Lymphomas

Lymphomas The Lymphomas are malignant transformation of normal B or T cells which reside predominantly in lymphoid tissues. The disease can be classified on the basis of histological appearance into two general headings: Hodgkin’s lymphoma (HL) and non-Hodgkin’s lymphoma (NHL) HL is distinguished from NHL by the presence of the pathognomonic Reed-Sternberg (RS) cell which is a ( large abnormal binucleate lymphocyte ) Note: binucleate means having two nuclei . pathognomonic is a term, often used in medicine, that means characteristic for a particular disease. Lymphoma cells predominate in the lymph nodes; however, they can infiltrate other tissues, such as the bone marrow, central nervous system (CNS), gastrointestinal (GI) tract, liver, skin, and spleen . Lymphomas are commoner than Leukemia

Hodgkin’s lymphoma (HL) Hodgkin’s lymphoma (HL) account for about 30% of lymphomas . It is predominately a disease of young adult and having a peak incidence between the age of 15-35 years . Etiology The cause of Hodgkin's lymphoma is unknown, but a number of risk factors has been identified . The Epstein-Barr virus which can cause glandular fever, has been shown to play an important role in Hodgkin's lymphoma, accounting for about 50 % of all cases. A genetic link is also involved . A patients who have reduced immunity, such as those with AIDS, or taking Immunosuppressants after an organ transplant, may have a slightly increased risk of developing Hodgkin's lymphoma

Clinical Presentation Symptoms 1- Lymphadenopathy ("swollen/enlarged lymph nodes) , generally in the cervical, axillary, supraclavicular, or inguinal lymph nodes (the groin or the lower lateral regions of the abdomen). 2- Splenomegaly 3- Shortness of breath, dry cough, chest pressure . 4- Gastrointestinal complications (e.g., nausea, vomiting, early satiety تخمة , constipation, and diarrhea) 5- Back, chest, or abdominal pain. Signs 1- Fever 2- Night sweats 3- Weight loss greater than 10% within last 6months (These three are known collectively as B-symptoms.)

Laboratory Finding : Laboratory finding include normochromic, normocytic anaemia & a raised ESR . One third of patients have a leucocytosis (( white blood cell count i.e.,(the leukocyte count) above the normal range in the blood)) due to an increase in neutrophils (There are five principal types of leukocytosis & Neutrophilia is the most common form) Advance disease is associated with Lymphopenia , a condition of having an abnormally low level of lymphocytes in blood. (lymphocytes < 0.6 x 109 / L ) . Plasma lactate dehydrogenase(LDH) is raised in 30-40% of patients at diagnosis and has been associated with poor prognosis . Diagnosis and Staging : The diagnosis of Hodgkin's lymphomas is established by histological examination of lymph node biopsy sample. The characteristic pathological finding in Hodgkin's lymphomas is the presence of a large abnormal lymphocyte called Reed- Sternberg (RS) cell which is a ( large abnormal binucleate lymphocyte )

Hodgkin's lymphoma is divided into two distinct categories: 1- Classical Hodgkin's lymphoma. 2- Nodular lymphocyte-pre­dominant Hodgkin's lymphoma & Classical Hodgkin's lymphoma is divided into four histological subclassifications 1-Nodular sclerosis Hodgkin’s lymphoma (grades 1&2) 2- Mixed cellularity Hodgkin’s lymphoma. 3-Lymphocyte-rich classical Hodgkin’s lymphoma. 4-Lymphocyte depletion Hodgkin’s lymphoma. Nodular sclerosis HL is the most common form of HL, representing 70% of cases. It is more common in young adults and it has excellent prognosis . The second most common form of HL, accounting for approximately 25% of cases, is the mixed-cellularity variant, while others accounting for less than 5% of cases

Prognostic factors that predict poor treatment outcome include : 1-Advanced stage 2-Age greater than 45 years 3-Male gender. 4- B symptoms (Fever, Night sweats & Weight loss greater than 10% within last 6months 5-High number of involved nodal regions 6- Large mediastinal mass ( A mass present in the mediastinum which is the cavity that separates the lungs from the rest of the chest) . 7-Extranodal disease, 8-Elevated erythrocyte sedimentation rate (ESR) 9- Hemoglobin less than 10.5 g/dL. 10-Leucocytosis )leukocyte count above the normal) 11-lymphocytopenia (abnormal low level of lymphocytes 12-low serum albumin (less than 4 g/dL ).

Cotswald Staging Classification for Hodgkin’s Disease Stages 1 Description Involvement of a single lymph node region of lymphoid structure (e.g., spleen, thymus ……). Note;The thymus is a specialized organ of the immune system , located in front of the heart and behind the sternum. Stages II Description Involvement of two or more lymph node regions on the same side of the diaphragm. Stages III Description Involvement of lymph node regions or structure on both sides of the diaphragm. III 1: With or without involvement of splenic, celiac or portal nodes. Note: celiac nodes means visceral nodes located along the celiac بطني trunk that drain lymph from the stomach, duodenum & spleen III 2: Involvement of para-aortic, iliac or mesenteric nodes Note: paraaortic lymph node is one of several masses of lymph tissue located near the aorta iliac (lowest lateral abdominal regions) , mesenteric (the mesentery is the double layer of peritoneum that suspends the jejunum & ileum from the posterior wall of abdomen).  Stages IV Description Involvement of extranodal site(s) i.e., affects not only the lymph nodes but also other parts of the body, such as the liver, lungs or bones.

Treatment Of Hodgkin’s lymphoma Desired Outcome: The principal goal in treating HL is to cure the patient of the primary malignancy . Radiation: Radiation to a single field that contains Hodgkin’s lymphoma is called involved-field radiation; Radiation to the involved field and a second uninvolved area is termed extended-field radiation or subtotal nodal radiation; Radiation of all areas is called total nodal radiation

A- Treatment of Early stage (favorable ) disease : The cure rate for patient with stage I and IIA disease is grater than 90 % . Patients with stage I and IIA disease may be cured with Extended field radiation alone. i.e., Radiation to the involved field and a second uninvolved area. However, due to high relapse rates (about 25-30 %) and fatal long-term effects (secondary malignancies or cardiac toxicity), this approach is now thought to be unacceptable by many . Risk of relapse can be reduced by combined treatment with chemotherapy i.e., chemotherapy + radiotherapy. The combined approach allows the use of shorter courses of chemotherapy ( this is usually consists of 2-4 cycles of ABVD (Adriamycin [doxorubicin ], bleomycin, vinblastine, dacarbazine) followed by more restricted radiotherapy (involved field radiation) , which reduces the toxic effects (Radiation to a single field that contains Hodgkin’s lymphoma) .

The aim of chemotherapy is to destroy subclinical disease outside the field of therapy . However, recent studies suggest that combined treatment increases (relapse –free survival) only but not (overall survival). Note:   In cancer, relapse –free survival means the length of time after primary treatment for a cancer ends, so that the patient survives without the return of any signs or symptoms of that cancer. The overall survival rate is often stated as a five- year survival rate, after the diagnosis or the start of treatment.

B-Treatment of Early stage (unfavorable) disease: Patients with stage I or II presenting with bulky disease, B symptoms or with more than two sites of disease are considered to be poor risk if treated by radiotherapy alone. Note: : Bulky disease(X): greater than 1/3 the width of the mediastinum(The mediastinum is the "middle" section of the chest cavity.) or greater than 10 cm maximal dimension of nodal mass. B symptoms (Fever, night sweats, and weight loss) These patients are treated with 4 cycles of Combination chemotherapy, e.g. ABVD Adriamycin (doxorubicin ), bleomycin, vinblastine, dacarbazine), and radiotherapy to sites of bulky disease

C- Treatment of Advanced disease: Treatment of advanced-stage (stage III–IV) HL is focused on the use of multi agent chemotherapy for 6-8 total cycles . The MOPP M (mechlorethamine) alkylating agent, works by binding to DNA, cross linking two strands and preventing cell duplication), O (Oncovin) vincristine an alkaloid cell toxin & mitotic inhibitor that inhibits mitosis, or cell division, P (procarbazine) (alkylating agent that cause breaking of DNA strands P (prednisolone) The MOPP was the first chemotherapy regimen to cure HL , it was introduced in the 1960s. However, it is associated with significant toxicity, including sterility and secondary leukemia . MOPP produces complete remissions in about 80% of patients and has a 10-year cure rate of about 50%

Now ABVD has replaced MOPP chemotherapy as the regimen of choice as it is as effective but less toxic A (Adriamycin) doxorubicin (anti-tumor antibiotic or anthracycline antibiotic it works by intercalating DNA) B (bleomycin) another anti-tumor antibiotic, V (vinblastine), an alkaloid cell toxin. It causes specific cell cycle arrest by disrupting microtubule assembly and proper formation of the mitotic spindle necessary for the separation of chromosomes during mitosis. D (dacarbazine) alkylating agent which destroy cancer cells by adding an alkyl group. 6-8 total cycles of ABVD is considered the current standard treatment of advanced disease Patient with partial remission after chemotherapy may benefit from involved field radiation, whereas those in complete remission may not receive any further benefit. Therefore the use of radiotherapy is determined on an individual basis .

A number of regimens have been investigated over the past decade. A weekly chemotherapy regimen administered for 12 weeks called Stanford V include Bleomycin, anti-tumor antibiotic Etoposide, a DNA toxin Adriamycin (Doxorubicin), anti-tumor antibiotic Cyclophosphamide (alkylating agent & immunosuppressant, or Mechlorethamine ( another alkylating agent) Vincristine, an alkaloid cell toxin Vinblastine, another alkaloid cell toxin Prednisone, Stanford V becomes increasingly popular, but also includes radiation therapy, which has been associated with life-threatening late toxicities such as premature coronary artery disease and second solid tumors. In Europe a high-dose regimen called BEACOPP has become popular and might have a better response rate in very high risk patients. BEACOPP means; Bleomycin, Etoposide, Adriamycin (Doxorubicin), Cyclophosphamide, Oncovin (Vincristine), Prednisone & Procarbazine (another alkylatin agents). Despite advance in HL, 30-40 % of patients progress or relapse and respond poorly to salvager chemotherapy.

Salvage therapy for relapsed disease : Response to salvage therapy depends on the extent and site of recurrence, previous therapy, and duration of first remission. Choice of salvage therapy should be guided by response to initial therapy and patient's ability to tolerate therapy. Since the success of salvage treatment has been shown to be influenced by the length of remission after initial chemotherapy." There­fore the disease can be classified as : 1-Primary refractory disease (patients who never achieved a complete remission) . 2-Early relapse (within 12 months of complete remission) . 3-Late relapse (after more than 12 months of complete remission) Patients with primary refractory disease or with early relapse are associated with poor prognosis. Patients with these prognostic factors are candidates for high-dose chemotherapy and hematopoietic stem cell transplantation HSCT. Patients with late relapse can be treated with the same regimen, a salvage regimen, radiation therapy, or high-dose chemotherapy and hematopoietic stem cell transplantation (HSCT). Note: in HSCT, the stem cells are collected from the patient and then returned following high –dose chemotherapy .

salvage regimens: In an effort to avoid cross-resistance, most salvage regimens incorporate drugs not used in the initial therapy. Commonly used salvage regimens include . 1-DHAP (dexamethasone , cytarabine, and cisplatin). 2-ESHAP (etoposide, methylprednisolone, cytarabine, and cisplatin). 3-ICE (etoposide, ifosfamide and carboplatin,) These chemotherapy is a newer regimen that has been used in patients with refractory disease. Cytarabine kills cancer cells by interfering with DNA synthesis cisplatin binding to and causing cross linking of DNA, which ultimately triggers apoptosis (programmed cell death). etoposide a DNA toxin ifosfamide a nitrogen mustard alkylating agent carboplatin interact with DNA to interfere with DNA repair.

Complications of Chemotherapy 1-Myelosuppression sometimes called bone marrow suppression, is a common side effect of chemotherapy that is characterized by a decrease in blood cell production. Three different kinds of blood cells are produced in the body's bone marrow – red blood cells, white blood cells and platelets.Myelosuppression can result in the decrease in one, two or all three types of blood cells. A decrease in red blood cells is the most common type of myelosuppression experienced by chemotherapy patients. This type of bone marrow suppression is referred to as anemia. Lowered production of white blood cells is also fairly common among cancer patients. When the chemotherapy results in the reduction of neutrophils, a specific type of white blood cell, the myelosuppression is subcategorized as neutropenia. A drop in platelet numbers is called thrombocytopenia. This type of bone marrow suppression is fairly rare, and only negatively affects less than 10 percent of all cancer patients. When an individual experiences a drop in all three types of blood cells, the condition is called pancytopenia.

2-Nausea and vomiting are frequently seen 2-Nausea and vomiting are frequently seen. The severity has diminished with the use of the 5-HT3 antagonists (e.g. Ondansetron, granisetron ,….) . Ondansetron & granisetron are a serotonin 5-HT3 receptor antagonist used mainly as an antiemetic (to treat nausea and vomiting), often following chemotherapy. It affects both peripheral and central nerves. They reduces the activity of the vagus nerve, which deactivates the vomiting center in the medulla oblongata, and also blocks serotonin receptors in the chemoreceptor trigger zone. 3-Neurotoxicity is frequently seen with vincristine . 4-Other acute toxic effects include alopecia, dermatitis, mucositis (is inflammation of or damage to the surface of G.I.T . In the mouth this may lead to painful mouth ulceration , local infection and difficulty in swallowing), phlebitis, malaise and fatigue, pulmonary reactions, and renal dysfunction . 5-Long-term complications include gonadal dysfunction, secondary malignancies, and cardiac disease. The risk of developing acute leukemia is highest after chemotherapy, with or without radiation therapy

Doxorubicin Dacarbazine Antiemetic therapy adverse effects associated with chemotherapy regimens used in lymphoma with supportive measures and counseling points Adverse effect Cytotoxic implicated Supportive measures Counseling points Bone marrow suppression Chlorambucil , Prednisone Vinblastine,, dacarbazine, Etoposide , Cyclophosphamid Blood transfusion, platelet transfusion, mouth care, antibiotic therapy for febrile episodes , Granulocyte-colony stimulating factors (G-CSF) (see note 1 below ) Expect tiredness, report bleeding or unusual bruising, importance of good personal hygiene , adhere to mouth care regimen, avoid people with infection , monitor temperature, report febrile episode or sign of infection immediately Nausea and vomiting Procarbazine Cyclophosphamide Doxorubicin Dacarbazine Antiemetic therapy Emphasize regular use . A short course is more effective than (as required ) treatment ,Take tablet before meals , report episode vomiting (especially if taking oral cytotoxic ) Mucositis Doxorubicin mouth care regimen importance of good personal hygiene, instruct how to use mouthwash,

High tumour load sensitive to chemotherapy Adverse effect Cytotoxic implicated Supportive measures Counseling points Tumour lysis syndrom Neuropathy High tumour load sensitive to chemotherapy Vincristine Hydration Allopurinol Rasburicase Discontinue use or substitute vinblastine Drink plenty of fluid. Report tingling sensation, jaw pain or stiffness , constipation. Refer to doctor Alopecia Etoposide , Cyclophosphamid Doxorubicin Provision of wig if wanted Hair usually regrows on completion of therapy. Gonadal dysfunction Cardiomyopathy Alkylating agents Procarbazine Doxorubicin Sperm storage Refer to doctor, some cases reversible Report SOB

Note 1 :Granulocyte-colony stimulating factor (G-CSF) ( e.g. Filgrastim & lenograstim, stimulates the production of neutrophils and may reduce the duration of chemotherapy-induced neutropenia and thereby reduce the incidence of associated sepsis. Note 2 : Tumor lysis syndrome is characterized by various combinations of hyperuricemia, hyperkalemia, hyperphosphatemia, caused by the destruction of a large number of neoplastic cells. Frequently, acute renal failure develops as a result of the syndrome. Rasburicase (recombinant urate oxidase :catalyzes the conversion of poorly soluble uric acid to readily soluble allantoin) can be effective in these instances .