Oncology: What You May Have Missed in 2023.

Advances in oncology treatment methods have improved outcomes and quality of life for patients with cancer. However, care of these patients can be complex, and the contribution of physicians from different specialties is crucial. This article highlights important publications from 2023 on topics across a wide spectrum relating to the management of oncology patients. The literature was screened for significant new evidence that is relevant to internal medicine specialists and subspecialists whose focus is not oncology. Two articles address the importance of social interventions targeting end-of-life care for low-income and minority patients and the well-being of caregivers. Two additional articles address screening considerations in patients at risk for colorectal and lung cancer. Two more articles address safe use of hormone-related therapies to treat symptoms of menopause and prevent disease recurrence or progression in patients diagnosed with noninvasive breast neoplasia. Finally, several articles were included on topics related to COVID-19 vaccination in patients with cancer, use of cannabinoids for cancer pain control, chronic autoimmune adverse effects related to use of immune checkpoint inhibitors, and the incidence of second primary neoplasms.

Miscoding of Melanoma Thickness in SEER: Research and Clinical Implications.

Melanoma-related deaths and metastases among patients with thin (≤1 mm) and ultrathin (≤0.25 mm) melanomas have been reported. These observations might reflect adverse biology and/or errors in administrative data. Cumulative melanoma-related death rates for thickness groups of patients with thin melanomas were compared among five cohorts including the Surveillance, Epidemiology, and End Results (SEER) registry. Thickness in one SEER region was reexamined in pathology reports. The 5-year cumulative melanoma-related death rate of patients with ultrathin melanomas was higher in SEER (2.8%) compared with other registries (0.6-0.9%). The rates across the 16 SEER regions were 0.25% to 8.4%. In SEER, 21% of thin melanomas were ultrathin; in other registries, they comprised 5.8-15%. A reexamination of thickness in one SEER site revealed that 114 of 447 ultrathin melanomas had errors; after correction, only 17 of the 114 remained ultrathin. The majority of errors were related to decimal point placement. The 86 thin melanomas reclassified to >1.00 mm included 96% of the original ultrathin-associated deaths and 100% of the original positive lymph nodes. Significant miscoding of thickness that is concentrated in ultrathin lesions is present in SEER and results in mischaracterization of patient outcomes. When using administrative data, validation of results can identify critical data issues.

Identification of Patients with Intermediate Thickness Melanoma at Low Risk for Sentinel Lymph Node Positivity.

INTRODUCTION: Sentinel lymph node (SLN) biopsy is recommended for all patients with intermediate-thickness melanomas. We sought to identify such patients at low risk of SLN positivity. METHODS: All patients with intermediate-thickness melanomas (1.01-4 mm) undergoing SLN biopsy at a single institution from 1995-2011 were included in this retrospective cohort study. Univariate and multivariate logistic regression determined factors associated with a low risk of SLN positivity. Classification and regression tree (CART) analysis was used to stratify groups based on risk of positivity. RESULTS: Of the 952 study patients, 157 (16.5 %) had a positive SLN. In the multivariate analysis, thickness <1.5 mm (odds ratio [OR] 0.29), age ≥60 (OR 0.69), present tumor-infiltrating lymphocytes (OR 0.60), absent lymphovascular invasion (OR 0.46), and absent satellitosis (OR 0.44) were significantly associated with a low risk of SLN positivity. CART analysis identified thickness of 1.5 mm as the primary cut point for risk of SLN metastasis. Patients with a thickness of <1.5 mm represented 36 % of the total cohort and had a SLN positivity rate of 6.6 % (95 % confidence interval 3.8-9.4 %). In patients with melanomas <1.5 mm in thickness, the presence of additional low risk factors identified 257 patients (75 % of patients with <1.5 mm melanomas) in which the rate of SLN positivity was <5 %. CONCLUSIONS: Despite a SLN positivity rate of 16.5 % overall, substantial heterogeneity of risk exists among patients with intermediate-thickness melanoma. Most patients with melanoma between 1.01 and 1.5 mm have a risk of SLN positivity similar to that in patients with thin melanomas.

Clark level risk stratifies patients with mitogenic thin melanomas for sentinel lymph node biopsy.

BACKGROUND: The role for sentinel lymph node biopsy (SLNB) in patients with thin melanoma (≤1 mm) remains controversial. We examined a large cohort of patients with thin melanoma to better define predictors of SLN positivity. METHODS: From 1995 to 2011, 781 patients with thin primary melanoma and evaluable clinicopathologic data underwent SLNB at our institution. Predictors of SLN positivity were determined using univariate and multivariate regression analyses, and patients were risk-stratified using a classification and regression tree (CART) analysis. RESULTS: In the study cohort (n = 781), 29 patients (3.7%) had nodal metastases. In the univariate analysis, mitotic rate [odds ratio (OR) = 8.11, p = 0.005], Clark level (OR 4.04, p = 0.003), and thickness (OR 3.33, p = 0.011) were significantly associated with SLN positivity. In the multivariate analysis, MR (OR 7.01) and level IV-V (OR 3.45) remained significant predictors of SLN positivity. CART analysis initially stratified lesions by mitotic rate; nonmitogenic lesions (n = 273) had a 0.7% SLN positivity rate versus 5.6% in mitogenic lesions (n = 425). Mitogenic lesions were further stratified by Clark level; patients with level II-III had a 2.9% SLN positivity rate (n = 205) versus 8.2% with level IV-V (n = 220). With median follow-up of 6.3 years, five SLN-negative patients developed nodal recurrence and four SLN-positive patients died of disease. CONCLUSIONS: SLN positivity is low in patients with thin melanoma (3.7%) and exceedingly so in nonmitogenic lesions (0.7%). Appreciable rates of SLN positivity can be identified in patients with mitogenic lesions, particularly with concurrent level IV-V regardless of thickness. These factors may guide appropriate selection of patients with thin melanoma for SLNB.

Prognosis of patients with melanoma and microsatellitosis undergoing sentinel lymph node biopsy.

INTRODUCTION: Melanoma microsatellitosis is classified as stage IIIB/C disease and is associated with a poor prognosis. Prognostic factors within this group, however, have not been well characterized. METHODS: We performed a retrospective analysis of 1,621 patients undergoing sentinel lymph node (SLN) biopsy at our institution (1996-2011) to compare patients with (n = 98) and patients without (n = 1,523) microsatellites. Univariate and multivariate logistic and Cox regression analyses were used to identify factors associated with SLN positivity and melanoma-specific survival (MSS) in patients with microsatellites. RESULTS: Patients with microsatellites were older and had lesions with higher Clark level and greater thickness that more frequently had mitoses, ulceration, and lymphovascular invasion (LVI) (all p < 0.0001). In microsatellite patients, the SLN positivity rate was 43 %. Lesional ulceration (odds ratio [OR] = 2.9, 95 % confidence interval [CI] 1.5-8.6), absent tumor infiltrating lymphocytes (OR = 2.8, 95 % CI 1.1-7.1), and LVI (OR = 3.3, 95 % CI 1.7-10) were significantly associated with SLN positivity by multivariate analysis. With a median follow-up of 4.5 years in survivors, ulceration (hazards ratio [HR] = 3.4, 95 % CI 1.5-7.8) and >1 metastatic LN (HR = 2.7, 95 % CI 1.1-6.6) were significantly associated with decreased MSS by multivariate analysis. In patients without these prognostic factors, the 5-year MSS was 90 % (n = 49) compared with 50 % (n = 23) among patients with ulceration only, 51 % (n = 12) in those with >1 metastatic LN only, or 25 % in those with both (n = 14, p < 0.01). DISCUSSION: Microsatellitosis was frequently associated with multiple adverse pathologic features. In the absence of ulceration and >1 metastatic LN; however, the outcome for patients with microsatellites compared favorably to stage IIIB patients overall.

Lymphatic invasion as a prognostic biomarker in primary cutaneous melanoma.

Melanoma has a propensity for lymph node metastasis. However, the incidence of lymphatic invasion detected by histology alone in primary melanoma is disproportionately low in comparison to the incidence of positive sentinel lymph nodes (SLN). With the discovery of lymphatic endothelial cell markers, such as podoplanin and LYVE-1, lymphatic vessels can be reliably detected in formalin-fixed paraffin-embedded (FFPE) tissues. There is a now consensus that lymphatic invasion detected by immunohistochemical stains in primary melanoma is much more common than previously reported by histological examination alone. Immunohistochemical stains show that lymphangiogenesis and lymphatic invasion in primary melanoma may occur intratumorally or peritumorally, and lymphatic invasion is common across the range of tumor thicknesses in primary vertical growth phase (VGP) melanomas. A number of studies have shown that lymphatic invasion in primary melanoma is associated with a positive sentinel lymph node biopsy and a worse clinical outcome. Although not currently a part of the standard of care for staging of melanoma, the detection of lymphatic invasion in primary melanoma using immunohistochemical markers may be helpful in planning of therapy in some cases and may find a routine role in primary melanoma microscopic attributes in future.

Local immune response predicts survival in patients with thick (t4) melanomas.

BACKGROUND: Tumor infiltrating lymphocytes (TIL) and histological regression in primary melanoma are generally considered indicators of the local immune response but their roles as prognostic factors have been variably reported. We examined the prognostic role of these variables in patients with high risk (T4) primary melanomas in a large series of patients with long-term follow-up. METHODS: From a prospectively maintained cohort of patients diagnosed between 1971 and 2004, 161 patients were retrospectively identified with primary thick melanomas (>4 mm), no clinical evidence of regional nodal disease (RND) at diagnosis and complete histopathologic data. Univariate and multivariate Cox regression models were performed to identify clinical and histopathologic predictors of disease-specific survival (DSS) and to identify subgroups with differential survival. RESULTS: Factors significantly associated with decreased DSS by univariate analysis included male gender, age ≥ 60 years, axial anatomic location, presence of ulceration, RND, absence of TIL, and presence of regression. In the final multivariate model, TIL and regression, as interacting variables, and RND status remained significantly associated with DSS. In the presence of TIL, concomitant regression was associated with significantly worse survival (p ≤ 0.0001). In the absence of TIL, there was no effect of regression on survival (p = 0.324). CONCLUSIONS: Primary TIL and regression status and RND status are independently associated with melanoma-specific survival in patients with T4 melanomas; presence of TIL in the primary melanoma with concomitant radial growth phase regression is associated with a poor prognosis and may reflect an ineffective local regional immune response.

Lymphatic invasion is independently prognostic of metastasis in primary cutaneous melanoma.

PURPOSE: Lymphatic invasion (LI) in primary cutaneous melanomas was recently found to be common. In this study, we evaluated LI as an independent prognostic factor. EXPERIMENTAL DESIGN: This study included 251 patients with vertical growth phase (VGP) primary cutaneous melanomas who had paraffin-fixed lesional tissue and were in a prospective cohort seen between 1972 and 1991, had no clinical evidence of regional nodal disease at diagnosis, and had at least ten years of follow-up. Dual immunohistochemical staining was used to detect lymphatic endothelium (podoplanin) and melanoma cells (S-100). Multivariate logistic regression for ten-year metastasis was used to define independent prognostic factors, and a prognostic tree was developed to characterize and discriminate risk groups. Kaplan-Meier disease-free survival curves for those with and without LI within current American Joint Committee on Cancer stages were compared using the log-rank statistic. RESULTS: LI was observed in 43% (108 of 251) of the study melanomas. The multivariate model for ten-year metastasis identified four independent prognostic factors: tumor thickness, mitotic rate, LI, and anatomic site. The prognostic tree identified a group of patients with thin (≤1 mm thick) melanomas and poor prognosis: stage IB melanomas with LI. Survival curves for time to first metastasis showed significantly poorer prognosis for patients with LI compared with those without it for both stages IB and IIA. CONCLUSIONS: LI is common across the range of tumor thicknesses in primary VGP melanomas. It is an independent prognostic factor and significantly increases the risk of metastasis in patients in clinical stages IB and IIA.

Sunbeds and sunlamps: who used them and their risk for melanoma.

Sunbed/sunlamp use was recently classified as carcinogenic. This report considers characteristics of those who use sunbeds/sunlamps and the effect of sunbed/sunlamp use on their risk for melanoma within a large case-control study carried out in 1991-1992. Females were more likely than males to have used sunbeds/sunlamps. Use by females increased strongly and significantly with younger ages and with the perceived ability to tan. For females, the individual risk for melanoma increased with typical session time and frequency of sessions. Use before age 20, current use and years of use were not significant. The use patterns of occasional and frequent users were very different. We estimate that typical 5-min sessions would increase the risk for melanoma by 19% for frequent users (10+ sessions) and by 3% for occasional users (1-9 sessions). Body sites that are not generally exposed to sunlight were more common sites of primary melanomas for frequent sunbed/sunlamp users. For males, measures of sunbed/sunlamp use were not significantly associated with melanoma risk.

High lymphatic vessel density and lymphatic invasion underlie the adverse prognostic effect of radial growth phase regression in melanoma.

Regression in the radial growth phase (RGP) of primary cutaneous melanomas is common and has been shown to be an adverse prognostic factor. However, the underlying mechanism is unclear. We performed dual immunohistochemical staining of podoplanin and S-100 on paraffin tissues from 321 patients with vertical growth phase primary melanomas, who had 10 years or more of follow-up. Lymphatic vessel density (LD) and lymphatic invasion (LI) were quantified and documented. The time to first metastasis and melanoma-specific death (MSD) from the date of definite treatment were analyzed using univariate and multivariate Cox models. Among the 116 vertical growth phase melanomas that had regression in the adjacent RGP, 75 (23%) were classified as complete and 41 (13%) were classified as partial. LD was significantly higher (P<0.001) in the 75 lesions with complete regression (mean±SD, 23.7±12.3/mm²) compared with the 41 lesions with partial regression (15.5±7.1/mm²) and was lower in 155 areas of the adjacent normal dermis (7.3±3.5/mm²) and 69 areas of the distant normal dermis (5.5±2.6/mm²). Patients whose lesions had areas of complete regression with LI and either high or low LD or had no LI with high LD, had shorter time to first metastasis (hazard ratio=2.5, 3.8, and 2.5, respectively) and increased risk of melanoma-specific death (hazard ratio=3.1, 1.3 and 3.0, respectively) than those with no LI, and low LD or those without areas of complete regression. These data indicate that complete RGP regression is associated with significantly increased LD. In addition, the adverse prognostic effect of RGP regression is at least partially mediated through lymphangiogenesis and LI in this area.

Prognostication in thin cutaneous melanomas.

CONTEXT: While most patients diagnosed with thin cutaneous melanoma will have a good prognosis, nearly 5% will die of their disease. Thin melanomas are common and approximately one-quarter of all melanoma-related deaths result from thin primary tumors. Patients with thin melanoma commonly have sentinel lymph node biopsies that are uncommonly positive. OBJECTIVE: To review the progress that has been made in the translation of prognostic and predictive biomarkers for patients with thin melanomas by focusing on the developments during the last 5 years in using measures of tumor proliferation. Given the paucity of biomarkers for patients with thin melanoma, we review some of the challenges in the development, validation, and translation of new biomarkers into clinical practice. DATA SOURCES: Surveillance, Epidemiology and End Results registry data, cohort data from a cancer center's program in melanoma, and focused literature review. CONCLUSIONS: The presence of dermal mitoses improves prognostication and prediction. To optimize patient management, biomarkers reflecting biologic processes underlying tumor progression will need to be included in panels and risk models, validated, generalized, and ratified.

Does MC1R genotype convey information about melanoma risk beyond risk phenotypes?

BACKGROUND: A study was carried out to describe associations of MC1R variants and melanoma in a US population and to investigate whether genetic risk is modified by pigmentation characteristics and sun exposure measures. METHODS: Melanoma patients (n = 960) and controls (n = 396) self-reported phenotypic characteristics and sun exposure via structured questionnaire and underwent a skin examination. Logistic regression was used to estimate associations of high- and low-risk MC1R variants and melanoma, overall and within phenotypic and sun exposure strata. A meta-analysis of results from published studies was undertaken. RESULTS: Carriage of 2 low-risk or any high-risk MC1R variants was associated with increased risk of melanoma (odds ratio [OR], 1.7; 95% confidence interval [CI], 1.0-2.8; and OR, 2.2; 95% CI, 1.5-3.0, respectively). However, risk was stronger in or limited to individuals with protective phenotypes and limited sun exposure, such as those who tanned well after repeated sun exposure (OR, 2.4; 95% CI, 1.6-3.6), had dark hair (OR, 2.4; 95% CI, 1.5-3.6), or had dark eyes (OR, 3.2; 95% CI, 1.8-5.9). We noted this same pattern of increased melanoma risk among persons who did not freckle, tanned after exposure to first strong summer sun, reported little or average recreational or occupational sun exposure, or reported no sun burning events. Meta-analysis of published literature supported these findings. CONCLUSIONS: These data indicate that MC1R genotypes provide information about melanoma risk in those individuals who would not be identified as high risk based on their phenotypes or exposures alone.

Characteristics associated with early and late melanoma metastases.

BACKGROUND: Differences in risk factors for metastases at different time intervals after treatment have been described in several malignancies; however, to the authors' knowledge, no extensive study examining this issue in melanoma has been conducted to date. METHODS: The authors performed a nested case-control study of patients with melanoma who presented with only local disease. Patients in the case group included 549 patients who developed metastases > or =6 months after surgery. Of these, 320 patients developed metastasis within 3 years after undergoing definitive surgery (early metastases [EM]), and 70 patients developed metastasis > or =8 years after undergoing definitive surgery (late metastases [LM]). For each case, a control patient was chosen who had melanoma but who did not develop metastases in the same interval. Univariate and conditional multivariate logistic regression were used in the analysis of 34 clinical and tumor characteristics. RESULTS: Multivariate analysis confirmed previously established risk factors for metastases, such as increasing tumor thickness. In addition, the authors discovered that a personal history of nonmelanoma skin cancer (P = .006) and a history of cancer other than skin cancer (P = .020) also were associated with metastasis. In comparing the 320 EM patients with the 70 LM patients, EM patients were more likely to have thicker lesions (P < .001), ulcerated lesions (P = .016), and a history of nonmelanoma skin cancer (P = .024). CONCLUSIONS: In this study, 2 potentially novel risk factors for melanoma metastases were identified, and different profiles of risk factors were constructed for EM versus LM. These differences may be important in future risk identification and stratification for clinical trials and for the management and treatment of patients with melanoma.

Lymphatic invasion revealed by multispectral imaging is common in primary melanomas and associates with prognosis.

Lymphatic invasion by tumor cells has been noted infrequently in primary melanomas. Our primary hypotheses were that using immunohistochemical markers of lymphatic vessels and of tumor cells would improve detection of lymphatic invasion and that lymphatic invasion would correlate with regional nodal metastatic disease. This study included 106 patients who were diagnosed between 1972 and 1991 and who had 10 years or more of follow-up. We performed dual immunohistochemical stains for podoplanin (for lymphatic vessels) and S-100 (for melanoma cells). Lymphatic invasion was identified by light microscopy and confirmed by multispectral imaging analysis. Lymphatic invasion was detected by morphology alone in 5 cases (4.7%) in contrast to immunohistochemical staining augmented by multispectral imaging analysis where 35 cases (33%) were identified (P < .0001). Lymphatic invasion was significantly associated with time to regional nodal metastatic disease, as well as first metastasis and melanoma-specific death. "Local metastasis," defined by immunohistochemistry-detected lymphatic invasion, satellites, or neural invasion, identified 64% of those who had regional nodal metastatic disease within 5 years of diagnosis. Lymphatic invasion is an underobserved phenomenon in primary melanomas that can be better detected by immunohistochemical staining. The presence of lymphatic invasion may be a clinically useful predictor of regionally metastatic disease.

Eruptive disseminated Spitz nevi.

Eruptive disseminated Spitz nevi represent an extremely rare variant of Spitz nevi, with only 13 previous cases reported in the literature. We describe a unique case marked by the eruptive onset of numerous lesions posing considerable diagnostic difficulty.

Shared MHC class II-dependent melanoma ribosomal protein L8 identified by phage display.

Antigens recognized by T helper (Th) cells in the context of MHC class II molecules have vaccine potential against cancer and infectious agents. We have described previously a melanoma patient's HLA-DR7-restricted Th cell clone recognizing an antigen, which is shared among melanoma and glioma cells derived from various patients. Here, this antigen was cloned using a novel antigen phage display approach. The antigen was identified as the ribosomal protein L8 (RPL8). A peptide of RPL8 significantly stimulated proliferation and/or cytokine expression of the Th cell clone and lymphocytes in four of nine HLA-DR7(+) melanoma patients but not in healthy volunteers. The RPL8 antigen may represent a relevant vaccine target for patients with melanoma, glioma, and breast carcinoma whose tumors express this protein.

Identification of high-risk patients among those diagnosed with thin cutaneous melanomas.

PURPOSE: Most patients with melanoma have microscopically thin (< or = 1 mm) primary lesions and are cured with excision. However, some develop metastatic disease that is often fatal. We evaluated established prognostic factors to develop classification schemes with better discrimination than current American Joint Committee on Cancer (AJCC) staging. PATIENTS AND METHODS: We studied patients with thin melanomas from the US population-based Surveillance, Epidemiology, and End Results (SEER) cancer registry (1988 to 2001; n = 26,291) and those seen by the University of Pennsylvania's Pigmented Lesion Group (PLG; 1972 to 2001; n = 2,389; Philadelphia, PA). AJCC prognostic factors were thickness, anatomic level, ulceration, site, sex, and age; PLG prognostic factors also included a set of biologically based candidate prognostic factors. Recursive partitioning was used to develop a SEER-based classification tree that was validated using PLG data. Next, a new PLG-based classification tree was developed using the expanded set of prognostic factors. RESULTS: The SEER-based classification tree identified additional criteria to explain survival heterogeneity among patients with thin, nonulcerated lesions; 10-year survival rates ranged from 89.1% to 99%. The new PLG-based tree identified groups using level, tumor cell mitotic rate, and sex. With survival rates from 83.4% to 100%, it had better discrimination. CONCLUSION: Prognostication and related clinical decision making in the majority of patients with melanoma can be improved now using the validated, SEER-based classification. Tumor cell mitotic rate should be incorporated into the next iteration of AJCC staging.

Regional nodal metastatic disease is the strongest predictor of survival in patients with thin vertical growth phase melanomas: a case for SLN Staging biopsy in these patients.

BACKGROUND: The benefit of sentinel lymph node (SLN) biopsy for patients with thin (< or =1.0 mm) melanomas, even for prognostic value, is controversial. This may partly result from the relatively small number and short follow-up of SLN-positive patients in this group. Previously, we have shown that clinical regional nodal metastatic disease (RNMD) serves as a good surrogate for SLN positivity. Here, we use RNMD as a validated surrogate for SLN positivity and examine its prognostic value in a large pre-SLN group of patients with thin vertical growth phase (VGP) lesions who would today commonly be offered SLN biopsy in our practice. METHODS: Between 1972 and 1991, 472 patients with thin VGP melanomas with at least 10 years' follow-up were eligible for the study. Kaplan-Meier survival curves were computed for patients with and without RNMD. A multivariate Cox model and classification tree analysis were used to evaluate clinical and histopathologic predictors of survival. RESULTS: Sixty-seven patients (14.2%) developed recurrence, 53.7% of whom developed RNMD. Forty-five patients (9.5%) experienced melanoma-related deaths (MRD). The most statistically significant predictor of MRD was RNMD (hazard ratio [HR] 13.5, P < .0001). Thickness (HR 10.5, P = .004), axial location (HR 4.6, P = .001), and age >60 years (HR 2.7, P = .005) additionally were independently associated with an increased risk of MRD. RNMD patients demonstrated a 44.4% 10-year disease-specific mortality. CONCLUSIONS: RNMD was the most statistically significant factor associated with MRD in patients with thin VGP lesions. This supports the prognostic use of SLN biopsy in this group, recognizing that additional factors, including thickness, axial location, and older age were independently associated with a worse survival outcome.