Articles from 2022 to 2023 to Inform Your Cancer Practice: Melanoma.

Modern effective systemic therapy for melanoma includes two important classes of treatment: immune checkpoint inhibitors (ICIs), comprising inhibitors of cytotoxic T-lymphocyte antigen 4, programmed cell death receptor 1, and lymphocyte-activation gene 3; and small molecule BRAF/MEK inhibitor therapy. These treatments have revolutionized the management of patients with advanced melanoma and have dramatically improved clinical outcomes. The melanoma treatment landscape continues to evolve as outcome data from completed trials continue to mature and as newer studies begin to report data. In 2022 and 2023, longer-term follow-up data for established single-agent ICI therapy has been published improving our understanding of both efficacy and durability of treatment responses. A trial of a novel combination ICI therapy has demonstrated enhanced efficacy, and a study examining the order/sequence of ICI therapy versus BRAF/MEK inhibitor therapy for first-line treatment of metastatic melanoma showed that survival is improved when patients start with ICI therapy. As the indications for these therapies have expanded to the adjuvant and neoadjuvant space, we also saw the publication of 5-year results of adjuvant therapy in resected stage III patients, new data on the role of adjuvant therapy in resected stage IIB and IIC patients, and, finally, a practice-changing trial demonstrating improved outcomes using a neoadjuvant approach for patients with macroscopic disease amenable to surgical resection. In this article, we review these articles and highlight key elements for surgical oncologists.

Oncologic Outcomes of Multi-Institutional Minimally Invasive Inguinal Lymph Node Dissection for Melanoma Compared with Open Inguinal Dissection in the Second Multicenter Selective Lymphadenectomy Trial (MSLT-II).

BACKGROUND: Minimally invasive inguinal lymphadenectomy (MILND) is safe and feasible, but limited data exist regarding oncologic outcomes. METHODS: This study performed a multi-institutional retrospective cohort analysis of consecutive MILND performed for melanoma between January 2009 and June 2016. The open ILND (OILND) comparative cohort comprised patients enrolled in the second Multicenter Selective Lymphadenectomy Trial (MSLT-II) between December 2004 and March 2014.The pre-defined primary end point was the same-basin regional nodal recurrence, calculated using properties of binomial distribution. Time to events was calculated using the Kaplan-Meier method. The secondary end points were overall survival, progression-free survival, melanoma-specific survival (MSS), and distant metastasis-free survival (DMFS). RESULTS: For all the patients undergoing MILND, the same-basin regional recurrence rate was 4.4 % (10/228; 95 % confidence interval [CI], 2.1-7.9 %): 8.2 % (4/49) for clinical nodal disease and 3.4 % (6/179) for patients with a positive sentinel lymph node (SLN) as the indication. For the 288 patients enrolled in MSLT-II who underwent OILND for a positive SLN, 17 (5.9 %) had regional node recurrence as their first event. After controlling for ulceration, positive LN count and positive non-SLNs at the time of lymphadenectomy, no difference in OS, PFS, MSS or DMFS was observed for patients with a positive SLN who underwent MILND versus OILND. CONCLUSION: This large multi-institutional experience supports the oncologic safety of MILND for melanoma. The outcomes in this large multi-institutional experience of MILND compared favorably with those for an OILND population during similar periods, supporting the oncologic safety of MILND for melanoma.

A Phase IIb Randomized Controlled Trial of the TLPLDC Vaccine as Adjuvant Therapy After Surgical Resection of Stage III/IV Melanoma: A Primary Analysis.

BACKGROUND: Melanoma therapy has changed dramatically over the last decade with improvements in immunotherapy, yet many patients do not respond to current therapies. This novel vaccine strategy may prime a patient's immune system against their tumor and work synergistically with immunotherapy against advanced-stage melanoma. METHODS: This was a prospective, randomized, double-blind, placebo-controlled, phase IIb trial of the tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine administered to prevent recurrence in patients with resected stage III/IV melanoma. Patients were enrolled and randomized 2:1 to the TLPLDC vaccine or placebo (empty yeast cell wall particles and autologous dendritic cells). Both intention-to-treat (ITT) and per treatment (PT) analyses were predefined, with PT analysis including patients who remained disease-free through the primary vaccine/placebo series (6 months). RESULTS: A total of 144 patients were randomized (103 vaccine, 41 control). Therapy was well-tolerated with similar toxicity between treatment arms; one patient in each group experienced related serious adverse events. While disease-free survival (DFS) was not different between groups in ITT analysis, in PT analysis the vaccine group showed improved 24-month DFS (62.9% vs. 34.8%, p = 0.041). CONCLUSIONS: This phase IIb trial of TLPLDC vaccine administered to patients with resected stage III/IV melanoma shows TLPLDC is well-tolerated and improves DFS in patients who complete the primary vaccine series. This suggests patients who do not recur early benefit from TLPLDC in preventing future recurrence from melanoma. A phase III trial of TLPLDC + checkpoint inhibitor versus checkpoint inhibitor alone in patients with advanced, surgically resected melanoma is under development. TRIAL REGISTRATION: NCT02301611.

Does use of axillary ultrasound in clinically node-negative patients receiving neo-adjuvant systemic therapy for breast cancer lead to surgical overtreatment?

Increased use of neo-adjuvant chemotherapy (NAC) for breast cancer has raised uncertainty regarding staging of the axilla, particularly for patients with a clinically negative axillary physical examination (PE). We sought to determine whether axillary ultrasound (AUS) prior to NAC to identify occult nodal disease is beneficial in patients with a clinically negative examination by evaluating the difference in nodal burden on final pathology in those with abnormal vs normal AUS. A retrospective review of an institutional cancer registry identified patients who underwent NAC for breast cancer and had a pretreatment AUS. Differences in the number of positive lymph nodes (PLN) in patients with a normal axillary PE and abnormal vs normal AUS prior to NAC were determined. A total of 120 patients who received NAC had a negative axillary PE prior to treatment. Fifty-three had an abnormal AUS and biopsy-proven lymph node (LN) involvement. In patients with an abnormal AUS, median number of PLNs at surgery was 1 vs 0 for those with a normal AUS (mean difference of 2.12, P < .0001). Of those patients with an abnormal AUS and biopsy-proven LN involvement, 87% underwent axillary lymph node dissection (ALND) and nearly half had no PLN on final pathology (N = 23, 43%). Patients with a clinically negative axilla and an abnormal AUS were more likely to have PLN at the time of surgery. However, almost half of those patients had no residual LN involvement. Routine AUS prior to NAC may lead to more extensive surgical management of the axilla.

The Emerging Role of Surgery for Patients With Advanced Melanoma Treated With Immunotherapy.

BACKGROUND: The emergence of immune checkpoint inhibitors (ICIs) has improved survival for patients with metastatic melanoma. The types of disease-response patterns to ICI therapy can be more complex relative to traditional chemotherapy and include mixed responses, pseudoprogression, and oligoprogression. The potential benefit of surgery after incomplete response to ICI therapy has not been explored. The purpose of this study was to explore outcomes of surgery after ICI therapy in patients with metastatic melanoma. METHODS: A retrospective study was conducted at two centers and included patients with melanoma who underwent surgery after treatment with monotherapy or combination therapy with anti-programmed cell death protein (PD) 1 and/or anti-cytotoxic T-lymphocyte associated protein (CTLA)-4 checkpoint blockade. RESULTS: Of 25 patients, nine received anti-CTLA-4 therapy, eight received anti-PD-1 therapy, and eight received both anti-CTLA-4 and anti-PD-1 therapies before surgery. Five patients were treated in the adjuvant setting and developed new lesions, whereas 20 patients were treated for metastatic disease and underwent surgery for persistent disease on imaging after ICI therapy. Twenty-five patients underwent 30 operations without complications. Twenty-seven of 30 masses were confirmed to be melanoma on pathology, one was a desmoid tumor and two were necrosis. At a median follow-up of 14.2 months, 2 patients died, 8 were alive with a known disease, and 15 continued to have no further evidence of disease. CONCLUSIONS: Surgery was well tolerated in this cohort of patients receiving ICI therapy for melanoma. Surgery may benefit select patients with an oligoprogressive disease after ICI therapy. After a mixed response, surgery remains the only definitive method to render some patients free of disease.

Radioactive seed vs wire localization for nonpalpable breast lesions: A single institution review.

The aim of this study was to compare wire localization (WL) and radioactive seed localization (RSL) for nonpalpable breast lesions with regard to margin status, re-excision rate, procedure length, and complications related to localization. A retrospective review of the electronic health records at a single institution was performed. There was no difference in re-excision rate, margin positivity, volume of tissue removed, and complication rate for RSL vs WL (P = 0.9934, P = 0.9934, P = 0.6645, and P = 0.4716 respectively). The only difference was a longer OR time, RSL = 104.408 minutes vs WL = 82.386 minutes. (P = 0.0163). RSL and WL are comparable techniques for localization of nonpalpable breast lesions.

Identification of the Thoracic Duct Using Indocyanine Green During Cervical Lymphadenectomy.

BACKGROUND: Injury to the thoracic duct (TD) is the most common complication after a left lateral neck dissection, and it carries a high degree of morbidity. Currently, no routine diagnostic imaging is used to assist with TD identification intraoperatively. This report describes the first clinical experience with lymphangiography using indocyanine green (ICG) during lateral neck dissections. METHODS: In six patients undergoing left lateral neck dissection (levels 2-4) for either thyroid cancer or melanoma, 2.5-5 mg of ICG was injected in the dorsum of the left foot 15 min before imaging. Intraoperative imaging was performed with a hand-held near infrared (NIR) camera (Hamamatsu, PDE-Neo, Hamamatsu City, Japan). RESULTS: In five patients, the TD was visualized using NIR fluorescence, with a time of 15-90 min from injection to identification. Imaging was optimized by positioning the camera at the angle of the mandible and pointing into the space below the clavicle. No adverse reactions from the ICG injection occurred, and the time required for imaging was 5-10 min. No intraoperative TD injury was identified, and no chyle leak occurred postoperatively. For the one patient in whom the TD was not identified, it is unclear whether this was related to the timing of the injection or to duct obliteration from a prior dissection. CONCLUSION: This is the first described application of ICG lymphangiography to identify the thoracic duct during left lateral neck dissection. Identification of TD with ICG is technically feasible, simple to perform with NIR imaging, and safe, making it a potential important adjunct for the surgeon.

Heterogeneity in Outcomes of Pathologic T1-2N1 Breast Cancer After Mastectomy: Looking Beyond Locoregional Failure Rates.

PURPOSE: A meta-analysis of 22 randomized trials accrued from 1964 to 1986 demonstrated significantly higher rates of locoregional failure (LRF) and breast-cancer mortality in women with 1-3 positive nodes without postmastectomy radiotherapy (PMRT) after mastectomy (mast.). Recent data demonstrate that PMRT reduces distant metastases (DM) in women with pN1 disease. The challenge today is whether all patients with pathologic T1-2pN1 disease have similar substantial LRF/DM risk that routinely warrants PMRT. METHODS: We reviewed patients with pT1-2N1 breast cancer treated with mast. ± adjuvant systemic therapy without PMRT from 2000 to 2013. The endpoints were LRF and DM rates, estimated by cumulative incidence method. RESULTS: We identified 468 patients with median follow-up of 6.3 years. Most (71%) were estrogen receptor/progesterone receptor + human epidermal growth factor receptor 2 (HER2). There were 269 patients with 1+ node, 140 patients with 2+ nodes, and 59 patients with 3+ nodes. The 6-year LRF/DM rates were 4.1%/8.4%. Patients with 1+, 2+, and 3+ nodes had 6-year LRF of 2.3, 5.1 and 8.9%, respectively (p = 0.13). The 6-year DM rate was higher in patients with 3+ nodes versus 1-2+ nodes: 15.7% versus 7.4% (p = 0.02). Several subgroups had low 6-year LRF and DM rates, including T1/1+ node (0.8%/4.1% LRF/DM) and micrometastases (0%/5.8% LRF/DM). CONCLUSIONS: Patients with pT1-2pN1 represent a heterogeneous group with a wide range of LRF/DM rates. In particular, patients with pT1 tumors and 1 + LN, and patients with micrometastases, had low event rates. These groups would derive small absolute reductions in LRF and DM with addition of PMRT, underscoring the importance of patient selection for PMRT in pT1-2pN1 breast cancer.

Does the number of sentinel lymph nodes removed affect the false negative rate for head and neck melanoma?

BACKGROUND AND OBJECTIVES: Head and neck (HN) cutaneous melanoma is associated with worse disease-free survival compared to non-HN cutaneous melanoma, possibly due to inadequate staging. We aim to determine if a higher yield of sentinel lymph nodes (SLNs) affected rates of sentinel lymph node biopsy (SLNB) positivity. METHODS: Two Cancer Registries were used to identify patients who underwent SLNB for HN melanoma. A false negative (FN) was defined by nodal recurrence after negative SLNB. RESULTS: Out of 333 patients who underwent SLNB, 20% (n = 69) had a positive SLN with a FN rate of 6.3%. Those with three or more SLNs had a higher rate of SLN positivity (23.8% [17.5-29.9% CI] vs 16.4% [10.7-23.6% CI]), a lower FN rate (16.7% [10.2-21.2% CI] vs 35.3% [27.1-42.9% CI]), and higher sensitivity (83.3% [82.59-84.09% CI] vs 65.7% [64.87-66.53% CI]) compared to those with one or two SLNs. Of patients in Group 1 (one or two SLNs) with a positive SLN who underwent completion lymph node dissection (20/23), 47% (33-61% CI) had one or more positive non-sentinel nodes compared to 29% (16-51%) of patients in Group 2 (three or more SLNs) (42/46). CONCLUSION: In HN melanoma cases in which multiple nodes are identified, removal of all SLNs will more adequately stage patients.

Safety and Feasibility of Minimally Invasive Inguinal Lymph Node Dissection in Patients With Melanoma (SAFE-MILND): Report of a Prospective Multi-institutional Trial.

BACKGROUND: Minimally invasive inguinal lymph node dissection (MILND) is a novel approach to inguinal lymphadenectomy. SAFE-MILND (NCT01500304) is a multicenter, phase I/II clinical trial evaluating the safety and feasibility of MILND for patients with melanoma in a group of surgeons newly adopting the procedure. METHODS: Twelve melanoma surgeons from 10 institutions without any previous MILND experience, enrolled patients into a prospective study after completing specialized training including didactic lectures, participating in a hands-on cadaveric laboratory, and being provided an instructional DVD of the procedure. Complications and adverse postoperative events were graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events Version 4.0. RESULTS: Eighty-seven patients underwent a MILND. Seventy-seven cases (88.5%) were completed via a minimally invasive approach. The median total inguinal lymph nodes pathologically examined (SLN + MILND) was 12.0 (interquartile range 8.0, 14.0). Overall, 71% of patients suffered an adverse event (AE); the majority of these were grades 1 and 2, with 26% of patients experiencing a grade 3 AE. No grade 4 or 5 AEs were observed. CONCLUSIONS: After a structured training program, high-volume melanoma surgeons adopted a novel surgical technique with a lymph node retrieval rate that met or exceeded current oncologic guidelines and published benchmarks, and a favorable morbidity profile.

Sentinel Lymph Node Biopsy for Recurrent Melanoma: A Multicenter Study.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is routinely performed for primary cutaneous melanomas; however, limited data exist for SLNB after locally recurrent (LR) or in-transit (IT) melanoma. METHODS: Data from three centers performing SLNB for LR/IT melanoma (1997 to the present) were reviewed, with the aim of assessing (1) success rate; (2) SLNB positivity; and (3) prognostic value of SLNB in this population. RESULTS: The study cohort included 107 patients. Management of the primary melanoma included prior SLNB for 56 patients (52%), of whom 10 (18%) were positive and 12 had complete lymph node dissections (CLNDs). In the present study, SLNB was performed for IT disease (48/107, 45%) or LR melanoma (59/107, 55%). A sentinel lymph node (SLN) was removed in 96% (103/107) of cases. Nodes were not removed for four patients due to lymphoscintigraphy failures (2) or nodes not found during surgery (2). SLNB was positive in 41 patients (40%, 95% confidence interval (CI) 31.5-50.5), of whom 35 (88%) had CLND, with 13 (37%) having positive nonsentinel nodes. Median time to disease progression after LR/IT metastasis was 1.4 years (95% CI 0.75-2.0) for patients with a positive SLNB, and 5.9 years (95% CI 1.7-10.2) in SLNB-negative patients (p = 0.18). There was a trend towards improved overall survival for patients with a negative SLNB (p = 0.06). CONCLUSION: SLNB can be successful in patients with LR/IT melanoma, even if prior SLNB was performed. In this population, the rates of SLNB positivity and nonsentinel node metastases were 40% and 37%, respectively. SLNB may guide management and prognosis after LR/IT disease.

Laparoscopic skill assessment of practicing surgeons prior to enrollment in a surgical trial of a new laparoscopic procedure.

BACKGROUND: Outcomes of surgical trials hinge on surgeon selection and their underlying expertise. Assessment of expertise is paramount. We investigated whether surgeons' performance measured by the fundamentals of laparoscopic surgery (FLS) assessment program could predict their performance in a surgical trial. METHODS: As part of a prospective multi-institutional study of minimally invasive inguinal lymphadenectomy (MILND) for melanoma, surgical oncologists with no prior MILND experience underwent pre-trial FLS assessment. Surgeons completed MILND training, began enrolling patients, and submitted videos of each MILND case performed. Videos were scored with the global operative assessment of laparoscopic skills (GOALS) tool. Associations between baseline FLS scores and participant's trial performance metrics were assessed. RESULTS: Twelve surgeons enrolled patients; their median total baseline FLS score was 332 (range 275-380, max possible 500, passing >270). Participants enrolled 87 patients in the study (median 6 per surgeon, range 1-24), of which 72 (83%) videos were adequate for scoring. Baseline GOALS score was 17.1 (range 9.6-21.2, max possible score 30). Inter-rater reliability was excellent (ICC = 0.85). FLS scores correlated with improved GOALS scores (r = 0.57, p = 0.05) and with decreased operative time (r = -0.6, p = 0.02). No associations were found with the degree of patient recruitment (r = 0.02, p = 0.7), lymph node count (r = 0.01, p = 0.07), conversion rate (r = -0.06, p = 0.38) or major complications(r = -0.14, p = 0.6). CONCLUSIONS: FLS skill assessment of surgeons prior to their enrollment in a surgical trial is feasible. Although better FLS scores predicted improved operative performance and operative time, other trial outcome measures showed no difference. Our findings have implications for the documentation of laparoscopic expertise of surgeons in practice and may allow more appropriate selection of surgeons to participate in clinical trials.

Timing of Breast Cancer Surgery-How Much Does It Matter?

Timing of surgical resection after breast cancer diagnosis is dependent on a variety of factors. Lengthy delays may lead to progression; however, the impact of modest delays is less clear. The aim of this study was to evaluate the impact of surgical timing on outcomes, including disease-free survival (DFS) and nodal status (NS). The cancer registry from one academic cancer hospital was retrospectively reviewed. Time from initial biopsy to surgical resection was calculated for patients with ductal carcinoma in situ (DCIS) and stage 1 and 2 invasive carcinomas. Early (0-21 days), intermediate (22-42 days), and late (43-63 days) surgery groups were evaluated for differences in NS and DFS for each cancer stage separately. A total of 3,932 patients were identified for analysis. There were no differences in DFS noted for DCIS. For stage 1, early surgery (ES) was associated with worse DFS compared to intermediate surgery (IS) (p = 0.025). There were no significant differences between ES and late surgery (LS) (p = 0.700) or IS and LS (p = 0.065). In stage II cancers, there was a significant difference in DFS in ES compared to IS (p < 0.001) and LS (p = 0.009). There was no significant difference between IS and LS (p = 0.478). Patients were more likely to undergo immediate reconstruction (p < 0.0001 for all stages) in later time-to-surgery groups, while patients in earlier groups were more likely to undergo breast conserving surgery. There was also no significant difference in NS at time of surgery in clinical stage 1 (p = 0.321) or stage 2 disease (p = 0.571). Delays of up to 60 days were not associated with worse outcomes. This study should reassure patients and surgeons that modest delays do not adversely affect breast cancer outcomes. This allows patients time to consider treatment and reconstruction options.

Treatment and Prognosis of Rare Breast Cancers.

Management algorithms for invasive and non-invasive ductal and lobular breast carcinomas are well-established. Because of their very nature, rare histologic types of primary breast cancers are not represented in practice guidelines and thus present a challenge to the practicing clinician who must make recommendations for surgical treatment, axillary staging, and adjuvant therapy, as well as counsel patients as to their expected disease course and prognosis. Herein, case reports and published series of rare types of primary breast cancer including adenoid cystic, mucoepidermoid, metaplastic, squamous, neuroendocrine, encysted papillary, and micropapillary types will be reviewed to provide a basis for treatment planning for patients presenting with these rare primary breast malignancies.

Adjuvant Radiation Does Not Affect Locoregional Control Following Resection of Melanoma Satellitosis or In-Transit Disease.

BACKGROUND: This study evaluates the association of adjuvant radiation therapy (RT) with improved locoregional (LR) recurrence for resected melanoma satellitosis and in-transit disease (ITD). MATERIALS AND METHODS: Data were collected retrospectively for resected melanoma satellitosis/ITD from 1996 to 2017. RESULTS: 99 patients were identified. 20 patients (20.2%) received adjuvant RT while 79 (79.8%) did not. Mean follow-up in the RT group was 4.3 years and 4.7 years in the non-RT group. 80% of patients who underwent RT suffered a complication, most commonly dermatitis. Locoregional recurrence occurred in 9 patients (45%) treated with adjuvant RT and 30 patients (38%) in the non-RT group (P = 0.805). Median LR-DFS was 5.8 years in the RT group and 9.5 years in the non-RT group (P = 0.604). On multivariable analysis, having a close or positive margin was the only independent predictor of LR-DFS (HR 3.8 95% CI 1.7-8.7). In-transit disease was associated with improved overall survival when compared to satellitosis (HR 0.260, 95% CI 0.08-0.82). DISCUSSION: The use of adjuvant RT is not associated with improved locoregional control in resected melanoma satellitosis or ITD. Close or positive margin was the only treatment-related factor associated with decreased LR-DFS after surgical resection of satellitosis/ITD.

CpG island methylator phenotype predicts progression of malignant melanoma.

PURPOSE: The CpG island methylator phenotype (CIMP) may be associated with development of malignancy through coordinated inactivation of tumor suppressor and tumor-related genes (TRG) and methylation of multiple noncoding, methylated-in-tumor (MINT) loci. These epigenetic changes create a distinct CIMP pattern that has been linked to recurrence and survival in gastrointestinal cancers. Because epigenetic inactivation of TRGs also has been shown in malignant melanoma, we hypothesized the existence of a clinically significant CIMP in cutaneous melanoma progression. EXPERIMENTAL DESIGN: The methylation status of the CpG island promoter region of TRGs related to melanoma pathophysiology (WIF1, TFPI2, RASSF1A, RARbeta2, SOCS1, and GATA4) and a panel of MINT loci (MINT1, MINT2, MINT3, MINT12, MINT17, MINT25, and MINT31) in primary and metastatic tumors of different clinical stages (n=122) was assessed. RESULTS: Here, we show an increase in hypermethylation of the TRGs WIF1, TFPI2, RASSF1A, and SOCS1 with advancing clinical tumor stage. Furthermore, we find a significant positive association between the methylation status of MINT17, MINT31, and TRGs. The methylation status of MINT31 is associated with disease outcome in stage III melanoma. CONCLUSIONS: These findings show the significance of a CIMP pattern that is associated with advancing clinical stage of malignant melanoma. Future prospective large-scale studies may determine if CIMP-positive primary melanomas are at high risk of metastasis or recurrence.

Age-related lymphatic dysfunction in melanoma patients.

BACKGROUND: Age-related outcomes have become increasingly common in evaluating patients with melanoma. For instance, as age increases, sentinel node (SN) nonidentification increases and SN positivity decreases. Furthermore, advanced age is a risk factor for in-transit disease. We hypothesized that increasing age is accompanied by alterations in lymphatic function, possibly explaining these findings. METHODS: Our center's melanoma database was queried to identify patients who underwent successful sentinel node biopsy after lymphoscintigraphy. Records of those treated between 2000 and 2005 were reviewed for age, sex, drainage basin, intraoperative radioactivity, and SN pathology. RESULTS: The 858 patients had a mean age of 55 years; 59% were men. Mean radioactivity in the hottest SN was 5232 counts per second; 179 patients (21%) had SN metastases. SN count rates were significantly and inversely related to age (P < .001 by Pearson correlation, analysis of variance, and chi(2) test). Mean counts per second were 6105, 5883, and 2720 for axillary, inguinal, and cervical basins, respectively (P < .01), and count rates in these basins were consistently lower with increasing age (neck and axilla, P < .001; groin, P = .060; Pearson correlation). Multivariate analysis confirmed an independent inverse association between age and count rates (P < .001), overall and within each primary tumor site. CONCLUSIONS: Lymphatic function, as assessed by radiocolloid transit to and uptake within the SN, declines with age. Altered lymphatic function in older patients may modify metastatic patterns; knowledge of this may help clarify findings of reduced nodal positivity and increased in-transit disease in this population.

Activation of CCR9/CCL25 in cutaneous melanoma mediates preferential metastasis to the small intestine.

PURPOSE: Specific chemokines and their respective receptors have been implicated in distant tumor cell metastasis. Cutaneous melanoma has a distinct pattern of metastasis, preferentially targeting the submucosa of the small intestine. However, the underlying pathogenic mechanism remains unknown. Migration of CCR9(+) lymphocytes to the small intestine is known to occur in response to the chemoattractant effects of CCL25 (thymus-expressed chemokine). The integrin heterodimers alphabeta are also known to be important mediators of cellular adhesion. We hypothesize that the mechanism of small intestinal metastasis by melanoma is via the CCR9-CCL25 axis and specific integrins. EXPERIMENTAL DESIGN: Quantitative reverse transcription-PCR, flow cytometry, and immunohistochemistry were used to assess melanoma tumors for CCR9 and CCL25. Integrin expression was assessed using flow cytometry. CCR9 expression by quantitative reverse transcription-PCR was assessed in primary (n = 23) and metastatic (n = 198) melanomas, and melanoma lines derived from small intestinal metastases (n = 23). RESULTS: We showed CCR9 expression in 88 of 102 paraffin-embedded metastatic melanomas from the small intestine, 8 of 8 melanoma lines derived from metastases in the small intestine, and 0 of 96 metastatic melanomas from other sites. In vitro migration and invasion studies done on CCR9(+) melanoma lines showed migration in response to CCL25 that was inhibited by anti-CCR9 antibody or by short interfering RNA CCR9. Flow cytometric analysis confirmed CCR9 expression by melanomas to the small intestine and showed concomitant alpha(4)beta(1) integrin expression. CONCLUSIONS: Our findings show that functionally active CCR9 on melanoma cells facilitates metastasis to the small intestine. The CCR9-CCL25 axis may explain the high incidence of melanoma metastasis to this specific location.