Non-Hodgkin's Lymphoma
Introduction and Facts
Lymphoma is a collection of primary malignancies in the lymph nodes and lymphoid tissue. Based on the histologic type, lymphomas can be divided into two major groups, namely Non-Hodgkin's Lymphoma and Hodgkin's Lymphoma. This protocol will only be limited to non-Hodgkin's lymphoma.
Non-Hodgkin's lymphoma (NHL) is a large group of primary malignancies of lymph nodes and extra-nodal lymphoid tissue, which can originate from B lymphocytes, T lymphocytes, and natural killer NK cells. Currently, there are 36 disease entities that are categorized as NHL in the WHO classification. In Indonesia, NHL together with Hodgkin's lymphoma and leukemia are in the 6th rank of malignancy.
Pathophysiology
NHL is a primary malignancy of lymphocytes originating from B lymphocytes, T lymphocytes and sometimes from natural killer cells in the lymph system with a very heterogeneous picture, both histologically, symptoms, clinical course, response to treatment and prognosis. Like other malignancies, NHL is the result of a gradual accumulation of genetic disorders resulting in the uncontrolled growth of clones of malignant cells. Repeated translocations that occur at multiple levels of B cell differentiation are the prelude to malignant transformation. This translocation results in deregulation of the expression of oncogenes that control cell proliferation, survival and differentiation. Interestingly, translocation alone is not sufficient to cause lymphoma, so a subsequent secondary genetic disorder is required for complete malignant transformation to occur.
Clinical Symptoms and Complications
Symptoms that are often found in patients with lymphoma are generally non-specific, including:
- Weight loss >10% in 6 months.
- Fever 38 degrees C > 1 week for no apparent reason.
- Night sweats a lot.
- Get tired quickly.
- Decreased appetite.
- Enlargement of the involved lymph nodes.
- There may also be a painless lump in the neck, armpit or groin (especially if the size is more than 2 cm); or shortness of breath due to enlarged mediastinal lymph nodes or splenomegaly.
The first three symptoms must be watched out for because they are associated with an unfavorable prognosis, as well as if there is bulky disease (KGB > 6-10 cm or mediastinum > 33% of the thoracic cavity). According to the Lymphoma International Prognostic Index, clinical findings that affect the prognosis of patients with NHL are age >60 years, involvement of both sides of the diaphragm or extranodal organs (Ann Arbor III/IV) and multifocality (>4 locations).
Diagnosis
The diagnosis is made based on history, physical examination, laboratory examination, and anatomic pathology.
Inspection:
1. General History:
- Enlargement of lymph nodes (KGB) or organs.
- General malaise.
- Weight loss >10% within 3 months.
- High fever 38°C for 1 week without cause.
- Night sweats.
- Complaints of anemia (weakness, dizziness, palpitations)?
- Use of certain drugs?
- Special:
o Autoimmune diseases (SLE, Sjögren, Rheumatoid)
o Blood disorders
o Infectious diseases (Toxoplasma, Mononucleosis, Tuberculosis, Lues, etc.)
o Immunodeficiency states
2. Physical Examination
- Enlargement of the KGB.
- Abnormalities / enlargement of organs (liver / spleen).
- Performance status: ECOG or WHO/Karnofsky.
3. Diagnostic Check
A. Excisional or core biopsy:
A lymph node biopsy is performed on only 1 most representative, superficial, and peripheral gland. If the most representative superficial/peripheral gland is present, there is no need for an intra-abdominal or intrathoracic biopsy. The recommended lymph nodes are from the neck and supraclavicular, the second option is axillary and the last option is inguinal. The gland specimen is examined:
a. Routine, Histopathology: according to the latest WHO classification
b. Specific, Immunohistochemistry and Molecular (in situ hybridization) EBV
The initial diagnosis should be made on the basis of histopathology and not on cytology alone. In certain conditions where the lymph nodes are difficult to biopsy, the combination of core biopsy FNAB together with other techniques (CPI, Flowcytometry and others) may be sufficient for diagnosis.
B. Laboratory
1. Hematology Routine:
o Complete Peripheral Blood (DPL): Hb, Ht, leukocytes, platelets, ESR, type count
o Peripheral Blood Picture (GDT): blood cell morphology
o Urine analysis: complete urine
2. Clinical chemistry:
o SGOT, SGPT, Bilirubin (total/direct/indirect), LDH, total protein, albumin-globulin
o Alkaline phosphatase, uric acid, urea, creatinine o Temporary blood sugar
o Electrolytes: Na, K, Cl, Ca, P
o HIV, TB, Hepatitis C (anti HCV, HBsAg) Specifically:
o Gamma GT
o Serum Protein Electrophoresis (SPE) o Immunoelectrophoresis (IEP)
o Coombs test
o B2 microglobulins
C. Bone Marrow Aspiration (BMP) and bone marrow biopsy from 2 sides of the iliac spine with a minimum specimen length of 1.5 cm, and recommended 2 cm.
D. Radiology. For routine/standard examinations, a CT Scan of the thorax/abdomen is performed. If facilities are available, a PET CT Scan can be performed.
E. ENT consultation. If the Waldeyer ring is involved, laryngoscopy is performed.
F. Other body fluids (pleural fluid, ascitic fluid, cerebrospinal fluid). If a puncture/aspiration is performed, the cytology is examined by means of a cytospin, in addition to other routine examinations.
G. Cardiac consultation. Using an echocardiogram to see heart function
Management and Treatment
The choice of therapy depends on several things, including: type of lymphoma (histological type), stage, nature of the tumor (indolent/aggressive), age, and general condition of the patient.
I. INDOLEN NHL / Low grade: (Ki-67 < 30%) Included in this group are:
- SLL/small lymphocytic lymphoma/CLL = chronic lymphocytic lymphoma.
- MZL (marginal zone lymphoma), nodal, extranodal and splenic).
- Lymphoplasmacytic lymphoma.
- Follicular lymphoma.
- Mycosis Fungoides.
- Primary cutaneous anaplastic large cell lymphoma.
A. LNH INDOLEN STADIUM I AND II
Radiotherapy prolongs disease free survival in some patients. Standard therapy options:
1. Irradiation
2. Chemotherapy followed by radiation
3. Chemotherapy (especially at stage = 2 (according to GELF criteria)
4. Combination of chemotherapy and immunotherapy
5. Observation
B. INDOLEN LNH / low grade STADIUM II bulky, III, IV Standard of choice of therapy:
1. Observation (category 1) if there is no indication for therapy. Included in the indications for therapy:
- There are symptoms.
- Threatening organ function.
- Cytopenia secondary to lymphoma.
- Bulky.
- Progressive.
- Clinic test.
2. Therapy that can be given:
1. Rituximab can be given as a combination of first-line therapy, namely R-CVP. In conditions where Rituximab cannot be given, combination chemotherapy is the first choice, for example: COPP, CHOP and FND.
2. Purine nucleoside analogs (Fludarabin) in primary NHL
3. Oral alkylating agents (with/without steroids), if combination chemotherapy cannot be given/tolerated (cyclophosphamide, chlorambucil)
4. Rituximab maintenance can be considered
5. Intensive chemotherapy ± Total Body irradiation (TBI) followed by stem cell resque can be considered in certain cases
6. Palliative radiation therapy, given to large tumors (bulky) to reduce pain/obstruction.
C. INDOLEN LNH/low grade RELAPS
Standard therapy options:
1. Palliative radiation
2. Chemotherapy
3. Bone marrow transplant
II. AGGRESSIVE / High grade NHL: (Ki-67 > 30%) Included in this group are:
- MCL (Mantle cell lymphoma, pleomorphic variant).
- Diffuse large B cell lymphoma, Follicular lymphoma gr III, B cell lymphoma unclassifiable with features between diffuse large B cell and Burkitt,
- T-cell lymphoma.
A. LNH STADIUM I AND II
In non-bulky tumor conditions (tumor diameter <7.5cm) with criteria: low- or low-medium risk young patients (aaIPI score = 1) and high or medium-high risk (aaIPI = 2), if facilities allow, combination chemotherapy R- CHOP 6 cycles is the current standard protocol and may consider radiotherapy (for consolidation), or 3 cycles of chemotherapy followed by radiotherapy.
B. LNH STADIUM I-II (BULKY), III AND IV
• If possible, 6 cycles of RCHOP chemotherapy ± consolidation radiotherapy, considered at stage I and II
• Clinical trials at stage III and IV
C. NHL REFRACTER/RELAPS
• Patients with refractory NHL who fail to achieve remission can be treated with salvage with radiotherapy if the affected area is not extensive. The treatment of choice if possible is salvage chemotherapy followed by bone marrow transplantation
• Salvage chemotherapy such as R-DHAP and R-ICE
III. LNH “LEUKEMIA-LIKE”: Lymphoblastic, Burkitt, “double hit” lymphoma.
• High dose chemotherapy plus radiotherapy followed by bone marrow transplant
Nutritional Support. Nutritional status is one of the factors that play an important role in the quality of life of cancer patients.
Medic rehabilitation. Medical rehabilitation aims to optimize the return of impaired functional abilities and activities of daily living as well as improve the patient's quality of life in a safe & effective manner, according to existing functional abilities. The medical rehabilitation approach can be given as early as possible before definitive treatment is given and can be carried out at various stages & treatment of the disease tailored to the goals of cancer rehabilitation: preventive, restorative, supportive or palliative.
Education, which includes:
1. Chemotherapy:
- Possible side effects of chemotherapy (CPIN, etc.)
- Exercises that need to be done to avoid impaired muscle strength (see principles of medical rehabilitation)
2. Nutrition. Educate the amount of nutrition, types and ways of providing nutrition according to needs
3. Others. Recommendations for routine post-treatment control
Reference:
1. Komite Penganggulangan Kanker Nasional. Panduan Penatalaksanaan Limfoma Non-Hodgkin. Internet [Cited 24/8/2021]. Available from: http://kanker.kemkes.go.id/guidelines_read.php?id=2&cancer=6
2. Karlina Isabella. Ki-67 Sebagai Parameter Prognosis pada Limfoma Non-Hodgkin. Internet [Cited 24/8/2021]. Available from: https://simdos.unud.ac.id/uploads/file_penelitian_1_dir/ef83468df2f3d04c7a6c61bd0ad56aa4.pdf
