Lymphatic System: Definition, Anatomy, Function, And Diseases

Lymphatics Lymph Vesseles And Lymphoma Introduction

Lymphatics and lymph vessels play the role of draining waste fluid from the body. Hence, they are vulnerable to various infections.

• The lymphatics are connected to a group of lymph nodes and drain into veins.
• Hence, infections of the lymphatics give rise to enlarged lymph nodes. In this chapter, significant surgical diseases affecting the lymphatics and lymph nodes are discussed.

Read And Learn More: General Surgery Notes

Lymphoedema

Describe pathophysiology, clinical features, investigations and principles of management of lymphedema, lymphangitis and lymphomas.

Lymphoedema Definition

Accumulation of lymph in the extracellular, extravascular compartment and subcutaneous tissues resulting in enlargement of the limb. It is a protein-rich interstitial fluid.

Common Sites of Lymphoedema

• Lower limbs are the most common site.
• Upper limbs.
• Scrotum: Elephantiasis of the scrotum is caused by filarial organisms (Wuchereria bancrofti).
• Elephantiasis of the penis caused by filarial organisms produces ram’s horn penis.

 

Lymphoedema Anatomy And Physiology

• Surgical Anatomy of the Lymphatic System
  • Lumbar trunks: Receive lymphatics from the lower limbs
  • Intestinal trunk: Receive lymphatics from the GIT
  • These trunks combine to form the cisterna chyli, which later twins into the thoracic duct (45 cm)
  • The thoracic duct also drains lymph from the left jugular, left subclavian, and left bronchomediastinal trunks.
  • The right lymphatic duct (1.25 cm) drains lymph from the right jugular, right subclavian, and right bronchomediastinal trunks and enters into the junction of the right IJV and subclavian veins.
  • The cisterna chyli is a lymphatic channel that receives lymphatic drainage from the lower limbs and GIT. It is found inferior to the aortic hiatus of the diaphragm, beyond which it continues as the thoracic duct.

Lymphoedema Functions of the Lymphatic System

• To return protein-rich fluid to circulation through lymphatic venous junctions in the jugular area.
• This fluid includes water, electrolytes, and low molecular weight substances such as polypeptides, growth factors, and cytokines.
• It also includes macromolecules, such as fibrinogen, albumin, and globulin.
• Transport of cholesterol, long-chain fatty acids, triglycerides, and fat-soluble vitamins (A, D, E, K) by intestinal lymph into circulation. They bypass the liver and enter circulation through the cisterna chyli and thoracic duct into the left internal jugular vein (lymph from lower limbs, abdomen, and left arm).
• The right lymphatic duct drains into the right internal jugular vein (lymph from the head and right arm).

Components of the Lymphatic System

• Lymphatic channels.
• Lymphoid organs—lymph nodes, spleen, Peyer’s patches, thymus, tonsils.
• Circulating cells—lymphocytes and mononuclear immune cells.

Lymphoedema Lymphatic Circulation

• Lymph flow is largely due to intrinsic lymphatic contractility by lymphangiomas (segment of lymphatics).
• A transient increase in interstitial pressure secondary to exercise and limb movements also helps to a certain extent.
• Valves prevent reflux in the lymphatics.

Types of Lymphoedema

1. Primary (congenital) lymphoedema
2. Secondary lymphoedema

Risk factors for Lymphoedema

• Risk factors for Lower Limb Lymphoedema
  • Inguinal block dissection, for example. carcinoma penis, melanoma
  • Postoperative pelvic radiotherapy
  • Varicose vein stripping and vein harvesting
  • Obesity
• Risk Factors for Upper Limb Lymphoedema
  • Axillary block dissection, for example. carcinoma breast
  • Radiation fibrosis, scar formation
  • Advanced cancer—breast with axillary lymph nodes
  • Obesity
  • Chronic infection

Primary (Congenital) Lymphoedema Introduction

• Incidence is 1 in 6000 persons.
• Lymphoedema is confined to the epifascial plane.
• It is due to an inherited abnormality of the lymphatic system.
• A few cases which occur later in life may be due to unnoticed factors—repeated bacterial and fungal infections, trauma to feet, etc.
• Loss of venoarteriolar reflux (VAR), which protects the lower limb capillaries from excessive hydrostatic forces in the erect posture, occurs in advanced age.
• Diseases such as diabetes and chronic venous insufficiency may also contribute.

Causes of Primary Lymphoedema

1. Hereditary: Associated with syndromes such as Turner’s (XO), Klinefelter’s (XXY), and Down’s (Trisomy 21).

2. Familial

• Nonne-Milroy—type 1 (congenital)
  • Occurs in 1 of 6000 live births
  • Inherited as an autosomal dominant trait
  • Brawny lymphoedema of both legs, genitalia, arms, face, etc. develops from birth.
  • Onset: <2 years of age
• Meige’s disease—type 2 (praecox)
  • Lymphoedema develops between puberty and middle age (50 years). It may also involve the arms.
  • A few are inherited in an autosomal dominant manner.
  • Onset: 2–35 years of age.

3. Tarda onset after 35 years of age

Primary (Congenital) Lymphoedema Pathophysiology

Lymphoedema leads to impaired immune surveillance and predisposes to other malignancies.

• Malignancies Associated with Lymphoedema
• Skin cancers
  • Squamous cell carcinoma
  • Malignant melanoma
  • Basal cell carcinoma
• Sarcomas
  • Lymphangiosarcoma (Stewart-Treves syndrome)
  • Kaposi’s sarcoma
  • Liposarcoma
  • Malignant fibrous histiocytoma
• Systemic disease
  • Lymphoma

Types of Primary Lymphoedema

• Lymphatic aplasia: The number of lymphatic channels and nodes is grossly reduced.
• Lymphatic hypoplasia: Lymphatic channels are of a small calibre.
• Milroy’s disease: A familial type of lymphoedema congenital.

Based on the time at which lymphoedema appears, it is classified as either:

• Birth: Lymphoedema congenita.
• Puberty: Lymphoedema praecox.
• Later: Lymphoedema tarda.

Secondary Lymphoedema (Acquired)

1. Filarial elephantiasis is caused by Wuchereria bancrofti, transmitted by the mosquito Culex fatigans. The disease is caused by adult worms which have an affinity towards lymphatic vessels and nodes. Microfilariae do not produce any lesions.

Initially, it causes lymphangitis which clinically presents with high-grade fever, chills and rigours, red streaks in the limb, tenderness, and swelling of the spermatic cord and scrotum.

Clinical manifestations of lymphatic filariasis

The lymph nodes are swollen and tender. Retroperitoneal lymphangitis produces acute abdominal pain.

• Due to repeated infections, fibrosis occurs and results in lymphatic obstruction. Later, this gives rise to lymphatic dilatation. Lower limb lymphatics are dilated and tortuous (lymphangiectasis).
• Initially, lymphoedema is pitting in nature but progressively becomes nonpitting. Lymph (protein) provides good nourishment for fibroblasts.
• After repeated infections, the skin over the limb becomes dry and thickened and is thrown into folds and even nodules that break open and result in ulcers. Hence, it is called elephant leg. Malnutrition and infection precipitate lymphoedema.
• Oedema is also due to reflux of lymph from para-aortic vessels into the smaller lymphatics draining the lower limb. The subcutaneous tissue is grossly thickened. The presence of deep fascia prevents the involvement of the deep muscles of the lower limb.

Elephant Leg

2. After inguinal block dissection for secondaries in the lymph nodes (upper limb lymphoedema following axillary block dissection).

3. Following radiotherapy to lymph nodes.

4. Advanced malignancies.

5. Repeated infections due to barefoot walking.

Secondary Lymphoedema Symptoms

• Swollen limb, dull-aching pain
• Tiredness, pins and needles, cramping pain
• Loss of ankle contour
• Buffalo hump on the dorsum of the foot
• Toes are square
• The skin on the dorsum of the toes cannot be pinched because of subcutaneous fibrosis—Stemmer’s sign
• In early cases, it pits on pressure. Later, oedema does not pit and does not reduce even with elevation
• Advanced cases: Chronic eczema, fungal infections of the skin (dermatophytosis) and nails (onychomycosis), fissuring, and warts.
• Ulceration is unusual.
• However, once ulcers start, recurrent bacterial infections are common, thus worsening the disease process.

Clinical features of lymphoedema

Secondary Lymphoedema was Diagnosed by detecting: Microfilariae on a blood smear complement fixation test.

Secondary Lymphoedema Treatment:

Diethylcarbamazine (DEC) 100 mg bid × 14 days.

Secondary Lymphoedema Grades of Filarial Lymphoedema

1. Grade 1: Oedema pitting: Completely relieved on rest and elevation. No skin changes.
2. Grade 2: Oedema pitting: Partially relieved on rest and elevation. No skin changes.
3. Grade 3: Oedema nonpitting: Skin involvement, subcutaneous thickening present.
4. Grade 4: Oedema nonpitting: Not relieved, warty projections, elephantiasis, lymphorrhoea present.

Secondary Lymphoedema Differential Diagnosis of Unilateral Elephantiasis of the Leg

1. Filariasis is the most common cause of secondary elephantiasis of the leg in endemic areas—coastal Karnataka, coastal Andhra Pradesh, Tamil Nadu, etc.

Comparison of primary and secondary lymphoedema

2. Congenital AV fistula may present with unilateral gigantism of the leg. Dilated veins, continuous murmur, gigantism, and a nonhealing ulcer in the leg in a young boy give the clue to the diagnosis.

3. Elephantiasis neuromatosa of the leg may cause diffuse enlargement of the leg. The leg is tender on palpation with a soft to firm diffuse swelling.

4. Extensive lipomatosis of the leg. The causes of lymphoedema are summarized

• Summary of Causes of Lymphoedema
  • Aplasia, hypoplasia (familial and genetic)
  • Parasitic (filariasis)
  • Lymph node obstruction—advanced malignancies
  • Altered motility—dysmotility (genetic)
  • Surgical extirpation—block dissection
  • Inflammatory or infection—recurrent
  • After radiotherapy, after barefoot walking ‘silica particles’
  • Remember as APLASIA

Causes of secondary lymphoedema

Secondary Lymphoedema Investigations (Lymphangiography)

By and large, no investigations are done in secondary lymphoedema. In selected cases of primary lymphoedema, investigations may be done but are largely of academic interest.

Lymphangiography

A dye is injected into the lymphatics and the entire draining lymphatics and lymph nodes are visualised.

Indications for Lymphangiography

• Lymphoedema, if surgery is planned.
• Lymphoma, to detect pelvic nodes, para-aortic nodes, etc. (but now CT is preferable).

Lymphangiography Procedure

• Commonly, pedal lymphangiograms are done.
• 5–10 ml of methylene blue (patent blue) is injected into the web spaces intradermally between the toes. This delineates the lymphatics of the dorsum of the foot which are identified. Then, an oily dye such as “ultra fluid lipiodol” is injected (10–15 ml).
• It may take 12–24 hours to delineate the inguinal and para-aortic nodes.
• Isotope lymphangiography refers to the injection of albumin labelled with technetium 99m colloid or I.

Lymphangiography Results

• Metastases appear as irregular filling defects in the lymph nodes.
• It may demonstrate hypoplasia or hyperplasia, as in primary lymphoedema.
• If there is obstruction, the dye may return back (dermal backflow).

Lymphangiographic Classification

Three types are recognised

1. Congenital hyperplasia (10%): This is a condition wherein lymphatics are increased in number. These mega lymphatics are defective, resulting in chylous ascites, chylothorax, and protein-losing enteropathy. Being congenital, it manifests at birth. It is progressive, involves the whole leg, and shows a variable response to compressive therapy.
2. Distal obliteration (80%).
   • Distal lymphatics are commonly affected
   • In and around puberty—praecox involved
   • Sex: Common in females
   • Treatment is by compression, good response
   • The ankle, and calf region is involved
   • Lymphatics are decreased or absent (aplasia)
   • Remember as DISTAL
3. Proximal obliteration (10%)
   • It is less common.
   • Obstruction is at the region of the aortoiliac or inguinal nodes.
   • The whole leg or thigh is involved.
   • No family history.
   • Rapid progression and poor response.

Complications of Lymphangiography

1. Lymphangitis and toxaemia
   • It is not routinely done nowadays because of the availability of ultrasound, CT, and other noninvasive investigations.
2. Rapid infusion should be avoided to prevent the risk of lipid pulmonary embolus.

Lymphangiography Lymphoscintigraphy

• It has a sensitivity and specificity of 92% and 100%, respectively.
• It has replaced lymphangiography.
• Radiolabelled (technetium 99m) colloid is injected into the web space between the 2nd and 3rd toes or fingers. The limb is exercised periodically and images are taken.
• If there is an abnormal accumulation of tracer with collaterals, it is a sign of lymphoedema.
• MRI and CT are the latest investigations in addition to lymphangiography for the evaluation of gross swelling of the limb.

Lymphangiography Treatment of Lymphoedema

• MLLB
  • Graduated pressure highest at the ankle (100%) to lowest in the groin (40%)
    should be applied.
  • It requires about 40–60 mmHg to the leg and 30–40 mmHg to the arm.
  • MLLB should be worn at the start of the day and removed at bedtime.
  • However, the limb should be kept elevated at night.
  • The aim is to get a graduated pressure in applying. If it is applied wrongly, it may result in an increase in lymphoedema.

Conservative

1. Control of swelling: Decongestive lymphoedema therapy (DLT)

• Bedrest, elevation
• Bandaging: Multilayered lymphoedema bandaging (MLLB).
• Compression garments
• Massage: Manual lymphatic drainage (MLD)
• It aims at draining fluid and protein from ISF space.
• It also stimulates lymphangion contraction.
• Guidelines for Treatment of a Patient with Lymphoedema
  • L – Y Lymphoedema bandage is multilayered
  • Manual lymphatic drainage (MLD) or massage
  • Prophylactic antifungal treatment to prevent athlete’s foot
  • Hygiene of skin and foot
  • Advice on diet—weight reduction
  • Treatment of infection—early and aggressive
  • Instructions about exercises
  • Compression garments
  • Surgery consultation as and when required.
  • Remember as LYMPHATICS

2. Care of skin

• Wash daily with warm water
• A moisturiser or liquid paraffin should be applied for dry skin
• Avoid injuries
• Hyperkeratosis should be treated with a keratolytic agent such as 5% salicylic acid.
• Avoid ointments/herbal medicines/soaps, etc., which are allergic.
• Antifungal treatment
• Treat infections early and effectively.

3. Relief of pain

• Pain is multifactorial. It may be due to swelling, infection, involvement of nerve/bone, etc.
• However, it is often psychosomatic and affected by mood and morale.
• Antianxiety drugs may help.

4. Control of infections

• Usually, it is due to streptococci/staphylococci.
• Oral or injectable penicillin and flucloxacillin or clindamycin are the drugs of choice.
• Other drugs are co-amoxiclavulinic acid and cephalosporins.

5. Exercises

• 40% of lymph is formed within skeletal muscle.
• It is directly proportional to central inflow.
• Slow systemic, isotonic movements such as swimming and massage increase venous and lymphatic return.
• Foot-end elevation of the bed.

6. Drugs

• Oxerutins are the drugs used for venous disease. These are not yet licensed in the UK but are used in India.
• They reduce capillary permeability, improve microcirculatory perfusion, stimulate interstitial macrophage proteolysis, and reduce erythrocyte and platelet aggregation.
• Diuretics: 20 mg of furosemide every day or alternate days. This helps in early cases of lymphoedema.
• Antifilarial treatment: Diethylcarbamazine citrate (DEC) 100 mg 3 times or day for 21 days with every attack of lymphangiitis and once in 6 months.
• Warfarin has been used to reduce lymphoedema due to filariasis. It acts by enhancing macrophage activity and extra lymphatic absorption of interstitial fluid.
• Antibiotics are used in cases of cellulitis and lymphangiitis.

Surgery

Surgery Aim: To reduce the limb size.

1. Swiss-roll operation (Thompson’s): A skin flap containing the dermis is raised and buried into the deep tissues (close to the vascular bundle). This is a dermal flap prepared by denuding the epidermis.

2. Charles excision operation: It is indicated in primary lymphoedema. It is performed for extensive swellings and skin changes.

• Thickened and diseased skin and subcutaneous tissue are excised till the healthy underlying structures are seen, followed by split skin grafting.
• The skin has dermal lymphatics which are never involved in filariasis. Thus, the subcutaneous lymph may flow via dermal lymphatics.

3. Nodovenous shunt: Dilated, enlarged inguinal lymph node is anastomosed to a vein nearby, for example. long saphenous vein or femoral vein.

Thus, these are 3 types of surgery commonly done for the filarial leg. There are many other surgeries which are of historical interest.

• However, the results of surgery for the filarial leg are disappointing. Many patients develop intractable ulcers and wetting of the limb due to loss of protein.
• The wound gets secondarily infected resulting in sepsis, recurrent lymphangiitis, etc. As a last resort, many patients beg for amputation to get rid of the ‘useless limb.’ After amputation, the limb can be fitted with a prosthesis.

Surgery Lymphoedema and Chronic Venous Insufficiency (CVI)

• Superficial venous thrombophlebitis (SVT) and deep vein thrombosis (DVT) can lead to lymphatic destruction and secondary lymphoedema. Lymphoedema can also predispose to DVT.
• Some degree of superficial reflux may be present in lymphoedema patients that must be managed conservatively rather than by ‘blunder surgery.’

Hodgkins Lymphoma (Hl)

Hodgkins Lymphoma Definition

It is a malignant neoplasm of the lymphoreticular system. Thus, it can involve the lymph nodes, spleen, and liver.

Risk Factors for Hodgkin’s Lymphoma

• A history of infectious mononucleosis increases the risk of HL two to threefold. Epstein-Barr virus (EBV) may be a causative agent.
• Immunosuppression caused by the drugs increases the risk of HL. The incidence of HL is significantly higher in the HIV-infected population than in the general population. Patients with systemic lupus erythematosus and rheumatoid arthritis on immune suppression and immunosuppression due to organ transplantation have an increased risk of Hodgkin’s lymphoma.
• Genetic or molecular: At least 95% of HL represent monoclonal B cell disorders.

Hodgkins Lymphoma Pathology

• The disease usually starts in one of the lymph nodes as a painless swelling.
• Commonly, it involves the left supraclavicular region. The nodes are enlarged and not matted. It spreads to other nodes in a downstream lymphatic drainage
  (contiguous spread).
• The cut surface of lymph nodes is smooth and homogeneous.
• The axial lymphatic system is almost always affected.
• Microscopy: ‘Cellular pleomorphism’—lymphocytes, histiocytes, eosinophils, and fibrous tissue with ReedSternberg cells, giant cells containing mirror-image nuclei.

Hodgkins Lymphoma WHO Classification/REAL (1994)—Revised European American Lymphoma

1. Lymphocyte predominance, nodular (both Hodgkin’s lymphoma and low-grade B cell lymphomas)

2. Classic Hodgkin’s lymphoma (HL)

• Lymphocyte-rich
• Nodular sclerosis—most common
• Lymphocyte depletion
• Mixed cellularity

However, classical HL and nodular lymphocyte predominant HL—LPHL are now the more practically used classification.

Hodgkin’s lymphoma (HL)

Hodgkins Lymphoma Clinical Features

• Age: Bimodal distribution. The first peak in the 3rd decade and the second peak after 50 years.
• Sex: Increased incidence in males.
• It presents as a generalised lymphadenopathy (more than one group of lymph nodes are significantly enlarged and non-contiguous). Significant lymphadenopathy refers to a lymph node of 2 cm size in the groin, 1 cm size in nodes in the neck or axilla, firm to hard in consistency, palpable left supraclavicular node of any size.
• The disease starts in the left posterior triangle as a group of lymph nodes with a ‘bunch of grapes’ appearance. This is seen in about 80% of cases.
• The nodes are firm (India rubber consistency) without matting. In advanced cases and in poorly differentiated variety, matting can occur.

By means of contiguous and centripetal spread, other lymph nodes in the neck, axillary, mediastinal, paraaortic and inguinal lymph nodes get enlarged.

Abdominal pain can occur due to hepatosplenomegaly. The enlarged liver and spleen are smooth and firm with round borders.

• Para-aortic nodes are felt in the umbilical region, more so on the left side. Its clinical features are:
  • Nodular, firm to hard mass, fixed mass
  • Does not move with respiration
  • Being retroperitoneal, the mass does not fall forward on the knee-elbow position
  • Pulsations may be felt over the mass (transmission from aorta)
• Alcohol-induced pain in the involved lymph nodes is a rare symptom.
• Para-aortic Node Enlargement Common Causes
  • Lymphoma
  • Testicular tumours
  • Malignant melanoma
  • Gastrointestinal malignancy
• There may be ascites.
• Intermittent fever (irregular) is sometimes seen. Skin rashes are rare in Hodgkin’s lymphoma. Severe pruritus without obvious skin lesions on clinical examination may suggest occult Hodgkin’s lymphoma. They may not respond to topical and systemic agents and can be an early clue to the presence of clinically occult HL23.
• Multiple bony pains may occur due to secondary deposits, especially in the lumbar vertebrae. The secondary deposits are usually osteoblastic giving
  rise to ivory vertebrae.
• Superior vena cava obstruction indicates enlarged mediastinal nodes. This is tested by asking the patient to raise the hand above the head. Engorgement of the veins indicates obstruction and the test is said to be positive (Pemberton’s test).

Hodgkins Lymphoma Mediastinal Lymphoma

• It is the most common malignancy in the mediastinum.
• Anterior compartment is most commonly involved (posterior—rare).
• The most commonly used treatment is chemotherapy or radiation.
• The most dramatic response to chemotherapy/radiotherapy with a cure rate of 90% in early Hodgkin’s and 60% in advanced stage.
• Even in patients with mediastinal bulky lymphoma, symptoms of cough, chest pain, dyspnoea or SVC obstruction are not common.
• Mediastinal mass ratio (MMR), defined as the ratio of the maximum transverse diameter of mediastinal mass to the maximum transverse intrathoracic diameter, must be calculated. MMR greater than 0.33 by chest X-ray or 0.35 by CT predicts a worse prognosis.

Hodgkins Lymphoma Staging

Cotswolds revision of the Ann Arbor staging system

Hodgkins Lymphoma Investigations

1. Complete blood count (CBC): Peripheral smear to rule out leukaemia. Anaemia indicates widespread bone marrow metastases.

2. Elevated creatinine and blood urea nitrogen (BUN) indicate ureteral obstruction or direct involvement of kidneys (increased uric acid levels indicate aggressive non-Hodgkin’s lymphoma).

3. Alkaline phosphatase, calcium, and albumin levels. The first two are elevated, whereas albumin and haemoglobin levels are lowered.

4. Uric acid levels: Increased levels indicate tumour burden or activity. It is associated with B symptoms. Also, when the tumour responds to chemotherapy, tumour lysis syndrome develops, and a large amount of uric acid is liberated which may result in obstructive nephropathy.

5. Chest X-ray is taken to rule out mediastinal lymph nodes, mediastinal widening, and or pleural effusion.

6. Abdominal USG: To look for para-aortic nodes, splenomegaly, secondaries in the liver or hepatomegaly.

• However, a CT scan of the abdomen is better.

7. CT scan

• The investigation of choice for staging. CT scans of the chest, abdomen, and pelvis are mandatory. CT of the neck is optional.
• CT to define para-aortic nodes when there is minimal enlargement (≥0.5 cm).
• To calculate MMR (see mediastinal lymphoma).
• To assess renal function and detect back pressure hydronephrosis.

8. PET scan: It is a better investigatory modality today

9. Lymph node biopsy: An incision biopsy is done and a neck node is usually removed. Fine needle aspiration cytology (FNAC) may give the diagnosis but a definite histological pattern cannot be made out by FNAC. A trust biopsy may also give the diagnosis.

10. Mediastinoscopy (Chamberlain procedure) is done if peripheral nodes are not available.

Treatment Of Hodgkins Lymphoma

Chemotherapy has made a great revolution in the treatment of lymphoma. It is given in almost all stages. Radiotherapy is given in early stage 1 cases as involves field therapy protecting the surrounding structures such as the abdomen.

• There are several regimens for the treatment of Hodgkin’s lymphoma. Students are advised to refer to medical oncology books, if necessary.
• However, a few commonly used regimens are given below. Please note: The MOPP regimen is no longer followed because of toxicity.

Treatment Of Hodgkins Lymphoma Regimen 1

ABVD: Adriamycin Bleomycin Vinblastine Doxorubicin. 4 to 6 Cycles have become the standard chemotherapy regimen (details are given below). Doxorubicin 25 mg/ m² 4, days 1 and 5, Bleomycin 10 mg/ m² 4, days 1 and 5, Vinblastine 6 mg/m²  4, days 1 and 5 and Dacarbazine 375 mg/ m² 4, days 1 and 5.

Treatment Of Hodgkins Lymphoma Early Complications of ABVD Regimen

• Adriamycin: Acute cardiac toxicity.
• Bleomycin: Pulmonary toxicity.
• Vinca alkaloids: Nausea, vomiting, tumour, neutropenia, peripheral neuropathy.
• DTIC: Hair loss.

Treatment Of Hodgkins Lymphoma Late Complications of ABVD Regimen

• Life-threatening cardiovascular disease: This is due to mediastinal radiation—pericarditis, cardiomyopathy, cardiac failure.
• Development of second cancer: Acute leukaemia: Incidence is less now as the MOPP regimen is rarely used. Lung cancer, breast cancer, melanoma, soft tissue sarcoma, thyroid cancer—may develop after 30 years.
• Hypothyroidism and hyperthyroidism (Graves’ disease).

Treatment Of Hodgkins Lymphoma Regimen 2

AAVD: Bleomycin is replaced by brentuximab vedotin. AAVD is given every 2 weeks for 6 months. Brentuximab vedotin is an antibody-drug conjugate. Ideally, patients who have CD 30 positive respond well to this drug as it delivers chemotherapy only to these cells.

Treatment Of Hodgkins Lymphoma Regimen 3

BEACOPP: Bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone.

Stagewise Treatment Of Hodgkins Lymphoma

Stagewise Treatment Of Hodgkins Lymphoma Stage 1 and Stage 2

• Chemotherapy is followed by involved site radiotherapy if the disease is favourable. It means the disease is not bulky, the disease is in less than 3 different lymph node sites on one side of the diaphragm without any B symptoms and ESR is not elevated.
• Otherwise, if these criteria mentioned above are present, treatment remains the same with or without the addition of immunotherapy using brentuximab vedotin or nivolumab, etc.
• Consider bone marrow transplant also. Extended mantle field radiotherapy may cause carcinoma of the breast. Pelvic radiotherapy (inverted Y) may cause infertility. Hence, they are not commonly used now.

Stagewise Treatment Of Hodgkins Lymphoma Stage 3 and Stage 4

The treatment remains the same except for radiotherapy. Different varieties of chemotherapy are given not only ABVD but other regimens such as BEACOPP, immunotherapy and stem cell transplant.

Stagewise Treatment Of Hodgkins Lymphoma Complications of Disease (Natural History)

1. Mediastinal disease—pleural effusion, superior vena cava obstruction
2. HL decreases cell-mediated immunity. It causes a depressed CD4+/CD8+ ratio. These patients are vulnerable to opportunistic infections—mycobacteria, herpes zoster, and cytomegalovirus.

• Advanced HL—Independent Prognostic Factors
  • Albumin less than 4 g/dl
  • Lymphocytopaenia <600/mm3
  • Blood Hb less than 10.5 g/dl
  • Under 44 years of age
  • Male sex
  • Involvement of liver, bone (advanced)
  • Neutrophils (WBC) >15,000 cells/mm3, leukocytosis
  • Remember as ALBUMIN

Stagewise Treatment Of Hodgkin’s Lymphoma What is no longer followed in Hodgkin’s Lymphoma?

1. Staging laparotomy: With the availability of CT, ultrasound, and lymphoscintigraphy, all details of intra-abdominal visceral involvement or pathology can be detected.
2. Splenectomy: Spleen is required for immunological functions.
3. Gallium scan: Detection of lymph nodes is done by scintigraphy if required.
4. Bipedal lymphangiogram: Same reasons as mentioned above.
5. Intravenous pyelography: Renal function can be easily assessed by a CT scan.
6. MOPP regimen: Not favoured—because of toxicity
7. Pelvic RT (responsible for infertility): Not favoured.
8. Classification: Ryle’s classification is no longer used.

Non Hodgkins Lymphoma (NHL)

Non Hodgkins Lymphoma Aetiology

1. Age and sex

• Small lymphocytic lymphoma: Elderly patients
• Lymphoblastic lymphoma: Male adolescents and young adults
• Follicular lymphoma: Middle-aged adults
• Burkitt’s lymphoma: Children, young adults

2. Viruses

• RNA viruses: Human immunodeficiency virus (HIV) produces AIDS. These patients may develop high-grade B cell lymphoma.
• DNA viruses: Epstein-Barr viruses (EBV) may produce Burkitt’s lymphoma.

3. Bacteria: H. pylori: Gastric extranodal marginal zone B cell lymphomas of MALT type.

4. Immunodeficiency states and immune disorders: AIDS and organ transplantation treated with immunosuppression. Sjögren’s syndrome, rheumatoid arthritis, systemic lupus erythematosus.

5. Genetic syndromes: Down syndrome and Klinefelter’s syndrome.

6. Inflammatory bowel disease in particular Crohn’s disease and its treatment.

7. Radiation exposure, to atomic bombs and nuclear reactor accidents are at an increased risk of developing NHL after 10–20 years.

Non Hodgkins Lymphoma Classification of Non-Hodgkin’s Lymphoma

1. Low grade
   • Small lymphocytic
   • Follicular, predominantly small cleaved cell
2. Intermediate grade
   • Follicular, predominantly large cell
   • Diffuse, small cleaved cell
   • Diffuse mixed small and large cell
   • Diffuse large cell
3. High grade
   • Large cell immunoblastic
   • Lymphoblastic
   • Burkitt’s or non-Burkitt’s lymphoma

Non Hodgkins Lymphoma Pathological Classification

1. B cell NHL: Small lymphocytic lymphoma, follicular lymphoma, Burkitt’s lymphoma.

• Follicular Lymphomas (FL) or Small Lymphocytic Lymphoma (SLL)
• • Called indolent lymphomas
  • Can be of many years’ duration
  • Present as painless lymphadenopathy
  • Spontaneous regression in 20% of patients
  • Also called waxing and waning adenopathy
  • ‘B’ symptoms are unusual
  • Uncommon before the age of 50
  • Good prognosis
  • Remission duration and survival improvement with ‘rituximab’ (anti-CD20 antibody specific for B lymphocytes)

2. T cell NHL: Cutaneous T cell lymphoma, mycosis fungoides and Sézary syndrome, lymphoblastic lymphoma.

Non Hodgkins Lymphoma Clinical Features

The outer horizontal group of lymph nodes are commonly enlarged.

Comparison of Hodgkin’s and non-Hodgkin’s lymphomas

Non Hodgkins Lymphoma Investigations

• Complete blood count
• Liver function tests including LDH: Increase LDH represents tumour burden
• Creatinine, Calcium
• Ultrasound, CT scan
• Core needle biopsy, lymph node biopsy, bone marrow biopsy
• Immunohistochemistry is required for subclassification. Examples: Small lymphatic lymphoma (CD5+, CD23+), Mantle cell (CD5+, CD23–), etc.

Different Sites Of Lymph Nodes In NHL

Different Sites Of Lymph Nodes In NHL Management of Non-Hodgkin’s Lymphoma

Depends on the Grade of the tumour and the stage of the disease.

• Stages 1 and 2: Low grade—radiotherapy/chemotherapy with CHOP—Cyclophosphamide, Doxorubicin, Oncovin and Prednisone in cases of indolent or low-grade lymphoma. If relapses another regimen is added.
• Stages 1 and 2: Intermediate and high grade—CHOPchemotherapy.
• Stages 3 and 4 and high-grade Rituximab are added. R-CHOP.
• Those who relapse can be treated with Rituximab monotherapy.

Aggressive large B cell lymphomas with CD20-positive cases are treated with R-CHOP.

• Gastric MALT lymphomas may completely regress with therapy against H. pylori with appropriate antibiotics and proton pump inhibitors.
• Anaplastic large cell lymphoma (ALCL): It is treated with immunotoxins: They act as homing devices to deliver the toxins directly to the cancer cells. An example of this is brentuximab vedotin, which contains an antibody to CD30 attached to a cell poison. This has been shown to help treat patients who are unresponsive to chemotherapy

Miscellaneous Burkitt’s Lymphoma (Small Noncleaved Lymphoma)

It is a type of high-grade non-Hodgkin’s lymphoma, first described by Burkitt, affecting the jaw bone (maxilla, mandible).

• It is rare everywhere except in a few places where malarial infestation is heavy.
• It is caused by the Epstein-Barr virus (EBV), which multiplies in the presence of a heavy malarial infestation.

Miscellaneous Types

• Endemic: Parts of Africa and other tropical locations. It is associated with EBV. It affects the jaw and orbit and has a good prognosis.
• Sporadic: Throughout the world. It is not associated with EBV. It affects the abdomen and GI tract, rather than bones, and has a poor prognosis.

Miscellaneous Diagnosis

The biopsy will reveal a typical ‘starry sky’ appearance with primitive lymphoid cells and large clear histiocytes.

Miscellaneous Treatment

• Endemic cases respond well to cyclophosphamide.
• Sporadic cases need to be treated with combination chemotherapy.

Sezarys Syndrome

It is also a type of cutaneous T-cell lymphoma. Here, skin involvement is manifested clinically as a generalised.

• Exfoliative erythroderma along with associated leukaemia of Sézary cells. These cells are characterised by a cerebriform nucleus.
• They are indolent tumours so patients have a good survival time.

Chyluria

It is the most common manifestation of ruptured lymph vessels due to filariasis (others being chylocoele, chylous ascites, and chylothrax).

• It occurs when intestinal lymphatics are obstructed by filarial fibrosis and the lymphatics are diverted to renal lymphatics.
• The dilated and tortuous lymphatics, due to high pressure, rupture into the renal pelvis and ureter, leading to chyluria. Passage of a large amount of chyle leads to a loss of protein and fat, resulting in malnutrition. Such patients are also debilitated with loss of immunity.
• Oral ingestion of fat labelled with Sudan Red 3 turns the urine pink in these cases.
• It is treated by diethylcarbamazine, bed rest, foot end elevation of the bed, and administration of a high-protein diet.