Tumor Budding as a Strong Prognostic Indicator in Invasive Ampullary Adenocarcinomas

Abstract

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 pre-invasive 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.

Tumor Budding Is an Independent Prognostic Factor for Prediction of Lymph Node Metastasis in Oral Squamous Cell Carcinoma

“…This is in accordance to previous studies in colorectal cancer, ampullary cancer, rectal cancer where it has been associated with lymph node metastasis and has been correlated with distance of invasion beyond the lamina propria. 5,6,16,19 This corroborates the possibility of tumor budding's ability in defining the biologic aggressiveness of the tumor and serving as an index for the metastatic potential in OSCC. This association with depth of invasion has also been confirmed recently by Almagush et al 12 recently in tongue cancer.…”

“…5,6,10,11 Furthermore, presence of intratumoral budding, that is, presence of tumor budding in preoperative biopsy specimens has also been described, which has demonstrated a strong linear correlation with peritumoral budding at the invasive front in the postoperative specimens opening another venue in its utility for prognostic determination. 20 Cervical lymph node metastasis has been considered as one of the major prognostic factor in patients with OSCC.…”

“…17 Its clinical significance lies in the simplicity of detection using conventional hematoxylin and eosin staining techniques without use of additional cost-intensive procedures. 5,6 Though use of cytokeratin has been suggested to highly facilitate its identification, 7 in the present study, tumor budding was evaluated in OSCC specimens in routine hematoxylin and eosin-stained slides, which was further graded as low-and high-intensity budding according to Ueno et al 15 Tumor budding was evident in 89% of Type of invasive front .031* 1: Pushing well-delineated borders 10 cases with 45.3% of the cases demonstrating highintensity budding while no budding was seen in 11% of cases. The frequency of tumor budding varies widely in literature in various cancers (20% to 89%).…”

Tumor budding in intestinal-type gastric adenocarcinoma is associated with nodal metastasis and recurrence

“…Multiple series have shown that increased tumor budding is associated with lymph node metastasis, distant metastasis, and recurrence in colorectal adenocarcinomas [15,16]. Similar studies have also shown a similar relationship in adenocarcinomas of the ampulla [21], esophagus [22,23], and pancreas [24]. However, very little research has been performed evaluating tumor budding in GAC [18,25,26].…”

“…Given the wide variety of different methods employed in both colorectal carcinoma and upper gastrointestinal malignancies [15,16,18,21,22,24] that provide largely compatible results, it is reasonable to hypothesize that a single standardized method could be applied to carcinomas throughout the luminal gastrointestinal tract. Another potential pitfall in the assessment of tumor budding assessment is the need to ensure an acceptable level of interobserver variability.…”