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Tumor Budding as a Strong Prognostic Indicator in Invasive Ampullary Adenocarcinomas

Ohike, Nobuyuki MD*; Coban, Ipek MD*; Kim, Grace E. MD; Basturk, Olca MD; Tajiri, Takuma MD§; Krasinskas, Alyssa MD; Bandyopadhyay, Sudeshna MD; Morohoshi, Toshio MD; Shimada, Yuki MS**; Kooby, David A. MD††; Staley, Charles A. MD††; Goodman, Michael MD, MPH‡‡; Volkan Adsay, Nazmi MD*

The American Journal of Surgical Pathology: October 2010 - Volume 34 - Issue 10 - p 1417-1424
doi: 10.1097/PAS.0b013e3181f0b05a
Original Articles

Prognostication of invasive ampullary adenocarcinomas (AACs) and their stratification into appropriate management categories have been highly challenging owing to a lack of well-established predictive parameters. In colorectal cancers, recent studies have shown that tumor budding confers a worse prognosis and correlates significantly with nodal metastasis and recurrence; however, this has not been evaluated in AAC.

To investigate the prevalence, significance, and clinical correlations of tumor budding in AAC, 244 surgically resected, stringently defined, invasive AAC were analyzed for tumor budding---defined as the presence of more than or equal to 5 isolated single cancer cells or clusters composed of fewer than 5 cancer cells per field measuring 0.785 mm2 using a 20× objective lens in the stroma of the invasive front. The extent of the budding was then further classified as “high” if there were greater than or equal to 3 budding foci and as “low” if there were <3 budding foci or no budding focus.

One hundred ninety-four AACs (80%) were found to be high-budding and 50 (20%) were low-budding. When the clinicopathologic features and survival of the 2 groups were compared, the AACs with high-budding had larger invasion size (19 mm vs. 13 mm; P<0.001), an unrecognizable/absent preinvasive component (57% vs. 82%; P<0.005), infiltrative growth (51% vs. 2%; P<0.001), nonintestinal-type histology (72% vs. 46%; P<0.001), worse differentiation (58% vs. 10%; P<0.001), more lymphatic (74% vs. 10%; P<0.001), and perineural invasion (28% vs. 2%; P<0.001); more lymph node metastasis (44% vs. 17%; P<0.001), higher T-stage (T3 and T4) (42% vs. 10%; P<0.001), and more aggressive behavior (mean survival: 50 mo vs. 32 mo; 3-year and 5-year survival rates: 93% vs. 41% and 68% vs. 24%, respectively; P<0.001). Furthermore, using a multivariable Cox regression model, tumor budding was found to be an independent predictor of survival (P=0.01), which impacts prognosis (hazard ratio: 2.6) even more than T-stage and lymph node metastasis (hazard ratio: 1.9 and 1.8, respectively).

In conclusion, tumor budding is frequently encountered in AAC. High-budding is a strong independent predictor of overall survival, with a prognostic correlation stronger than the 2 established parameters: T-stage and lymph node metastasis. Therefore, budding should be incorporated into surgical pathology reports for AAC.

Departments of *Pathology

††Department of Surgery, Emory University Hospital

**Department of Mathematics, Georgia Institute of Technology

‡‡Department of Epidemiology, Emory University, Atlanta, GA

Department of Pathology, University of California-San Francisco, San Francisco, CA

Department of Pathology, Memorial Sloan-Kettering Cancer Center, NY

Department of Pathology, University of Pittsburgh, PA

Department of Pathology, The Karmanos Cancer Institute and Wayne State University, MI

§Department of Pathology, Showa University, Fujigaoka Hospital, Yokohama

Department of Pathology, Showa University, Tokyo, Japan

This study was presented in part at the annual meeting of the United States and Canadian Academy of Pathology in Washington, DC, March 2010.

This study is supported in part by the National Cancer Institute Specialized Program in Research Excellence (SPORE) CA101936 in Pancreas Cancer (PAR-02-068) and in part by the Georgia Cancer Coalition Distinguished Cancer Clinicians and Scientists Program.

Correspondence: Nazmi Volkan Adsay, MD, Anatomic Pathology, Emory University Hospital, Department of Pathology and Laboratory Medicine, 1364 Clifton Road NE, Room H-180B, Atlanta, GA 30322 (e-mail:

© 2010 Lippincott Williams & Wilkins, Inc.