Metastatic Disease of the Liver: a Common Sense Approach to a Disclosure of Relevant Common Problem Financial Relationships

3/23/2017

Metastatic Disease of the Liver: A common sense approach to a Disclosure of Relevant common problem Financial Relationships

USCAP requires that all planners (Education Committee) in a position to Lawrence Burgart influence or control the content of CME disclose any relevant financial relationship WITH COMMERCIAL INTERESTS which they or their Allina Health spouse/partner have, or have had, within the past 12 months, which relates to the content of this educational activity and creates a conflict of interest. Dr. Burgart University of Minnesota has nothing to disclose. Minnesota Gastroenterology Minneapolis/St. Paul, MN

Temporary metastasis to Haridwar, India Hepatic Metastases • Common, multiple per day

1 3/23/2017

Hepatic Metastases Hepatic Metastases • Common, multiple per day • Common, multiple per day • Image guided (ultrasound, CT) • Image guided (ultrasound, CT) – Nearly half with adequacy assessment – Nearly half with adequacy assessment • • Suspected/known primary site Suspected/known primary site – Confirm, obtain ancillary predictive studies – Confirm, obtain ancillary predictive studies • Unknown primary site • Unknown primary site – Broader evaluation; don’t forget liver primary – Broader evaluation; ddx includes liver primary • Therapeutic resections, CRC – Therapeutic response evaluation

Hepatic Metastases ‐ Adequacy Multiple masses, suspected unusual primary

• Touch prep of US or CT needles • Cytotechnologist where available • Regional hospitals, scheduled when pathologist present for lab management • Diff‐Quik stain

Hepatic Metastases ‐ General 72 year old woman • Common primary sites – Colorectal and upper GI – Pancreatobiliary – Lung – Breast • Less common primary sites – Everything happens… – Melanoma, GYN, GU, soft tissue, hematolymphoid, etc

2 3/23/2017

Clinical Information Critical 72 year old woman (and, anything can happen)

• 12 yrs ago, parotid tumor • Resected, locally extensive, Rad Rx • 5 yrs ago, local recurrence, add’l resection • 1.5 yrs ago, local recurrence Metastatic acinic cell carcinoma • 0.5 yrs ago liver masses, one large, several small

Suspected / known primary site Suspected / known primary site Example #1

• Confirmation, definitive therapy • 47M, morbid obesity, T2 diabetes • Ancillary predictive studies • ED for 2 weeks left lower back pain – Anticipated and unanticipated • CT, sigmoid colon thickening and multiple – Conserve tissue!! liver masses • Liver biopsy was elected • Plan for neoadjuvant chemotherapy

47M, AdCA with necrosis 47M, “normal” background liver

3 3/23/2017

47M, classic histology DNA MMR only IHC performed

DNA MMR intact (MLH1)

Suspected / known primary site Suspected / known primary site Example #1 Example #2

• Metastatic adenocarcinoma c/w CRC • 89F, weight loss, cough, 30 pk‐yr smoker • Kras, nras, braf assays wildtype • 5.3 cm necrotic lung mass, extending into mediastinum • 4.9 cm liver mass suspicious for met • Image guided liver biopsy

89F S16-77497

Necrosis

4 3/23/2017

S16-77497 S16-77497

Small amount of tumor Strongly TTF1 positive

Suspected / known primary site Example #2 Example #2 FMP system for ancillary studies • DIAGNOSIS • Liver Non‐small cell lung carcinoma (NSCLC), favor adenocarcinoma

• COMMENT • Immunostains were performed on this case. The results follow, and support the above interpretation.

• TTF1: Positive • p40: Negative

• **LUNG ANCILLARY TESTING PROTOCOL** • Case number: Sxx‐xxxxxx Patient name: xxxxxx xxxxxx

• HISTOLOGIC TYPE • Non‐small cell lung carcinoma (NSCLC), favor adenocarcinoma • STAGE IV STATUS • Histologically proven stage IV disease • TISSUE BLOCK AVAILABLE FOR ANCILLARY TESTING • A1 • COMMENT • This patient’s sample meets Allina Lung Cancer Committee criteria* for reflex EGFR, ALK, ROS1, and PDL1 (for pembrolizumab (Keytruda) eligibility) testing. EGFR, ALK, ROS1, and PDL1 testing will be performed and results will be communicated in addenda. There is no need to call to order EGFR, ALK, ROS1, and PDL1 testing. If there is a need for ancillary tests other these, please call 612‐863‐ 4670 (option 2). • • *Allina Lung Cancer Committee EGFR, ALK, ROS1, and PDL1 reflex testing criteria: • Stage IV disease (histologically proven or clinically suspicious) • Adenocarcinoma or TTF‐1 positive adenosquamous cell carcinoma.

Suspected / known primary site S17‐5512 Example #2b

• 71F, extensive perirectal abscess, sepsis • Hospitalized, sequential imaging • Large RML lung mass, multiple liver masses • Image guided liver biopsy

5 3/23/2017

S17‐5512 S17‐5512

TTF1

Suspected / known primary site Suspected / known primary site Example #2b Example #3

• **LUNG ANCILLARY TESTING PROTOCOL** Case number: Sxx‐xxxxxx Patient name: xxxx xxxxxxx HISTOLOGIC TYPE Small cell carcinoma STAGE IV STATUS • 75F, ductal breast CA 2 years earlier Histologically proven stage IV disease TISSUE BLOCK AVAILABLE FOR ANCILLARY TESTING A1 • Stage IIA, ER+, HER2 amplified COMMENT This patient’s sample does NOT meet Allina Lung Cancer Committee criteria* for reflex EGFR, ALK, ROS1, or PDL1 (for pembrolizumab (Keytruda) eligibility) testing. The block identified above • will be stored in pathology for 10 years for possible future ancillary testing. If you would like ALK, Now develops 5.5 cm liver mass EGFR, or any other ancillary tests in the future, please call 612‐863‐4670 (option 2). *Allina Lung Cancer Committee EGFR, ALK, ROS1, and PDL1 reflex testing criteria: Stage IV disease (histologically proven or clinically suspicious) Adenocarcinoma or TTF‐1 positive adenosquamous cell carcinoma for EGFR, ALK, ROS1, and PDL1 Squamous cell carcinoma or NSCLC, favor squamous cell carcinoma for PDL1.

75F 75F

6 3/23/2017

75F 75F

ER negative HER2 3+ positive

Known Primary, final points Unknown Primary

• Conserve tissue • Metastases to cirrhotic liver? – Consider splitting cores into separate cassettes • Metastasis versus cholangiocarcinoma – Minimize IHC, get history, compare • Broad workup issues, based on original • Comment on background liver tissue, or histologic impression “no background liver tissue present” • Review clinical record carefully

Unknown primary site 62M cirrhosis Example #1

• 62M, alcoholic cirrhosis, ascites, anasarca, SOB, thrombocytopenia • Imaging notes multiple liver masses

7 3/23/2017

62M cirrhosis S17-2406

S17-2406 Unknown primary site Example #1

• 62M, alcoholic cirrhosis, ascites, anasarca, SOB, thrombocytopenia • Imaging notes multiple liver masses • IHC: – Positive: Chromogranin, synaptophysin, cdx2 – Negative: Hepar

Unknown Primary Unknown Primary • Undifferentiated large cell malignancy: • Cytokeratin cocktail (AE1/AE3/Cam 5.2), CD45, S100, HMB45, CD117, synaptophysin. Others based on individual features and/or initial immunohistochemistry. May be • Undifferentiated large cell malignancy useful to optimize tissue utilization by pre‐cutting additional unstaineds for immunohistochemistry. • Oncocytic large cell malignancy • Oncocytic large cell malignancy: • Small cell carcinoma/undifferentiated large cell neuroendocrine • Cytokeratin cocktail (AE1/AE3/Cam 5.2), Hepar, arginase, S100, HMB45, CD117, synaptophysin, inhibin. • Well differentiated neuroendocrine carcinoma • Small cell carcinoma/undifferentiated large cell neuroendocrine: • Adenocarcinoma • Cytokeratin cocktail (AE1/AE3/Cam 5.2), TTF1, CK7, CK20, synaptophysin, chromogranin. Consider anorectal squamous carcinoma (aka cloacagenic carcinoma). • Spindle cell lesion or overt hematopoietic neoplasm: See other • Well differentiated neuroendocrine carcinoma conference! • Adenocarcinoma • Spindle cell lesion or overt hematopoietic neoplasm: See other conference!

8 3/23/2017

Unknown Primary Unknown primary site • Undifferentiated large cell malignancy Example #2 • Oncocytic large cell malignancy • Small cell carcinoma/undifferentiated large cell neuroendocrine • Well differentiated neuroendocrine carcinoma • 72F, f/u high grade invasive urothelial CA • Adenocarcinoma: – 5 years ago, treated by TURB & chemo • CK7, CK20, cdx2 &/or CDH17, TTF1. If woman, GATA3, estrogen – Imaging shows 4.5 cm liver lesion, gastrohepatic receptor. Some use CK17 & CK19 as an adjunct for LNs cholangiocarcinoma (negative & positive, respectively, in many cases) versus metastasis. When the primary is likely upper GI or • EUS FNAB, liver mass and LN pancreatobiliary, there is typically a comment regarding likelihood of specific primary site. Of note, cholangiocarcinoma often • Cystoscopy and CT => normal bladder presents with multiple masses.

• Spindle cell lesion or overt hematopoietic neoplasm: See other conference!

72F 72F

CDX2 CK20

9 3/23/2017

72F 72F

CK7 GATA3

Unknown primary site Therapeutic Resection, CRC Example #2

• 72F, f/u high grade invasive urothelial CA • Confirm CRC – 5 years ago, treated by TURB & chemo – Imaging shows 4.5 cm liver lesion, gastrohepatic LNs • Evaluate margins • EUS FNAB, liver mass and LN • Cystoscopy and CT => normal bladder • Evaluate chemorads effect • Normal upper, lower endoscopy • Chemotherapy ass’d liver injury • CPC most c/w cholangiocarcinoma

Case 1 Therapeutic Resection, CRC TRG

• Tumor Regression Grade: TRG1‐ Absence of tumor cells, replaced by fibrosis TRG2‐ Rare scattered tumor cells, abundant fibrosis TRG3‐ Significant residual tumor, predominant fibrosis TRG4‐ Tumor cells predominating over fibrosis TRG5‐ Almost exclusively tumor cells without fibrosis

Annals of Oncology 2007;18:299‐304

TRG4

10 3/23/2017

Case 1 Case 2

TRG4 TRG2

Case 2 Case 3

Fibrosis TRG1

Case 3 Case 4

TRG1 TRG3

11 3/23/2017

Case 2, TRG 2 Therapeutic Resection, CRC TNI

• Tumor Thickness at Tumor‐Normal Interface: "The focus in which the maximum contiguous tumor cell thickness was observed at the TNI {perpendicular to TNI in mm} was measured by a ruler. This focus was composed of uninterrupted layers of tumor cells without admixed fibrotic stroma, acellular mucin, or nonneoplastic liver parenchyma."

Am J Surg Pathol 2010;34:1287‐94 TNI 1.5

Case 4, TRG2 Radiologic response ‐ RECIST

Journal of Surgical Oncology 2016;113:456–462

TNI 0

Pathologic response ‐ TRG Pathologic response ‐ untreated

Journal of Surgical Oncology 2016;113:456–462

12 3/23/2017

Therapeutic Effect, Liver Therapeutic Resection, CRC CALI

Sinusoidal dilatation: SOS 0‐ absent • Confirm CRC SOS 1‐ mild (centrilobular involvement limited to one‐third of the lobular surface) SOS 2‐ moderate (centrilobular involvement limited to two‐thirds of the lobular surface) SOS 3‐ severe (complete centrilobular involvement) • Evaluate margins Nodular Regenerative Hyperplasia: NRH 0‐ absent • Evaluate chemorads effect NRH 1‐ nodules present but indistinct NRH 2‐ nodules present but only occasionally distinct NRH 3‐ nodules distinct in most examined areas • Chemotherapy ass’d liver injury Fatty Liver Disease: Steatosis % Grade steatohepatitis (Brunt 0‐3) Stage steatohepatitis (Brunt 0‐4) Annals of Oncology 2004;15:460‐6 Ann Surg 2013;258:731‐42

F17‐315 F17‐315

Cytokeratin CD45 (CD20)

13 3/23/2017

F17‐315 F17‐315

CD138 Kappa ISH

F17‐315

Lambda ISH