The 6-week rule for unexplained lymphadenopathy is the most important clinical decision rule in primary care — lymph nodes that are still enlarged at 6 weeks without an identified benign cause have a significantly increased probability of malignancy and require investigation (FBC, blood film, LDH, ESR, urate) and/or referral. This applies even if the node is not hard or fixed — early lymphoma can present with soft, non-tender nodes that resemble reactive lymphadenopathy. Studies of unexplained lymphadenopathy in primary care show that approximately 1% of cases referred to haematology/oncology prove to have lymphoma, but the consequences of missing this diagnosis are severe. Virchow's node (left supraclavicular fossa) is one of the most clinically important examination findings in medicine — it receives lymphatic drainage from abdominal organs via the thoracic duct (which empties into the left subclavian vein). A palpable left supraclavicular node in an adult should trigger urgent investigation for GI malignancy (gastric cancer is the classic association — described by Troisier in 1886). It can also reflect thoracic malignancy (lung cancer, lymphoma). Any supraclavicular node warrants CXR + abdominal USS + FBC as a minimum immediately, followed by appropriate cancer referral. Primary HIV seroconversion is one of the most commonly missed diagnoses in general practice — the mononucleosis-like illness (fever, sore throat, lymphadenopathy, rash, malaise) is indistinguishable clinically from EBV or CMV. Testing for HIV must be offered proactively at the time of this presentation in any patient with risk factors — the seroconversion window is short, viral load is extremely high, and transmission risk is maximal during this period.

The distinction between reactive (tender, soft, mobile) and malignant (non-tender, firm/rubbery/hard, fixed, progressive) lymphadenopathy is the most clinically useful bedside distinction — but it has significant limitations. Lymphoma nodes are classically described as "rubbery" (the texture of an eraser) and non-tender. However, Hodgkin's lymphoma nodes can be tender (especially after alcohol intake — Hodgkin's-associated alcohol-induced pain is a rare but pathognomonic symptom), and reactive nodes in a thin patient can feel surprisingly firm. The key principle is that no single characteristic is diagnostic — it is the combination of features (consistency + mobility + tenderness + duration + patient age + associated symptoms) that determines the clinical probability. The alcohol-induced pain in Hodgkin's lymphoma (pain in affected lymph node regions within minutes of drinking alcohol) is one of medicine's most specific symptoms — it is virtually pathognomonic of Hodgkin's lymphoma and should always be asked about when taking the history. The mechanism is thought to involve eosinophil infiltration in Hodgkin's tumour tissue and prostaglandin release triggered by alcohol. Drug-induced pseudolymphoma (phenytoin being the classic example) can cause widespread lymphadenopathy indistinguishable from lymphoma — always perform a thorough medication review in generalised lymphadenopathy. Stopping the offending drug results in resolution within weeks.

The axillary lymph node in women deserves specific attention — it is a key site for breast cancer sentinel node involvement, and any unilateral axillary lymphadenopathy in a woman without a clear infective cause (no ipsilateral arm or hand infection) warrants urgent breast examination and USS/mammography. Breast cancer presenting as an isolated axillary node without a palpable breast mass (occult primary breast cancer) accounts for approximately 0.3% of all breast cancers but has a reasonable prognosis with appropriate treatment — it should not be delayed. The NICE NG12 (Suspected Cancer) guidelines recommend 2WW breast assessment for any new unilateral axillary node in a woman aged ≥30 without an identifiable infective cause. Inguinal lymphadenopathy requires a full STI risk assessment and a lower limb examination — many GPs examine the groin without examining the feet, missing the infected toe, tinea pedis, or plantar wart that is draining to the inguinal chain. The most common cause of bilateral inguinal lymphadenopathy is reactive nodes from lower limb skin conditions (eczema, psoriasis, chronic tinea) — but unilateral, progressive, or hard inguinal nodes need STI testing and malignancy exclusion. LGV (lymphogranuloma venereum — Chlamydia trachomatis serovars L1–L3) causes massively enlarged, tender, matted inguinal nodes (buboes) — it is increasing in frequency in the UK, particularly in MSM, and requires doxycycline 100 mg BD × 21 days (longer course than standard chlamydia treatment).

The blood film is one of the most diagnostically rich investigations available in primary care for lymphadenopathy — it should be specifically requested alongside the FBC (not assumed to be automatically performed). A haematologist reviewing the film can identify: atypical lymphocytes (EBV, CMV, drug reaction), smear cells / CLL cells (chronic lymphocytic leukaemia — CLL is the most common leukaemia in the UK and typically presents with bilateral cervical and axillary lymphadenopathy in patients over 60), lymphoblasts (acute lymphoblastic leukaemia — paediatric emergency), Reed-Sternberg cells (rarely seen on a film in Hodgkin's — diagnosis requires lymph node biopsy), and the monocytosis of CMV. LDH (lactate dehydrogenase) is the most important biochemical marker of lymphoma — it reflects tumour bulk and cellular turnover. An elevated LDH in a patient with lymphadenopathy is a key indicator that haematological malignancy needs urgent evaluation. The International Prognostic Index (IPI) for lymphoma includes LDH as one of its five prognostic factors. The Monospot test (Paul-Bunnell heterophile antibody test) is positive in 80–90% of EBV infectious mononucleosis cases but may be negative in the first week and in young children — if clinical suspicion is high, request EBV-specific serology (VCA IgM — acute infection; VCA IgG + EBNA — past infection).

The 6-week watch-and-wait period for cervical lymphadenopathy in adults is often cited but is increasingly being challenged in clinical practice — NICE NG12 specifies 3 weeks for head and neck 2WW referral in patients ≥40 with unexplained cervical lymphadenopathy. The 6-week period is appropriate for younger patients with clear reactive/infective features where spontaneous resolution is expected, but in patients aged ≥40 (higher prior probability of malignancy), ≥50 (smoking or alcohol history), or with any concerning features (hardness, fixation, progressive growth), 3 weeks is the appropriate threshold. The practical management is: at the first consultation, if features are clearly reactive (tender, soft, associated URTI, young patient) → watchful waiting with review at 4–6 weeks and blood tests. At the review — if not resolving → FBC + LDH + ESR + monospot + HIV test + USS, and 2WW referral if still unexplained. If any concerning features at first presentation (hard, fixed, non-tender, patient ≥40, B symptoms) → investigate and refer at the same visit. Lymph node biopsy (excision biopsy or core needle biopsy) is always performed by the specialist — it should never be attempted in primary care. The approach to biopsy is: USS-guided core needle biopsy first for accessible nodes (avoids general anaesthesia), proceeding to excision biopsy if core biopsy is non-diagnostic or insufficient tissue. Fine-needle aspiration (FNA) cytology alone is insufficient for lymphoma diagnosis — it cannot provide the architectural information needed for classification.

The amoxicillin rash in EBV is one of the most important drug-disease interactions in primary care — if a patient with EBV infectious mononucleosis (or any active herpesvirus infection) is given amoxicillin or ampicillin, they develop a widespread maculopapular rash in 80–100% of cases. This rash is not a true penicillin allergy — it is a T-cell mediated reaction specific to the combination of the aminopenicillin and the EBV-altered immune state. Patients who have this reaction are NOT penicillin-allergic and should not be labelled as such in their records. The rash typically appears 5–10 days after starting amoxicillin. This matters because many patients with EBV present with a very sore throat — GPs must resist prescribing amoxicillin for the pharyngitis component without first excluding EBV (Monospot test in clinical practice — accepting the false negative rate in the first week). If antibiotics are genuinely needed for concurrent bacterial tonsillitis in EBV, use phenoxymethylpenicillin (penicillin V) rather than amoxicillin. Contact sport restriction in EBV splenomegaly is evidence-based — the spleen is enlarged in approximately 50% of EBV cases, and splenic rupture (spontaneous or traumatic) is the most dangerous acute complication, with mortality of approximately 1%. The restriction should be for 4–6 weeks after symptom onset, or until USS confirms normal spleen size. This is particularly important for young athletes and must be documented in the clinical records.

Drug-induced pseudolymphoma from phenytoin is historically important and clinically relevant — patients on long-term phenytoin can develop widespread lymphadenopathy, fever, skin rash, and even hepatosplenomegaly that is histologically indistinguishable from lymphoma on biopsy (follicular hyperplasia). The key feature that distinguishes pseudolymphoma from true lymphoma is complete resolution on drug cessation. Confusingly, there is a well-documented association between phenytoin use and an increased incidence of true Hodgkin's and non-Hodgkin's lymphoma — so any patient who develops lymphadenopathy while on phenytoin requires the drug to be stopped AND lymphoma to be excluded if the lymphadenopathy does not resolve. Sarcoidosis with bilateral hilar lymphadenopathy warrants a brief explanation for trainees: the bilateral hilar pattern on CXR is symmetric, with node enlargement at the hilum (where the bronchi and pulmonary vessels enter the lung) bilaterally. It must be distinguished from: unilateral hilar (lung cancer, more common on the right), lymphoma hilar (often asymmetric + mediastinal involvement), and TB hilar (usually with paratracheal involvement and calcification in old disease). The classic sarcoidosis presentation (Lofgren's syndrome) in a young woman with erythema nodosum and ankle arthritis has a 95% specificity for sarcoidosis — tissue biopsy is not required when this clinical triad is present.

Post-EBV fatigue (post-viral fatigue syndrome following infectious mononucleosis) affects approximately 10–15% of patients at 6 months and 5% at 12 months — it is the most common cause of prolonged fatigue in young adults and is one of the proposed triggers of ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome) in genetically susceptible individuals. NICE NG206 (ME/CFS, 2021) guidance applies to post-viral fatigue states — the previous advice to "gradually increase exercise" (graded exercise therapy) has been removed from NICE guidance, replaced by an energy management approach (pacing, avoiding post-exertional malaise). GPs should not advise patients with post-EBV fatigue to push through tiredness or increase activity beyond their energy envelope. The anxiety associated with unexplained lymphadenopathy waiting for biopsy results is clinically significant — studies show that the period between GP referral and biopsy result is associated with high rates of anxiety, depression, and impact on work and relationships. Setting a clear, specific communication plan at the time of referral ("I'll ring you personally with the result" or "the results clinic is on [date]") significantly reduces anxiety and improves the doctor-patient relationship. This is an RCGP SCA-assessed communication competency — the ability to explain investigation plans, timescales, and safety-net while managing uncertainty is a core GP competency.

Febrile neutropenia in lymphoma chemotherapy patients is one of the most important emergencies that GPs will encounter in patients with haematological malignancy. The standard definition is: temperature ≥38°C AND neutrophil count <1.0 × 10⁹/L (or expected to be, given chemotherapy timing). Febrile neutropenia is a medical emergency with a mortality of 5–10% even with treatment — patients must call the haematology 24-hour hotline number or attend A&E for IV antibiotics (typically piperacillin-tazobactam 4.5 g IV) within 1 hour of temperature onset, not the GP. Every patient commencing lymphoma chemotherapy should receive a "chemotherapy alert card" — GPs should ensure this is in the patient's records and that the practice knows to advise the patient to call 999 or the haematology hotline for any temperature ≥38°C. CLL watchful waiting monitoring is a significant primary care responsibility — many patients with Stage A CLL are monitored entirely in primary care (after diagnosis and initial staging). The key parameters to monitor are: lymphocyte count trajectory (doubling time <6 months = progression = haematology referral), haemoglobin and platelet count (autoimmune cytopenias common in CLL), lymph node size, and constitutional symptoms. Regular FBC every 3 months with comparison to baseline is the surveillance tool.