Cancer of Unknown Primary Site: One or more diseases
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This document discusses the changing landscape of cancer of unknown primary (CUP) over four decades from 1976 to the present. It describes the evolution from recognition of favorable prognostic subsets in 1976-1986, to improved diagnostic techniques in 1986-1996, to empiric chemotherapy in 1996-2006, and currently to improved pathologic and genetic diagnostic technologies and better outcomes for many CUP patients from 2006 onward. The document provides details on histologic classification, clinicopathologic entities, diagnostic approaches including imaging, histopathology, immunohistochemistry, and molecular analysis, as well as discussion of favorable and unfavorable prognostic subsets and treatment approaches.
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Cancer of Unknown Primary Site: One or more diseases
- 1. Cancer of Unknown Primary: Knowing the Unknown Mary Ondinee M. Igot, MD, MSCM, FPCP, FPSMO, FPSO Medical Oncologist / Neuro – Oncologist August 2016 / Acacia Hotel
- 2. Four Decades of Changing Clinical Landscape In CUP 1. 1976-1986: Decade of Recognition of Favorable Clinicopathologic Subsets 2. 1986-1996: Decade of Improved Clinical Diagnostic Techniques/Testing 3. 1996-2006 : Decade of Empiric Chemotherapy 4. 2006-present : Decade of Improved Pathologic and Genetic Diagnostic Technologies and Better Outcomes for Many CUP patients
- 3. Outline • Definition, clinical presentation, histology • Clinicopathological entities • Approach in searching for the primary • Therapeutics on good and poor prognosis subtypes
- 4. WHAT IS CANCER OF UNKNOWN PRIMARY (CUP)? • Is a clinical disorder where patients present with histologically confirmed metastatic cancer for which standard diagnostic investigations failed to identify the primary site • Median age is 65 years, more common in men • It accounts for 3-5% of all human cancers • It is considered to be the 7th-8th most frequent malignant tumor
- 5. CLINICAL CHARACTERISTICS AT PRESENTATION • Early dissemination • Clinical absence of primary • Aggressiveness • Unpredictable metastatic pattern (i.e. hidden pancreatic cancer has higher incidence of bone or lung metastases)
- 10. Cancer of Unknown Primary Site : One or more diseases?
- 11. HISTOLOGICAL CLASSIFICATION Adenocarcinoma Well to moderately differentiated 50% Poorly or undifferentiated 35% Squamous cell carcinoma 10% Undifferentiated neoplasms 5% Not specified carcinoma Neuroendocrine tumors Lymphomas Germ cell tumors Melanomas Sarcomas Embryonal malignancies HISTOLOGY INCIDENCE
- 12. CLINICOPATHOLOGICAL ENTITIES OF CUP LIVER (mainly AdenoCA Mod or Poorly Diff and/or other organs) LYMPH NODES Mediastinal – Retroperitoneal Undifferentiated or Poorly Diff Ca (midline distribution) Axillary AdenoCa Well to Poorly Diff Cervical Squamous Cell Ca Inguinal Undiff Ca, Squamous Cell Ca, Mixed Squamous and AdenoCa ORGAN HISTOLOGY
- 13. PERITONEAL CAVITY Peritoneal adenocarcinomatosis Papillary or serous adenoCa in females ( ± psamomma bodies) Malignant ascites of other Mucin adenoCa Mod or Poorly Diff unknown origin ( ± signet ring cells) LUNG Pulmonary metastases AdenoCa of various differentiation Pleural effusion AdenoCa Mod or Poorly Diff ORGAN HISTOLOGY
- 14. BONES (solitary or multiple) AdenoCa of Various Diff BRAIN (solitary or multiple) AdenoCa of Various Diff or Squamous Cell Ca NEUROENDOCRINE TUMORS Poorly diff Ca with neuroendocrine features (mainly), low grade NE Ca, small cell Ca, anaplastic Ca MELANOMA Undifferentiated neoplasm with melanoma features ORGAN HISTOLOGY
- 15. HOW DO WE SEARCH FOR THE PRIMARY ? By IMAGING Immunohisto- chemistry Advanced Molecular Technology ENT panendoscopy Bronchoscopy Colonoscopy Proctoscopy Colposcopy Conventional Radiology Ultrasonography CT scan MRI PET scan Mammography By HISTOPATHOLOGY By ENDOSCOPY
- 17. STEPS OF IMMUNOHISTOCHEMICAL DIAGNOSTIC APPROACH FOR CUP CARCINOMA AE 1/3 pancytokeratin LYMPHOMA Common leucocyte antigen (CLA) MELANOMA S100, HMB45 SARCOMA S100, Vimentin STEP1: (Detects broad type of cancer)
- 18. ADENOCARCINOMA CK 7/20, PSA GERM CELL TUMOR PLAP, OCT4, AFP, HCG HEPATOCELLULAR CARCINOMA Hepar1, canalicular pCEA / CD10 / CD13 RENAL CELL CARCINOMA RCC, CD10 THYROID CARCINOMA TTF-1, thyroglobulin NEUROENDOCRINE CARCINOMA Chromogranin, synaptophysin PGP 9.5, CD56 SQUAMOUS CARCINOMA CK 5/6, p63 STEP 2: (Detects subtype of carcinoma)
- 19. PROSTATE PSA, PAP LUNG TTF-1 BREAST GCDFP-15, mammaglobulin, ER COLON CDX2, CK 20 PANCREAS / BILIARY CDX2, CK 20, CK 7 OVARY ER, CA-125, mesothelin STEP 3: (Detects origin of an adenocarcinoma)
- 21. Weiner C: Harrison’s Principles of Internal Medicine: Self-Assessment and Board Review, 17th ed. CK7+ CK20+ CK7+ CK20- CK7- CK20+ CK7- CK20- Urothelial tumors Ovarian mucinous adenoCa Pancreatic adenoCa CholangioCa Lung AdenoCa Breast carcinoma Thyroid carcinoma Endometrial carcinoma Cervical carcinoma Salivary gland carcinoma CholangioCa Pancreatic carcinoma Colorectal carcinoma Merkel cell carcinoma Hepatocellular carcinoma Renal cell carcinoma Prostate carcinoma Squamous cell and small cell lung carcinoma Head and neck carcinoma CK7 CK20
- 22. By MOLECULAR ANALYSIS (Microarray Platforms) 80 – 90 % accuracy
- 23. Molecular Analysis: General Approach In recent years, molecular cancer classification has emerged as a standardized, objective technique to help identify tumor type in patients with CUP Concept: neoplasms retain gene expression profile based on cellular origin; this profile can be exploited to identify tumor type Quantification of differential gene expression from a patient’s tumor Molecular Cancer Classification: General Approach Compare patient profile to gene expression profile of known tumors from a reference database Patient biopsy RNA extraction Algorithm compares sample to Reference Database Molecular Classifier Predict Tumor Type
- 24. GENE EXPRESSION PROFILING ASSAY PLATFORM TISSUE NO. OF TUMOR TYPES NO. OF GENES ACCURACY IN KNOWN TUMORS (%) 1.) Veridex RT-PCR FFPE 6 and “other” 10 76 2.) Pathwork Diagnostics Tissue of Origin Test cDNA microarray Frozen / FFPE 15 1500 89 3.) Rosetta Genomics MiReview met RT-PCR miRNA FFPE 22 48 miRNAs 86 4.) bioTheranostics CancerType ID RT-PCR mRNA FFPE 39 (including subypes) 92 86
- 25. ENDOSCOPY - Should always be symptoms - signs oriented investigational procedures SERUM TUMOR MARKERS - In general, routine evaluation of current commonly used markers have not been proven of any prognostic or diagnostic assistance
- 26. What is the OPTIMAL THERAPEUTIC approach of CUP?
- 27. Pavlidis N et al. European Journal of Cancer, 39(14):1990-2005, 2003.
- 28. CUP FAVOURABLE or GOOD PROGNOSIS SUBSETS UNFAVOURABLE or POOR PROGNOSIS SUBSETS Pavlidis N et al. European Journal of Cancer, 39(14):1990-2005, 2003.
- 29. Do we have EFFECTIVE DRUGS for CUP or We just have RESPONSIVE SUBSETS of patients???
- 30. THE FAVORABLE SUBSETS or GOOD PROGNOSIS SUBSETS
- 31. FAVOURABLE SUBSETS 1. Women with adenocarcinoma involving only axillary lymph nodes. 2. Women with papillary adenocarcinoma of peritoneal cavity. 3. Squamous cell carcinoma involving cervical lymph nodes. 4. Poorly differentiated neuroendocrine carcinomas. Merkel cell carcinoma of unknown primary (localized disease). 5. Adenocarcinoma with a colon profile (CK 20+ / CK 7- / CDX2+). 6. Men with blastic bone metastases and elevated PSA (adenocarcinoma). 7. Isolated inguinal adenopathy (squamous carcinoma). 8. Patients with a single, small, potentially resectable tumor. Pavlidis N & Pentheroudakis G. The Lancet 379: 1428-35, 2012.
- 32. Subset 1 • Mostly ductal adenocarcinoma (40% positive for ER/PR) • Mean age 52 years • Should be managed as STAGE II BREAST CANCER (axillary dissection, ipsilateral radiotherapy, adjuvant chemo/hormone therapy) • 5-year survival : 72% Women with adenocarcinoma involving axillary lymph nodes Pavlidis N & Pentheroudakis G. The Lancet 379: 1428-35, 2012.
- 33. Subset 2 • Similar presentation with advanced ovarian cancer. • Median age 60 years • Histopathology: serous or papillary adenoCa • Serum CA125 is frequently increased • Should be treated as Stage III-IV ovarian cancer (cytoreduction ± intraperitoneal chemo, followed by platinum ± taxanes) • Responses: 80% (CR:30-40%), Median survival : 36 months Women with primary papillary adenocarcinoma of peritoneal cavity Pavlidis N & Pentheroudakis G. The Lancet 379: 1428-35, 2012.
- 34. Subset 3 • It constitutes 5% of all head and neck cancers • Median age of 60 years • Sensitivity of PET scan to detect primary is 60% • Treatment • N1 or N2A disease without capsular extension: surgery alone [ locoregional control ; 80-90%, 5-yr survival : 65% ] • ≥N2B stage or with extracapsular extension : post-operative chemoradiation Squamous cell carcinoma involving cervical lymph nodes Pavlidis N & Pentheroudakis G. The Lancet 379: 1428-35, 2012.
- 35. Subset 4 • Frequently affects retroperitoneal, mediastinal, peripheral nodes, less frequently liver or bones. • Should be treated with platinum and/or taxane combinations • Response : 55% (CR 20%) • Survival : 15 months (10-15% long survivors) Poorly differentiated neuroendocrine carcinoma Pavlidis N & Pentheroudakis G. The Lancet 379: 1428-35, 2012.
- 36. Subset 5 • Clinical presentation : abdominal nodes 51%, peritoneum 50%, liver 30%, ascites 27% • Should be treated as advanced colorectal cancer with chemotherapy / targeting treatment • Response : 50% (CR 15%, PR 35%) • Median Survival : 21-37 months Adenocarcinoma with a colon profile (CK 20+, CK7-, CDX2+) Pavlidis N & Pentheroudakis G. The Lancet 379: 1428-35, 2012.
- 37. • Men with blastic bone metastases from an adenocarcinoma and elevated serum PSA treat as advanced prostate cancer • Isolated inguinal adenopathy from squamous cell carcinoma local excision ± radiation • Patients with a single, small, potentially resectable tumors local excision ± radiation O T H E R F AV O U R A B L E S U B S E T S Pavlidis N & Pentheroudakis G. The Lancet 379: 1428-35, 2012.
- 38. THE UNFAVORABLE SUBSETS or POOR PROGNOSIS SUBSETS
- 39. 1. Adenocarcinoma metastatic to the liver or other organs 2. Poorly differentiated carcinoma 3. Non-papillary malignant ascites (adenocarcinoma) 4. Multiple cerebral metastases (adenoCa or squamous Ca) 5. Multiple lung/pleural metastases (adenocarcinoma) 6. Multiple metastatic bone disease (adenocarcinoma) 7. Squamous cell carcinoma of the abdominal cavity U N F AV O U R A B L E S U B S E T S Pavlidis N & Pentheroudakis G. The Lancet 379: 1428-35, 2012.
- 40. THE UNFAVOURABLE OR POOR PROGNOSIS SUBSETS • This group of CUP patients represents 80% of cases • Usually treated with empiric chemotherapy (i.e. platinum ± taxanes) • Responses : 20% • Median survival : 6-9 months Pavlidis N & Pentheroudakis G. The Lancet 379: 1428-35, 2012.
- 41. Fizazi K, et al. ESMO CPG on CUP. Annals of Oncology, 26 (Supplement 5): v133–v138, 2015 .
- 42. Does the identification of PRIMARY SITE by MOLECULAR TUMOR PROFILING following site specific therapy improve patients’ outcome? WHAT IS THE EVIDENCE TODAY?
- 43. Is the 92-gene RT-PCR assay accurate in predicting primary tumor site? • Sensitivity = 87% (95% CI, 0.84 to 0.89) • Accuracy stable in metastatic tumors, high-grade tumors, and cases with limited tissue “This assay demonstrated excellent performance for classification of a diverse set of tumor histologies in known tumors.”
- 44. CONCLUSION • The median survival time of 12.5 months for patients who received assay- directed site-specific therapy compares favorably with previous results using empiric CUP regimens. • Molecular tumor profiling contributes to the management of patients with CUP and should be a part of their standard evaluation.
- 46. OVERALL SURVIVAL: Assay-directed vs empiric treatment • 37% increase in overall survival with assay-directed therapy
- 47. CORRESPONDENCE • I respectfully suggest, with regret, that their trial is insufficient to support this claim. • A trial in which patient with CUP are randomly assigned to the best empiric therapy versus expression profile-directed therapy, or some similar design, remains needed.
- 48. ONGOING PHASE III RANDOMIZED TRIALS WITH THE USE OF MOLECULARLY ASSIGNED THERAPY TRIAL SPONSOR DESIGN ARMS GEFCAP 104 GEFCAPI, France RCT Phase III cDDP + Gemcitabine vs Pathwork Test - Based Therapy CUP-ONE CR UK RCT Phase III ECX vs Molecularly Assigned Therapy
- 49. When should a molecular assay be ordered in CUP? • Any patient without IHC patterns diagnostic of a single primary site or tissue of origin. • In patients with small biopsy specimens when sufficient IHC evaluation will not be feasible (e.g., FNAs, pleural effusions, small needle biopsies). • In patients with metastasis and a history of 1 or more previous cancers, when IHC is inconclusive. • In patients with atypical presentation / clinical presentation does not match pathologic characterization. • In any tumor that is very poorly differentiated and there is question of lineage and/or tissue of origin from IHC.
- 50. RECOMMENDATIONS “Until more robust outcomes and comparative effectiveness data are available, pathologists and oncologists must collaborate on the judicious use of these modalities (IHC and GEP) on a case-by-case basis, with the best possible individualized patient outcome in mind.”
- 51. Changing Clinical Landscape of CUP over the Decades CUP in 1976 CUP in 1996 CUP in 2017 Clinical Evaluation • Rudimentary • CT not yet available • CT scans • Endoscopies • Can be extensive • CT, PET, MRI, endoscopy, ultrasound, etc Pathology • H&E • No IHC • Limited IHC • Evolving IHC, useful panels • Molecular diagnosis very useful Favorable Subsets • NOT appreciated • Multiple subsets appreciated with specific therapy (20% of all CUP) • Specific IHC and molecular diagnosis • Outcome improved with site- specific therapy Treatment • Symptomatic/supportive • No effective therapies • Empiric regimens • Treatment helpful in favorable subsets • Empiric regimens • Site-specific therapy • Most CUP patients can have primary site diagnosed by molecular dx Prognosis • Very poor • All patients lumped together • Only a few known solid tumors had useful therapy • Good for favorable subsets • Empiric regimens helpful for some tumors • Improved with site-specific therapy based upon an accurate diagnosis of the primary site • Poor for specific tumors with ineffective therapy
- 52. STEPS IN DIAGNOSTIC & THERAPEUTIC MANAGEMENT DIAGNOSIS OF METASTATIC CARCINOMA (by histopathology) SEARCH FOR PRIMARY SITE Clinical, immunohistochemistry, imaging, endoscopy studies RULE OUT POTENTIALLY TREATABLE or CURABLE TUMORS (immunohistochemistry & other studies) i.e. Breast Ca, Germ Cell Tumors, Lymphomas TREAT THE PATIENT CHARACTERIZE THE SPECIFIC CLINICOPATHOLOGICAL ENTITY FAVOURABLE SUBSET [similarly to relevant primaries with “curative intent”] UNFAVOURABLE SUBSET [with empirical chemotherapy with “palliative intent” or with specific treatment following gene profiling] STEP 1 STEP 2 STEP 3
- 54. THEORIES: 1. BURNED OUT PRIMARY: primary cancers may inexplicably regress or involute entirely despite the fact that metastases have occurred. 2. LOST PRIMARY: The primary may have arisen from embryonic “rest cells” that are fully differentiated but did not complete its migration. 3. UNRECOGNIZED PRIMARY NEOPLASMS 4. May result from a specific germ line genetic lesions present in all cells 5. TUMORS of ADULT STEM CELLS: some of these neoplasms may arise from adult stem cells with an ability to differentiate to multiple lineages.
Editor's Notes
- Thank you for inviting me to speak. This is actually a very hard topic. And in fact, I haven’t heard anyone lecture this at all in the past 6 years that I was training and in the past 1 and a half year that I was in private practice. Maybe this is because they are usually not included in clinical trials.
- I would have to say that the improvement in diagnosing and treating cancer of unknown primary has been modest. From recognizing favorable subgroups, improved diagnostic techniques, to providing empiric chemotherapy to improving pathologic techniques to provide a more tailored treatment.
- What I’m going to talk about for the next 20 minutes will be the Clinical Aspect of Cancer of Unknown Primary or CUP
- First of all I would like to give you a definition of cancer of unknown primary. Cancer of unknown primary is a clinical disorder where patients present with histologically confirmed metastatic cancer for which standard diagnostic investigations failed to identify the primary site. CUP diagnosis can be considered a result of diagnostic failure. Many primary anatomical primary sites are just too small to identify despite improved clinical diagnostic testing. The median age is 65 It is not a rare disease, it accounts for 3-5% of all human cancers And it is considered to be the 7th – 8th most frequent malignant tumor. tumor.
- The clinical characteristics of CUP is the early dissemination of the disease, where you cannot find the primary at the beginning. It is considered to be an aggressive disease, and sometimes has this peculiar and unpredictable metastatic pattern which means that you find different natural histories of the disease in comparison with the known primary tumors.
- This is a typical case of a man with a supraclavicular lymphadenopathy without any mass elsewhere.
- This is a man presenting with just subcutaneous lesions
- A man with a huge liver full of metastatic sites
- Or someone else with bilateral lung metastases, as typified by these cannon ball lesions on chest xray, BUT without any primary site.
- If you ask me, Cancer of Unknown Primary… Is it one disease or its not one disease… The question here is a bit difficult to answer, BUT ITS REALLY NOT ONE DISEASE…
- What do I mean by that… If you look at this histological classification, you’ll find out that the majority of these cancers are adenocarcinoma. Almost 85%. Only 10% are squamous cell carcinoma and all the rest are the so-called undifferentiated neoplasms.
- If you pay attention to the next 2 to 3 slides, you will get at least the meaning of this talk. We divide cancer of unknown primary into different clinicopathological entities. We have patients with mainly liver metastases which is almost adenocarcinoma. We have patients with mediastinal or retroperitoneal lymphadenopathy. Or patients with axillary lymphadenopathy, or cervical or inguinal lymphadenopathy ONLY.
- We also have patients with peritoneal disease, either the so-called primary peritoneal carcinomatosis which is papillary or serous adenocarcinoma which looks like your ovarian cancer. Or the malignant ascites of other unknown origin, which is not serous or papillary adenocarcinoma. We also have patients with only lung metastases or patients with only pleural effusion.
- We also have patients with only bone disease. Either just one or more than one. The same thing with brain. We have patients just brain metastases without a primary site. We have the neuroendocrine tumors and also the melanoma of unknown primary. So these are clinicopathological entities that gives you an idea that Cancer of Unknown Primary is definitely not just one disease.
- How do we search using laboratory tests to identify the primary site? First of all you need a very good histopathology with immunohistochemistry and sometimes advanced molecular technology. You need imaging with conventional radiology, ultrasonography, CT scan, MRI, mammography, PET scan. And also you need endoscopy, starting from ENT panendoscopy, bronchoscopy, colonoscopy, proctoscopy or colposcopy. Of course we don’t do all these just to find the primary site.
- What about the histopathology?
- If you want to identify your primary site, you have to follow 3 steps. The first step is to detect the BROAD type of your malignancy. Is this a carcinoma? Is this a lymphoma? Is this a melanoma? Or is this a sarcoma? So youll have to apply a number of different immunohistochemical staining.
- Step 2… You have to detect the subtype of carcinoma. Is this an adenocarcinoma? A germ cell tumor, a hepatocellular tumor, renal cell carcinoma, thyroid carcinoma, neuroendocrine carcinoma, or squamous cell carcinoma?
- And the last step, is that once you have diagnosed an adenocarcinoma, then you need to identify whether the primary site could be hidden somewhere in the prostate, in the lung, breast, colon, pancreas or the ovary. You will need EXTENSIVE immunohistochemical staining.
- Cytokeratins are very useful, especially CK 7 and CK 20.
- This is an algorithm which can be very useful to you. If you have a CK7+ and CK20+, you might be dealing with… If you have a CK7+ and CK20-, then you might be dealing with any of the diseases in this box. If you have a CK7- and CK20+, then it might be a colorectal carcinoma or a merkel cell carcinoma. If you have a CK7- and CK20-, then it might be any of these diseases.
- What about molecular analysis? Yup, it gives you the accuracy of the primary site in up to 90% of the cases.
- Basically doing a molecular or genetic analysis entails the quantification of the gene expression of the patient’s tumor and then the assay compares it to the gene expression profile of known tumors from a reference database then this will predict the tumor type.
- These are several assays that we have in the market that can help us identify the primary tumor (but are not locally available)
- Let me go to endoscopy. Please don’t do endoscopy to all patients. Only if your patient has symptoms or signs which are relevant to the suspicious disease. Don’t do endoscpies to everybody. Also don’t do all the serum tumor markers to everybody because they are useless in CUP and might just confuse you They do not have any prognostic or any diagnostic o any predictive value except for some cases like CA-125 in peritoneal carcinomatosis or PSA which is specific for prostate cancer
- Then we come to the treatment. How are we going to treat these patients?
- In 2003, an article in the European Journal of Cancer divided cancer of unknown primary into two diseases.
- We have the good prognosis subsets and the poor prognosis subsets.
- The next questions to answer is “Do we have effective drugs for cancer of unknown primary or do we just have responsive subsets of patients?
- So if you go to the good prognosis subsets
- Youll find patients with ….. (enumerate) So these are the GOOD PROGNOSIS type of patient.
- Survival is just like any metastatic colon cancer ranging from 21-37 months.
- We also have some other favourable subsets. If you have blastic bone metastases with elevated PSA, you have to treat this as advanced prostate cancer. And if you have these 2 lucky groups, then you just do local excision then radiation.
- Lets see now the unfavorable subsets or the poor prognosis patients…
- (enumerate) The point here that you have to keep in mind is that these UNFAVOURABLE SUBSETS represent the 80% of patients with CUP. Only 20% belongs to the good prognosis subset.
- If you treat these patients with empiric chemotherapy, the responses are quite poor and the median survival is also poor.
- This is lifted from the Clinical Practice Guidelines given by ESMO, we can use this for the poor prognosis subsets.
- Does the identification of the primary site by molecular tumor profiling following site specific therapy improve patient’s outcome? What is the evidence today? These questions are yet to be answered in the coming years..
- This is a paper investigating the accuracy of the 92-gene RT-PCR assay. It says here that the sensitivity to detect the primary site was 87% accurate.
- This is a paper published in the Journal of Clinical Oncology a couple of years ago, they treated patients with the help of gene profiling and what they found was that the median survival was 12.5 months.
- These are the site specific treatments, they were given conventional chemotherapy regimens.
- This is the difference between the two groups of patients. As you can see here, the assay directed group fared better with 12.5 months vs those treated with conventional chemotherapy with only 9.1 months. However, not that this study only used historical controls.
- After a couple of weeks, some nasty editorials came back saying that solid conclusions cannot be made unless randomized controlled studies are done. It also said that we should not make gene profiling as the gold standard for treating CUP.
- We have two randomized studies going on, on in France and one in UK, we expect the results to give a more solid conclusion on gene profiling.
- If you open the NCCN Version 2 of 2017, it says there that we should talk to our pathologists so that we can give them the clinical picture of our patient so that we can use immunostains and genetic profiling on a case to case basis.
- So in summary, we have seen a lot of developments in the diagnosis and treatment of CUP. From the 1970s when CT scans, immunostains were not yet available fast forward to the present time when we have MRI and PET scans, with evolving immunostaining and available gene profilers, we can now identify the likely site of primary and offer site-directed therapy.
- So with that, this is my last sIide. I would like to give you the take home message and the steps that you need to diagnose and treat cancers of unknown primary site. If you have a patient with metastatic carcinoma, STEP 1, search for the primary site by good clinical examination, immunohistochemistry, imaging and endoscopy studies. And then STEP 2, rule out potentially treatable or curable tumors by immunohistochemisty. Nobody wants to miss a breast cancer or a germ cell tumor or most of all a lymphoma. STEP 3, characterize the specific clinicopathological entity. If you end up with a patient with a favourable subset, treat your patient accdg to the known and accepted regimen with curative intent. If the patient belongs to the unfavourable subgroup, treat them with palliative intent or if you have the money, send the tissue for tumor profiling and then treat it accdingly. And with that, I would like to thank you for your attention.