MRS PC, 63YO WOMAN  Initially presented with chronic RIF pain  Found to have cholelithiasis, underwent a laparoscopic cholecystectomy  On the laparoscopy, nothing abnormal was noted in the abdomen  The pain persisted

MEDICAL HISTORY  Panic attacks  Varicose veins  Cholelithiasis  Distant ex-smoker (ages 18-27)

FAMILY HISTORY  Mother: ovarian ca (age 70+)  Maternal aunt: breast ca (age ~70)  Father: lung ca (smoker)

HOPC (CONT.)  Went on to have transvaginal ultrasound, which showed a cystic lesion on the R) ovary  CT and PET scan showed:  Large avid pelvic mass  Avid serosal/peritoneal areas elsewhere  Small volume ascites in the pelvis which was mildly avid  Underwent laparotomy for radical debulking and biopsies

PATHOLOGY  Histology showed multicystic mucinous cells on samples of:  Serosal surface of the ovaries and fallopian tubes  R) and L) parametria  R) pelvic side wall  Staining:  Strong, diffuse CK7 and CDX2 positivity  Patchy CK20 positivity  ER negative  Felt by pathologist to be of pancreatobiliary origin

DIAGNOSIS  Adenocarcinoma of unknown primary  Possibly pancreatobiliary source  Distribution of disease not

TREATMENT  Following surgery, was given chemotherapy  FOLFOX + Avastin  Had an adverse drug reaction to oxyplatin x2  Maintenance treatment  Xeloda  Achieved complete metabolic remission (on PET) for a period of 4-5 months

RECURRENCE  6 weeks ago, PET showed:  Avid serosal/peritoneal deposits on sigmoid colon  Avid peritoneal fluid in the pelvis  Started on chemotherapy  CBDCA + Paclitaxel + Avastin

TREATMENT COMPLICATIONS Acute:  Oxyplatin hypersensitivity  Fatigue  Dry skin  Mucosal ulcers  Occasional nausea Permanent:  Incisional hernia  Peripheral neuropathy, stable  Manifest as paraesthesia and neuropathic pain in feet and fingers  Nil trouble with weakness, gait disturbance, unsteadiness, falls  Some trouble with getting out medications as a result

CARCINOMA OF UNKNOWN PRIMARY (CUP)  Heterogenous group of metastatic cancers where the primary site cannot be found  Small primaries may remain undetected  Primaries may have regressed  Primaries may be incidentally removed in treatment for other conditions  Accounts for 3% of cancer diagnoses  As they are heterogenous, they vary widely in prognosis and response to specific treatments

CLASSIFYING CUP  Clinical manifestations  i.e. isolated axillary lymphadenopathy in women vs. peritoneal disease  Pathological examination  Cytology  Immunohistochemistry  Gene expression profiling

CYTOLOGY  May differentiate tissue of origin but will not definitively determine primary site  SCC is likely to have come from respiratory tract, but may come from skin  Adenocarcinoma is particularly troublesome, as it may originate in many organs  Very poorly differentiated cancers may not be identifiable

IMMUNOHISTOCHEMISTRY  Involves stains for specific proteins which may help to predict the primary site  CK7 and CK20 are commonly tested initially  Results of initial stains inform selection of further stains  The amount of tissue is often a limiting factor  IHC staining algorithms have been shown to predict the primary site correctly in approximately two thirds of cancers with KNOWN primary in blinded studies

GENE EXPRESSION PROFILING  Tests gene expression of malignant cells using techniques such as rt-PCR and microarrays  Focuses on genes which help delineate organ of origin  Assays may test for up to 92 genes to delineate between up to 42 tumour types  GEP assays have been shown to predict the primary site correctly in approximately 85% of cancers with KNOWN primary in blinded studies (probably closer to 75% of CUP)  In CUP studies, shows ~78% concordance with IHC predictions  When IHC is more definitive (i.e. predicts single tumour type), GEP is more highly concordant than when IHC is ambiguous