1. Delving into the Occult

2. Introduction Occult From the Latin word occultus meaning clandestine, hidden or secret Occult Cancer Carcinoma of unknown primary (CUP)

3. Introduction Case Study Diagnostic Work-Up of CUP Role of Pathology Future Advances

4. Case Study Mr X Presented to his GP with a 3-week history of left- sided neck swelling Referred to ENT for diagnostic work-up Past History: None of note Non-smoker

5. Case Study History of Presenting Complaint Noticed swelling in left neck  no increase in size, non-painful No other symptoms  no dysphagia, hoarseness, weight loss, fevers, night sweats etc.

6. Case Study Diagnostic Work-up

7. Case Study Clinical Examination Neck:  Palpable enlarged node in the left neck at Level IV  Firm and mobile  Non-fluctuant No other significant findings

8. Case Study Biopsy Fine Needle Aspirate Cytology Malignant epithelial cells with keratinisation and necrosis Consistent with metastatic squamous cell carcinoma

9. Case Study Biopsy Fine Needle Aspirate Histology Malignant epithelial cells with keratinisation and necrosis Consistent with metastatic squamous cell carcinoma

10. Case Study Biopsy Fine Needle Aspirate Histology Malignant epithelial cells with keratinisation and necrosis Consistent with metastatic squamous cell carcinoma Where is the primary?

11. Case Study CT Scan of Neck, Thorax, Abdomen & Pelvis 2 lesions in left neck behind sternocleidomastoid muscle, 2cm each Most likely necrotic lymph nodes No other abnormality identified

12. Case Study Whole Body PET-CT FDG avid left-sided cervical lymphadenopathy Small focus of increased FDG uptake at left base of tongue No other abnormality identified

13. Case Study Whole Body PET-CT FDG avid left-sided cervical lymphadenopathy Small focus of increased FDG uptake at left base of tongue No other abnormality identified

14. Case Study Panendoscopy with Left Tonsillectomy & Tongue Biopsies Panendoscopy revealed no obvious tumour Left Tonsillectomy:  Reactive lymphoid hyperplasia Biopsy Left Base of Tongue Biopsy:  No evidence of malignancy

15. Case Study Case Summary Metastatic SCC No known primary despite extensive clinical work-up CUP

16. Definition Metastatic tumour detected when the site of the primary origin cannot be identified despite a detailed work-up Accounts for 3 - 5% off all cancers 7 th – 8 th most frequent malignant tumour 4 th most common cause of cancer death

17. CUP Incidence in Ireland 10 – 13 cases per 100,000 per year Up to 4.7% of all cancer deaths Males > Females Median age at presentation is 65 – 70 years Average survival of 4 – 12 months

18. CUP with Cervical Nodes Location of the positive node can indicate the location of the primary tumour Upper & Middle Neck LN Head & neck primary Lower Neck LN Primary below the clavicles

19. CUP with Cervical Nodes Primary tumours tend to be small  65% less than 1.0 cm  30% less than 0.5 cm  May be deep in tonsil Why do we get early nodal metastatic disease from a small primary tumour?

20. Characteristics of CUP Early metastases Absence of symptoms of the primary tumour Unpredictable pattern of metastases Undifferentiated metastases Aggressive clinical course

21. Diagnostic Work-Up History & physical examination Routine laboratory studies Serum tumour markers Chest X-ray Symptom-directed endoscopy CT thorax, abdomen & pelvis  Further imaging: PET-CT, Mammogram Biopsy

22. Role of Pathologist Determine the histopathological subtype to aid in  Locating the primary tumour  Optimising treatment options

23. Histopathological Subtype Carcinoma  Adenocarcinoma  Squamous Cell Carcinoma Melanoma Lymphoma Sarcoma

24. Histopathological Subtype Carcinoma  Adenocarcinoma  Squamous Cell Carcinoma Melanoma Lymphoma Sarcoma

25. Histopathological Subtype Carcinoma  Adenocarcinoma  Squamous Cell Carcinoma Melanoma Lymphoma Sarcoma

26. Histopathological Subtype Carcinoma  Adenocarcinoma  Squamous Cell Carcinoma Melanoma Lymphoma Sarcoma

27. Histopathological Subtype Carcinoma  Adenocarcinoma  Squamous Cell Carcinoma Melanoma Lymphoma Sarcoma

28. Histopathological Subtype Carcinoma  Adenocarcinoma  Squamous Cell Carcinoma Melanoma Lymphoma Sarcoma

29. Histopathological Subtype Carcinoma  Adenocarcinoma  Squamous Cell Carcinoma Melanoma Lymphoma Sarcoma

30. Determining Primary Site Immunohistochemistry AE1/3, CAM5.2 S100, MelanA, HMB45 CD45 Vimentin Tumour Subtype Carcinoma Melanoma Lymphoma Sarcoma

31. Immunohistochemistry CK7 / CK20CK7 + / CK20 +CK7 + / CK20 -CK7 - / CK20 +CK7 - / CK20 -

32. Immunohistochemistry CK7 / CK20CK7 + / CK20 + Upper GIT Pancreas CK7 + / CK20 -CK7 - / CK20 +CK7 - / CK20 -

33. Immunohistochemistry CK7 / CK20CK7 + / CK20 + Upper GIT Pancreas CK7 + / CK20 - Thyroid Lung Breast Endometrium CK7 - / CK20 +CK7 - / CK20 -

34. Immunohistochemistry CK7 / CK20CK7 + / CK20 + Upper GIT Pancreas CK7 + / CK20 - Thyroid Lung Breast Endometrium CK7 - / CK20 +ColonCK7 - / CK20 -

35. Immunohistochemistry CK7 / CK20CK7 + / CK20 + Upper GIT Pancreas CK7 + / CK20 - Thyroid Lung Breast Endometrium CK7 - / CK20 +ColonCK7 - / CK20 - Prostate Kidney Adrenal

36. Adenocarcinoma Primary SiteImmunohistochemistry LungTTF-1 PancreasCK19 Upper GITCDX2, CK7 ColonCDX2, CK20 LiverHepar-1 ThyroidTTF-1 BreastER, GCDFP-15 ProstatePSA KidneyRCC, PAX8

37. Squamous Cell Carcinoma Primary SiteImmunohistochemistry Lungp63, CK5/6 Head & Neck: -Oropharyngeal -Nasopharyngeal -Oral (Mouth) CK5/6 p16 (HPV) EBV p16 and EBV negative

38. Future Advances Molecular Profiling Gene expression profiling to identify the genetic signature of the CUP Uses RT-PCR and microRNA assays to identify the tissue of origin of the tumour Prediction accuracies of 80 – 90%

39. Case Study

40. Left modified radical neck dissection

41. Case Study Histology Forty lymph nodes 2 lymph nodes positive for metastatic SCC

42. Case Study Histology Forty lymph nodes 2 lymph nodes positive for metastatic SCC

43. Case Study Histology Forty lymph nodes 2 lymph nodes positive for metastatic SCC p16 positive

44. Case Study Histology Forty lymph nodes 2 lymph nodes positive for metastatic SCC p16 positive Possible oropharyngeal origin

45. Case Study Staging N2b  Ipsilateral nodes < 6 cm in greatest dimension

46. Conclusion CUP accounts for 3 – 5% of all cancers and has a poor prognosis. Diagnostic work-up includes:  Careful clinical history & thorough examination  Routine laboratory tests and tumour markers  Imaging  Biopsy IHC is an essential part of histopathological assessment in determining the primary site.

47. Take Home Messages CUP in Neck Node Cystic neck node in male > 40 years is metastatic malignancy until proven otherwise Inadequate/negative aspiration must be followed up with further tissue evaluation p16 (HPV) positive carcinoma in cervical node may be an oropharyngeal primary  Tonsil and base of tongue are primary suspects EBV positive carcinoma in cervical node may be a nasopharyngeal primary

48. Future Model for CUP

49. Thank you