1. Joint Hospital Surgical Grand Round 21 st July, 2012 RH

2. Liver Secondaries with Occult Primary How far should we go? Dr Chan Man Pan Caritas Medical Centre

3. Terminology Different terms has been used by investigators Different terms has been used by investigators Unknown or occult primary tumor, Metastasis of unknown origin, Tumor of unidentified origin …. Unknown or occult primary tumor, Metastasis of unknown origin, Tumor of unidentified origin …. Currently, the most widely accepted term is “ Cancer of Unknown Primary ” (CUP) Currently, the most widely accepted term is “ Cancer of Unknown Primary ” (CUP)

4. Definition Pavlidis, N., et. al. (2003). Diagnostic and therapeutic management of cancer of an unknown primary. European Journal of Cancer, 39(14), 1990-2005.

5. Magnitude of problem Pavlidis, N., et. al. (2003). Diagnostic and therapeutic management of cancer of an unknown primary. European Journal of Cancer, 39(14), 1990-2005.

6. Epidemiology Annual age-adjusted incidence is 7 – 12 cases per 100,000 population / year in USA Annual age-adjusted incidence is 7 – 12 cases per 100,000 population / year in USA Median age at presentation ~ 60 years old Median age at presentation ~ 60 years old Slightly male predominant Slightly male predominant No obvious aetiological or risk factor can be identified No obvious aetiological or risk factor can be identified Commonly presented as lymph node or liver metastasis Commonly presented as lymph node or liver metastasis Pavlidis, N. et. al. (2009). Carcinoma of unknown primary (CUP). Critical reviews in oncology/hematology, 69(3), 271-8.

7. Lazaridis, G., et. al (2008). Liver metastases from cancer of unknown primary (CUPL): a retrospective analysis of presentation, management and prognosis in 49 patients and systematic review of the literature. Cancer treatment reviews, 34(8), 693-700.

8. Liver secondaries with occult primary Aggressive and resistant disease with a grim outcome …… Aggressive and resistant disease with a grim outcome …… How far should we go in investigating? How far should we go in investigating? Does surgery have a role? Does surgery have a role?

9. How far should we go? Searching for primary is meaningful only if management can be affected Searching for primary is meaningful only if management can be affected Chance of successfully locating the primary? Chance of successfully locating the primary?

10. Armamentarium History taking & physical exam History taking & physical exam Basic blood test, Urinalaysis, Fecal occult blood Basic blood test, Urinalaysis, Fecal occult blood Serum tumor markers Serum tumor markers Imaging (CXR CT PET MRI Mammography) Imaging (CXR CT PET MRI Mammography) Endoscopy Endoscopy Histology Histology

11. Tumour marker Pavlidis, N., et. al.(2003). Diagnostic and therapeutic management of cancer of an unknown primary. European Journal of Cancer, 39(14), 1990-2005. Non specific elevation of multiple markers in majority of CUP patient

12. Tumour marker Routine measurement of epithelial tumour markers is not recommended Routine measurement of epithelial tumour markers is not recommended However, in some cases, it might be diagnostically helpful—eg, beta-HCG and AFP are increased in patients with poorly di ff erentiated carcinoma of midline distribution, as are PSA in men with bone metastases However, in some cases, it might be diagnostically helpful—eg, beta-HCG and AFP are increased in patients with poorly di ff erentiated carcinoma of midline distribution, as are PSA in men with bone metastases CA-125 in women with primary serous peritoneal adenocarcinoma, and CA15-3 in women with isolated axillary adenocarcinoma. CA-125 in women with primary serous peritoneal adenocarcinoma, and CA15-3 in women with isolated axillary adenocarcinoma. Pavlidis N, et. al. (2012). Cancer of Unknown Primary site. Lancet. 14;379(9824 ):1428-35

13. PET CT Kwee, Thomas C.et. al. (2009). Combined FDG-PET/CT for the detection of unknown primary tumors: systematic review and meta-analysis. European Radiology. 19(3):731-744.

14. PET CT Kwee, Thomas C.et. al. (2009). Combined FDG-PET/CT for the detection of unknown primary tumors: systematic review and meta-analysis. European Radiology. 19(3):731-744.

15. PET CT Kwee, Thomas C.et. al. (2009). Combined FDG-PET/CT for the detection of unknown primary tumors: systematic review and meta-analysis. European Radiology. 19(3):731-744.

16. PET CT Kwee, Thomas C.et. al. (2009). Combined FDG-PET/CT for the detection of unknown primary tumors: systematic review and meta-analysis. European Radiology. 19(3):731-744.

17. PET scan VS PET CT Gutzeit, A. et al. (2005). Unknown primary tumors: detection with dual-modality PET/CT--initial experience. Radiology, 234(1), 227-34.

18. Whole body MRI No published data on this topic No published data on this topic

19. Diagnostic Endosocpy Panendoscopy, OGD, Colonoscopy, bronchoscopy Panendoscopy, OGD, Colonoscopy, bronchoscopy Guided by Clinical and Laboratory finding Guided by Clinical and Laboratory finding GI endoscopy in patients with abdominal symptoms or fecal occult blood + ve, or histology point to a GI tract origin GI endoscopy in patients with abdominal symptoms or fecal occult blood + ve, or histology point to a GI tract origin Pavlidis, N. et. al. (2009). Carcinoma of unknown primary (CUP). Critical reviews in oncology/hematology, 69(3), 271-8. Pavlidis, N. et. al. (2009). Carcinoma of unknown primary (CUP). Critical reviews in oncology/hematology, 69(3), 271-8. Endoscopic studies of asymptomatic areas identify the primary tumour in less than 10% of such cases Endoscopic studies of asymptomatic areas identify the primary tumour in less than 10% of such cases Gaber AO, et al. (1983). Metastatic malignant disease of unknown origin. Am J Surg. 145:493-497 Gaber AO, et al. (1983). Metastatic malignant disease of unknown origin. Am J Surg. 145:493-497

20. Pavlidis N, et. al. (2012). Cancer of Unknown Primary site. Lancet. 14;379(9824 ):1428-35

21. In searching for primary Primary tumor can only be located in 20% to 30% of case (with combination of imaging, endoscopy and histology) Primary tumor can only be located in 20% to 30% of case (with combination of imaging, endoscopy and histology) Most common primary site is lung, colorectal and pancreas Most common primary site is lung, colorectal and pancreas Pavlidis, N., et. al. (2010). Cancer of unknown primary site: 20 questions to be answered. Annals of oncology: official journal of the European Society for Medical Oncology / ESMO, 21 Suppl 7(Supplement 7), vii303-7

22. Prognostic factors Lazaridis, G., et. al (2008). Liver metastases from cancer of unknown primary (CUPL): a retrospective analysis of presentation, management and prognosis in 49 patients and systematic review of the literature. Cancer treatment reviews, 34(8), 693-700.

23. Prognostic factors

24. Prognostic factor Certain histological subgroup are more amenable to treatment Certain histological subgroup are more amenable to treatment Liver biopsy is essential as a primary diagnostic procedure. Liver biopsy is essential as a primary diagnostic procedure.

25. Neuroendocrine carcinoma with liver metastasis Pancreas, right hemicolon and small intestine are most frequent primary site Pancreas, right hemicolon and small intestine are most frequent primary site Surgical resection in curative intent can offer survival benefit in selected cases Surgical resection in curative intent can offer survival benefit in selected cases 5 year survival rate 60-80% 5 year survival rate 60-80% Pavel, M., et al. (2012). ENETS Consensus Guidelines for the management of patients with liver and other distant metastases from neuroendocrine neoplasms of foregut, midgut, hindgut, and unknown primary. Neuroendocrinology, 95(2), 157-76.

26. The American surgeon; Jun 2004

27. Median follow up 9 months Median Disease free survival 6.5 months

28. Summary How far should we go in investigating? How far should we go in investigating? Hawksworth et al, (2004) Surgical and Ablative Treatment for Metastatic Adenocarcinoma to the liver from Unknown Primary tumor. The American surgeon, 70(6), 512 - 517 PET/PET-CT

29. Summary How far should we go in management How far should we go in management A multidisciplinary approach A multidisciplinary approach More studies are needed More studies are needed

30. Thank you