Lymphadenopathy

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222 Lymphadenopathy

Instruction

Perform a general examination.

Examine this patient’s neck.

Salient features

History and examination

Use the mnemonic ALL AGES to approach a patient with lymphadenopathy:

ALL:

Age at presentation (e.g. infectious mononucleosis is commoner in younger age groups, Hodgkin’s disease has a bimodal peak)
Location(s) of enlarged lymph nodes: those outside the inguinal regions, enlarged for >4 weeks and measuring 1 cm2 or larger without an obvious diagnosis should be considered for biopsy (Semin Oncol 1993;20:570–82)
Length of time the lymph nodes are present.

AGES:

Associated symptoms and signs including fever (‘B’ symptoms: temperature >38°C, drenching night sweats, unexplained weight loss >10% body weight)
Generalized lymph node enlargement
Extranodal organ involvement
Splenomegaly: consider infectious mononucleosis, lymphoma, chronic lymphocytic leukaemia, and acute leukaemia; rare in metastatic cancer (Cancer 1987;60:100–2).

• As soon as you feel a group of lymph nodes, examine drainage areas for obvious pathology. For example:

• Inguinal lymph nodes: examine the lower limbs and external genitalia
• Axillary lymph nodes: examine the chest, breasts and upper limbs
• Upper cervical lymph nodes: examine the chest, breast and upper limbs; also, perform an ear, nose and throat (ENT) examination for nasopharyngeal carcinoma
• Lower cervical and supraclavicular lymph nodes: examine the thyroid, chest, abdomen for gastric carcinoma (Virchow’s nodes) and testis.

• Examine other lymph node areas in a systemic manner: submental, submandibular, deep cervical (upper and lower), occipital, posterior triangle, supraclavicular, axillary, epitrochlear and inguinal.

• Examine the mouth for the following signs:

• Tonsillar lymph nodes
• Palatal petechiae and pharyngitis (glandular fever)
• Neoplastic tumours or ulcers.

• Examine the abdomen for liver and spleen.

• Examine the chest and do a chest radiography: for bronchogenic carcinoma, TB.

Diagnosis

This patient has generalized lymphadenopathy, probably a lymphoma— either Hodgkin’s or non-Hodgkin’s (aetiology)—and has severe disease, as evidenced by alopecia, presumably caused by chemotherapy (functional status). I would like to discuss other causes of generalized lymphadenopathy.

Questions

What are the causes of regional lymphadenopathy?

Cervical lymphadenopathy. Causes include infections and malignancies. Infectious causes include bacterial pharyngitis, dental abscess, otitis media, infectious mononucleosis, cytomegalovirus, gonococcal pharyngitis, toxoplasmosis, hepatitis and adenovirus. Malignancies include non-Hodgkin disease, Hodgkin disease and squamous cell carcinoma of head and neck.

Virchow node (anterior left supraclavicular lymph node; also known as Troiser’s ganglion). Enlargement suggests the presence of a thoracic or abdominal neoplasm (Am J Surg 1979;138:703). Common causes include carcinoma of breast, bronchus, lymphomas and GI neoplasms.

Delphian node (a midline prelaryngeal lymph node). Heralds thyroid disease, laryngeal malignancy or lymphoma.

Axillary lymphadenopathy. Causes include infections and malignancies. Infectious causes include staphylococcal, streptococcal infections of the arm, cat-scratch fever, tularaemia and sporotrichosis. Malignant causes, including Hodgkin’s disease, non-Hodgkin lymphoma, carcinoma of breast and melanoma, are common.

Epitrochlear lymphadenopathy. The most common causes are lymphoma/chronic lymphatic leukaemia and infectious mononucleosis. Other diagnoses include HIV, sarcoidosis and connective tissue disorders. In developing countries, secondary syphilis, lepromatous leprosy, leishmaniasis and rubella are important causes.

Inguinal lymphadenopathy. In adults, some degree of lymph node enlargement is not uncommon. In those who walk outdoors with footwear, benign reactive lymphadenopathy is common. Malignant causes include lymphoma, malignant melanoma, carcinoma of external genitalia. Benign causes include cellulitis, syphilis, chancroid, genital herpes and lymphogranuloma venereum.

Node of Cloquet (also known as Rosenmüller node). A deep inguinal lymph node located near the femoral canal. When palpable it may be mistaken for an inguinal hernia.

What are the causes of generalized lymphadenopathy?

• Lymphomas, chronic lymphatic leukaemia, acute lymphoblastic leukaemia

• Glandular fever, cytomegalovirus

• HIV infection, toxoplasmosis

• SLE, rheumatoid arthritis, sarcoid

• Chronic infections such as TB, secondary syphilis, brucellosis

• Drugs: phenytoin.

(Use the mnemonic CHICAGO: cancers, hypersensitivity, infections, connective tissue disorders, atypical lymphoproliferative disorders, granulomatous disorders, other unusual causes.)

What do you understand by the term Hodgkin’s disease?

Hodgkin’s disease is a group of neoplasms characterized by Reed–Sternberg cells in an appropriate reactive cellular background. It is divided into several subtypes histologically: lymphocyte predominance, nodular sclerosis, mixed cellularity and lymphocyte depletion. The Reed–Sternberg cell is a giant cell with two or more nuclear lobes and huge eosinophilic inclusion like nucleoli. The classic Reed–Sternberg cell has a symmetrical, mirror image nucleus that creates an ‘owl-eye’ appearance.

Advanced-level questions

What is the cause of egg-shaped calcification in hilar lymph nodes?

Silicosis.

What do you know of Sister Joseph’s nodule?

It is a classic sign of gastric adenocarcinoma i n the umbilical area and may represent a metastatic deposit or an enlarged anterior abdominal wall lymph node (Fig. 222.1).

image

Fig. 222.1 Sister Joseph’s nodule.

(With permission from Leow, Lau 2008.)

What is the mode of presentation of Hodgkin’s disease?

• Usually as a painless lymphadenopathy

• Other presenting symptoms include systemic symptoms such as fever, weight loss, drenching night sweats, generalized pruritus or pain in the affected lymph node following the ingestion of alcohol.

How is Hodgkin’s disease staged?

The staging system has four stages (I–IV) plus a system of letters to indicate symptoms, bulk, lymph node involvement.

Stage I: one lymph node region involved

Stage II: more than two lymph node regions involved on one side of the diaphragm

Stage III: lymph nodes involved on both sides of the diaphragm

3.1 with splenic hilar, coeliac or portal nodes
3.2 with para-aortic, iliac or mesenteric nodes

Stage IV: involvement of extranodal sites(s) beyond that designated as ‘E’ below.

Systemic symptoms:

A: absent

B: significant weight loss >10% in six months, fever or night sweats.

Disease bulk and spread:

X: bulky disease: greater than a third widening of mediastinum, >10 cm maximum diameter of nodal mass

E: involvement of single, contiguous or proximal extranodal site.

Clinical stage (CS) is determined by history, physical examination, radiological studies, isotope scans, laboratory tests of urine and blood, and the initial biopsy results.

Pathological stage (PS) relates to the tissue sampled and the results of histopathological examination.

How is a patient with Hodgkin’s disease treated?

• Localized disease (i.e. stages IA, IIA) is treated with radiotherapy. Five-year cure rates are in excess of 80% and relapses are treated with chemotherapy.

• Disseminated disease (stages IIIB, IV) is treated with combination chemotherapy with the ABVD regimen (adriamycin, bleomycin, vincristine, dacarbazine) alternating with the MOPP regimen (mechlorethamine, oncovin, procarbazine and prednisolone). Five-year survival rates are about 50%. Patients who relapse after initial chemotherapy may be cured with autologous bone marrow transplantation.

• In stages IIB and IIIA, optimal management is controversial but current evidence suggests an advantage to combination chemotherapy (N Engl J Med 1993;328:560).

What do you understand by the term non-Hodgkin’s lymphomas?

These are a heterogeneous group of cancers of lymphocytes. They are variable in their presentation and natural history, varying from a slow indolent course to a rapidly progressive illness (N Engl J Med 1993;328:1023).

How are non-Hodgkin’s lymphomas classified?

A working classification is as follows.

Low grade or favourable. There is a slow, indolent course with good response to minimal therapy and long survival. These include small lymphocytic, plasmocytoid, follicular small cleaved cell and follicular mixed cell. Patients are usually treated with alkylating agents such as chlorambucil or a CVP regimen (cyclophosphamide, vincristine and prednisolone).

High grade or unfavourable. This includes immunoblastic, small non-cleaved (Burkitt’s and non-Burkitt’s), lymphoblastic and true histiocytic lymphoma. The mainstay of therapy is combination chemotherapy; traditionally the CHOP regimen (cyclophosphamide, doxorubicin, vincristine and prednisolone) is used. In highly aggressive lymphomas, autologous bone marrow transplantation may increase the chances of cure.

Intermediate grade. Follicular large cell, diffuse small cleaved cell, diffuse mixed cell, diffuse large cell.

Others. Cutaneous T cell (mycosis fungoides, adult T cell leukaemia/lymphoma).

What symptoms of Non-Hodgkins’s lymphoma merit urgent referral to an oncologist?

Symptoms of non-Hodgkin lymphoma needing urgent referral include (Lancet 2003; 362:139–46):

• lymphadenopathy (>1 cm persisting for 6 weeks)

• hepatosplenomegaly

• three or more of the following symptoms:

• Fatigue
• Night sweats
• Weight loss
• Itching
• Breathlessness
• Bruising
• Recurrent infection
• Bone pain.

What are the risk factors in localized Hodgkins’ lymphoma?

European Organisation for the Research Treatment of Cancer risk factors in localized disease (Lancet 2003; 361:943–51):

• Favourable: patients must have all features:

• Clinical stage 1 and 2
• Maximum of three nodal areas involved
• Age younger than 50 years
• ESR <50 mm/h without B symptoms or ESR <30 mm/h with B symptoms
• Mediastinal/thoracic ratio <0.35

• Unfavourable: patients have any features:

• Clinical stage 2 with involvement of at least four nodal areas
• Age >50 years
• ESR >50 mm/h if asymptomatic or ESR >30 mm/h if B symptoms
• Mediastinal/thoracic ratio >0.35.

What are the poor prognostic factors of advanced Hodgkin’s lymphoma?

Hasenclever index is an international prognostic score including the following seven factors:

• Age >45 years

• Male sex

• Serum albumin <40 g/l

• Haemoglobin concentration <105 g/l

• Stage IV disease

• Leukocytosis (white cell count greater than or equal to 15_109/l

• Lymphopenia (<0·6 × 109/l or <8% of the total white-cell count).

These factors individually reduced predicted 5-year freedom from progression rate by around 8% (Lancet 2003; 361:943–51).

What are the late effects of Hodgkin’s lymphoma and its treatment?

• Second malignancies

• Cardiac disease

• Endocrine dysfunction

• Psychological trauma

• Lung damage (usually subclinical)

• Hyposplenism (after splenectomy or splenic irradiation)

• Dental caries.

(See Lancet 2003; 361:943–51.)

What are the investigations done before initiation of treatment on non-Hodgkins’s lymphoma?

Essential procedures (Lancet 2003; 362:139–46):

• A full history, recording growth rate, symptoms present, performance status

• A detailed physical examination, with special attention to all node-bearing areas including Waldeyer’s ring

• Adequate surgical biopsy specimen, allowing immunophenotyping and examined by a skilled pathologist

• Laboratory procedures:

• FBC, including ESR
• Serum lactate dehydrogenase, calcium, uric acid, proteins and electrophoresis, alkaline phosphatase
• Assessment of renal and liver function

• Radiological studies:

• Chest radiograph
• Thoracic and abdominal-pelvic CT scan.

• Bone marrow aspirate and trephine, to include molecular genetic analysis if available.

Optional procedures, depending on clinical picture:

• β2-microglobulin

• Endoscopy, e.g. for gastric MALT lymphoma

• Plain radiographs, bone scan or MRI

• Positron electron tomography (PET)

• Head or spinal MRI for neurological symptoms

• CSF analysis in patients at risk.

Thomas Hodgkin (1798–1866), an English physician at St Thomas’s Hospital, London. He was the Curator of the Pathology Museum at Guy’s Hospital before this.

RLK Virchow (1821–1902), successively Professor of Pathology at Würzberg and Berlin. He also described Virchow cell (lepra cell), Virchow space (perivascular space of Virchow–Robin) and Virchow triad of the pathogenesis of thrombosis.

Dorothy Reed (1874–1964) graduated from Johns Hopkins Hospital, Baltimore, and worked successively in New York and Wisconsin.

K Sternberg (1872–1935), an Austrian pathologist who described the cells in 1898. Burkitt’s lymphoma was described by Dennis Burkitt in children in West Africa who presented with a lesion in the jaw, extranodal abdominal involvement and ovarian tumours. Most patients have Epstein–Barr antibodies in the serum.

The disease was first described in China in 1937 by Kim and Szeto but became more widely known as Kimura disease after a description in 1948 by Kimura and co-workers.

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