Undifferentiated Weight Loss — Written Clinical Reasoning

Prompt 1 — Diagnostic approach and investigation strategy (12 marks)

A 68-year-old man presents with 3 months of involuntary weight loss (8 kg, 10 per cent of his usual body weight), anorexia, early satiety, and night sweats. He is a non-smoker with no significant past medical history. His Tier 1 bloods show a haemoglobin of 102 g per litre (MCV 72 fL), an alkaline phosphatase of 320 U per litre, an LDH of 480 U per litre, an albumin of 32 g per litre, a white cell count of 14.2, normal electrolytes, normal TFTs, normal glucose, and a CRP of 48. His faecal immunochemical test is positive. His CXR and abdominal ultrasound are pending. Discuss the diagnostic approach, the differential diagnosis, the investigations, and the initial management plan. [1]

Model answer — Prompt 1

The answer first: This patient has the significant involuntary weight loss (10 per cent in 3 months, well above the 5 per cent in 6 months threshold) with the multiple red flags for the malignancy: the anorexia, the early satiety (the gastric outlet obstruction), the night sweats (the lymphoma or the malignancy), the microcytic iron deficiency anaemia (the GI blood loss), the elevated ALP and LDH and the low albumin and the elevated white cell count (three of the five Hernandez malignancy prediction score variables), the positive faecal immunochemical test, and the elevated CRP. The most likely diagnosis is the GI malignancy — the gastric, the pancreatic, or the colorectal. The priority is the Tier 2 malignancy workup without delay: the CT chest abdomen and pelvis, the upper GI endoscopy, and the colonoscopy. [1]

The diagnostic approach (4 marks): [1]

The weight loss is the clinically significant involuntary loss (10 per cent in 3 months). The objective documentation is assumed from the presented history. The two first-minute branch points are addressed: the loss is involuntary (not intentional), and the appetite is lost (the anorexia) — this points to the malignancy, the chronic infection, the depression, or the GI obstruction, NOT to the hypermetabolic or the malabsorptive causes. [1]

The associated symptoms direct the workup:

• The early satiety suggests the gastric outlet obstruction (the gastric malignancy, the pancreatic malignancy compressing the duodenum, or the gastric atony from the infiltrative disease).
• The night sweats suggest the lymphoma or the disseminated malignancy.
• The microcytic anaemia (the iron deficiency) indicates the chronic GI blood loss — the oesophageal, the gastric, or the colorectal malignancy, or the coeliac disease.
• The elevated ALP may indicate the liver or the bone involvement (the metastatic disease or the primary hepatobiliary malignancy).
• The elevated LDH is the non-specific marker of the high cell turnover (the lymphoma, the malignancy).
• The positive faecal immunochemical test confirms the GI bleeding or the mucosal abnormality. [1]

The differential diagnosis (3 marks): [1]

Ranked by the probability given the clinical picture: [1]

1. The GI malignancy (the highest probability) — the gastric cancer (the early satiety, the iron deficiency anaemia, the positive FIT, the elevated ALP from the liver metastases), the pancreatic cancer (the weight loss, the early satiety from the gastric outlet compression, the elevated ALP from the biliary obstruction), the colorectal cancer (the iron deficiency anaemia, the positive FIT, the change in the bowel habit — not mentioned here but should be asked), the oesophageal cancer (the dysphagia — not mentioned here but should be asked).
2. The haematological malignancy — the lymphoma (the night sweats, the elevated LDH, the weight loss; the early satiety from the mesenteric or the retroperitoneal lymphadenopathy).
3. The metastatic disease of the unknown primary — the liver metastases (the elevated ALP), the bone metastases (the elevated ALP), the peritoneal carcinomatosis (the early satiety from the ascites).
4. The coeliac disease — the iron deficiency anaemia and the weight loss and the positive FIT from the mucosal inflammation, but the night sweats and the elevated LDH and the elevated ALP are less typical.
5. The chronic infection — the TB (the night sweats, the weight loss, the elevated CRP) but the iron deficiency anaemia and the positive FIT point more to the GI cause. [1]

The investigations (3 marks): [1]

The Tier 2 investigations are indicated without delay given the multiple red flags: [1]

1. The CT chest, abdomen, and pelvis with the intravenous contrast — to identify the primary tumour (the gastric mass, the pancreatic mass, the colorectal mass), the metastatic disease (the liver, the peritoneum, the nodes), and the staging.
2. The upper GI endoscopy — to identify the oesophageal, the gastric, and the duodenal malignancy, to obtain the biopsy, and to perform the duodenal biopsy for the coeliac disease.
3. The colonoscopy — to identify the colorectal malignancy and to obtain the biopsy. The bidirectional endoscopy is the standard for the iron deficiency anaemia in the older man.
4. The iron studies and the ferritin — to confirm the iron deficiency anaemia (the low ferritin, the low iron, the high TIBC).
5. The tumour markers — the CEA (the colorectal), the CA 19-9 (the pancreatic), the CA 125 (the ovarian), the alpha-fetoprotein (the hepatocellular), and the PSA (the prostate) — as the adjuncts, not the primary diagnostic tools. [1]

The initial management (2 marks): [1]

• The urgent referral to the gastroenterology and the oncology team.
• The nutritional support (the oral supplements, the dietitian referral) to maintain the nutritional state during the workup.
• The iron replacement (the oral ferrous sulphate 200 mg three times daily, or the intravenous iron if the oral is not tolerated) for the iron deficiency anaemia.
• The symptom control (the antiemetic for the nausea, the analgesic for the pain if present).
• The communication: the honest and the clear discussion with the patient and the family about the concern for the malignancy, the planned investigations, and the timeline for the results. [1]

Prompt 2 — The normal workup and the management of the unexplained weight loss (13 marks)

A 62-year-old woman presents with 4 months of involuntary weight loss totalling 6 kg (8 per cent of body weight). She has no specific symptoms. Her Tier 1 workup — the FBC, the U and E, the LFTs including the ALP and the albumin, the TFTs, the glucose and the HbA1c, the CRP, the iron studies, the B12 and the folate, the calcium, the CXR, the abdominal ultrasound, the urinalysis, the faecal immunochemical test, and the depression screen — is entirely normal. Her HIV serology is negative. Her coeliac serology (the tTG-IgA and the total IgA) is negative. Discuss the evidence supporting the observation strategy, the counselling of the patient, the conditions for the earlier reassessment, and the indications for the further (Tier 2) investigation. [1]

Model answer — Prompt 2

The answer first: The completely normal Tier 1 workup in this patient with the significant involuntary weight loss has a 99 per cent negative predictive value for the malignancy at the one-year follow-up (the Metalidis 2008 study). The appropriate strategy is the 3 to 6 month observation with the repeat weight measurement and the reassessment for the new symptoms, with the honest and the reassuring communication. The further (Tier 2) investigation is indicated if the weight loss continues, if the new symptoms develop, or if the initial workup was incomplete. [1]

The evidence for the observation strategy (4 marks): [1]

The Metalidis 2008 prospective study of 101 patients with the involuntary weight loss evaluated the negative predictive value of the completely normal baseline workup (the history, the examination, the FBC, the biochemistry, the inflammatory markers, the CXR, the abdominal ultrasound, and the urinalysis) for the malignancy at the one-year follow-up. The result: the completely normal baseline workup had a 99 per cent negative predictive value for the malignancy at one year [4]. This means that fewer than 1 in 100 patients with the completely normal workup will have the malignancy identified within the subsequent year. The study concluded that the watchful-waiting approach is preferable to the undirected invasive testing in this setting.

The Gaddey and Holder 2014 review corroborates this: a readily identifiable cause is not found in 16 to 28 per cent of the cases, and the 3 to 6 month observation is justified when the baseline evaluation is unremarkable [1].

The counselling of the patient (3 marks): [1]

The patient is counselled honestly and reassuringly:

• "The blood tests and the scans and the chest X-ray are normal, which is very reassuring. This reduces the chance of a serious cause like cancer to less than 1 per cent over the next year."
• "I will see you again in 3 months to re-weigh you and to reassess. Please return earlier if any new symptom develops — a change in your bowel habit, a new pain, a fever, a new lump, or any other concern."
• "In about one-quarter of the cases, we do not find a cause despite a thorough workup, and the weight often stabilises or improves with the time and the nutritional support." [1]

The conditions for the earlier reassessment (2 marks): [1]

The patient is asked to return earlier if:

• The weight loss continues (the further objective loss).
• The new symptoms develop — the dysphagia, the change in the bowel habit, the rectal bleeding, the abdominal pain, the fever, the night sweats, the new lump, the jaundice, or the new fatigue.
• The functional decline (the reduced ability to perform the ADLs, the falls, the confusion). [1]

The indications for the Tier 2 investigation (4 marks): [1]

The Tier 2 investigations (the CT chest abdomen and pelvis, the upper GI endoscopy, the colonoscopy, the serum and the urine electrophoresis, the autoimmune screen) are indicated if:

1. The weight loss continues despite the observation (the further objective loss at the 3-month review).
2. The new symptoms develop during the observation.
3. The initial Tier 1 workup was incomplete (for example, the coeliac serology, the HIV test, or the abdominal ultrasound was not done).
4. The patient or the clinician remains concerned despite the normal workup, and the shared decision is to proceed with the further testing.
5. The red flags emerge at the follow-up (the new anaemia, the new elevated CRP, the new abnormal LFTs). [1]

The Hernandez prediction score may be applied: if the patient has two or more of the five variables (the elevated ALP, the elevated LDH, the low albumin below 40 g per litre, the elevated white cell count, the age above 80), the probability of the malignancy is higher and the Tier 2 imaging is warranted [2] [3].

References

1. Gaddey HL, Holder K. Unintentional weight loss in older adults. Am Fam Physician 2014;89(9):718-722. PMID 24784334.
2. Hernández JL, Riancho JA, Matorras P, González-Macías J. Clinical evaluation for cancer in patients with involuntary weight loss without specific symptoms. Am J Med 2003;114(8):631-637. PMID 12798450.
3. Hernández JL, Matorras P, Riancho JA, González-Macías J. Involuntary weight loss without specific symptoms: a clinical prediction score for malignant neoplasm. QJM 2003;96(9):649-655. PMID 12925720.
4. Metalidis C, Knockaert DC, Bobbaers H, Vanderschueren S. Involuntary weight loss. Does a negative baseline evaluation provide adequate reassurance? Eur J Intern Med 2008;19(5):355-359. PMID 18549937.
5. Fearon K, Strasser F, Anker SD, et al. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol 2011;12(5):489-495. PMID 21296615.
6. Wallace JI, Schwartz RS, LaCroix AZ, Uhlmann RF, Pearlman RA. Involuntary weight loss in older outpatients: incidence and clinical significance. J Am Geriatr Soc 1995;43(4):329-337. PMID 7706619. [1]