1. Mediterranean School of Oncology Rome, March 6, 2010 Università degli Studi di Palermo Facoltà di Medicina e Chirurgia Dipartimento di Oncologia Cattedra di Oncologia Medica Uos Terapie Oncologiche Innovative Prof. S. Palmeri Clinical approach to the patient

2. What is my tumor origin?

3. “Despite the increasing array of sophisticated diagnostic tools, oncologists have struggled to understand a subset of pts with metastatic cancer in whom detailed investigations fail to identify a primary anatomic site (3-5%)” Unknown primary tumor

4. Unknown primary tumor: definition  Histologically confirmed metastatic cancer  Failing to identify the primary site after: 1. Detailed medical history 2. Complete physical examination (including breast and pelvic in women,testicular and prostate in men) 3. Full blood count and biochemistry, urinalysis and stool occult blood testing 4. Chest rx 5. Abdomen and pelvis CT 6. Mammography 7. Other (sign or symptom-guided!!)….but:  Not yet standardized (different diagnostic work up)!

5. Unknown primary tumor A clinical study of 302 consecutive autopsied patients (Le Chevalier 1988) Pancreas26% Lung17% Unknown16% Kidney0.5% Gynaecological0.4% Colon0.3% Gastric0.3% Esophagus0.3% H&N0.3% Thyroid0.3% Adrenal glands0.3% N=302 pz

6. Unknown primary tumor: clinical and biological features  The most frequent primary tumors in CUP pts don’t include some of the most common neoplasms in the general pop, as breast and prostate  Early dissemination  Clinical absence of the primary tumor at diagnosis  Unpredictable metastatic pattern  Wide spectrum of signs and symptoms (> 50% of pts present with multiple sites of disease)  Aggressive behaviour  Life expectancy:6-9 mo

7. Unknown primary tumor: main sites of disease Le Chevalier Kirsten Abbruzzese (n=302) (n=286) (n=657) Nodes 37% 14%37% Lung 19% 16%28% Bone 13% 16%28% Liver 5% 19%31% Pleura 2% 12%12% Peritoneum 1% 6% 6% Brain 10% 8% 8% Skin 9% 1% 2% Adrenal gl 0 0 2%

8. Unknown primary tumor: comparison of metastatic involvement of common sites with known primary carcinomas vs CUP BoneLungLiver Primary siteKnownCUP- Primary* KnownCUP- Primary* KnownCUP- Primary* Lung384028NA1519 Breast493427193419 Pancreas414 38276 Prostate88506 40 Colorectal3421207792 Metastatic organ site involvement (%)* *Pts presenting with CUP in whom the primary site was subsequently discovered Known primaries:2287, CUP in whom primary site discovered:413

9. Unknown primary tumor: the dilemma for the oncologist

10. Search?Rapidly treat?

11. Unknown primary tumor  More tailored therapy  Better knowledge about prognosis and natural history  The physician may believe to fail serving the patient adequately  The patient is reassured  The family is reassured Why search?

12. Unknown primary tumor  Poor prognosis  Extensive diagnostic work-up may be expensive and not conclusive  < 20% of CUP pts have a primary site of their cancer identified antemortem and in 15-30% of cases the origin remain occult even at autopsy  Avoid long waitings  Risks from invasive diagnostic modalities  The patient is reassured  The family is reassured Why rapidly treat?

14. Unknown primary tumor: clinical approach to the patient

15. Unknown primary tumor The natural history is diverse and dependent on multiple variables:  Age  N. of metastatic sites  Dominant area of disease  Histology

16. Unknown primary tumor evaluation of the patient

17. Unknown primary tumor: evaluation of the patient Obiettivi:  History  Physical Examination  Clinical manifestations  Laboratory studies  Pathologic evaluation  Imaging

18. Unknown primary tumor: evaluation of the patient Obiettivi:  History  Physical Examination  Clinical manifestations  Laboratory studies  Pathologic evaluation  Imaging

19. Unknown primary tumor: evaluation of the patient History:  Critical !!  It can define areas of concerns (e.g. respiratory system in a smoker with a supraclavicular node,cough and hemoptysis)  History of previous biopsies or removed lesions or past spontaneously regressing lesions  Family history can be helpful (specific ethnic group, hereditary syndromes)

20. Unknown primary tumor: evaluation of the patient Obiettivi:  History  Physical Examination  Clinical manifestations  Laboratory studies  Pathologic evaluation  Imaging

21. Unknown primary tumor: evaluation of the patient Physical Examination:  Should be rigorous  Include careful palpation of the thyroid, breasts, nodes, liver, prostate  DRE  Genital examination  Aspects often overlooked in CUP patients  Can provide the probable diagnosis  Formulate a directed laboratory and radiographic evaluation

22. Unknown primary tumor: evaluation of the patient Obiettivi:  History  Physical Examination  Clinical manifestations  Laboratory studies  Pathologic evaluation  Imaging

23. Unknown primary tumor: evaluation of the patient Clinical manifestations:  Extremely varied  Symptoms and signs similar to those of pts with advanced malignancies of known origin  The most common symptoms/signs at presentation: - general deterioration : 73% - digestive symptoms: 58% - liver enlargement: 58% - abdominal pain: 56% - respiratory symptoms: 45% - ascites: 26% - node enlargement: 16%

24. Unknown primary tumor Site of metastasisPresumptive origin Above the diaphragm All sitesLung Axillary nodesBreast, lung, GI Supraclavear nodesH&N,thyroid,lung,GI Cervical nodesH&N,thyroid,lung Below the diaphragm All sitesPancreas UmbilicalGI (++ stomach),ovary, uterine InguinalAnal canal, rectum, prostate, vulva, testicular

25. Unknown primary tumor: evaluation of the patient Obiettivi:  History  Physical Examination  Clinical manifestations  Laboratory studies  Pathologic evaluation  Imaging

26. Unknown primary tumor: evaluation of the patient Laboratory studies:  Complete blood cell count (anemia)  Iron metabolism (iron deficiency  possible chronic GI blood loss)  Urinalysis (microscopic hematuria or proteinuria)  Liver function studies including HBV,HCV markers  Tumor markers (b-HCG, AFP, PSA, CEA, CA 125) ?

27. Unknown primary tumor: tumor markers CLINICAL PRESENTATION SUSPECTMARKER Young pts with mediastinal or retroperitoneal mass Extragonadal germ cell tumor α FP, β HCG ♀,adenoca,axillary nodes BreastCA 15-3,CEA ♀, ascitis ± pelvic mass Ovarian CA 125 ♂, multiple bone or lung mts Prostate PSA,PAP Pts with disseminated adenopaties Lymphomas β 2 microglobulin

28. Unknown primary tumor: evaluation of the patient Obiettivi:  History  Physical Examination  Clinical manifestations  Laboratory studies  Pathologic evaluation  Imaging

29. Unknown primary tumor: definition  Not standardized (extent of evaluation)  Histologically confirmed metastatic cancer  Failing to identify the primary site after: 1. Detailed medical history 2. Complete physical examination (including breast and pelvic in women,testicular and prostate in men) 3. Full blood count and biochemistry, urinalysis and stool occult blood testing 4. Chest rx 5. Abdomen and pelvis CT 6. Mammography 7. Other (sign or symptom-guided)

30. Unknown primary tumor: evaluation of the patient Obiettivi: Pathologic evaluation:  Accurate pathologic assessment is essential  The lesion is neoplastic and primary/metastatic  Light microscopy  Immunohistochemistry  Electron microscopy  Biological studies

31. Unknown primary tumor: histology  Well-moderately differentiated adenoca 50%  Undifferentiated or poorly differentiated ca 30%  Squamous cell ca 15%  Undifferentiated neoplasms 5% (including neuroendocrine tumors, lymphomas, germ cell tumors, melanomas, sarcomas and embryonal malignancies)

32. Unknown primary tumor: evaluation of the patient Pathologic evaluation:  Light microscopy (classify the tumor into broad groups such as carcinoma, sarcoma or lymphoma; not helpful in 35% of cases)  Immunohistochemistry (peroxidase-labeled Ab against AFP,b- HCG, PSA, CK7, CK 20, TTF-1)  Electron microscopy (adenoca: microvilli and mucin,neuroendocrine tumors: secretory granules, melanoma: premelanosomes)  Biological studies (abnormalities of chrom 12 in germ cell tumors, gene profiling, overexpression of p53, bcl-2, Her- 2/neu)

33. Unknown primary tumor Close communication clinician  pathologist

34. Unknown primary tumor: evaluation of the patient Obiettivi:  History  Physical Examination  Clinical manifestations  Laboratory studies  Pathologic evaluation  Imaging

35. Unknown primary tumor: evaluation of the patient Imaging:  Initial radiographic studies: chest x-ray and abdomen CT  Abdomen CT :detection of the primary site in 30-35%  Imaging or endoscopy of the upper and lower GI tract indicated if abdominal complaints, ascites, liver metastases  Mammography and MRI (in the setting of isolated axillary adenopathy MRI very sensitive in detecting occult primary >75%)  PET (occult primary H&N cancers)

36. History A 52-year-old patient with history of metastatic squamous cell cancer of left posterior cervical lymph node from unknown primary. PET Findings PET/CT localized the primary in the region of the left tonsil.

37. Unknown primary tumor Integration of various diagnostic modalities in CUP management Varadhachary, Semin Oncol 2009

38. Recommended general approach  directed evaluation based upon clinical presentation and pathologic findings Unknown primary tumor

42. Unknown primary tumor: main aims in the evaluation of the patient

43. Obiettivi:  Research of the primary tumor  Evaluation of the extent of disease  Rapid identification of curable patient subsets

44. Unknown primary tumor: prognosis  Histology: -squamocellular ca  OS= 6 mo - adenoca  OS =8 mo - undifferentiated or poor differentiated ca OS=19 mo - neuroendocrine ca  better prognosis OS=23 mo  T  N° of involved sites ( OS  1 site= 10 mo, 2 = 8 mo, 3 = 6 mo)  PS  N vs liver

45. MD Anderson approach to the patient with newly diagnosed carcinoma of unknown primary site Important treatable subsets and their management  Women with isolated axillary adenopathy  Same as for stage II breast cancer  Present recommended management: axillary dissection, axillary RT, systemic CT, breast RT if MRI positive or suspicious  10 y DFS=65%  Prognosis not as favorable in men with axillary adenopathy only

46. MD Anderson approach to the patient with newly diagnosed carcinoma of unknown primary site Important treatable subsets and their management  Women with peritoneal carcinomatosis (papillary adenocarcinoma)  Same as for stage III ovarian cancer  Median survival=16 -24 mo

47. MD Anderson approach to the patient with newly diagnosed carcinoma of unknown primary site Important treatable subsets and their management  Extragonadal germ cell syndrome  Same as for nonseminomatous germ cell tumor

48. MD Anderson approach to the patient with newly diagnosed carcinoma of unknown primary site Important treatable subsets and their management  Neuroendocrine carcinoma  Same as for carcinoid/pancreatic islet cell carcinoma;  cisplatin-based CT for poorly differentiated neuroendocrine tumors

49. MD Anderson approach to the patient with newly diagnosed carcinoma of unknown primary site Important treatable subsets and their management  High- and mid-cervical adenopathy (squamous cell carcinoma)  Surgical resection of palpable disease + curative RT to the neck  30-50% 5-y survival rates

52. Unknown primary tumor: conclusions  Rational and calculated clinical approach  Empathic physician-patient relation  Oncological team  Consider the individual patient’s needs  Cost/benefit ratio  60% of CUP cases don’t fit into favorable clinical subsets  > of pts visceral metastases  New therapies  Future trends: molecular characterization of CUP  Need for centralized patient referral