Diagnostic strategies for carcinoma of unknown primary

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Outline of presentation. DefinitionEpidemiologyBasic WorkupHistological Subtypes Identifying favorable groupsImmunohistochemistryRadiologic dataGene expression profilingPrognosisConclusions. Definition. Carcinoma of unknown primary (CUP) is biopsy-proven malignant tumor for which the primary site cannot be identified after initial workup consisting of:Thorough H

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Diagnostic strategies for carcinoma of unknown primary

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1. Diagnostic strategies for carcinoma of unknown primary Saiama N Waqar, MD

2. Outline of presentation Definition Epidemiology Basic Workup Histological Subtypes Identifying favorable groups Immunohistochemistry Radiologic data Gene expression profiling Prognosis Conclusions

3. Definition Carcinoma of unknown primary (CUP) is biopsy-proven malignant tumor for which the primary site cannot be identified after initial workup consisting of: Thorough H &PE breast and pelvic examination in women testicle and prostate examination in men Laboratory and radiologic tests CBC, blood chemistries, PSA CXR, and CT abdomen/pelvis, mammogram Detailed histological evaluation exclude lymphoma, melanoma & sarcoma

4. Where is the primary? primary tumor either remains microscopic and escapes clinical detection or disappears after seeding the metastasis Do metastases occur late? debatable. Propensity to metastasize might be hardwired early in tumorigenesis3 Primary tumor has a poor prognosis signature from the start and is angiogenically incompetent to present clinically (failed neoangiogenesis or from locally secreted antiangiogenic factors), but it can metastasize to various organs4

5. Epidemiology 3-5% of all cancer diagnoses1 2 % of all cancer diagnoses in the Surveillance, Epidemiology, and End Results (SEER) registries between 1973 and 1987 In most cases, primary site not found in patient’s lifetime Post-mortem: 20% have no detectable primary tumor site2

6. Medical history and physical examination History past biopsy results history of surgery Removed lesions Family history: HNPCC or hereditary breast carcinoma physical examination palpation of the thyroid, breasts, lymph nodes, and prostate and a DRE left supraclavicular Virchow's node or periumbilical Sister Mary Joseph's node -GI tract poorly differentiated carcinoma perianal mass- anal carcinoma in a patient with inguinal adenopathy

7. Pathologic evaluation: H&E Tissue specimens from a FNA or core needle biopsy subjected to light microscopic examination after they are stained with hematoxylin and eosin Adenocarcinoma -70 % Poorly differentiated carcinoma - 15 to 20 % Poorly differentiated neoplasm - less than 5 % Squamous cell carcinoma (SCC) - uncommon Neuroendocrine carcinoma - uncommon

8. Adenocarcinoma of unknown primary Metastatic sites: liver, lungs, lymph nodes, and bones. Autopsy series: 40-50% of primary sites were pancreas, hepatobiliary and lung Breast and prostate origins are relatively infrequent in this setting PSA, mammogram PET in 20 to 30% IHC for PSA, ER, PR, mammaglobin Stool occult blood and endoscopy if positive, low yield if asymptomatic Tumor markers (CEA, CA 19-9, CA 15-3, CA-125) not useful for diagnosis or prognosis though frequently elevated May help to monitor response to therapy

9. Poorly differentiated carcinoma These patients have a high frequency of mediastinal and retroperitoneal involvement. chest and abdominal CT scans should be routinely performed ? serum hCG & AFP may suggest the diagnosis of extragonadal germ cell tumor IHC staining treatable tumors from unsuspected primary sites can be identified in 10 to 20%

10. Poorly differentiated neoplasm Pathologist is confident of the diagnosis of malignancy, but is unable on light microscopy to distinguish between a carcinoma, sarcoma, or lymphoma IHC-vimentin, CK, CEA, PSA LCA: lymphoma vs carcinoma Vimentin: sarcoma Electron microscopy (EM) can distinguish lymphoma from carcinoma, adenocarcinoma from squamous cell, and can detect sarcomas, melanomas, and neuroendocrine tumors Chromosomal analysis : NHL (account for 35-65%), some sarcomas, testicular and extragonadal germ cell tumors Most of the remaining tumors are carcinomas

11. Squamous cell carcinoma  Inguinal adenopathy primary site in the genital or anorectal area Pelvic exam/genital exam, DRE, proctoscopy Upper and mid cervical adenopathy head and neck cancer CT of the head and neck, direct laryngoscopy, and nasopharyngoscopy. PET scan if CT and endoscopy negative Lower cervical or supraclavicular adenopathy primary lung cancer CT of the chest and bronchoscopy.

12. Poorly differentiated neuroendocrine carcinoma exhibit neuroendocrine features on IHC, but are not sufficiently differentiated to suggest the diagnosis of a small cell cancer or a carcinoid/islet cell tumor usually clinical evidence of a high grade or aggressive malignancy, with metastases in multiple sites RP and mediastinal LN are frequently involved A specific primary site is rarely identified, even with extensive testing

13. Treatments for specific subsets of patients with CUP

14. Immunohistochemstry IHC markers help to define tumor lineage when peroxidase-labeled antibodies are used against specific tumor antigens. select the appropriate battery of antibodies and cannot be replaced by using a universal battery of marker No IHC test is 100% specific, including PSA, which can be positive in patients with salivary gland carcinoma IHC markers are for guidance in conjunction with the patient's presentation and imaging studies to select the best therapy

15. Immunohistochemistry markers

16. Additional Markers Used as Suggested by Clinical Data (after a Preliminary Workup with CK7 and CK20)

17. Chest X-ray and CT Neg CXR- should a chest CT be obtained? retrospective study :chest CT compared with CXR in 32 patients with brain metastasis without a known primary tumor 12 patients (38%), CXR reported as negative or nonspecific, but a chest CT revealed a primary neoplasm Lesion size: major factor in detecting a primary tumor on chest X-ray Lung cancer is one of the most common identifiable primary in CUP, therefore a chest CT is usually performed, especially if the pathologic tests are suggestive of a lung primary tumor A CT scan of the abdomen and pelvis is routinely performed

18. Mammography Mammograms should be performed for all women who present with metastatic adenocarcinoma regardless of the results of the pathologic evaluation

19. MRI The role of MRI is unclear unless there is a contraindication to CT scan Accepted use: isolated axillary LN mets and suspected occult breast primary with negative mammograms (<1% of breast cancer) Morris et al - 12 women with isolated axillary metastatic adenocarcinoma. 9 patients: enhancement was observed on MRI. Surgery revealed primary tumors at the same site Mastectomy in 2 patients with negative MRI findings did not reveal breast tumor Olson et al - 40 women with metastatic disease to the axillary lymph nodes and no primary tumor was found on mammograms. 28 (70%), primary tumor was found on an MRI 12 women had negative MRI. 5 of these 12 underwent MRM and 4 of them had no evidence of tumor in the mastectomy specimen Negative breast MRI scans predicted a low yield at mastectomy, irradiate the breast instead

20. MRI in occult breast cancer Overall sensitivity of MRI was 94% with a specificity of 94% to 100% and estimated positive predictive value (PPV) was 90%. MRI as the imaging study of choice potential for breast cancer detection staging, which can then be used to guide treatment planning identification of localized disease may offer some women the option of breast-conservation therapy as an alternative to mastectomy. f/u of patients with lumpectomy and radiation therapy have similar outcome to the patients with breast cancer with LN+

21. PET Meta-analysis of 28 studies (total of 910 patients) published between 1990-2007 Selection criteria: studies of detection of CUP using FDG-PET or FDG-PET/CT conventional workup failed to detect primary tumor study population of at least four patients with CUP the histology and/or follow-up data were used as a gold standard sensitivity, specificity, LR+ LR- calculated.

22. PET The combination of functional and anatomic imaging (PET and CT scans) reduces the false-positive rate PET/ PET-CT reveals a primary tumor in 60-100% and has a false-positive rate of approximately 12.5-40% Several studies of the utility of the PET scan in patients with occult primary head and neck carcinomas help to guide the biopsy, determine the extent of disease, and determine the appropriate treatment Outside of this indication, PET scans cannot currently be recommended for the standard workup of all patients with UPC cost-effectiveness in this setting has not been studied

23. Gene expression profiling in CUP 2cohorts of CUP patients Retrospective tissue specimens from 78 patients treated at Sarah Cannon Cancer Center, Nashville, TN April 1998-2005 72/78 treated on clinical trials using various taxanes and platinum, 5th paclitaxel/carbo/etoposide vs gemcitabine/irinotecan Prospective cohort – tissue specimens from 42 patients at MD Anderson, Houston, TX March 2004- June 2007 Treatment tailored to patient, clinical features, IHC

24. Methods Veridex CUP assay with 10 gene markers tested by RT-PCR, distinguished 6 primary sites: Lung HUMPB, TTF-1, DSG3 Pancreas PSCA, F5 Colon CDH17 Breast MGB, PDEF Prostate PSA Ovarian WT-1 If the profile did not fit any of these 6, it was designated as “other” Performed on RNA isolated from 6 to 9 10m FFPE tissue sections H &E stains done to ensure that specimen contained >10% tumor cells Therapy for prospective cohort guided by results of diagnostic evaluation including IHC, but not the Veridex assay

25. Tissue of origin prediction results

26. Results Assay yielded a result in 104 patients (87%) In the rest, the extracted mRNA was of insufficient quality or yield The Veridex assay assigned tissue of origin in 63 patients (61% of those with suitable RNA and 52% of total) 55 patients were designated lung, pancreas, or colon, which equates to 53% of the total, this is consistent with previous CUP autopsy studies Remaining 8 patients were assigned to an origin in ovary, breast or prostate Thus in 48% patients, the assay either did not yield a result or was unable to assign an origin

27. Results The predicted primary site was compatible in most patients with the clinicopathologic information IHC performed variably, and not in all cases Done in 37 patients, and suggested primary site only in 4 (11%), compared with 23 (62%) by veridex assay comprised of a minimal panel of CK7,20 and TTF-1 with some additional markers in a few cases, so suboptimal for comparison Patients with lung and pancreas profiles had poor response to treatment Patients with colon cancer profiles (on both veridex and IHC) in the prospective cohort had a better outcome (sustained partial response) to colon-cancer specific therapies than with emperic taxane-platinum CUP therapy administered to the retrospective cohort

28. Gene expression profiling in adenocarcinoma of unknown primary Formalin-fixed, paraffin-embedded (FFPE) samples were obtained from 84 patients with a known primary adenocarcinoma 38 patients with adenocarcinoma unknown primary (ACUP) extensive immunohistochemical panel classified 16 22 patients remained unclassified for their histogenetic origin The expression data were analyzed in relation to clinicopathologic variables and immunohistochemical results.

29. Agendia CupPrint assay used 495 predictive genes in a custom oligonucleotide microarray correctly classified 70 (83%) of the 84 known cancers tested Primary/mets of known primary, comprising 10 cancer types including breast, lung, colon, kidney, stomach, pancreas, ovary, thyroid, bladder, dysgerminoma (not all of which are adenocarcinomas) was excellent at classifying many primary sites, such as breast and colon misclassified metastases included seven (63%) of the 11 originating from lung and all three (100%) from pancreas, as well as two of three from stomach. This lack of sensitivity for lung and pancreas is an important limitation because these are the most common primary sites giving rise to ACUP

30. Discussion 38 patients with ACUP were studied 16 cases had already been resolved by IHC, in 15, the CupPrint prediction agreed Weakness Single origin in 22 unresolved cases, though some suggestions surprising (rhabdomyosarcoma or germ cell tumor, in an elderly man and woman, respectively) Strength of the study all tumors yielded a prediction with CupPrint all biopsies were reexamined by a single pathologist with application of an IHC panel comprising 10 to 12 markers

31. Summary-expression profiling First large-scale validation studies of mRNA-based gene signatures for the prediction of primary site in CUP patients Assay lacks sensitivity for lung and pancreatic origins IHC is superceded by mRNA-based assays in up to 1/2 of cases, however, this can be argued only if IHC has been optimally selected, performed, and interpreted The outcome data comprise response rate rather than survival, and the patient numbers are still somewhat small Future directions: Prospective studies in which expression profiling results direct primary site-specific therapy and determine whether this approach is superior to empirically selected CUP treatment regimens in terms of patient outcome

32. Prognosis Classification and regression tree (CART) Analysis of 1,000 patients referred to UT MD Anderson from 1987 to 1994 Median age – 59 (range 17 to 89) < 50 – 26% 50-69 – 57% > 70 – 17% Male 52%, female 48%

33. Prognosis

34. Conclusions CUP represents a group of heterogeneous tumors sharing the unique characteristic of metastatic disease without identifiable origin at the time of initial therapy Although identification of the primary tumor may provide valuable information regarding both treatment and prognosis, aggressive diagnostic workup is usually of little value and not cost effective The recommended approach is to pursue a limited diagnostic approach to identify favorable subsets Potential role for gene expression profiling in identifying primary site

35. References Varadhachary GR, Abbruzzese JL, Lenzi R. Diagnostic strategies for unknown primary cancer. Cancer. 2004 May 1;100(9):1776-85 Koesnikov-Gauthier H, Levy E, Merlet P, et al. FDG PET in patients with cancer of an unknown primary. Nucl Med Commun. 2005 Dec;26(12):1059-66. Naresh KN. Do metastatic tumours from an unknown primary reflect angiogenic incompetence of the tumour at the primary site? - a hypothesis. Med Hypotheses. 2002; 59: 357-360 Van't Veer LJ, Weigelt B. Road map to metastasis. Nat Med. 2003; 9: 999-1000. Varadhachary GR, Talantov D, Raber MN et al. Molecular profiling of carcinoma of unknown primary and correlation with clinical evaluation. J Clin Oncol. 2008 Sep 20;26(27):4442-8. Dong M, Zhao K, Lin X et al. Role of fluorodeoxyglucose-PET versus fluorodeoxyglucose-PET/computed tomography in detection of unknown primary tumor: a meta-analysis of the literature.. Nucl Med Commun.2008 Sep;29(9):791-802. Hess KH et al, Clin Cancer Res 1999; 5: 3406-3410 Horlings HM, van Laar RK, Kerst JM et al. Gene expression profiling to identify the histogenetic origin of metastatic adenocarcinomas of unknown primary. J Clin Oncol. 2008 Sep 20;26(27):4435-41. Orel S. Who Should Have Breast Magnetic Resonance Imaging Evaluation? Journal of Clinical Oncology, Vol 26, No 5 (February 10), 2008: pp. 703-711 Morris EA, Schwartz LH, Dershaw DD, van Zee KJ, Abramson AF, Liberman L. MR imaging of the breast in patients with occult primary breast carcinoma. Radiology. 1997; 205: 437-440 Olson JA Jr., Morris EA, Van Zee KJ, Linehan DC, Borgen PI. Magnetic resonance imaging facilitates breast conservation for occult breast cancer. Ann Surg Oncol. 2000; 7: 411-415

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