Undifferentiated Lymphadenopathy — Written Clinical Reasoning

SAQ 1 — Integrated Diagnostic Approach to the Patient with Generalised Lymphadenopathy and B Symptoms (20 marks, 30 minutes)

Prompt: Outline your integrated diagnostic approach to Mr Okafor's presentation, addressing: (a) the localised-versus-generalised framework and the prioritised differential; (b) the red-flag screen and how it drives the biopsy decision; (c) the choice of biopsy technique and why; (d) the parallel work-up of the differential (lymphoma, tuberculosis, metastatic carcinoma); (e) the staging and the prognostication after the histology; and (f) the common exam trap in this patient. ^[1]

Model Answer

(a) Localised-versus-generalised framework and prioritised differential (3 marks): ^[1]

Mr Okafor has generalised lymphadenopathy — the involvement of two or more non-contiguous node regions (the supraclavicular, the mediastinal, the para-aortic, the iliac) indicates a systemic process, not a regional one. The leading diagnosis is lymphoma (Hodgkin or non-Hodgkin), supported by the B symptoms (the night sweats and the weight loss), the hepatosplenomegaly, the raised LDH and the generalised nodal pattern. The differential is disseminated tuberculosis, given his country of origin and the positive IGRA, and metastatic carcinoma from an intra-abdominal primary (gastric, pancreatic), given the left supraclavicular node and the early satiety. The EBV serology is consistent with remote infection, and the HIV test is negative, which reduces (but does not eliminate) the infectious mononucleosis-like differential. The prioritised differential is therefore: first, lymphoma; second, disseminated tuberculosis; third, metastatic carcinoma; fourth, the rarer systemic causes (sarcoid, the autoimmune lymphoproliferative syndrome). ^[1]

(b) The red-flag screen and the biopsy decision (4 marks): ^[1]

Mr Okafor has five red-flag features, any one of which would mandate biopsy: a supraclavicular node (the single highest-risk location, with a malignancy probability of 30 to 90 per cent), the B symptoms (the night sweats and the weight loss), a raised LDH, the node above 2 cm, and the hepatosplenomegaly ^[1]. The supraclavicular node alone mandates biopsy in an adult, regardless of the other features. The observation period that is reasonable for a low-risk localised cervical node in a young patient with a viral illness does not apply here — Mr Okafor is biopsied, not observed. The supraclavicular node carries the highest priority for the urgent suspected-cancer referral per the NICE NG12 pathway ^[1].

(c) The choice of biopsy technique (4 marks): ^[1]

The biopsy of choice is the excisional biopsy of the most accessible abnormal node, with the tissue sent fresh for the histology, the immunohistochemistry (the B-cell and T-cell markers, the Hodgkin markers, the cell-cycle markers), the flow cytometry (the surface immunophenotyping), and the molecular studies (the clonality by PCR, the translocations by FISH) ^[5]. The excisional biopsy preserves the nodal architecture (the follicular versus diffuse pattern, the growth pattern, the capsule), which the FNA cannot provide. The FNA samples cells, not architecture, and it is inadequate for the primary diagnosis of lymphoma — it may 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 that the modern therapy requires. The FNA is acceptable for the suspected metastatic carcinoma or the infective node, but the leading diagnosis here is lymphoma, and the excisional biopsy is the gold standard. The inguinal node is avoided if alternatives are available, because the inguinal nodes are often fibrotic and reactive. Corticosteroids must not be given before the biopsy — they induce apoptosis in the lymphoma cells and distort the nodal architecture ^[1].

(d) The parallel work-up of the differential (3 marks): ^[1]

The tuberculosis is worked up in parallel with the biopsy. Three sputum samples are sent for the acid-fast bacilli stain, the mycobacterial culture and the PCR (the nucleic acid amplification test for the M. tuberculosis complex). The node itself is sent for the same stains and cultures at the time of the biopsy. The latent TB is treated (the rifampicin for 4 months or the isoniazid for 6 to 9 months per the local guideline) after the active TB is excluded and before or during the lymphoma therapy, in consultation with the infectious diseases team — because the immunochemotherapy that will follow a lymphoma diagnosis would reactivate a latent TB. The metastatic carcinoma differential is addressed by the histology — if the biopsy shows adenocarcinoma, the upper endoscopy and the tumour markers (the CEA, the CA 19-9) follow, but I do not speculate on the primary before the biopsy, because the biopsy answers the question. The HIV test is done (negative here), and the EBV serology is done (remote infection), because the infectious mononucleosis and the primary HIV are in the differential of any generalised lymphadenopathy. ^[1]

(e) Staging and prognostication (4 marks): ^[1]

The staging is performed 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 Hodgkin lymphoma, the diffuse large B-cell lymphoma, the follicular and the mantle cell. 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 — a change that spares the patient a painful and often non-contributory procedure ^[5]. The prognostication uses the revised International Prognostic Index (R-IPI) if the diagnosis is diffuse large B-cell lymphoma — the five factors are 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 ^[4]. Mr Okafor has stage IV by the CT (the para-aortic and the iliac nodes are below the diaphragm) and the elevated LDH, placing him in the good risk group (R-IPI 1 to 2, 4-year overall survival approximately 79 per cent) unless his performance status is reduced, which would shift him to the poor risk group. The Deauville 5-point scale is used for the PET-CT response assessment after the therapy.

(f) The common exam trap (2 marks): ^[1]

The trap is the observation of a supraclavicular node — the registrar who reassures a patient with a left supraclavicular node that "it's probably nothing" and observes for a month has lost time that the underlying lymphoma or the metastatic carcinoma will use. The supraclavicular node is a red flag in any adult, and the observation window applies only to the low-risk localised node without red flags. The second trap is the acceptance of an FNA diagnosis of lymphoma — the FNA is inadequate for the primary diagnosis, and the registrar who accepts it will need to repeat the biopsy as an excisional biopsy. The third trap is the corticosteroid before the biopsy — the steroids may mask the histology of lymphoma by inducing apoptosis in the lymphoma cells, and they must not be given before the tissue diagnosis. ^[1]