PA6.1-7 | Neoplasia — Case Study

CLINICAL SCENARIO

A 58-year-old male ex-smoker presents with a 6-week history of cough, weight loss, and facial puffiness. Chest X-ray reveals a central hilar mass. Serum sodium is 122 mmol/L (hyponatraemia). Fasting blood glucose is elevated, and his face has a rounded, plethoric appearance. CECT thorax confirms a 4.2 cm poorly-defined mass at the right hilum with ipsilateral mediastinal lymphadenopathy. Bronchoscopic biopsy is obtained. This case will guide you through the clinico-pathological reasoning from presentation to definitive diagnosis and staging of small-cell lung carcinoma (SCLC) with paraneoplastic SIADH and ectopic ACTH syndrome.

Section 1 — Clinical Clues and Paraneoplastic Reasoning (PA6.1, PA6.2)

The patient has hyponatraemia, a Cushingoid face, and a central lung mass. (a) Name the two paraneoplastic syndromes suggested by these findings. (b) Identify the ectopic hormones responsible and explain the mechanism linking tumour biology to each syndrome. (c) List two additional clinical or biochemical features you would seek to confirm each syndrome.

Guidance: Focus on ectopic peptide secretion as a defining feature of neuroendocrine neoplasms. Distinguish SIADH (ectopic ADH/AVP) from ectopic ACTH syndrome mechanistically. Your answer should demonstrate understanding of why neuroendocrine tumours are prone to hormone production (PA6.1 — neoplasm characteristics). Aim for 200–250 words.

Section 2 — Histological Features: Benign vs Malignant Criteria (PA6.3)

The bronchoscopic biopsy report describes: 'sheets of small cells with scant cytoplasm, hyperchromatic nuclei with finely granular chromatin, nuclear moulding, abundant mitoses (>80/10 HPF), extensive necrosis, and lymphovascular invasion.' (a) Map each finding to a criterion of malignancy on the benign–malignant spectrum. (b) Identify two anaplasia features present. (c) Explain why the mitotic count and necrosis independently predict aggressive behaviour.

Guidance: Use the seven histological hallmarks of malignancy (Robbins, Ch 7). Anaplasia features include pleomorphism, abnormal mitoses, and loss of polarity. Do not confuse mitotic count with Ki-67 here — address both morphological criteria and their biological significance. Aim for 200–250 words.

Section 3 — Immunohistochemistry and Tumour Markers (PA6.4)

The pathologist requests an IHC panel. Results: synaptophysin +, chromogranin A +, CD56 +, TTF-1 focal +, CK7 +, CK20 −, p40 −, Ki-67 index 92%. (a) Interpret this panel and confirm the tumour lineage. (b) Explain what the Ki-67 index of 92% signifies in SCLC. (c) Identify one serum tumour marker relevant to SCLC monitoring and state its limitation.

Guidance: Neuroendocrine markers (synaptophysin, chromogranin A, CD56) are lineage-defining. TTF-1 positivity in SCLC reflects lung primary origin. p40 negativity excludes squamous carcinoma. Serum NSE (neuron-specific enolase) or pro-GRP are acceptable markers; discuss specificity vs sensitivity. Aim for 150–200 words.

Section 4 — Molecular Profile and Targeted Therapy Relevance (PA6.5)

Molecular testing reports: TP53 mutation (homozygous), RB1 deletion, MYCL amplification, no EGFR/ALK/ROS1 alterations. (a) Explain the role of TP53 and RB1 loss in SCLC carcinogenesis. (b) Why are EGFR and ALK mutations clinically important to exclude even though they are absent here? (c) State one emerging molecular target in SCLC and whether it is currently actionable.

Guidance: TP53 and RB1 are the two signature alterations in SCLC — their combined loss disrupts both apoptosis and cell-cycle checkpoints. EGFR/ALK exclusion matters for differential (non-small cell subtypes) and to avoid futile targeted therapy. DLL3, ASCL1, or PARP inhibitors are acceptable emerging targets. Aim for 150–200 words.

Section 5 — Grading, Staging, and TNM Classification (PA6.6)

Staging investigations reveal: right hilar mass 4.2 cm, ipsilateral mediastinal nodes positive (station 4R), no contralateral nodes, no distant metastasis on PET-CT. (a) Apply the 8th edition TNM staging for lung cancer to assign T, N, and M categories and the overall stage group. (b) Explain why SCLC uses a two-tier Limited vs Extensive Disease classification in clinical practice. (c) State how staging influences treatment choice for this patient.

Guidance: T2b (>3–4 cm), N2 (ipsilateral mediastinal), M0 → Stage IIIA. SCLC's rapid doubling time and early haematogenous spread mean TNM granularity matters less clinically than LD vs ED. Treatment implication: LD-SCLC receives concurrent chemo-radiotherapy (cisplatin/etoposide + thoracic RT ± PCI). Aim for 200–250 words.

Section 6 — Metastasis Route and Prognosis (PA6.7)

At a multidisciplinary tumour board meeting, the team notes that SCLC is notorious for early widespread metastasis. (a) Describe the two main routes of metastasis (haematogenous and lymphatic) and identify the three most common distant sites for SCLC. (b) Explain the molecular steps of the invasion–metastasis cascade relevant to this tumour (at least four steps). (c) Given all findings, critically appraise the prognosis for this patient, citing median survival data and one prognostic factor.

Guidance: Common SCLC metastatic sites: brain, liver, bone, adrenals. Steps of the cascade: loss of E-cadherin → EMT → basement membrane degradation (MMPs) → intravasation → survival in circulation → extravasation → colonisation. LD-SCLC median OS ~16–24 months with treatment; brain prophylactic irradiation (PCI) improves OS. PS/LDH are accepted prognostic factors. Aim for 200–250 words.

PEER REVIEW

You will be assigned one anonymous classmate submission to review. Use the six rubric criteria to assess their work. For each criterion: (1) assign a score (1–5) and (2) write 2–3 sentences of constructive feedback explaining your score and what could be improved. Be specific — quote or paraphrase the section you are commenting on. Your review must be respectful, evidence-based, and focused on the pathology content, not writing style. Total review: ~300 words. Submit your review within 48 hours of receiving the assignment.