3-Hodgkin lymphoma

Definition:

Primary malignant tumors of lymphoid tissue, they represent 5% of all malignant tumors. Incidence: Male: Female

HD. N.H.L.

2:1 1.4 : 1

According to the U.S. National Institutes of Health, lymphomas account for about five percent of all cases of cancer in the United States, and Hodgkin's lymphoma in particular accounts for less than one percent of all cases of cancer in the United States.

Because the whole system is part of the body's immune system, patients with a weakened immune system, such as from HIV infection or from certain drugs or medication, also have a higher incidence of lymphoma.

Aetiology of Predisposing factors: 1- Hodgkin’s disease :

a-Infectious aetiology (may be initiated by an infection but may not be transmitted) *may be hypersensitive immune response to a virus. *relation to Ebstein Barr virus as evidenced by: - +ve antibodies - Increase incidence in-patient with inf. Ononucleosis b-Abnormal immune response - depression of cellular immunity should be considered an inherent character of the patient who ultimatIy develop H.D 2-Non Hodgkin’s lymphoma: * Neoplasia of the immune system * Can be considered is a disorder of lymphoid differentiation.

Possible Aetiologic factors of NHL: I-Host Factors:a- Primary Immune deficiency b- Immuno suppressive ttt. 2-Invironmental Factors:a- Ionizing radiations. b-Drugs: (Hydantion, Anaesthesia) c- Chemicals: (Petrol. Viny1 Chloride) d- E.B.V

Age Incidence:-

Histopathology:1- H.D.: Disease of Lymphatic tissue characterized by the presence of Reed Sternberg cells and variable proliferations of lymphocytes. *Rye Classification Sub Type Lymphatic predominance (L.P.) Nodular sclerosis (N.S.) Mixed Cellularity (MC.) Lymphocytic Deplition (L.D.)

Average % 10 – 12% 45 - 55% 30 - 35% 8- 10%

L.P., or, N.S. are more favourable than M.C and L.D.

Classifications of Non Hodgkin’s Lymphoma

Many classifications according toHistopathology:-

a-Rappaport classification:- depends on: 1-Pattern of growth:-

- Nodular (N.) [ Follicular, Indolent] - Diffuse (D.) [Aggressive]

2- Cell population:

- Lymphocytic (L.) - Histiocytic (H.) - Mixed (L & H.)

Types : * Favorable histology: N.L.,N. Mixed, DL.W.D(well differentiated) *Unfavorable histology: N.H. + all D., except DL. W.D * Histioocytic of several varities: - majority (large cell L. immunoblastic L.) - true H is very rare

B-A number of different classification systems exist for lymphoma.

Kiel:

Karl Lennert of Kiel, Germany, proposed a new system of classifying lymphomas based on cellular morphology and their relationship to cells of the normal peripheral lymphoid system

REAL:

In the mid 1990s, the Revised European-American Lymphoma (REAL) Classification attempted to apply immunophenotypic and genetic features in identifying distinct clinicopathologic NHL entities

C-Working Formulation: I- Low Grade Malignancy: - small lymphocytic (C.L.L.) - Follicular small cleaved. - Follicular mixed small and large cleaved. 2- Intermediate Grade Malignancy: - Follicular large cell - Diffuse small cleaved - Diffuse mixed small and large cells. - Diffuse large cells: i- cleaved ii- non cleaved 3- High Grade Malignancy: - Immunoblastic Lymphoma. - Lymphoblastic Lymphoma - Small non cleaved (Burkitt’s)

*In NHL: The presence of a

nodular pattern (follicular) remains an important prognostic feature in addition to the cell type

D-WHO Classification: The WHO Classification, published in 2001 and updated in 2008, is the latest classification of lymphoma . This system attempts to group lymphomas by cell type (i.e. the normal cell type that most resembles the tumour) and defining phenotypic, molecular or cytogenetic characteristics.

There are three large groups: the B cell, T cell, and natural killer cell tumours. Other less common groups, are also recognized. Hodgkin's lymphoma, although considered separately within the WHO classifications, is now recognized as being a tumour of, albeit markedly abnormal, lymphocytes of mature B cell lineage

-1-Mature B cell neoplasms: . •Chronic lymphocytic leukemia/Small lymphocytic lymphoma •B-cell prolymphocytic leukemia •Lymphoplasmacytic lymphoma (such as Waldenström macroglobulinemia) •Splenic marginal zone lymphoma •Plasma cell neoplasms: •Plasma cell myeloma •Plasmacytoma • •Heavy chain diseases •Extranodal marginal zone B cell lymphoma, also called MALT lymphoma •Nodal marginal zone B cell lymphoma (NMZL) •Follicular lymphoma •Mantle cell lymphoma •Diffuse large B cell lymphoma •Mediastinal (thymic) large B cell lymphoma • •Primary effusion lymphoma •Burkitt lymphoma/leukemia

-2-Mature T cell and natural killer (NK) neoplasms:cell T cell prolymphocytic leukemia

T cell large granular lymphocytic leukemia Aggressive NK cell leukemia Adult T cell leukemia/lymphoma Extranodal NK/T cell lymphoma, nasal type Enteropathy-type T cell lymphoma Hepatosplenic T cell lymphoma Blastic NK cell lymphoma Mycosis fungoides / Sezary syndrome Primary cutaneous CD30-positive T cell lymphoproliferative disorders Primary cutaneous anaplastic large cell lymphoma Lymphomatoid papulosis Angioimmunoblastic T cell lymphoma Peripheral T cell lymphoma, unspecified Anaplastic large cell lymphoma

-3-Hodgkin lymphoma

Classical Hodgkin lymphomas: *Nodular sclerosis Mixed cellularity *Lymphocyte-rich *Lymphocyte depleted or not depleted *Nodular lymphocyte-predominant Hodgkin lymphoma

-4-Immunodeficiency-associated lymphoproliferative disorders: *Associated with a primary immune disorder *Associated with the Human Immunodeficiency Virus (HIV) *Post-transplant *Associated with methotrexate therapy

General Considerations: I-H-D.: * usually have a unicentric origin & usually starts by involvement L.N. in one or more adjacent areas esp. in cervical region. N.H.L. : * usually multicentric from the start. * in 1/3 onset occur in extranodal sites. 2- Mode of spread: H. D. * in the great majority via lymphatics to contagious L.N. and other lymphatic structures N.H.L. : * more often rapidly spread to distant nodal and extranodal sites via blood stream

1- Asymptomatic Lymphadenopathy:-

* the majority of patients with H.D. (extranodal only in 10%) . * 2/3 of patients with N.H.L. (1/3 extranodal). Usually in cervical L.N.(cervical onset 65- 80%, in H.D. ,while in N.H.L. only in 30 - 40%).

a-H.D.: *Characterized by central L.N. involvement (cervical, mediastinal & para-aortic) esp. in N.S. subtype * Certain groups of L.N are rarely involved in H.D.: - epitrochlear, popliteal. - mesentric, hypogastric - hepatic, hilar. * 10-20% of early stage H.D. is presented with mediastinal L.N. but higher incidence with N.S. and is usually associated systemic symptoms.

N.B L.N in H.D. are firm rubbery (not stoney hard), non-tender (except if rapid enlargement), equal in size in each group, initially discrete.

b-N.H.L.: *More widely disseminated in nodal and extranodal sites. *L.N. distribution is often peripheral (axillary, inguinal, mesentric). *Mediastinal L.N. in less than 15% and only in aggressive lymphoma esp Lymphoblastic lymphoma.

2-Extra Nodal Lesions:

*In N.H.L.: the most commonly involved sites are the head & neck areas (Waldeyer’s ring, nasal cavities, sinuses & orbit) followed by G.I.T. *In H.D.: splenic & hepatic involvement esp. in presence of :-L.N enlargement above and below the diaphragm. -systemic symptoms - and in M.C and L.D. subtypes. N.B Hepatic involvement usually in association with concomitant splenic involvement.

a-G.I.T.: * diarrhoea , malabsorption syndrom ( G.I.T. infiltration) * ulceration & bleeding. * retroperitoneal masses esp. in N.H.L. resulting in I.V.C obstruction, leading to ascitis and oedema. Primary GI N.H.L: - Adults: stomach > intestine. - Children: intestine > stomach esp. for Burkitt’s (iliocaecal valve) -There is association between affection of Waldeyer's ring & G.I. lymphoma esp. the stomach. Jaundice in H.D: may be due to: - intrahepatic cholestasis: involvement of portal tracts. - extrahepatic cholestasis due to glands in porta hepatis. - auto immune haemolytic anaemia.

b- Chest: * involvement of lung parenchyma (nodules, cavitations). * usually due to infiltration by contiguity from adenopathy . * Pleural and / or pericardial involvement (usually with massive mediastinal L.N. enlargement.) * massive mediastinal L.N. enlargement leading to mediastinal syndrome esp. with : - N.S. (H.D.) - Lymphoblastic (N.H.L.)

C-Bone Pain & Tenderness: * may be oesteolytic or oesteoblastic and may be pathological fractures. d- Neurological Manifestation;

* Herpes Zoster. * Spinal cord compression (H.D.) . * Peripheral nerve palsies. [Horner's, brachial plexus, phrenic nerve, vocal cords]. * Cranial nerve palsies. * Cerebral signs and symptoms

e-Cutaneous Manifestations:* Pruritis * Skin nodules. * Herpes zoster * Alopecia and icthyosis * Hyperpigmentation.

3- Systemic or constitutional symptoms: * May occur with L.N. enlargement or may precedes it. * Common with H.D. (30-40%) than N.H.L. (10%). * Fever > 38 ,night sweats, wt . loss, pruritis, other systemic symptoms. * Alcohol intolerance (H.D.): - localized acute pain at one or more sites of Hodgkin's involvement - anorexia, malaise. fatigue * Systemic symptoms means unfavorable prognosis.

Diagnostic Evaluation and Staging: Proper ttt depends on:

- Hisopathologic Type. - Anatomic extent of disease (staging)

*Diagnosis: - The precise unequivocal diagnosis requires histopathologic confirmation by the examination of suitable biopsy material.

- Most satisfactory nodes: (lower cervical & axillary). - If there is a group of L.N. take the central ones. - If there is only mediastinal L.N.:(mediastinascopy or thoracotomy).

Hodgkin’s lymphoma.

Lymph node with CD30-positive Hodgkin cells and binucleated Reed-Stemberg cells.

Immunophenotyping is an important diagnostic modality and is crucial for the classifi cation of non-Hodgkin’s lymphoma. Certain markers, such as the CD-20 receptor, have become crucial for treatment as newer biologic agents have utilized this receptor therapeutically .

Classical HL

Characteristic Reed-Sternberg cell cell Surface antigens CD15+,CD30+, CD20+/–, CD45–, EMA–

EBV

+EBV in 50%

NLPHL

Lymphocytic and histiocytic cell “popcorn cells” CD15–, CD30–, CD20+, CD45+, EMA+ EBV–

NLPHL is the most favorable HL with an indolent course.

Clinical Staging: I- Detailed history esp. systemic symptoms. 2- Clinical exam. including Waldeyer's ring, areas of bone tenderness. 3- Adequate surgical biopsy 4- Routine laboratory tests(CBC,ESR. liver function test, serum uric acid) 5- Plain chest X ray & bilateral lower extremity lymphangiography. 6- Radiologic examination of GIT & gastroscopy. If +ve Waldeyer's ring.

Imaging and laboratory work-ups for non-Hodgkin’s lymphoma Imaging studies ■ Laboratory tests – CT scan of chest, abdomen, – Complete blood and pelvis

count

– FDG-PET scan or PET/CT

– Serum chemistry

– Gallium-67 scan (if PET

– Lactate dehydro

unavailable)

genase (LDH)

– MRI or CT of the brain

– Liver function tests

(if symptomatically indicated) – Renal function tests – Bone scan

– Erythrocyte sedi-

(if symptomatically indicated) mentation rate (ESR)

Positron emission tomography (PET) using fluorodeoxyglucose has been found useful for the staging and follow-up of patients with HL. PET is sensitive and, in most instances, specific enough to detect involvement by HL. In untreated patients, a higher stage is found in at least 20% of cases using PET imaging as compared with conventional imaging. PET may also be used in patients with residual tumor masses to discriminate

Pathologic staging: 1- Bone marrow biopsy 2- Staging laparotomy, after -ve bone narrow biopsy in Clinical stage I & II H.D. 3- Lumbar puncture with cytologic exam. Of C.S.F in all N.H.L with bone marrow involvement. 4- Cytologic exam. of any effusion The Ann Arbor staging :mentioned before.

classification

Bone marrow biopsy (bilateral) is recommended for all cases of NHL because of the high probability of bone marrow involvement for certain types of NHL in : 70% in small lymphocytic lymphoma, 50% in follicular lymphoma, and >10% in diffuse large-cell lymphoma or marginal zone lymphoma. Cytological examination of cranial spinal fluid (CSF) is indicated for stage IV disease with bone marrow, testis, and parameningeal involvement .

Ann Arbor staging system

Stage I Involvement of single lymph node (I) or extralymphatic site (IE) Involvement of two or more involved lymph node sites on the Stage II same side of the diaphragm (II) or localized involvement of one extra-lymphatic organ or site plus one or more lymph node regions on the same side of diaphragm (IIE)

Involvement of lymph node regions on both sides of diaphragm Stage III (III), which can also include involvement of the spleen (IIIS) or localized extralymphatic site or organ extension (IIIE) or both (IIISE)

Stage IV Diffuse (multifocal) involvement of one or more extralymphatic organs or sites A=No “B” symptoms B=Unexplained fever >38°C, weight loss >10% in previous 6 months, drenching night sweats X=Bulky disease

Prognostic Factors: Histology subtype of lymphoma is the most important determinant of prognosis of non-Hodg-kin’s lymphoma. ■ NHL of certain origins, such as primary CNS lymphoma and testicular NHL, have particularly poor outcome after treatment. ■ The presenting stage is an important prognostic factor. For example, the 10 -year cause-specifi c survival for patients with stage I, II, III, and IV follicular cell type are 68%, 56%, 42%, and 18%, respectively (Gospodarowicz et al. 1984). ■ “B” symptoms, including unexplained weight loss >10% over 6 months prior to diagnosis, unexplained fever >38°C, and/or drenching night sweats are associated with poor outcome (Greene et al. 2002). ■ Other significant prognostic factors include patient age (younger or older than 60 years), gender (female gender has a better prognosis in low grade lymphoma), tumor size (less or more than 10 cm in diameter), performance status, level of serum lactate dehydrogenase (LDH), extent of ex-tranodal involvement, beta-2 microglobulin, and S-phase fraction. ■

The International Prognostic Index (IPI) for aggressive NHL includes five of the abovementioned significant risk factors to predict overall survival :

1-stage (I or II vs. III or IV), 2- serum LDH (normal vs. abnormal), 3-extranodal site involvement (0 or 1 vs. >1), 4- age of the patient (younger than 60 vs. older than 60), 5- and performance status (ECOG 0 or 1 vs. 2-4).

The IPI risk groups are determined by the numerical summation of the number of adverse risk factors (0 to 5), and a higher number of adverse risk factors are associated with poor prognosis

International prognostic index for aggressive nonHodgkin’s lymphoma Risk group IPI score Low-risk Lowintermediate Highintermediate High-risk

5-Year survival (%)

0–1 2

73% 51%

3

43%

4–5

26%

Prognostic Factors for HD The frequency subtypes of HD differs in different parts of the world. At present, with effective treatments for HL, the subtypes are no longer prognostically relevant. However, some of these types have particular clinical features: nodular sclerosis is more frequent in young women with a large mediastinal mass. The lymphocytepredominant HL resembles a low-grade, B-cell lymphoma, and can be treated with limited irradiation at least in early stages.

Prognostic factors in HL are age, sex, stage, and some serum markers such as sedimentation rate and soluble CD25. Recently, a prognostic score was established for advanced HL. This score, into which seven unfavorable clinical and laboratory parameters , predicts treatment failure (low serum albumin, anemia, male sex, age > 45 yr, stage IV, leukocytosis, and lymphocytopenia).

Treatment Strategy: A Role of Surgery : Limited to five clinical situations:

1- Initial diagnosis P.S. 2- ttt of concurrent unrelated diseases 3- Complications of lymphomas as hypersplenism. 4- Extirpaition of disease involving L.N. as pressure symptoms related to a localized L.N. enlargement not responding to local ttt. 5- Management of G.I.T lymphoma (to decrease incidence of perforation or Hge due to rapid tumour necrosis after effective chemotherapy.)

B-Role of Radiotherapy: I- H.D.: Now mainly in the form of involved field radiotherapy to localized disease or in bulky lymphadenopathy in more advanced stages High incidence of recurrence after radiotherapy in: I- IIA with bulky mediastinal disease 2- Extra nodal involvement lEA , IIEA. 3- Mixed cellularity & lymphocytic depletion subtypes. II- N. H. L.: * compared to H.D. less firm guid lines for routine Iry radiotherapy can be provided in PS, I, II N.H.L. * For localised NHL :PSI, II. - low grade  regional extended radiotherapy (4500 R) - aggressive radiotherapy + chemotherapy

Lymphatic areas and radiotherapy fields (mantle field, left, and inverted Y with spleen, right).

C-Chemotherapy: H.D.: the commonest protocoles are: 1- MOPP 2- ABVD: 3-MOPP/ABVD 4-escalated BEACOPP * chemotherapy is to be given for a minimum 6 monthly cycles at maximally tolerated doses until achievement complete CR, confirmed by restaging +2 more cycles as consolidation.

TREATMENT OPTIONS AND RESULTS in HD . EARLY-STAGE DISEASE (CLINICAL STAGE I AND II):



extended-field radiotherapy has been replaced in favor of combined modality treatment consisting of a short-duration chemotherapy (e.g., two to four cycles of ABVD [Adriamycin® (doxorubicin), bleomycin, vinblastine, and dacarbazine]) followed by involved-field radiotherapy (20-30 Gy).

. Advanced Stage HD(Clinical Stages III IV) and ABVD , The main advantage of ABVD alone is the relatively low incidence of long-term toxic effects as compared with alkylating agents-based regimens. escalated BEACOPP regimen : achieved an 87% freedom from progression and a 91% overall survival after 5 yr. Both schemes are toxic and therefore should only be administered in larger centers with much experience and within clinical trials

TREATMENT OPTIONS AND RESULTS

Non-Hodgkin’s Lymphoma Treatment of Stage I and II Indolent NHL: Radiation Therapy ■ Radiation therapy is the mainstay treatment of stage I and II grade I and II follicular lymphoma, marginal zone lymphoma (non-gastric), and small lymphocytic lymphoma .

■ IFRT delivers treatment to the clinically involved region

Treatment of Stage III & IV Indolent Lymphoma

■ Asymptomatic patients with more advanced stage III or stage IV low-grade NHL can be closely monitored (watchful waiting) .

■ Rituximab is a “humanized” anti-CD20 monoclonal antibody that can be recommended for the treatment of indolent non-Hodgkin’s lymphoma (CD20 positive), and its efficacy in the treatment of relapsed or refractory indolent NHL has been repeatedly demonstrated . ■ Combined rituximab and chemotherapy should be recommended for indolent NHL patients who have indication for treatment . .

Treatment of Stage III & IV Indolent Lymphoma

Indications for treatment include: 1- active symptoms 2-cytopenias 3-progression of disease 4- potential organ compromises. Results from trials comparing R-CHOP to CHOP and R-CVP to CVP revealed that overall chemoimmunotherapy appears to be superior to chemotherapy alone

Treatment of Gastric Mucosa-Associated Lymphoid Tumors (MALT (: General Principles: )

■ For H. Pylori-positive stage IE gastric MALT, antibiotic treatment of H. Pylori should be used as the initial treatment . Radiation therapy is an effective modality for definitive treatment of localized (stage IE or II) gastric MALT and is recommended for H. Pylori-negative cases, as well as for patients with deep invasion, active symptoms, or disease progression after antibiotic treatment .

■ For stage III or IV gastric MALT, chemotherapy and/or rituximab should be considered . Radiation therapy is indicated for local symptomatic control. ■ Treatment strategy of the more commonly diagnosed large B-cell lymphoma of the stomach (comprises approximately 60% of all gastric lymphoma cases) is identical to that of the intermediate-grade NHL.

Treatment of Intermediate-Grade (Aggressive) Non-Hodgkin’s Lymphoma General Principles:

■ Treatment strategies of the more commonly diagnosed aggressive NHL, including diffuse large B-cell lymphoma, grade III follicular lymphoma,peripheral T-cell lymphoma, and mantle-cell lymphoma, follow similar recommendations: ■ For stage I and II aggressive NHL, CHOP-based chemotherapy followed by adjuvant IFRT is the standard treatment. Rituximab is indicated for CD20-positive largecell non-Hodgkin’s lymphoma . ■ For stage III and IV aggressive NHL, CHOP-based chemotherapy is the mainstay treatment. Rituximab is indicated for CD20 positive large-cell non-Hodgkin’s lymphoma.

COURSE AND PROGNOSIS: H.D.: - 10 years actuarial survival has progressively increased from 1% with no therapy to 70% with modern ttt.

N.H.L.: - Modern chemotherapy progress have revolutionized the prognosis for many aggressive lymphomas esp., large cell type and Burkitt’s lymphoma.

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