Endoscopic Ultrasound for Cancer Staging

Dr. Yuk Tong LEEMBChB, MD(CUHK), FRCP (Edin), FRCP(Lond), FHKCP, FHKAMSpecialist in Gastroenterology and Hepatology

Cancer stagingn Tumour staging – TNM classification

q T stage – local extension / invasion of the disease

q N stage – local lymph node metastases

q M stage – distant metastases, non-regional lymph node metastases

n TNM stage determine resectability and treatment options.

7th Edition, AJCC Cancer Staging Manual, Jan 2010

EUS for cancer staging

n Good for local stage – T and Nn Good for certain common metastatic sites that close to

the GI tractq Mediastinum q Left adrenal glandq Left lobe of the liverq Celiac axis and intraabdominal lymph nodeq Peri-rectal regionq Ascites (peritoneal metastases)

n Could perform FNA for tissue diagnosis

EUS for cancer staging

n Esophageal cancern Stomach cancern Pancreatic cancern Lung cancern Cholangiocarcinoman Ampullar tumourn Rectal cancer

Useful for stage dependent treatment / protocol

EUS for cancer staging

n Esophageal cancern Stomach cancern Pancreatic cancern Lung cancern Cholangiocarcinoman Ampullar tumourn Rectal cancer

Endoscopic Ultrasonography (EUS)

n Combines both endoscopic and ultrasonic examination in one

n High frequency (5-20MHz) US transducer used

n Close proximity to the GIT and surrounding organs

n Highly accurate in diagnosing both mural and extramural structural abnormality

Electronic Radial EUS

GF-UE260

n Electronic radial scopen Color and Power Doppler

study

Linear EUSn Scanning plane is

along the scope shaft

n Blood flow study

n Could monitor FNA

Needle

Tumour

Miniature probes

UM2R / 3RUM-G20-29R

UM-G20-26R

3D miniature probes

UM-DP12-25R

3D miniature probes

Volume calculation 3D reconstruction

Non-optic rectal probe

RU-75M-R1

Working channel

(2.0mm)

7.5 MHz Convex

Optical system

Forward oblique

Shaft (6.9mm)

Endobronchial ultrasound (EBUS)

EUS accuracy in staging oesophageal cancer

n Consensus conference

n The sensitivity of EUS-FNAC TNM staging of

oesophageal cancer is > 85%.

n In patients with oesophageal cancer, EUS-FNAC is more

accurate than CT for local staging of mediastinal lymph

nodes.

n Predict long term survival

Maluf-Filho F, Endoscopy 2009

EUS in oesophageal cancer

n N=125 patient with EUS and PET done.

n All undergoing resection

n Only EUS T staging is an independent predictor of long term survival.

Omloo JMT, Endoscopy 2008

T1-2

T3

Spiral CT vs EUS vs EUS-FNA for LN staging

Sensitivity Specificity Accuracy

CT 29% 89% 51%

EUS 71% 79% 74%

EUS-FNA 83% 93% 87%P-values

CT vs EUSCT vs EUS-FNAEUS vs EUS-FNA

<0.001<0.0010.058

0.2570.6550.102

0.003<0.0010.012

Vazquez-Sequeiros, et al. Gastroenterology 2003

n First prospective blinded comparison study

CA oesophagus: Spiral CT vs EUS vs EUS-FNA

T stage Stage I-IIA (%) Stage IIb-III (%) Stage IV (%)CT 65% 23% 12%EUS 38% 46% 16%EUS FNA 36% 50% 14%

Vazquez-Sequeiros, et al. Gastroenterology 2003

32.8% were upgraded by the EUS-FNA: no direct surgery.

n Cohort of patients from merged Medicare-SEER

(Surveillance, Epidemiology, and End Results) database

n Developed jointly by the National Cancer Institute and

the Centers for Medicare and Medicaid Services

n 2830 patients identified.

n 303 (10.7%) patients undergone EUS for staging

EUS staging in CA oesophagus improves survival

Das A, et al. Clin Gastroenterol Hepatol 2006

Das A, et al. Clin Gastroenterol Hepatol 2006

EUS staging in CA oesophagus improves survival

Received stage-appropriate treatment

EUS for early oesophageal caner / High grade dysplasia

n Meta-analysis - 12 studies,

n Compared with surgical or EMR pathology staging, EUS

had T-stage concordance of 65%

n EUS is not sufficiently accurate in determining the T-

stage of high-grade dysplasias or superficial

adenocarcinomas; other means of staging, such as

EMR, should be used.

Young PE, Clin Gastroenterol Hepatol 2010

Esophageal Cancer

CT / EUS / PET

No adenopathy Adenopathy Distant metastasis (M1b)

EUS FNA Palliative

Stage IV (M1a, M1b)Stage IIb / III

(T3-4 or N1)

Stage IIa

(T2-3, N0)Mucosal disease

Neoadjuvant chemo/RTPalliative

Chemo/RT

SurgerySurgery

>SM1

Staging EMR / ESD

EUS FNA of the CLN has an invaluable role in esophageal cancer management and should be incorporated

Modified from Palmar KS, et al. Ann Thorac Surg 2002

Cure

Gastric cancer - 3D Spiral CT vs EUS

N=63 T staging N StagingSensitivity Specificity Sensitivity Specificity

EUS 82.4% 96% 57% 89.5%CT 69.1% 94.4% 57.4% 89.3%

Bhandari, Gastrointest Endosc 2004

EUS vs CT vs PET for LN met

Sen Spec PPV NPV Accuracy

EUS 42% 91% 82% 60% 66%

CT 35% 93% 83% 58% 63%

PET 49% 87% 79% 63% 68%

Combined 65% 80% 77% 69% 72%

Choi J, Surg Endosc. 2010

n N = 109 Gastric CA, n LN met - pathology verified

Ascites in gastric cancer

n Peritoneal metastases (PM) is found in 25-50% of patients with GC at presentation

n PM is frequently associated with ascitesn 6 years prospective study n Consecutive GC patients underwent EUS in

PWHn Compared with US, CT and surgery

Lee YT, et al. Gut 2005

Detection of ascites in GC patients

Overall 93 patients had ascites being detected and 71 patients confirmed to have PM

Sensitivity in detecting ascites:EUS - 87.1%Combining US and CT scan - 16.1%Operative findings - 40.9%

Lee YT, et al. Gut 2005

Predicting Peritoneal Metastases

Sen Spec PPV NPV Accu

EUS 73% 84% 64% 89% 81%

CT/US 18% 99% 87% 75% 76%

Surgery 77% 94% 83% 91% 89%

In multivariate logistic-regression analysis, EUS detected ascites was the only significant independent predictor for the presence of PM (p < 0.001, O.R. 4.7, 95% C. I. [2.0 –11.2]).

Lee YT, et al. Gut 2005

Predicting Peritoneal Metastases

Lee YT, et al. Gut 2005

Gastric cancerCT / EUS / PET

No distant metastasis Ascites, liver or mediastinal LN met

Distant metastasis

EUS FNA

Palliative

positive

Mucosal disease / Tsm1

Surgery

Stage II-III

Staging ESD

Stage IV

PalliativeCure

≥SM2

Rectal cancer recurrencen Neoadjuvant RT significantly decrease local recurrence

rate and improve survivalGray R, Lancet 2001

n Pre-op RT + standard total mesorectal excision > TME only

n Recurrence rate 2.4% (RT) vs 8.2% (no RT)Kapiteijn E, New Engl J Med 2001

n Pre-op RT > post-op RTn Recurrence 6% (pre) vs 13% (post)

Glimelius B, Br Med Bull 2002, Sauer R, N Engl J Med 2004

EUS in rectal cancer

Harewood GC, Am J Gastroenterol 2004

T staging accuracy EUS (80% - 95%)CT (65–75%)MRI (75–85%)

EUS can facilitate selection of those patients with advanced locoregional disease (T3 or T4) for preoperative neoadjuvant chemoRT

EUS in rectal cancer

EUS in rectal cancer68 (non-EUS control group) and 73 (EUS group) patients with nonmetastatic rectal cancer

EUS group - adjuvant 45 patients (84.9%) (preop 31, postop 14)

Non-EUS group - adjuvant therapy 37 patients (78.7%) (preop 7, postop 30)

Kaplan-Meier curve demonstrating recurrence-free survival

Harewood GC, Am J Gastroenterol 2004

Rectal carcinoid

n Prospective study

n 120 patients clinically suspected to have pancreatic CA

q Sensitivity in detecting the tumour: EUS (98%) > CT (86%)

n In 53 patients that received surgery, accuracy in T stage EUS > CT (67% vs. 41%); N stage EUS ~ CT (44% vs. 47%).

n Resectability EUS ~ CT

Confirm the clinical or radiological diagnosis – Pancreatic mass

DeWitt L, Ann Int Med 2004

CT vs EUS in PNETn Johns Hopkins review of pancreatic neuro-endocrine

tumour (PNET) diagnosis.

n 217 patients (with 231 PNETs) studied, CT detected 84% of tumors (54.3% of insulinomas).

n Improved sensitivity with latest CT technology (P = 0.02).

n CT was more likely to miss lesions <2 cm (P =0.005) and insulinomas (P <0.0001).

n In 56 patients who had both CT and EUS,

Sensitivity EUS vs CT (91.7% vs 63.3%; P =0.0002),

For insulinomas (84.2% vs 31.6%; P = 0.001).

n EUS detected 20 of 22 CT-negative tumors (91%).

Khashab MA, Gastrointest Endosc 2011

EUS for vascular invasion in pancreatic and periampullary CA

n Meta-analysis n 29 studies, N=1308. n The pooled sensitivity (73%), specificity

(90.2%), positive likelihood ratio 9.1, negative likelihood ratio was 0.3.

Puli SR, Gastrointest Endosc 2007

n Cohort of patients from merged Medicare-SEER

(Surveillance, Epidemiology, and End Results) database

n Developed jointly by the National Cancer Institute and

the Centers for Medicare and Medicaid Services

n 1994-2002, age >65 yr old,

n 8616 patients identified.

n 610 (7.1%) patients undergone EUS for evaluation 1

month before or 3 months after

EUS improves CA pancreas survival

Ngamruengphong S, Gastrointest Endosc, 2010

EUS improves CA pancreas survivaln In patients with locoregional cancer, the median survival (interquartile

range) in EUS group and non-EUS group was 10 (5-17) and 6 (2-12)

months, respectively, (P <0.0001).

n Early-stage disease in EUS group > non-EUS group (69.3% vs

36.2%, P <0.001).

n Curative-intent surgery, chemotherapy, and radiation therapy more in

EUS group.

n Adjusted for age, race, sex, tumor stage, curative-intent surgery,

chemotherapy, radiation therapy, and comorbidity score, performing

EUS was an independent predictor of improved survival (relative

hazard, 0.71; 95% CI, 0.63-0.79).

Ngamruengphong S, Gastrointest Endosc, 2010

EUS improves CA pancreas survival

n Detection of earlier cancers

n Improved stage-appropriate management including more selective

performance of curative-intent surgery.

Ngamruengphong S, Gastrointest Endosc, 2010

Group 1 – EUSGroup II – non-EUS

Serous cystadenoma

Mucinous cystadenoma

Levy, Clin Gastroenterol Hepatol 2004

Pancreatic cystic lesion

Cooperative Pancreatic Cyst Study

n Multicenter, prospective study

n EUS imaging, EUS-FNA for cyst fluid cytology

n Cyst fluid tumor markers (CEA, CA 72-4, CA 125, CA 19-9, and CA 15-3)

n Histology as the final diagnostic standard.

Brugge W, Gastroenterology 2004

Cooperative Pancreatic Cyst Study

n N = 341; 112 histological proof (68 mucinous, 7 serous,

27 inflammatory, 5 endocrine, and 5 other).

n The accuracy of CEA (88 of 111, 79%) > EUS

morphology (57 of 112, 51%) or cytology (64 of 109,

59%) (P < 0.05).

n There was no combination of tests that provided greater

accuracy than CEA alone (P < 0.0001).

Brugge W, Gastroenterology 2004

Suspected pancreatic cancer

MDCT

Solid pancreatic mass Cystic pancreatic mass

Distant metastasis

EUS +/- FNA

Young age Old age

EUS-FNA to confirm distant metastases such as mediastinum, liver, celiac axis LN, ascites, etc has an invaluable role in staging

PET

Resectable

Unresectable

Surgery Palliative

Chemo/RT

No pancreatic mass

Normal

HK Cancer Registry 2008

Lung Male FemaleIncidence 2,793 1,443

Rank 1 3Crude rate (/100,000) 84.7 39.2

Mortality 2,302 1,195Rank 1 1Crude rate (/100,000) 69.8 32.5

About 60% of all lung cancer cases are presented at advanced stage

Lung cancer, accounting for 17.2% of all newly diagnosed cancer and 28.1% of all cancer deaths in HK

Irresectable tumor: T4, N3, M1

The key to staging is the mediastinal LN status

Mediastinal LN stationsn American Joint Committee on Cancer (AJCC) and American

Thoracic Society (ATS) classification

Mountain CF, Dresler CM, Chest 1997

Noninvasive staging

N Sen Spec PPV NPVCT 3438 57% 82% 56% 83%

PET 1045 84% 89% 79% 93%

Toloza EM, Chest 2003

n Meta-analysis

Noninvasive staging of lung cancer

Toloza EM, Chest 2003

n CT +ve MLN: 44% false positiven CT –ve MLN: 17% false negative

n PET +ve MLN: 21% false positiven PET –ve MLN: 7% false negative

n “Tissue is the issue”

Invasive staging of lung cancer

Study no./ N Sen Spec PPV NPV

TBNA 17 / 1339 78% 99% 99% 72%

TTNA 5 / 215 89% 100% 100%

EUS-FNA 16 / 1003 84% 99.5% 99.3% 81%

EBUS-FNA 8 / 918 90% 100% 100% 80%

Cervical mediastinoscopy

19 / 6505 78% 100% 100% 89%

VATS 7 / 419 75% 100% 100% 93%

Detterbeck FC, Chest 2007

n Meta-analysis

Figure from National Cancer Institute

EUS -FNA

Subcarinal Lymph Node

Pulmonary Artery

FNA

超聲內鏡Subcarinal

Lymph Node

ThrombusPulmonary

Artery

EUS and EUS-FNA for mediastinal lymphadenopathy: Metaanalysis

n 76 studies (n =9310)n 44 studies EUS alone and 32

EUS-FNAn Sensitivity

q EUS (84.7%) q EUS-FNA (88.0%)

n Specificity q EUS (84.6%)q EUS-FNA (96.4%)

n No publication bias

Puli SR, World J Gastroenterol 2008

Could EUS-FNA reduce futile surgery?n 242 patients: suspected (n=142) or proven (n=100) lung cancer

n CT - enlarged (>1 cm) mediastinal LNs

n Plan for mediastinoscopy/tomy (94%) or exploratory thoracotomy (6%). Before surgery, EUS-FNA was done.

n EUS-FNA: Prevented 70% of scheduled surgeryq LN metastases in NSCLC (52%)

q tumor invasion (T4) (4%),

q tumor invasion and LN metastases (5%)

q SCLC (8%)

q Benign diagnoses (1%).

n EUS-FNA: sensitivity (91%), specificity (100%), and accuracy (93%)

n No complication

Annema JT, J Clin Oncol 2005

EBUS-TBNA

Herth FJ, Thorax 2006

EUS-FNA plus EBUS-FNA for mediastinal staging

n N = 138, n TBNA vs EUS-FNA vs EBUS-FNAn 42 (30%) had malignant LNn PET sensitivity - 24%, CT sensitivity - 67%, n Procedure duration (median, min):

q TBNA 15, EUS-FNA 21, EBUS-FNA 26.

Wallace MB. JAMA 2008

Algorithm for staging NSCLC (Simplified)Lung mass

Bronchoscopy, CT-FNA

CT & PET – MLN, distant met

NSCLC

Stage 1

Surgery

Stage II & III?

Invasive staging

-ve +ve N2/3 ChemoRT Surgery

EUS-FNA +/-EBUS-FNA for

tissue diagnosis and staging

Stage IV (M1)

Palliation

Conclusion

n EUS improves tumour diagnosis and staging accuracy, which can guide patient to receive stage - appropriate therapies.

n Performing EUS in cancer patients may improve patient survival.