The prognostic value of HPV status and p16 expression in patients with carcinoma of the anal canal.

BACKGROUND: In anal cancer studies, the detection frequency of high-risk HPV (human papillomavirus) is variable, depending on the method used. There are limited data reporting results of different HPV detection techniques in the same clinical series, and very few correlating results with clinical outcome. OBJECTIVES: To evaluate tumor expression of p16/HPV16 using three different methods, and to determine their association with clinical outcome in patients with anal canal squamous cell carcinomas (SCC). DESIGN: This retrospective study included patients with anal canal SCC treated with definitive radiotherapy or chemoradiotherapy at a single institution between 1992 and 2005. Formalin-fixed paraffin-embedded tumor samples from 53 of the 89 (60%) patient pre-treatment biopsies were adequate for tissue microarray construction. HPV status was determined using: p16 expression by conventional immunohistochemistry (IHC) and quantitative IHC (AQUA), HPV genotype analysis by chromogenic in situ hybridization (CISH) and HPV linear array sub-typing. Expression status was correlated with clinical outcome. RESULTS: 80% (28/35) of patient tumors had high p16 expression using conventional IHC. HPV16 CISH was positive in 81% (34/42) of tumors, and 78% (28/36) of tumors were HPV subtype 16. HPV16 CISH correlated with p16 evaluated by conventional IHC (correlation coefficient 0.46; p = 0.01) and by p16 AQUA score (correlation coefficient 0.49; p = 0.001). A subset of cases (15%) had very high p16 quantitative IHC scores (>244) and were associated with a higher incidence of local or distant recurrence (p = 0.04). CONCLUSIONS: The vast majority (80%) of anal canal SCC in our series were positive for HPV16/p16, regardless of the testing method used. The exploratory analysis of automated quantitative IHC scoring was the only technique to define a subset of patients with a worse prognosis by p16 expression status on univariate analysis. Further exploration of the molecular mechanisms of treatment resistance in association with very high p16 expression is warranted

CISH for HPV16 and AQUA score correlation.

<p>CISH for HPV16 and AQUA score correlation.</p

Progression-free survival according to P16 AQUA score.

<p>P16 AQUA score with a cutpoint at 244 in patients with pretreatment hemoglobin≥120 g/L.</p

Histogram of AQUA scores with cutpoint identifying very high expression of p16.

<p>Histogram of AQUA scores with cutpoint identifying very high expression of p16.</p

P16 expression by AQUA according to HPV subtype.

<p>P16 expression by AQUA according to HPV subtype.</p

Characteristics of 89 patients with anal canal carcinoma.

<p>ECOG PS: Eastern Cooperative Oncology Group Performance Status; RT: radiotherapy.</p><p>Characteristics of 89 patients with anal canal carcinoma.</p

Overall survival according to P16 AQUA score.

<p>P16 AQUA score with a cutpoint at 244 in patients with pretreatment hemoglobin≥120 g/L.</p

CISH for HPV16 and DAB score correlation.

<p>DAB: conventional p16 diaminobenzydene.</p

Univariate analysis: 5-year progression-free survival (PFS).

<p>ECOG PS: Eastern Cooperative Oncology Group Performance Status; RT: radiotherapy; CRT: chemoradiotherapy; Hb: hemoglobin; DAB: diaminobenzydene, CISH: chromogenic <i>in situ</i> hybridization</p><p>Univariate analysis: 5-year progression-free survival (PFS).</p

Initial Treatment Patterns Over Time for Anaplastic Oligodendroglial Tumors

Anaplastic oligodendroglial tumors are rare neoplasms with no standard approach to treatment. We sought to determine patterns of treatment delivered over time and identify clinical correlates of specific strategies using an international retrospective cohort of 1013 patients diagnosed from 19812007. Prior to 1990, most patients received radiotherapy (RT) alone as initial postoperative treatment. After 1990, approximately 50 of patients received both RT and chemotherapy (CT) sequentially and/or concurrently. Treatment with RT alone became significantly less common (67 in 19801984 vs 5 in 20052007, P \u3c .0001). CT alone was more frequently administered in later years (0 in 19801984 vs 38 in 20052007; P \u3c .0001), especially in patients with 1p19q codeleted tumors (57 of codeleted vs 4 with no deletion in 20052007; P \u3c .0001). Temozolomide replaced the combination of procarbazine, lomustine, and vincristine (PCV) among patients who received CT alone or with RT (87 vs 2 in 20052007). In the most recent time period, patients with 1p19q codeleted tumors were significantly more likely to receive CT alone (with temozolomide), whereas RT with temozolomide was a significantly more common treatment strategy than either CT or RT alone in cases with no deletion (P \u3c .0001). In a multivariate polytomous logistic regression model, the following were significantly associated with type of treatment delivered: date (5-year interval) of diagnosis (P \u3c .0001), 1p19q codeletion (P \u3c .0001), pure anaplastic oligodendroglioma histology (P \u3c .01), and frontal lobe predominance (P \u3c .05). Limited level 1 evidence is currently available to guide treatment decisions, and ongoing phase III trials will be critical to understanding the optimal therapy