Abstract
Background
Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine carcinoma of the skin. As the clinical course can be variable, prognostic markers are needed to better stratify patients. Prior literature, composed of small series with limited sample size, has demonstrated that tumor‐infiltrating lymphocytes (TILs) are an important prognostic marker in MCC. To validate these findings on a population level, we sought to analyze and report the prognostic value of TILs in a large national data set.
Materials and Methods
A retrospective observational cohort study was conducted of patients with nonmetastatic MCC from 2010 to 2015 using the National Cancer Database. Individual variables trending toward significance using a univariable analysis were included in a multivariable Cox proportional hazards model to assess their independent effect on overall survival (OS). TILs were subclassified into none, nonbrisk, and brisk and the survival analysis was performed. Propensity score–weighted multivariable analysis (PS MVA) was performed to adjust for additional confounding.
Results
A total of 2,182 patients met inclusion criteria: 611 (28.0%) were identified as having TILs present, and 1,571 (72.0%) had TILs absent in the tumor. On MVA, subdivision of TIL status into nonbrisk (hazard ratio [HR], 0.750; 95% confidence interval [CI], 0.602–0.933) and brisk (HR, 0.499; 95% CI, 0.338–0.735) was associated with incrementally improved OS compared with no TILs. The association of nonbrisk and brisk TILs with improved OS was retained on PS MVA (Nonbrisk: HR, 0.720; 95% CI, 0.550–0.944; Brisk: HR, 0.483; 95% CI, 0.286–0.814).
Conclusion
The presence of nonbrisk and brisk TILs is associated with incrementally improved OS in patients with nonmetastatic MCC in a large national data set. This pathologic feature can aid with risk stratification, estimation of prognosis, and, importantly, decision‐making with respect to treatment intensification in high‐risk patients.
Implications for Practice
Merkel cell carcinoma (MCC) is an aggressive neuroendocrine cutaneous malignancy with variable clinical course. Prognostic markers are needed to better risk stratify patients. We present the largest retrospective observational cohort study of patients with nonmetastatic MCC using the National Cancer Database. Our analysis demonstrates an association between increasing degrees of tumor‐infiltrating lymphocytes and incrementally improved survival. These conclusions improve pathologic risk stratification, and decision‐making with respect to treatment intensification. Intensification may include adjuvant radiation therapy to the primary site after wide excision despite small tumor size, to the nodal basin in sentinel lymph node‐negative patients, or offering closer follow‐up.
Keywords: Tumor‐infiltrating lymphocytes, Merkel cell carcinoma, Nonbrisk, Brisk, National Cancer Database, Survival
Short abstract
Recent evidence suggests that tumor‐infiltrating lymphocytes (TILs) are a potential pathologic biomarker in Merkel cell carcinoma. This article evaluates the prognostic value of TILs using a large national dataset.
Introduction
Merkel cell carcinoma (MCC) is a rare and highly aggressive neuroendocrine carcinoma of the skin, accounting for approximately 2,000 annual diagnoses in the U.S. [1]. As the clinical course of patients with MCC can be variable [2] and unpredictable, further prognostic markers are needed.
The impact of the tumor immune microenvironment is vitally important in determining disease progression and response to therapy [3]. As such, an important prognostic biomarker being investigated is the quantification of tumor‐infiltrating lymphocytes (TILs). In fact, the prognostic value of TILs has been implicated in a variety of malignancies including colon cancer [4], bladder/urothelial cancer [5], oropharyngeal cancer [6], thyroid cancer [7], breast cancer [8], and melanoma [9, 10].
Similar to their significance in other malignancies, TILs have been associated with improved MCC‐specific survival [11, 12]. To that effect, international organizations have begun standardizing pathologic reports of immune infiltrate for consistency [13].
Importantly, although recent evidence suggests that TILs are an important prognostic marker in MCC, this association is primarily based on small series with limited patient numbers. Therefore, we sought to evaluate the prognostic value of TILs using a large national data set. Specifically, we performed a retrospective observational cohort study of patients with nonmetastatic MCC using the National Cancer Database (NCDB) to assess the impact of TILs on overall prognosis.
Materials and Methods
This analysis was deemed exempt from review by the University of Pennsylvania institutional review board per the Health Insurance Portability and Accountability Act as a deidentified data set was used. The need for signed informed consent by participants was waived.
Inclusion criteria consisted of patients in the NCDB who were 18 years or older and diagnosed with nonmetastatic (i.e., non‐M1) MCC from 2010 to 2015 per the American Joint Committee on Cancer 7th Edition Staging System. Patients with locoregional disease (i.e., N1 or N2 disease) were considered nonmetastatic. TILs were classified as (a) absent/none (lymphocytes present but not infiltrative), (b) nonbrisk (focal lymphocyte infiltration or not present across entire base of vertical growth phase), and (c) brisk (diffuse infiltration of entire base of dermal tumor or invasive component of tumor) [14]. Immunosuppression was defined as having any or multiple of the following: human immunodeficiency virus infection, organ transplant, chronic lymphocytic leukemia, or non‐Hodgkin lymphoma. Patients were excluded if TIL status was classified as not otherwise specified or unknown. Patients with T0 or Tis tumors were also excluded as they technically did not harbor invasive malignancy for TIL analysis (Fig. 1, CONSORT diagram).
Figure 1.
Merkel cell carcinoma. CONSORT flow diagram. Abbreviations: NCDB, National Cancer Database; TIL, tumor‐infiltrating lymphocyte.
Baseline patient characteristics (Table 1) were compared using chi‐squared tests. Overall survival (OS) was defined as the time from diagnosis to death or until last follow‐up. Patients without follow‐up data were not included in the survival analysis. Individual variables trending toward significance (p < .1) using a univariable analysis (UVA) were included in a multivariable Cox proportional hazards model to assess their independent effect on OS (Table 2; only the multivariable analysis [MVA] is shown). TILs were subclassified into none, nonbrisk, and brisk and the survival analysis was performed. Survival curves were generated using Kaplan‐Meier methods, and log‐rank tests were used to compare OS between cohorts. Propensity score–weighted MVA (PS MVA) was performed on all covariates achieving threshold significance of p < .1 on univariate analysis to adjust for additional confounding. Covariate balance following propensity weighting was assessed using standardized differences of means. Survival analyses were then performed again.
Table 1.
Baseline patient characteristics
| Characteristics | TIL | Chi‐Squared X2 | |||
|---|---|---|---|---|---|
| None, n (%) | Nonbrisk, n (%) | Brisk, n (%) | Total, n (%) | ||
| TIL | 1,571 (72) | 450 (20.6) | 161 (7.4) | 2,182 (100) | — |
| Gender | |||||
| Male | 982 (62.5) | 306 (68) | 95 (59) | 1,383 (63.4) | .050 |
| Female | 589 (37.5) | 144 (32) | 66 (41) | 799 (36.6) | |
| Age, years | |||||
| 18–49 | 27 (1.7) | 6 (1.3) | 2 (1.2) | 35 (1.6) | .024 |
| 50–69 | 439 (27.9) | 134 (29.8) | 65 (40.4) | 638 (29.2) | |
| ≥70 | 1,105 (70.3) | 310 (68.9) | 94 (58.4) | 1,509 (69.2) | |
| Race | |||||
| Non‐Hispanic White | 1,483 (94.4) | 431 (95.8) | 149 (92.5) | 2,063 (95.5) | .388 |
| Non‐Hispanic Black | 19 (1.2) | 2 (0.4) | 2 (1.2) | 23 (1.1) | |
| Hispanic | 36 (2.3) | 7 (1.6) | 3 (1.9) | 46 (2.1) | |
| Other | 33 (2.1) | 10 (2.2) | 7 (4.3) | 50 (2.3) | |
| Facility area | |||||
| Metropolitan | 1,315 (83.7) | 376 (83.6) | 134 (83.2) | 1,825 (83.6) | .828 |
| Urban | 181 (11.5) | 52 (11.6) | 19 (11.8) | 252 (11.5) | |
| Rural | 28 (1.8) | 10 (2.2) | 1 (0.6) | 39 (1.8) | |
| Unknown | 47 (3.0) | 12 (2.7) | 7 (4.3) | 66 (3) | |
| Facility location | |||||
| East | 315 (20.1) | 58 (12.9) | 33 (20.5) | 406 (18.6) | <.001 |
| South | 613 (39) | 113 (25.1) | 42 (26.1) | 768 (35.2) | |
| Central | 374 (23.8) | 177 (39.3) | 60 (37.3) | 611 (28) | |
| West | 263 (16.7) | 100 (22.2) | 25 (15.5) | 388 (17.8) | |
| Unknown | 6 (0.4) | 2 (0.4) | 1 (0.6) | 9 (0.4) | |
| Facility type | |||||
| Nonacademic | 862 (54.9) | 164 (36.4) | 74 (46) | 1,100 (50.4) | <.001 |
| Academic | 703 (44.7) | 284 (63.1) | 86 (53.4) | 1,073 (49.2) | |
| Unknown | 6 (0.4) | 2 (0.4) | 1 (0.6) | 9 (0.4) | |
| Distance to facility, miles | |||||
| ≤40 | 1,263 (80.4) | 308 (68.4) | 126 (78.3) | 1,697 (77.8) | <.001 |
| >40 | 302 (19.2) | 137 (30.4) | 34 (21.1) | 473 (21.7) | |
| Unknown/Missing | 6 (0.4) | 5 (1.1) | 1 (90.6) | 12 (0.5) | |
| Education level (percentage without high school diploma) | |||||
| ≥21% | 150 (9.5) | 33 (7.3) | 10 (6.2) | 193 (8.8) | .134 |
| 13%–20.9% | 338 (21.5) | 89 (19.8) | 27 (16.8) | 454 (20.8) | |
| 7%–12.9% | 557 (35.5) | 165 (36.7) | 69 (42.9) | 791 (36.3) | |
| <7% | 520 (33.1) | 158 (35.1) | 55 (34.2) | 733 (33.6) | |
| Unknown | 6 (0.4) | 5 (1.1) | 0 (0) | 11 (0.5) | |
| Median income (by zip code), $ | |||||
| <38,000 | 178 (11.3) | 48 (10.7) | 13 (8.1) | 239 (11) | .226 |
| 38,000–47,999 | 333 (21.2) | 93 (20.7) | 30 (18.6) | 456 (20.9) | |
| 48,000–62,999 | 462 (29.4) | 116 (25.8) | 48 (29.8) | 626 (28.7) | |
| ≥63,000 | 592 (37.7) | 188 (41.8) | 70 (43.5) | 850 (39) | |
| Unknown | 6 (0.4) | 5 (1.1) | 0 (0) | 11 (0.5) | |
| Charlson Comorbidity Index [25] | |||||
| 0 | 1,168 (74.3) | 345 (76.7) | 115 (71.4) | 1,628 (74.6) | .207 |
| 1 | 308 (19.6) | 74 (16.4) | 34 (21.1) | 416 (19.1) | |
| 2 | 71 (4.5) | 19 (4.2) | 11 (6.8) | 101 (4.6) | |
| 3 | 24 (1.5) | 12 (2.7) | 1 (0.6) | 37 (1.7) | |
| Primary site | |||||
| Lip | 23 (1.5) | 12 (2.7) | 2 (1.2) | 37 (1.7) | .093 |
| Ear | 484 (30.8) | 140 (31.1) | 60 (37.3) | 684 (31.3) | |
| Scalp and neck | 169 (10.8) | 36 (8) | 10 (6.2) | 215 (9.9) | |
| Trunk | 158 (10.1) | 52 (11.6) | 17 (10.6) | 227 (10.4) | |
| Upper limb and shoulder | 469 (29.9) | 132 (29.3) | 48 (29.8) | 649 (29.7) | |
| Lower limb and hip | 244 (15.5) | 77 (17.1) | 24 (14.9) | 345 (15.8) | |
| NOS | 24 (1.5) | 1 (0.2) | 0 (0) | 25 (1.1) | |
| Grade of primary tumor | |||||
| 1 | 4 (0.3) | 1 (0.2) | 0 (0) | 5 (0.2) | .391 |
| 2 | 7 (0.4) | 2 (0.4) | 1 (0.6) | 10 (0.5) | |
| 3 | 159 (10.1) | 41 (9.1) | 7 (4.3) | 207 (9.5) | |
| Unknown/Missing | 1,401 (89.2) | 406 (90.2) | 153 (95) | 1,960 (89.8) | |
| Size, cm | |||||
| <2 | 948 (60.3) | 283 (62.9) | 102 (63.4) | 1,333 (61.1) | <.001 |
| 2.1–5 | 389 (24.8) | 130 (28.9) | 49 (30.4) | 568 (26) | |
| >5 | 65 (4.1) | 18 (4) | 6 (3.7) | 89 (4.1) | |
| Unknown | 169 (10.8) | 19 (4.2) | 4 (2.5) | 192 (8.8) | |
| Pathological T stage | |||||
| T1 | 906 (57.7) | 269 (59.8) | 97 (60.2) | 1,272 (58.3) | <.001 |
| T2 | 348 (22.2) | 113 (25.1) | 44 (27.3) | 505 (23.1) | |
| T3 | 52 (3.3) | 14 (3.1) | 5 (3.1) | 71 (3.3) | |
| T4 | 42 (2.7) | 22 (4.9) | 7 (4.3) | 71 (3.3) | |
| Tx | 223 (14.2) | 32 (7.1) | 8 (5) | 263 (12.1) | |
| Pathological N stage | |||||
| N0 | 841 (53.5) | 189 (42) | 82 (50.9) | 1,112 (51) | <.001 |
| N1 | 328 (20.9) | 159 (35.3) | 45 (30) | 532 (24.4) | |
| N2 | 28 (1.8) | 16 (3.6) | 3 (1.9) | 47 (2.2) | |
| Nx | 374 (23.8) | 86 (19.1) | 31 (19.3) | 491 (22.5) | |
| Primary surgery | |||||
| No | 56 (3.6) | 12 (2.7) | 1 (0.6) | 69 (3.1) | .141 |
| Local treatment/excision | 646 (41.1) | 189 (42) | 67 (41.6) | 902 (41.3) | |
| Wide excision with margin | 849 (54) | 243 (54) | 90 (55.9) | 1,182 (54.2) | |
| Amputation | 8 (0.5) | 6 (1.3) | 1 (0.6) | 15 (0.7) | |
| Surgery NOS | 12 (0.8) | 0 (0) | 2 (1.2) | 14 (0.6) | |
| Margin status | |||||
| Negative | 1,366 (87) | 390 (86.7) | 141 (87.6) | 1,897 (86.9) | .043 |
| Positive | 130 (8.3) | 45 (10) | 19 (11.8) | 194 (8.9) | |
| Unknown | 75 (4.8) | 15 (3.3) | 1 (0.6) | 91 (4.2) | |
| Receipt of radiation | |||||
| No RT | 769 (48.9) | 194 (43.1) | 72 (44.7) | 1,035 (47.4) | .215 |
| RT | 798 (50.8) | 255 (56.7) | 89 (55.3) | 1,142 (52.3) | |
| Unknown | 4 (0.3) | 1 90.2) | 0 (0) | 5 (0.2) | |
| Receipt of chemotherapy | |||||
| No | 1,431 (91.1) | 402 (89.3) | 147 (91.3) | 1,980 (90.7) | .219 |
| Yes | 97 (6.2) | 40 (8.9) | 9 (5.6) | 146 (6.7) | |
| Unknown | 43 (2.7) | 8 (1.8) | 5 (3.1) | 56 (2.6) | |
| Immunosuppression | |||||
| No | 1,024 (65.2) | 261 (58) | 95 (59) | 1,380 (63.2) | .007 |
| Yes | 94 (6) | 44 (9.8) | 9 (5.6) | 147 (6.7) | |
| NA/Unknown | 453 (28.8) | 145 (32.2) | 57 (35.4) | 655 (30) | |
| Year of diagnosis | |||||
| 2010 | 214 (13.6) | 38 (8.4) | 12 (7.5) | 264 (12.1) | <.001 |
| 2011 | 259 (16.5) | 55 (12.2) | 20 (12.4) | 334 (15.3) | |
| 2012 | 254 (16.2) | 56 (12.4) | 28 (17.4) | 338 (15.5) | |
| 2013 | 320 (20.4) | 101 (22.4) | 33 (20.5) | 454 (20.8) | |
| 2014 | 241 (15.3) | 84 (18.7) | 36 (22.4) | 361 (16.5) | |
| 2015 | 283 (18) | 116 (25.8) | 32 (19.9) | 431 (19.8) | |
Abbreviations: —, no data; NA, not applicable; NOS, not otherwise specified; RT, radiation therapy; TIL, tumor‐infiltrating lymphocyte.
Table 2.
Factors associated with overall survival (multivariable analysis)
| Factors | Hazard ratio | p value | 95% confidence interval |
|---|---|---|---|
| TIL | |||
| None | 1 | — | — |
| Nonbrisk | 0.750 | .01 | 0.602–0.933 |
| Brisk | 0.499 | <.001 | 0.338–0.735 |
| Gender | |||
| Male | 1 | — | — |
| Female | 0.740 | .001 | 0.619–0.884 |
| Charlson Comorbidity Index [25] | |||
| 0 | 1 | — | — |
| 1 | 1.07 | .508 | 0.874–1.31 |
| 2 | 1.69 | .002 | 1.22–2.34 |
| 3 | 1.71 | .048 | 1.005–2.90 |
| Tumor size, cm | |||
| <2 | 1 | — | — |
| 2.1–5 | 1.16 | .434 | 0.804–1.66 |
| >5 | 2.14 | .01 | 1.20–3.83 |
| Unknown | 0.895 | .492 | 0.652–1.23 |
| Nodal stage | |||
| N0 | 1 | — | — |
| N1 | 1.88 | <.001 | 1.53–2.30 |
| N2 | 1.65 | .047 | 1.00–2.71 |
| Nx | 1.74 | <.001 | 1.40–2.16 |
| Surgical margin | |||
| Negative | 1 | — | — |
| Positive | 1.77 | <.001 | 1.39–2.26 |
| Unknown | 1.42 | .234 | 0.797–2.54 |
| Immunosuppression | |||
| No | 1 | — | — |
| Yes | 2.16 | <.001 | 1.63–2.86 |
| Not applicable/Unknown | 1.12 | .221 | 0.936–1.33 |
Abbreviations: —, no data; TIL, tumor‐infiltrating lymphocyte.
Results
A total of 2,182 patients were included in our cohort. The median age was 76 years (interquartile range [IQR], 67–83 years) and the median follow‐up time was 29 months (IQR, 17–47 months). Of the total population, 1,383 (63.4%) were male and 799 (36.6%) were female; 1,112 (50.9%) and 579 (26.5%) had stage I/II and III disease, respectively; and 611 (28.0%) were identified as having TILs present, and 1,571 (72.0%) had TILs absent in the tumor. Of those that had TILs present, 450 (73.6%) were characterized as nonbrisk and 161 (26.4%) were characterized as brisk. There was no association of adjuvant radiation or chemotherapy with TILs for all patients (Table 1) or specifically for patients with stage III disease (supplemental online Table 1). Complete baseline characteristics are provided in Table 1.
On MVA, subdivision of TIL status into nonbrisk (hazard ratio [HR], 0.750; 95% confidence interval [CI], 0.602–0.933, p = .01) and brisk (HR, 0.499, 95% CI, 0.338–0.735, p < .001) was associated with incrementally improved OS (Table 2, multivariable Cox proportional hazards model; and Fig. 2, univariate log‐rank test). Other relevant factors associated with survival decrement include male gender, worse performance status as measured by Charlson/Deyo score, larger tumors, lymph node positivity, positive margins after surgery, and presence of immunosuppression (Table 2). Supplemental online Table 2 further breaks down the association of TIL status with survival by stage.
Figure 2.
Merkel cell carcinoma. Overall survival and degree of tumor‐infiltrating lymphocytes. Abbreviation: TIL, tumor‐infiltrating lymphocyte.
After conducting a PS MVA (Table 3), the association of nonbrisk and brisk TILs with incremental improvements in OS persisted (Nonbrisk: HR, 0.720; 95% CI, 0.550‐0.944, p = .017; Brisk: HR, 0.483; 95% CI, 0.286–0.814, p = .006).
Table 3.
Propensity score–weighted multivariable analysis
| TIL | Hazard ratio | p value | 95% confidence interval |
|---|---|---|---|
| None | 1 | — | — |
| Nonbrisk | 0.720 | .017 | 0.550–0.944 |
| Brisk | 0.483 | .006 | 0.286–0.814 |
Abbreviations: —, no data; TIL, tumor‐infiltrating lymphocyte.
Discussion
To our knowledge, this represents the largest cancer registry–based analysis focusing on the prognostic utility of TILs with respect to MCC. We demonstrate an association between TILs and incrementally improved OS among patients with nonmetastatic MCC, a finding that remained after PS MVA. Our conclusions are concordant with prior literature [11, 12, 15, 16, 17] and are unique in representing the largest population‐level study illustrating the prognostic significance of host immune infiltration in MCC. This information has the potential to be valuable to physicians when risk stratifying patients and may inform treatment intensification when used in conjunction with other prognostic variables.
Intensification may include offering adjuvant radiation therapy (RT) to the primary site after wide excision despite small (<1 cm) tumor size, to the nodal basin in sentinel lymph node–negative patients, or offering closer follow‐up with routine imaging to rule out recurrent or metastatic disease.
Notably, this survival improvement is in keeping with those described in other highly immunogenic malignancies such as melanoma, in which cancer‐specific death rates were significantly and incrementally reduced in tumors with nonbrisk and brisk TILs (30% and 50%, respectively) compared with absent TILs [10].
Furthermore, our findings of incrementally improved survival with degree of immune infiltration are bolstered by the high rates (80%) of Merkel cell polyomavirus (MCPyV) found in MCC [18], suggesting that the disease is virally mediated. It then logically follows that MCPyV‐positive (MCPyV+) cancers harbor higher levels of TILs than their negative counterparts (MCPyV−) [16] and are associated with brisk immune responses [17]. In keeping with this theory, MCPyV+ MCC is thought to have improved cancer outcomes compared with MCPyV− variants [19], and MCPyV‐specific T cells in particular have been associated with significantly improved MCC‐specific survival [15]. This finding is interestingly not limited to lymphocytes, as pathologic retrospective reviews have also demonstrated improved outcomes with myeloid infiltrates in MCC [20].
Limitations
A limitation of this study lies in the retrospective nature of the analysis and the selection and misclassification bias to which it is susceptible. In particular, TIL data were unavailable for numerous patients in our NCDB data set. It is possible that TILs tend to be reported more frequently in larger tumors where there is more tissue available for analysis. This might overestimate the prognostic significance of TILs as smaller tumors presumably portend better prognoses compared with their larger counterparts, even in the absence of infiltrating lymphocytes.
To minimize this, we performed a PS MVA adjusting for a range of measured confounding variables. Nevertheless, this is not without flaws of its own and cannot account for important factors such as quality of surgery, radiation therapy dose or target volumes, type and duration of chemotherapy, or toxicities associated with treatment impacting outcomes.
Furthermore, as we were unable to select for patients undergoing primary surgery and sentinel lymph node biopsy/nodal surgery, some patients may have been clinically staged. As such, it is possible that other factors, including patient frailty, were not adequately captured in the database that affected these patients’ ability to undergo an operation, which may have also impacted their survival. As such, the primary outcomes of overall, and not disease‐specific, survival may represent a limitation as well.
Conclusion
We demonstrated an association with incrementally improved OS among patients with nonmetastatic MCC with pathologic nonbrisk and brisk TILs compared with no TILs in a large national data set. These findings can be used by clinicians to assist with risk stratification and treatment decision‐making, especially when counseling high‐risk patients who may benefit from treatment intensification (which may include adjuvant RT in small or sentinel lymph node–negative patients, and offering routine imaging in follow‐up). Such data should also prompt clinicians managing patients with MCC to ensure that TILs are reported more consistently at their respective institutions.
Further research in viral oncoprotein antibody testing [21, 22] and the MCC TIL microenvironment, including geographic location of infiltrate [23] and programmed death‐ligand 1 (PD‐L1) expression [24], can be conducted to identify additional characteristics that confer prognostic benefit or therapeutic potential. The latter is especially relevant as programmed cell death protein 1/L1 blockade is now a Food and Drug Administration–approved intervention in disseminated MCC [14] and can potentially have a role in the adjuvant or definitive settings. Ultimately, the care of patients with MCC warrants a multidisciplinary approach with input from dermatology, medical oncology, surgical oncology, and radiation oncology. The aggressive nature of this malignancy also necessitates close follow‐up for monitoring of recurrent disease.
Author Contributions
Conception/design: Anish A. Butala, Jacob E. Shabason
Collection and/or assembly of data: Anish A. Butala, Varsha Jain, Jacob E. Shabason
Data analysis and interpretation: Anish A. Butala, Varsha Jain, Yun Song, J. Nicholas Lukens, Jacob E. Shabason
Manuscript writing: Anish A. Butala, Ronnie A. Sebro, Yun Song, Giorgos Karakousis, Tara C. Mitchell, J. Nicholas Lukens, Jacob E. Shabason
Final approval of manuscript: Anish A. Butala, Varsha Jain, Vishruth K. Reddy, Ronnie A. Sebro, Yun Song, Giorgos Karakousis, Tara C. Mitchell, J. Nicholas Lukens, Jacob E. Shabason
Disclosures
The authors indicated no financial relationships.
Supporting information
See http://www.TheOncologist.com for supplemental material available online.
Supplemental Table 1 Adjuvant Treatment by Tumor Infiltrating Lymphocytes (TIL), Stage III
Supplemental Table 2. Multivariable Analysis by Stage
Disclosures of potential conflicts of interest may be found at the end of this article.
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Supplementary Materials
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Supplemental Table 1 Adjuvant Treatment by Tumor Infiltrating Lymphocytes (TIL), Stage III
Supplemental Table 2. Multivariable Analysis by Stage