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]

SAQ 2 — The Biopsy Decision and the Choice of Technique in Suspected Lymphoma (10 marks)

Prompt: A junior doctor asks you to explain: (a) why the excisional biopsy is the gold standard for the diagnosis of lymphoma and why the fine-needle aspiration is inadequate; (b) the clinical scenarios in which the FNA and the core biopsy are acceptable alternatives; and (c) the principle that corticosteroids must not be given before the biopsy, and the rare exception. [1]

Model Answer

(a) Excisional biopsy as the gold standard (4 marks): [1]

The excisional biopsy is the gold standard for the diagnosis of lymphoma because it preserves the nodal architecture — the follicular versus diffuse pattern, the growth pattern, the capsule, the interfollicular distribution — which the FNA cannot provide. The architecture is the first piece of information the haematopathologist uses to classify the lymphoma: the follicular lymphoma has the neoplastic follicles, the diffuse large B-cell lymphoma has the sheets of large cells, the Hodgkin lymphoma has the Reed-Sternberg cells in the inflammatory background, the mantle cell lymphoma has the nodular or the diffuse pattern with the cyclin D1 overexpression. The excisional biopsy also provides ample tissue for the immunohistochemistry (the B-cell markers CD19, CD20, CD79a; the T-cell markers CD3, CD4, CD8; the Hodgkin markers CD15, CD30, PAX5; the cell-cycle markers Ki-67, cyclin D1), the flow cytometry (the surface immunophenotyping, the kappa and lambda light chain restriction), and the molecular studies (the clonality by the PCR for the immunoglobulin and the T-cell receptor gene rearrangements, the translocations by the FISH for the BCL2, the BCL6, the MYC, the CCND1) [5]. The FNA samples cells not architecture, and it cannot provide any of these — an FNA report of "atypical lymphoid cells" cannot distinguish the Hodgkin from the non-Hodgkin lymphoma, it cannot provide the cell-of-origin (the germinal centre versus the activated B-cell) that the targeted therapy now requires, and it cannot provide the translocation status (the double-hit lymphoma with the MYC and the BCL2 translocations that drives the high-risk therapy decision).

(b) When the FNA and the core biopsy are acceptable (3 marks): [1]

The FNA is acceptable for the suspected metastatic carcinoma — a supraclavicular node in a patient with a known or suspected lung, gastric or breast primary. The FNA identifies the malignant cells and may permit the immunohistochemistry (the thyroid markers TTF-1 and thyroglobulin, the prostate marker PSA, the oestrogen and progesterone receptors, the gastrointestinal marker CK20) that identifies the primary. The FNA is also acceptable for the suspected infective node — tuberculosis (the acid-fast bacilli on the Ziehl-Neelsen stain, the mycobacterial culture, the PCR), the bacterial lymphadenitis (the Gram stain and the culture). The core biopsy (usually ultrasound-guided, 14- to 18-gauge) is a reasonable second-line when the excisional biopsy is not feasible — the deep retroperitoneal node, the patient who is not fit for a general anaesthetic. The core provides some architecture and tissue for the immunohistochemistry and some molecular studies, but it is inferior to the excisional biopsy for the sub-classification of the lymphoma, and the definitive diagnosis is not always achievable. 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, the core biopsy as the fallback when the excisional biopsy is not technically possible [1].

(c) Corticosteroids before the biopsy (3 marks): [1]

The principle is that corticosteroids must not be given before the tissue diagnosis in unexplained lymphadenopathy, because they induce apoptosis in the lymphoma cells and distort the nodal architecture, compromising the diagnostic tissue [1]. A registrar who prescribes prednisone for a suspected reactive node that is in fact lymphoma may render the subsequent biopsy non-diagnostic, delaying the diagnosis and the therapy. The rare exception is the patient who is critically ill with a mediastinal mass and the airway or the great-vessel compromise — the steroids may be necessary as a life-saving measure to reduce the mass effect, but only after a rapid tissue diagnosis has been obtained (a rapid FNA or a core biopsy), and with the explicit understanding that the definitive excisional biopsy will follow once the patient is stabilised. The haematology team is involved at the outset, and the decision to give steroids in this context is a multidisciplinary one, not a unilateral registrar decision. The teaching point is that the corticosteroid before the biopsy is the classic exam trap, and the registrar who is tempted to "give a short course of prednisone to see if the node shrinks" has revealed a knowledge gap that the examiner will press on.