The clinically challenging entity of liver metastasis from tumors of unknown primary

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1 The clinically challenging entity of liver metastasis from tumors of unknown primary Xuchen Zhang, MD, PhD Associate Professor of Pathology Department of Pathology Yale University School of Medicine

2 Liver Mass Lesions Cirrhotic liver Hepatocellular Carcinoma (HCC) Macroregenerative Nodule Dysplastic Nodule Cholangiocarcinoma Metastases Other rare primary liver tumors Non-cirrhotic liver <50 years Hepatocellular Adenoma Focal Nodular Hyperplasia Hepatocellular Carcinoma (HCC) Other Primary Tumors of Liver Metastases >50 years Metastases Hepatocellular Carcinoma (HCC) Focal Nodular Hyperplasia Cholangiocarcinoma Other Primary Tumors of Liver

3 Liver Mass: Work up Main issue: Primary vs. Metastases Clinical history Tumor morphology IHC markers Molecular testing Metastases: Known vs. Unknown Primary Clinical history Tumor morphology and comparison with previous tumor IHC markers Molecular testing

4 In the setting of known or highly suspected primary site: Goals of the biopsy 1. Confirm the metastasis 2. Limited or no IHC markers to preserve tissue for any further ancillary tests for guiding therapy

5 Diagnosis: Metastatic adenocarcinoma of lung primary Clinical History Case 1 71-year-old man presented with large lung mass with multiple liver masses TTF1

6 Non-Small Cell Lung Cancer, Version , NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2017;15(4):504-53

7 Cancer of Unknown Primary: Goals of the biopsy Figure out the likely primary site At the same time preserve tissue for any ancillary tests for targeted therapy or clinical trials

8 Cancer of Unknown Primary: Approach to biopsies The clinical work-up of Cancer of Unknown Primary heavily relies on a pathologist No studies to help optimize the work-up of such case and most of the guidelines are based on personal preference or experience Three approaches are possible in this setting: Use a standardized set of markers for all cases Use a standardized set of markers for each morphologic pattern of tumor Design the IHC panel in each case depending on the clinical setting and morphology

9 Conner JR, Hornick JL. Adv Anat Pathol. 2015;22(3): Approach to Cancer of Unknown Primary Most Frequent CK7 and CK20 Profiles of Various Primary Carcinomas

10 Pavlidis N, et al. J Adv Res. 2015;6(3): Approach to Cancer of Unknown Primary Immunohistochemistry tests for investigating CUP

11 Approach to Cancer of Unknown Primary Stelow EB, Yaziji H. Semin Diagn Pathol. 2018;35(2):

12 Primary site specific Markers Lung TTF-1 GI tract: CK7 CK20 CDX2/SATB2 Thyroid TTF-1 Thyroglobulin Kidney: PAX8 Prostate NKX3.1 PSA ERG Breast GATA3 ER Mammaglobin GCDFP-15 GYN: PAX8 WT1 p53

13 Expression of TTF-1 in Carcinomas From Various Primary Sites Conner JR, Hornick JL. Adv Anat Pathol. 2015;22(3):149-67

14 Expression of CDX2 in Carcinomas From Various Primary Sites Conner JR, Hornick JL. Adv Anat Pathol. 2015;22(3):149-67

15 Expression of PAX8 in Carcinomas From Various Primary Sites Conner JR, Hornick JL.. Adv Anat Pathol. 2015;22(3):149-67

16 Clinical History - Case 2 68 year old female with liver mass lesions Breast carcinoma 9 years ago - Triple-negative (ER, PR and Her2) invasive ductal carcinoma CK7 GATA3 CK7+, GTAT3+, ER-, PR-, Her2-, CK20-, TTF1-, CDX2-

17 Clinical History - Case 2 The carcinoma is positive for CK7 and GATA3. What is the best diagnosis based on the clinical history, histology and IHCs? 1. Metastatic breast carcinoma 2. Poorly differentiated carcinoma of pancreaticobiliary origin 3. Poorly differentiated carcinoma from other sites Can any other ancillary tests will be helpful?

18 Cancer of Unknown Primary Our Experience Liver, Mass, Biopsy: - Metastatic poorly differentiated carcinoma, most consistent with metastatic carcinoma of breast primary, see note Note: The patient s prior history of breast carcinoma (ER-, PR- and Her2-) was noted; however, the prior material is not available for review. The current liver mass biopsy shows a poorly differentiated carcinoma, which is positive for CK7 and GATA3; but negative for other breast markers (ER, PR, Her2, mammaglobin), lung marker (TTF1) and lower GI tract markers (CK20, CDX2). Although the tumor cell morphology and immunoprofile are nonspecific, the findings are most consistent with metastatic carcinoma of breast primary, correlation with clinical history and imaging studies is suggested.

19 What is the best approach? Is there any best approach??

20 Cancer of Unknown Primary Our Experience No pre-decided IHC panels: The work-up is customized based on the clinical setting and morphology of the tumor : 406 liver biopsies from metastasis The cases were categorized based on morphology as: Adenocarcinoma (Adca) Squamous cell carcinoma (SqCC) Poorly differentiated carcinoma/ carcinomas(nos) Neuroendocrine tumor (NET) Melanoma Spindle cell tumor Hematologic neoplasms were excluded from this study

21 Cancer of Unknown Primary Our Experience We analyzed the IHC markers used in each case Final diagnosis in each case was based on pathologic evaluation and further clinical work-up Cases where the primary site remained unknown despite pathologic work up and clinical investigation were called true-cup The data of ancillary molecular tests was analyzed when performed

22 Cancer of Unknown Primary Our Experience 5% 4% 2% 15% 52% 12% 10% Adenocarcinoma Carcinoma PDC NET SCC Melanoma Spindle

23 Cancer of Unknown Primary Our Experience Various morphologic categories and suggested makers Morphologic pattern Adenocarcinomas Suggested markers CK7 and/or CK20, then accompanied by site specific markers: CDX2 or SATB2, TTF1 or Napsin A, PAX8 (RCC or Mullerian), NKX3.1 or PSA, GATA3, SF-1, etc. Poorly differentiated epithelioid malignancy Small cell carcinoma/undifferentiated large cell neuroendocrine carcinoma Well differentiated neuroendocrine tumor Spindle cell lesions Cytokeratin cocktail (AE1/AE3/Cam 5.2), CD45, S100 or SOX10, CD117, p40/p63, synaptophysin or INSM1 Cytokeratin cocktail (AE1/AE3/Cam 5.2), TTF1, synaptophysin, INSM1, NKX3.1, CDX2 Synaptophysin, chromogranin, INSM1, Ki-67, hep par-1, CDX2, TTF1, PAX8 Dog-1, CD34, SMA, Desmin, SOX10, Stat6, etc.

24 Cancer of Unknown Primary Our Experience Morphologic category: Adenocarcinoma 216 Adenocarcinom as 76 CUP 140 Known Primary 1 Breast 18 Cholangiocarcinoma 6 Colon 2 Esophagus 1 Gallbladder 14 Lung 25 Pancreas 2 Prostate 2 Stomach 3 Small Intestine 1 Appendix 1 True-CUP (1.3%) -

25 Cancer of Unknown Primary Our Experience Morphologic category: Carcinoma (NOS) 9 CUP 1 Adrenal 1 Breast 1 Colon 1 Prostate 5 Kidney 51 Carcinomas 42 Known Primary 0 True-CUP (0%) 28 Breast 1 Colon 3 Mullerian (Endometrial) 1 Mullerian (Serous) 1 Pancreas 1 Pancreas (adenosquamous) 1 Prostate 2 Ampullary (adenosquamous) 4 Kidney

26 Cancer of Unknown Primary Our Experience Morphologic category: Poorly Differentiated Carcinoma 20 CUP 2 Cholangiocarcinoma 2 Breast 1 Lung 3 Pancreas 7 Lung 2 Urothelial 1 Renal 48 PDCs 2 True-CUP (10%) 28 Known Primary -

27 Cancer of Unknown Primary Our Experience Morphologic category: Neuroendocrine tumors 54 NET 40 CUP 14 Known Primary 21 Lung 5 Pancreas 1 Colon 6 Small Intestine 1 Paraganglioma 6 True-CUP (15%) 7 Lung 1 Small Intestine 1 Colon (rectum) 1 Colon (IC valve) 3 Pancreas 1 Skin (Merkel Cell Carcinoma)

28 Cancer of Unknown Primary Our Experience Morphologic category: Spindle cell neoplasm 8 Spindle cell tumors 7 CUP 1 Known Primary 3 Mullerian (Leiomyosarcomas) 1 Angiosarcoma 1 Cholangiosarcoma 1 GIST (Duodenum) 1 GIST (Stomach) 0 True-CUP 1 Carcinosarcoma (Ovary)

29 Cancer of Unknown Primary Our Experience Common morphology: Adca, NET, Ca (NOS), PDC, SqCC, melanoma and spindle cell neoplasm Overall, the true-cup consists about 8% of originally recognized CUP cases CK7 is the mostly used marker (176 cases, 43%) with a positivity rate of 76% (133 cases) and CK7-oma 12.8% in CPU cases Average use: 3.8 Abs/case (Adeca: 3.3/case; Ca-NOS: 2.7/case; NET 4.8/case; PD-Ca: 5.6/case) Despite use of limited marker approach based on morphology, the number of t-cup are minimal This approach not only be more cost-effective compared to preselected extensive panels, but also preserves tissues for other ancillary tests

30 Cancer of Unknown Primary Our Experience Let s go back case 2 68 year old female with liver mass lesions Breast triple-negative carcinoma 9 years ago Liver, Mass, Biopsy: - Metastatic poorly differentiated carcinoma, most consistent with metastatic carcinoma of breast primary, see note CK7 GATA3 Note: The patient s prior history of breast carcinoma (ER-, PR- and Her2-) was noted; however, the prior material is not available for review. The current liver mass biopsy shows a poorly differentiated carcinoma, which is positive for CK7 and GATA3; but negative for other breast markers (ER, PR, Her2, mammaglobin), lung marker (TTF1) and lower GI tract markers (CK20, CDX2). Although the tumor cell morphology and immunoprofile are nonspecific, the findings are most consistent with metastatic carcinoma of breast primary, correlation with clinical history and imaging studies is suggested.

31 Expression of GATA3 in Carcinomas From Various Primary Sites Conner JR, Hornick JL. Adv Anat Pathol. 2015;22(3):149-67

32 Cancer of Unknown Primary Our Experience Case 2 : Targeted NGS Cancer Gene Panel (Oncomine Assay) Variants detected in the tumor: FGFR2 Y376C IDH1 R132C BAP1 L429F

33 Cancer of Unknown Primary Our Experience Intrahepatic cholangiocarcinoma (icca) can mimic liver metastasis Tumor samples from patients with cholangiocarcinoma were analyzed using the MSK-IMPACT platform, a targeted next-generation sequencing assay that analyzes all exons and selected introns of 410 cancer-associated genes icca: IDH1 (30%), ARID1A (23%), BAP1 (20%), TP53 (20%), and FGFR2 gene fusion (14%) BAP1 mutation and FGFR2 gene fusion: exclusively in icca Liver, Mass, Biopsy (Case 2): - Poorly differentiated carcinoma, consistent with intrahepatic cholangiocarcinoma Lowery MA, et al. Clin Cancer Res May 30. [Epub ahead of print]; Rizvi S and Gores GJ. J Hepatol. 2017;67(3):

34 Cancer of Unknown Primary Molecular diagnostics 172/406 (42%) liver biopsies received molecular testing 144/406 (35%) liver biopsies had detectable mutations Example: Colon Cancer Primary Site (62 liver biopsies) 20 Colon primary liver metastases have TP53 mutations 22 Colon primary liver metastases have KRAS mutations 17 Colon primary liver metastases have APC mutations 3 Colon primary liver metastases have BRAFv600E mutations 5 Colon primary liver metastases have PIK3A mutations 2 Colon primary liver metastases have RB1 mutations. Clinically relevant targetable genomic alterations were found in 85% -Ross JS, et al.. JAMA Oncol 2015;1:40 49.

35 Cancer of Unknown Primary Summary Beware of prior clinical history Morphology of many carcinomas overlaps, but is the best clue to choose your IHC panels Cost-effective than preselected extensive panels Conserves tissues as well Some cases are only CK-7 positive (CK7-omas) and remain most challenging in practice Molecular diagnostics May be helpful for determination of primary site May help identify predictive markers or markers for targeted therapy

36 Acknowledgement Yale Pathology Jeff Wang, MD Dhanpat Jain, MD Yale Oncology Jill Lacy, MD

37 Cancer of Unknown Primary Our Experience Morphologic Category: Squamous Cell Carcinoma 6 Lung 8 CUP 20 SqCC 2 True-CUP (25%) 12 Known Primary 2 Esophagus 3 Anus 1 Mullerian (Cervix) 2 Oral Cavity 1 Tongue 1 Tonsillar 2 Lung

38 Cancer of Unknown Primary Our Experience Morphologic category: Melanoma - 1 CUP 15 Melanoma 1 True-CUP 14 Known Primary 8 Eye (Choroidal) 4 Skin 2 Nasal Cavity

39 Case 2 : Targeted NGS Cancer Gene Panel (Oncomine Assay)

40 Cancer of Unknown Primary Our Experience At our institution there are no pre-decided IHC panels, and the workup is customized based on the clinical setting and morphology of the tumor We identified 406 liver metastasis biopsies from For analysis, the cases were categorized based on morphology as: - Adenocarcinoma (Adca) - Squamous cell carcinoma (SqCC) - Poorly differentiated carcinoma, other carcinomas (NOS) - Neuroendocrine tumor (NET) - Melanoma - Spindle cell tumor