Undifferentiated Lymphadenopathy — Clinical Case

DCE Long Case

Patient brief (provided to trainee)

Patient: Mr David Okafor, 58 years old, taxi driver, born in Nigeria, migrated to Australia 10 years ago. [1]

Presenting complaint: Six-week history of a painless lump in the left supraclavicular fossa. Three months of drenching night sweats that soak the sheets. A 6 kg unintentional weight loss (from 82 to 76 kg). Early satiety for two months. [1]

Past history: Hypertension (on amlodipine 10 mg daily). Gastro-oesophageal reflux (on pantoprazole 40 mg daily). No prior surgery. No prior malignancy. No allergies. Never smoked. Drinks 4 standard drinks a week. Works long hours as a taxi driver, has not seen a doctor in three years. [1]

Examination findings (trainee elicits):

• Thin but comfortable. No pallor, no jaundice, no bruising, no skin lesions.
• Left supraclavicular fossa: 2 cm rubbery, mobile, non-tender node.
• Right supraclavicular fossa: 1.5 cm rubbery, mobile, non-tender node.
• Axillae: shotty nodes bilaterally, no dominant node.
• Epitrochlear: no palpable nodes.
• Inguinal: small, mobile, non-tender nodes bilaterally (less than 1 cm).
• Abdomen: liver edge palpable 3 cm below the costal margin, spleen palpable 2 cm. No ascites. No masses.
• Oral cavity: no lesion. No oropharyngeal mass.
• Skin: no rash, no melanoma, no suspicious lesion on the scalp, head, neck or trunk.
• Testes: normal.
• Chest: clear. No stridor.
• Observations: temperature 37.6, heart rate 88 regular, blood pressure 138/86, respiratory rate 16, SpO2 98 per cent on room air. [1]

Investigations (available results):

• Haemoglobin 118, white cell count 9.2 (normal differential), platelets 210, ESR 68, CRP 42, LDH 520 (normal less than 250), albumin 32. U&E and LFTs otherwise normal.
• Blood film: normocytic normochromic anaemia, no blasts, no atypical lymphocytes.
• EBV serology: VCA IgG positive, VCA IgM negative, EBNA IgG positive (consistent with remote infection).
• HIV fourth-generation antigen-antibody test: negative.
• IGRA (QuantiFERON-TB Gold): positive.
• Chest X-ray: widened mediastinum.
• CT of the neck, chest, abdomen and pelvis: enlarged supraclavicular (bilateral), mediastinal, para-aortic and iliac nodes, with the largest node measuring 3.5 cm in the mediastinum. No definite lung lesion. No definite intra-abdominal mass. Liver and spleen enlarged. [1]

Drug chart (current): amlodipine 10 mg daily, pantoprazole 40 mg daily. [1]

Candidate's structured presentation (model)

Opening statement (SASPOP): [1]

"Mr Okafor is a 58-year-old Nigerian-born taxi driver presenting with a six-week history of a painless left supraclavicular node, three months of drenching night sweats, a 6 kg weight loss and early satiety. His main problems are: first, a generalised lymphadenopathy with supraclavicular, mediastinal, para-aortic and iliac nodes on the CT, with B symptoms and a raised LDH — the leading diagnosis is lymphoma, with the differential of disseminated tuberculosis given the positive IGRA and his country of origin, and metastatic carcinoma from an intra-abdominal primary given the left supraclavicular node; second, the hepatosplenomegaly, consistent with a systemic haematological or infiltrative process; third, the positive IGRA, indicating a latent tuberculosis that must be managed before any immunosuppressive therapy; and fourth, the constitutional decline. My immediate priority is a tissue diagnosis — the next step is an excisional biopsy of the most accessible abnormal node, with the tissue sent fresh for the histology, the immunohistochemistry, the flow cytometry and the molecular studies, and I would not give corticosteroids at any point before the biopsy. I would investigate for tuberculosis in parallel. I would stage the disease with a PET-CT after the histology, per the Lugano classification." [1]

Management plan: [1]

1. Excisional biopsy of the most accessible abnormal node — the supraclavicular node is the most accessible; the tissue is sent fresh for the histology, the immunohistochemistry, the flow cytometry and the molecular studies. The biopsy is the priority and is performed within days. No corticosteroids before the biopsy.
2. Tuberculosis work-up in parallel — three sputum samples for the acid-fast bacilli stain, the culture and the PCR; the node is sent for the same stains and cultures at the time of the biopsy. The latent TB treatment (the rifampicin for 4 months or the isoniazid for 6 to 9 months per the local guideline) is planned after the active TB is excluded and before any immunosuppressive or cytotoxic therapy.
3. PET-CT for staging after the histology, per the Lugano classification [5]. The routine bone marrow biopsy is not required if the PET-CT shows no marrow involvement and the diagnosis is Hodgkin lymphoma or diffuse large B-cell lymphoma.
4. Prognostication with the R-IPI if the diagnosis is diffuse large B-cell lymphoma [4].
5. Multidisciplinary review — the haematology and the infectious diseases teams are involved from the biopsy stage.
6. Supportive care — the nutrition, the analgesia, the psychological support, the fertility preservation (the sperm banking before the chemotherapy).
7. Communication — the honest discussion of a possible cancer diagnosis with the patient and the family, with the interpreter if needed.

Communication and shared decision-making: Explain to Mr Okafor that the node is concerning because of its location (the supraclavicular fossa) and the accompanying symptoms (the night sweats and the weight loss), and that the next step is a tissue diagnosis. Explain that the biopsy is the priority, that the answer will follow the biopsy, and that I cannot tell him with certainty whether this is cancer or inflammation until the biopsy. Surface the possibility of a cancer diagnosis early, and offer the interpreter and the family support. Address the latent TB as a separate comorbidity that will be managed alongside whatever the biopsy shows. [1]

Examiner discussion questions

Q1: "Walk me through your interpretation of his red-flag screen and how it drives the biopsy decision." [1]

"Mr Okafor has five red-flag features, any one of which would mandate biopsy [1]. First, a supraclavicular node — the single highest-risk location, with a malignancy probability of 30 to 90 per cent across series; any supraclavicular node of any size in an adult is a red flag. Second, the B symptoms — the drenching night sweats and the unintentional weight loss are the B-symptom triad of lymphoma. Third, a raised LDH — the non-specific tumour marker of lymphoma. Fourth, a node above 2 cm. Fifth, the hepatosplenomegaly. The supraclavicular node alone mandates biopsy, and the observation window that is reasonable for a low-risk localised cervical node in a young patient with a viral illness does not apply. The supraclavicular node carries the highest priority for the urgent suspected-cancer referral per the NICE NG12 pathway. The teaching point is that the red-flag screen is the discriminator between the node that is biopsied and the node that is observed, and Mr Okafor is firmly in the biopsy limb."

Q2: "Why an excisional biopsy rather than a fine-needle aspiration?" [1]

"The FNA samples cells, not architecture, and it is inadequate for the primary diagnosis of lymphoma. The excisional biopsy preserves the nodal architecture and provides ample tissue for the immunohistochemistry, the flow cytometry and the molecular studies that sub-classify the lymphoma and direct therapy [5]. An FNA might identify 'atypical lymphoid cells,' but it cannot distinguish the Hodgkin from the non-Hodgkin lymphoma, it cannot distinguish the diffuse large B-cell from the follicular, and it cannot provide the cell-of-origin or the translocation status. The principle is that the choice of biopsy is matched to the leading diagnosis: the excisional biopsy for the suspected lymphoma, the FNA for the suspected metastatic carcinoma or the infective node. Mr Okafor's leading diagnosis is lymphoma, and the excisional biopsy is the gold standard."

Q3: "He has a positive IGRA. How does that change your management?" [1]

"The positive IGRA indicates a latent tuberculosis infection, common in a man born in a high-prevalence country. It raises two issues. First, I must exclude active tuberculosis before I consider any immunosuppressive or cytotoxic therapy — the immunochemotherapy that will follow a lymphoma diagnosis would reactivate a latent TB, and the TB itself is in the differential of the lymphadenopathy. I send three sputum samples for the acid-fast bacilli and the PCR, and the node is sent for the AFB stain, the culture and the PCR. Second, I will treat the latent TB after the active TB is excluded and before or during the lymphoma therapy, in consultation with the infectious diseases team. The latent TB is not the explanation for the B symptoms or the LDH — those are more consistent with the lymphoma — but it is a comorbidity that must be managed to prevent the reactivation." [1]

Q4: "Could this be metastatic gastric cancer? He has a left supraclavicular node." [1]

"Yes, it is in the differential. The left supraclavicular node — the Virchow node — drains the abdominal cavity via the thoracic duct, and it classically signals a gastric, pancreatic, hepatic, renal or testicular primary. The early satiety and the weight loss raise the gastric cancer possibility. However, the picture overall is more consistent with a lymphoma: the generalised lymphadenopathy (the supraclavicular, the mediastinal, the para-aortic, the iliac nodes), the hepatosplenomegaly, and the raised LDH. A gastric cancer would more typically give a single dominant left supraclavicular node with the intra-abdominal primary. I would request an upper endoscopy if the histology of the node is metastatic adenocarcinoma — but I expect the histology to show lymphoma, and the endoscopy is not the first step. The histology directs the search for the primary — I do not speculate before the biopsy, because the biopsy answers the question." [1]

Q5: "How would you stage and prognosticate him after the histology?" [1]

"I would stage with a PET-CT, per the Lugano classification [5]. The PET-CT is the standard for the staging and the response assessment of the FDG-avid lymphomas. The Ann Arbor staging (I to IV) provides the anatomical framework. The routine bone marrow biopsy is no longer indicated if the PET-CT shows no marrow involvement and the diagnosis is Hodgkin lymphoma or diffuse large B-cell lymphoma. I would prognosticate with the revised International Prognostic Index if the diagnosis is diffuse large B-cell lymphoma — the R-IPI uses the age over 60, the stage III or IV, the more than one extranodal site, the performance status 2 to 4, and the elevated LDH, and it stratifies the outcome into the very good, the good and the poor risk groups [4]. Mr Okafor has the elevated LDH and the likely stage IV, placing him in the good or the poor R-IPI group depending on his performance status."

Q6: "What is the single most important lesson from this case for a registrar managing undifferentiated lymphadenopathy?" [1]

"The single most important lesson is that the biopsy is the priority, and the choice of biopsy matters. Mr Okafor has a supraclavicular node with B symptoms and a raised LDH — the leading diagnosis is lymphoma, and the next step is an excisional biopsy, not an observation period and not an FNA. The registrar who observes a supraclavicular node, or who accepts an FNA diagnosis, or who gives corticosteroids before the biopsy, has lost time and compromised the diagnostic tissue. The corollary is the parallel work-up — the tuberculosis is in the differential, and the latent TB is a comorbidity that must be managed before the immunosuppressive therapy. The integrated approach — the red-flag screen, the correct biopsy, the parallel work-up of the differential, the staging per the Lugano classification, and the prognostication per the R-IPI — is what keeps the complex lymphadenopathy patient safe and gets the diagnosis right the first time." [1]

DCE Short Case — The Systematic Lymph Node Examination

Instruction

"You are the medical registrar assessing a 24-year-old woman in the outpatient clinic with a three-week history of a painful lump in the right side of the neck and low-grade fever. Examine her lymph nodes, present your findings, and offer a differential diagnosis. You have 5 minutes to outline your examination approach and 5 minutes for discussion." [1]

Provided data: The patient is a 24-year-old woman, previously well, with a three-week history of a painful right-sided neck lump and fatigue. On examination: a 2 cm tender, mobile node in the right posterior cervical triangle, with no other lymphadenopathy, no hepatosplenomegaly and no oropharyngeal lesion. Full blood count shows atypical lymphocytes. The monospot is negative. EBV serology shows past immunity. [1]

Presentation template

"I have examined all the peripheral lymph node groups. The significant finding is a 2 cm tender, mobile node in the right posterior cervical triangle, with no other lymphadenopathy. The epitrochlear, the axillary, the intraclavicular, the inguinal and the popliteal nodes are not enlarged. The abdomen reveals no hepatosplenomegaly. The oral cavity and the oropharynx are normal. The skin of the head, neck and scalp is normal. My findings are consistent with a localised painful cervical lymphadenopathy in a young woman with a negative monospot and a self-limited course, and my leading differential is Kikuchi-Fujimoto disease (the histiocytic necrotising lymphadenitis), with the differential of lymphoma (especially Hodgkin lymphoma, which can be painful if it is enlarging rapidly), toxoplasma lymphadenitis, and cat-scratch disease. The next step is an excisional biopsy of the node to distinguish the Kikuchi-Fujimoto disease from the lymphoma, because the clinical picture alone cannot make the distinction." [1]

Discussion

Examiner: "What is your differential diagnosis, and how would you discriminate?" [1]

"My leading diagnosis is Kikuchi-Fujimoto disease — the painful cervical lymphadenopathy in the young woman, the negative monospot and the self-limited course are the classic presentation, and the histology (the paracortical necrosis with the karyorrhectic debris and the crescentic histiocytes, without the neutrophils) is diagnostic. The differential within the painful cervical lymphadenopathy includes: Hodgkin lymphoma, which is classically a painless, rubbery node but can be tender if it is enlarging rapidly; toxoplasma lymphadenitis, which gives a painless cervical node and a positive IgM; cat-scratch disease, which gives a regional lymphadenitis 1 to 3 weeks after a cat scratch, with a papule at the inoculation site; and the acute bacterial lymphadenitis, which gives a more acutely inflamed, warm, erythematous node, often with an overlying skin infection. The discrimination is histological — the excisional biopsy distinguishes the Kikuchi-Fujimoto disease from the lymphoma, and the serology (the toxoplasma IgM, the Bartonella serology) distinguishes the infective causes. The teaching point is that the Kikuchi-Fujimoto disease is self-limiting and the steroids are not first-line, and the diagnosis avoids the unnecessary chemotherapy of a misdiagnosed lymphoma. The disease is associated with the systemic lupus erythematosus, and the patient should be screened for the evolving SLE." [1]

Examiner: "Why do you examine all node groups when she has only a right-sided neck lump?" [1]

"Because the classification of the lymphadenopathy as localised or generalised depends on the complete examination. The patient with a single dominant right-sided neck node who also has an enlarged left supraclavicular node, an epitrochlear node or para-aortic nodes on the CT has a generalised lymphadenopathy that shifts the differential from a regional reactive node to a systemic process. The registrar who examines only the node the patient noticed has examined only a fraction of the patient, and may misclassify a generalised lymphadenopathy as localised, with a consequent under-investigation. The systematic examination of all node groups — the occipital, the pre- and post-auricular, the submental and submandibular, the anterior and posterior triangles, the supraclavicular fossae (from behind, with the head flexed), the axillae (arm supported, all five groups), the epitrochlear nodes, the intraclavicular nodes, the inguinal nodes (horizontal and vertical groups), and the popliteal fossae — is the standard that prevents this error. The extension to the primary drainage sites (the skin, the oral cavity, the thyroid, the breast) and the systemic signs (the abdomen for hepatosplenomegaly, the skin for rashes) completes the assessment." [1]

Examiner: "What is the lesson about the painful versus the painless node?" [1]

"The lesson is that the pain is a poor discriminator. The classic teaching is that the painful node is infective (the acute capsule stretch of the lymphadenitis) and the painless node is malignant — but this is an oversimplification. The enlarging lymphoma can be tender (the rapid capsule stretch), and the chronic infective node (the tuberculosis, the atypical mycobacterium) can be painless. The registrar who is falsely reassured by the pain, or who dismisses the painless node as reactive, has misused the discriminator. The reliable discriminators are the location (the supraclavicular node is always concerning), the consistency (the hard or the fixed node is malignant until proven otherwise), the size (the node above 2 cm is concerning), the duration (the node persisting beyond 4 to 6 weeks is investigated), the B symptoms (the night sweats and the weight loss mandate the work-up), and the associated systemic signs (the hepatosplenomegaly). The pain is a clue, not a discriminator — and the registrar who uses it as the sole basis for reassurance or for concern has made the common error." [1]