypes are CD2 (+),CD3 (+),CD56 (+),TIA-1 (+),granzyme B (+) and EBV-EBER (+).The diagnosis of EBV-EBER negative should be cautious.If CD56 (+),CD3 (+) and cytotoxic markers are expressed,patients can be diagnosed as ENKTL.If CD3 (-) and CD56 (-) are expressed,patients should be diagnosed as PTCL-NOS.ENKTL(60%-90%) had noTCRgene rearrangement.In addition,it should also be noted that ENKTL should be distinguished from undifferentiated carcinoma,and the detection of epithelial markers such as CK and EMA were also needed.

Bone marrow cytology: The tumor cells are round or oval,with pseudopodia-like protrusions;the nuclei are mostly round,with finely granular chromatin and multiple but inconspicuous nucleoli;the cells are medium in quality,dark blue,and vacuoles were visible.When the pleural cavity is involved,tumor cells can be seen in the pleural effusion.

(3) Treatment

(a) Treatment principle: It is necessary to distinguish patients with primary nasal type or non-nasal type.Due to their sensitivity to radiotherapy,early-stage patients should be treated with a combination of chemotherapy and radiotherapy.Stage I/II (primary nasal type): For patients who are not suitable for chemotherapy,radiotherapy alone or participating in a suitable clinical trial is recommended;for patients suitable for chemotherapy,it is recommended to participate in a suitable clinical trial or combined chemotherapy and radiotherapy,with 2-4 cycles of chemotherapy.For stage IV (primary nasal type) or stage I-IV (non-nasal type),it is recommended to participate in appropriate clinical trials or asparaginase-based combined chemotherapy ± radiotherapy.

(b) First-line chemotherapy regimens: P-GemOx(pegaspargase,gemcitabine and oxaliplatin),DDGP(dexamethasone,cisplatin,gemcitabine and pegaspargase),SMILE (dexamethasone,methotrexate,ifosfamide,Lasparaginase and etoposide).Recommended regimen for concurrent chemoradiotherapy: DeVIC (dexamethasone,etoposide,ifosfamide and carboplatin),VIPD (etoposide,ifosfamide,cisplatin and dexamethasone).

(c) Second-line treatment regimens: DAHP,DHAX,ESHAP,GDP,GemOx,ICE and chidamide,etc.

(4) Prognostic factors

Currently,the commonly used prognostic models in the world are Prognostic Index of Natural Killer Lymphoma(PINK) and Prognostic Index of Natural Killer Lymphoma with EBV DNA (PINK-E).Poor prognostic factors for the PINK model include age ＞60 years,distant lymph-node involvement,stage III/IV disease and non-nasal type disease.The PINK-E model incorporates one more item:whether EBV-DNA can be detected in plasma (Appendix 4.6).

Note:This diagnosis and treatment guideline is based on clinical research evidence and expert consensus.The recommended treatment regimens are mainly based on drugs that have been approved in China with treatment indications,and domestic and foreign research progress is also introduced.When deciding a patient’s treatment plan,the patient should be given standardized and individualized treatment according to the disease characteristics and clinical manifestations of each patient.

Working group members

Group leader: Yuankai Shi

Group members:Jun Ma,Huaqing Wang,Xiaoyang Lu,Li Feng,Jun Zhu,Mingqing Zhu,Xiongzeng Zhu,Yexiong Li,Tongyu Lin,Xiaomao Guo,Wenqi Jiang,Zifen Gao,Yan Qin,Chuanmiao Xie

Translation group members

Group leader

Lingyan PingKey Laboratory of Carcinogenesis and TranslationalResearch (Ministry of Education/Beijing),Peking University Cancer Hospital＆Institute

Group members

Xing WeiKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing),Peking University Cancer Hospital＆Institute

Yuling HeKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing),Peking University Cancer Hospital＆Institute

Hui YuKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing),Peking University Cancer Hospital＆Institute

Jili DengKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing),Peking University Cancer Hospital＆Institute

Jianing ZhangKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing),Peking University Cancer Hospital＆Institute

Jiaxin LiuKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing),Peking University Cancer Hospital＆Institute

Jie LyuKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing),Peking University Cancer Hospital＆Institute

Jie ChenKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing),Peking University Cancer Hospital＆Institute

Yanfei LiuKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing),Peking University Cancer Hospital＆Institute

Jin ChaiKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing),Peking University Cancer Hospital＆Institute

Appendix 1 World Health Organization (WHO) classification of lymphoid neoplasms (2017 revision)

Prolymphoid tumor

1.B-lymphoblastic leukemia/lymphoma,non-specific type

2.B-lymphoblastic leukemia/lymphoma with abnormal frequency gene

B lymphoblastic leukemia/lymphoma with t (9;22) (q34.1;q11.2);BCR-ABL1

B lymphoblastic leukemia/lymphoma with t (v;11q23.3);KMT2A rearrangement

B lymphoblastic leukemia/lymphoma with t (12;21) (p13.2;q22.1);ETV6-RUNX1

B lymphoblastic leukemia/lymphoma with hyperdiploid

B lymphoblastic leukemia/lymphoma with low diploid

B lymphoblastic leukemia/lymphoma with t (5;14) (q31.1;q32.3);IL3-IGH

B lymphoblastic leukemia/lymphoma with t (1;19) (q23;p13.3);TCF3-PBX1

B lymphoblastic leukemia/lymphoma,BCR-ABL1

B lymphoblastic leukemia/lymphoma with iAMP21

3.T lymphoblastic leukemia/lymphoma

Early T-prolymphoblastic leukemia

4.Natural killer lymphoblastic leukemia/lymphomaa

Mature B-cell neoplasms

1.Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL)

2.Monoclonal B-cell lymphocytosis (MBL)

3.B-cell prolymphocytic leukemia

4.Splenic marginal zone lymphoma

5.Hairy cell leukemia

6.Splenic B-cell lymphoma/leukemia,unclassifiablea

Splenic diffuse red pulp small B-cell lymphomaa

Hairy cell leukemia-varianta

7.Lymphoplasmacytic lymphoma

Waldentrom’s macroglobulinaemia

8.IgM monoclonal gammopathy of undetermined significance

μ heavy-chain disease

α heavy-chain disease

γ heavy-chain disease

9.Plasma cell tumor

Non-IgM monoclonal gammopathy of undetermined significance

Plasma cell myeloma

Solitary plasmacytoma of bone

Extraosseous plasmacytoma

Monoclonal immunoglobulin deposition diseases

Primary amyloidosis

Light chain and heavy chain deposition disease

10.Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) lymphoma

11.Nodal marginal zone lymphoma

Pediatric nodal marginal zone lymphomaa

12.Follicular lymphoma

In situfollicular neoplasia

Duodenal-type follicular lymphoma

Testicular follicular lymphoma

13.Pediatric-type follicular lymphoma

14.Large B-cell lymphoma with IRF4 rearrangementa

15.Primary cutaneous follicle center lymphoma

16.Mantle cell lymphoma

In situmantle cell neoplasia

17.Diffuse large B-cell lymphoma (DLBCL),NOS

Germinal center B-cell typea

Activated B-cell type

18.T-cell/histiocyte-rich large B-cell lymphoma

19.Primary DLBCL of CNS

20.Primary cutaneous DLBCL,leg type

21.EBV (+) DLBCL,NOS

22.EBV (+) mucocutaneous ulcer

23.DLBCL associated with chronic inflammation

Diffuse large B-cell lymphoma with fibrin exudation

24.Lymphomatoid granulomatosis,grade I/II

25.Lymphomatoid granulomatosis,grade III

26.Primary mediastinal (thymic) large B-cell lymphoma

27.Intravascular large B-cell lymphoma

28.ALK (+) large B-cell lymphoma

29.Plasmablastic lymphoma

30.Primary effusion lymphoma

31.Lymphoproliferative diseases related to HHV8

Multicentric Castleman disease

HHV8 (+) DLBCL,NOS

HHV8 (+) biological center lymphoproliferative disease

32.Burkitt lymphoma

33.Burkitt-like lymphoma with 11q aberrationa

34.High-grade B-cell lymphoma

High-grade B-cell lymphoma,with MYC and BCL2 and/or BCL6 rearrangements

High-grade B-cell lymphoma,NOS

35.B-cell lymphoma,unclassifiable,with features intermediate between DLBCL and classical Hodgkin lymphoma

Mature T and NK neoplasms

1.T-cell prolymphocytic leukemia

2.T-cell large granular lymphocytic leukemia

3.Chronic lymphoproliferative disorder of NK cellsa

4.Aggressive NK-cell leukemiaa

5.EBV (+) T cells and NK cell proliferative diseases in children

Systemic EBV (+) T-cell lymphoma of childhood

Chronic active EBV infection (T cell and NK cell type),systemic

Hydroa vacciniforme-like lymphoproliferative disorder

Severe allergy to mosquito bites

6.Adult T-cell leukemia/lymphoma

7.Extranodal NK/T-cell lymphoma,nasal type

8.Intestinal T-cell lymphoma

Enteropathy-associated T-cell lymphoma

Intestinal T-cell lymphoma,NOS

9.Enteropathy-associated T-cell lymphoma

10.Monomorphic epitheliotropic intestinal T-cell lymphoma

11.Indolent T-cell lymphoproliferative disorder of the GI tracta

12.Hepatosplenic T-cell lymphoma

13.Subcutaneous panniculitis-like T-cell lymphoma

14.Mycosis fungoides

15.Sézary syndrome

16.Primary cutaneous CD30 (+) T-cell lymphoproliferative disorders

Lymphomatoid papulosis

17.Primary cutaneous peripheral T-cell lymphoma,rare subtype

Primary cutaneous anaplastic large cell lymphoma

Primary cutaneous γ/δ T-cell lymphoma

Primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphomaa

Primary cutaneous acral CD8-positive T-cell lymphomaa

Primary cutaneous CD4-positive small/medium T-cell lymphoproliferative disordera

18.Peripheral T-cell lymphoma,NOS

19.Angioimmunoblastic T-cell lymphoma (AITL) and other T follicular helper cell lymphomas (TFH PTCL)

Angioimmunoblastic T-cell lymphoma

Follicular T-cell lymphoma

Nodal peripheral T-cell lymphoma with TFH phenotype

20.Anaplastic large-cell lymphoma,ALK (+)

21.Anaplastic large-cell lymphoma,ALK (-)

22.Breast implant-associated anaplastic large-cell lymphomaa

Hodgkin lymphoma

1.Classical Hodgkin lymphoma

Nodular sclerosis classical Hodgkin lymphoma

Lymphocyte-rich classical Hodgkin lymphoma

Mixed cellularity classical Hodgkin lymphoma

Lymphocyte-depleted classical Hodgkin lymphoma

2.Nodular lymphocyte predominant Hodgkin lymphoma

Note: IRF4,interferon regulatory factor 4;EBV,Epstein-Barr virus;HHV8,human herpes virus 8;ALK,anaplastic lymphoma kinase;a,indicate tentative name.

Appendix 2 Stage system of lymphoma

Appendix 2.1 Ann-Arbor (Cotswolds revised) stage system

Table A1 Ann-Arbor (Cotswolds revised) stage system

Appendix 2.2 Rai and Binet system of chronic lymphocytic leukemia

Table A2 Rai system

Table A3 Binet system

Immune-mediated cytopenias are not the basis for these stage definitions.

Appendix 2.3 TNMB classification and staging of mycosis fungoides and sézary syndrome

Table A4 TNMB classification and staging of mycosis fungoides and sézary syndrome

Table A5 TNMB staging of MF and SS

Appendix 2.4 Lugano gastrointestinal lymphoma stage system

Table A6 Lugano gastrointestinal lymphoma stage system

Appendix 2.5 CA staging system for nasal NK/T-cell lymphoma

Table A7 CA staging system for nasal NK/T-cell lymphoma

Appendix 3 Criteria for evaluation of efficacy of lymphoma

Appendix 3.1 Deauville five-point scale

Table A8 Deauville five-point scale

Appendix 4 Prognostic scoring system for lymphoma

Appendix 4.1 Prognostic score for HL

Table A10 Adverse prognostic factors of early HL

Table A11 IPS of advanced HL

Table A12 IPS and survival rate of advanced HL

Appendix 4.2 Prognostic score of diffuse large B-cell lymphoma

Table A13 International prognostic index

Table A14 Prognosis of DLBCL patients according to IPI score

Table A15 Revised-IPI

Table A16 Prognosis of DLBCL patients according to revised IPI score

Table A17 Age adjusted IPI

Table A18 Prognosis of DLBCL patients according to age adjusted IPI score

Appendix 4.3 Prognostic score of follicular lymphomas

Table A19 Folicullar lymphoma IPI

Table A20 Risk grouping and survival rate of FLIPI

Table A21 FLIPI2

Table A22 Risk grouping and survival rate of FLIPI2

Appendix 4.4 Prognostic score of MCL

Table A23 MCL international prognostic index

Table A24 Prognosis of MCL patients according to MIPI

Table A25 International prognostic index of mantle cells combined with Ki-67

Appendix 4.5 Prognostic score of peripheral T-cell lymphoma,not otherwise specified (PTCL-NOS)

Table A26 Prognostic score of peripheral T-cell lymphoma

Appendix 4.6 Prognostic system of NK/T-cell lymphoma

Table A27 Prognosis of PTCL patients according to PIT score

Table A28 Prognostic index of natural killer lymphoma

Table A29 Prognosis of natural killer/T-cell lymphoma patients according to PINK score

Table A30 Prognostic index of natural killer lymphoma with Epstein-Barr virus DNA

Table A31 Prognosis of natural killer/T-cell lymphoma patients according to PINK-E score