Acral lentiginous melanoma is a distinct subtype of melanoma on acral skin. Patient presentation at later stages and delayed diagnosis by physicians contribute to a worse associated prognosis and ...survival rate. Despite our progress in understanding the key features of this disease, the diagnosis of early-stage acral melanoma is still challenging. It is essential to integrate clinical, dermoscopic, and histologic findings in the diagnosis of acral lentiginous melanoma. In addition, molecular studies can be helpful. In this review, we have summarized our current understanding of this disease entity from articles that were published between 1969 and 2018. We have outlined clinical and dermoscopic features as well as pathologic and molecular findings regarding acral melanoma and have presented an algorithm for diagnosis. Understanding and integrating these characteristics may assist clinicians in the early detection of acral melanomas.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
Stratification of patients who undergo curative resection for early gastric cancer (EGC) is warranted due to the heterogeneity in the risk of developing extragastric recurrence (EGR). ...Therefore, we aimed to stratify the need for postoperative surveillance for EGR detection in patients with EGC by developing a model for predicting EGR-free survival.
Methods
This retrospective cohort study included patients who underwent postoperative surveillance after curative resection of EGC (
n
= 4149). Cox proportional hazard models were used to identify predictors to build a model for predicting EGR-free survival. Bootstrap-corrected c-index and calibration plots were used for internal and external (
n
= 2148) validations.
Results
A risk-scoring system was constructed using variables significantly associated with EGR-free survival: pathologic T stage (pT1bsm1, hazard ratio HR 4.928; pT1bsm2, HR 5.235; pT1bsm3, HR 7.748) and N stage (pN1, HR 4.056; pN2, HR 9.075; pN3, HR 30.659). Patients were dichotomized into a very-low-risk group or a low-or-greater-risk group. The 5-year EGR-free survival rates differed between the two groups (99.9 vs. 97.3%). The discriminative performance of the model was 0.851 (Uno’s c-index) and 0.751 in the internal and external cohorts, respectively. The calibration slope was 0.916 and 1.131 in the internal and external cohorts, respectively.
Conclusions
Our model for predicting EGR-free survival based on the pathologic T and N stages may be useful for stratifying patients who have undergone curative surgery for EGC. The results suggest that patients in the very-low-risk group may be spared from postoperative surveillance considering their extremely high EGR-free survival rate.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
This study aimed at determining the incidence and clinical implications of HER2 status in primary colorectal cancer (CRC). HER2 status was investigated in two retrospective cohorts of 365 consecutive ...CRC patients (cohort 1) and 174 advanced CRC patients with synchronous or metachronous distant metastasis (cohort 2). HER2 status was determined by performing dual-color silver in-situ hybridization (SISH), mRNA in-situ hybridization (ISH), and immunohistochemistry (IHC). The incidence of HER2 protein overexpression (IHC 2+/3+) was approximately 6% (22 of 365 in cohort 1; 10 of 174 in cohort 2). HER2 gene amplification was observed in 5.8% of the patients from cohort 1 and 6.3% of the patients from cohort 2. HER2 gene amplification was more frequently observed in CRCs located in the rectum than in the right and left colon (P = 0.013 in cohort 1; P = 0.009 in cohort 2). HER2 status, determined by IHC, ISH, and dual-color SISH, was not significantly associated with aggressive CRC behaviour or patients' prognosis in both the cohorts. Of the combined cohort with a total of 539 cases, the concordance rate was 95.5% between dual-color SISH and IHC detection methods. On excluding equivocally immunostained cases (IHC 2+), the concordance rate was 97.7%. HER2 mRNA overtranscription, detected by ISH, significantly correlated with protein overexpression and gene amplification (P<0.001). HER2 gene amplification was identified in a minority of CRC patients with high concordance rates between dual-color SISH and IHC detection methods. Although HER2 status did not predict patients' prognosis, our findings may serve as a basis for future studies on patient selection for HER2 targeted therapy.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Remarkable developments in immuno-oncology have changed the landscape of gastric cancer (GC) treatment. Because immunotherapy intervenes with tumor immune response rather than directly targeting ...tumor cells, it is important to develop a greater understanding of tumor immunity. This review paper summarizes the tumor immune reaction and immune escape mechanisms while focusing on the role of T cells and their co-inhibitory signals, such as the immune checkpoint molecules programmed death-1 and programmed deathligand 1 (PD-L1). This paper also describes past clinical trials of immunotherapy for patients with GC and details their clinical implications. Strong predictive markers are essential to improve response to immunotherapy. Microsatellite instability, Epstein-Barr virus, PD-L1 expression, and tumor mutational burden are now regarded as potent predictive markers for immunotherapy in patients with GC. Novel immunotherapy and combination therapy targeting new immune checkpoint molecules such as lymphocyte-activation gene 3, T cell immunoglobulin, and mucin domain containing-3, and indoleamine 2,3-dioxygenase have been suggested, and trials are ongoing to evaluate their safety and efficacy. Immunotherapy is an important treatment option for patients with GC and has great potential for improving patient outcome, and further research in immuno-oncology should be carried out.
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FFLJ, NUK, ODKLJ, UL, UM, UPUK
Individual cell types of human tissues have their own CpG site methylation profiles, which might be utilized for the development of methylation markers to denote tumor-infiltrating lymphocytes ...(TILs). We aimed to develop DNA methylation markers that recapitulate the densities of TILs in gastric carcinoma (GC). Through genome-wide methylation profiling, NCOR2, PARK2, and ZSCAN12 were found to be highly methylated in CD3-positive and CD8-positive cells and rarely methylated in tumor cells. Scores of the three methylation markers were analyzed for their relationship with the overall survival and recurrence-free survival of patients with advanced GC (n = 471). The scores of three methylation markers were closely associated with densities of CD3-positive or CD8-positive cells at the tumor center or invasive front of GCs and found to be a significant prognostic factor in univariate analysis of overall survival and recurrence-free survival. In multivariate analysis, the highest score showed hazard ratios of 0.513 (CI 0.306-0.857) and 0.434 (CI 0.261-0.720) for overall survival and recurrence-free survival, respectively. The findings suggest that methylation markers signifying TILs might be utilized for the recapitulation of TIL density in GCs and serve as biomarkers for predicting prognosis in patients with GC.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
In this study, we investigated the clinical relevance of CD274 (PD-L1) protein expression by tumor cells and tumor-infiltrating immune cells in colorectal cancer (CRC). To this end, 186 ...microsatellite instability-high (MSI-H) and 153 microsatellite stable (MSS) CRCs were subjected to immunohistochemistry (IHC) analysis for the expression of CD274 and mismatch repair proteins. CD274 expression was evaluated in tumor cells at the center (TC) and periphery (TP), and immune cells at the center (IC) and periphery (IP) of CRC. IHC slides stained for CD3 and CD8 were scanned using an Aperio ScanScope for precise calculation of tumor-infiltrating T cell density. Additionally, samples were screened for the B-Raf (BRAF)-V600E mutation using a Cobas 4800 System and IHC. In total, CD274
TC
, CD274
TP
, CD274
IC
, and CD274
IP
were observed in 43 (23.1%), 47 (25.3%), 107 (57.5%), and 102 (54.8%) of the MSI-H CRCs examined, and in three (2.0%), four (2.6%), 47 (30.7%), and 56 (36.6%) of the 153 MSS CRCs tested. Meanwhile, intratumoral heterogeneity of CD274 expression in tumor cells and immune cells was detected in 24 (12.9%) and 47 (25.3%) MSI-H CRCs, respectively. Notably, in both MSI-H and MSS CRC, CD274
IC
and CD274
IP
were independently associated with improved prognosis (
P
< 0.05), while
BRAF
mutation was associated with CD274
TP
, poor differentiation, sporadic type, and hMLH1(−)/hMSH2(+)/hMSH6(+)/PMS2(−) in MSI-H CRC (
P
< 0.006). In conclusion, CD274 expression in tumor-infiltrating immune cells was an independent factor for improved prognosis in CRC patients. A deeper understanding of CD274 status may yield improved responses to future CRC immunotherapies.
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EMUNI, FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Giant congenital melanocytic nevi (GCMN) are usually defined as nevi that exceed 20 cm in maximal diameter or 15% of the total body surface area. There have been reports of life-long malignant change ...risks arising from GCMN, leading to surgical excision of GCMN. This study aims to evaluate the thickness of melanocytes based on clinical factors in order to provide objective information for the complete resection of the lesion.
Overall, 75 patients diagnosed with GCMN between 2000 and 2021 were included, and their clinical records were collected retrospectively. 117 pathologic slides obtained during excision were reviewed to measure nevus thickness. Clinical factors were assessed with a generalized estimated equation model for association with nevus thickness.
The thickness of nevus was significantly associated with the location and size. Nevus thickness was more superficial in the distal extremity than in the head and trunk (P = 0.003 head; P < 0.001 trunk; P = 0.091 Proximal extremity). Nevi sized 60 cm or more were significantly deeper than those measuring 20-29.9 cm (P = 0.035). An interaction between size and location existed (P < 0.001). Trunk and distal extremity lesions consistently exhibited uniform thickness regardless of lesion size, whereas head and proximal extremity lesions showed variations in thickness based on lesion size.
GCMNs have differences in thickness according to location and size. Therefore, it is necessary to devise an approach optimized for each patient to treat GCMN. In the study, it was emphasized that the thickness of GCMN is correlated with clinical factors, specifically the location and size of the nevus. Consequently, these findings underscore the need for individualized treatment plans for effective surgical intervention.
We sought to determine the clinicopathological significance of PD-1, LAG3, and TIM3 in gastric cancer (GC) by examining their expression and immune context. Immunohistochemistry (IHC) for PD-1, TIM3, ...LAG3, and tumor-infiltrating immune cell (TIIC) markers was performed in 385 stage II/III GCs. Epstein-Barr virus (EBV) and microsatellite stability (MSI) testing were performed for molecular classification. Chromogenic multiplex IHC (mIHC) for PD1, TIM3, LAG3, CD3, CD8, FOXP3, CD68, and cytokeratin was performed in 58 of the total samples. PD-1, LAG3, and TIM3 expression in TIICs was observed in 91 (23.6%), 193 (50.1%), and 257 (66.8%) GCs by single IHC, respectively. The expression was associated with EBV
+
and MSI-H molecular subtypes (p ≤ 0.001). A positive expression of LAG3 in the invasive margin of the tumor was associated with better prognosis in univariate (p = .020) and multivariate (p = .026) survival analyses. The expression of different immune checkpoint receptors (ICRs) was significantly positively correlated. Dual or triple ICR expression was more frequent in high PD-1 and TIM3 density groups than in low-density groups by mIHC (all p ≤ 0.05). ICRs were mainly expressed in CD3
+
CD8
+
and CD3
+
CD8
−
T cells. Fifty-eight GCs were classified into three groups by clustering analysis based on mIHC, and the group with the highest ICR expression in TIICs showed significantly better outcomes in progression-free survival (p = .020). In GC, PD-1, LAG3, and TIM3 expression is positively correlated and associated with better prognosis. Our study provides information for the application of effective immune checkpoint inhibitors against GC.
Caudal-type homeobox 2 (CDX2), special AT-rich sequence-binding protein 2 (SATB2), and keratin 20 (KRT20) are frequently used as intestinal epithelium-specific markers in immunohistochemical studies. ...However, subsets of colorectal carcinomas (CRCs) show loss of these markers. We analyzed The Cancer Genome Atlas data to explore molecular correlates of
CDX2
,
SATB2
, and
KRT20
genes in 390 CRCs. The decreased mRNA expression of each of the three genes commonly correlated with microsatellite instability-high (MSI-H), CpG island methylator phenotype-high (CIMP-H),
BRAF
/
RNF43
mutations, consensus molecular subtype 1, and high tumor mutational burden. The downregulation of
CDX2
or
SATB2
was dependent on both MSI-H and CIMP-H, whereas that of
KRT20
was more dependent on MSI-H than on CIMP-H. Next, we evaluated the immunohistochemical expression of CDX2, SATB2, and KRT20 in 436 primary CRCs. In contrast to RNA-level expression, decreased expression of CDX2 and SATB2 was more dependent on CIMP-H than on MSI-H. However, consistent with RNA-level expression, decreased expression of KRT20 was more dependent on MSI-H than on CIMP-H. CIMP-H and lymphatic invasion were consistently associated with both CDX2 loss and SATB2 loss in CRCs, regardless of MSI status. In microsatellite stable CRCs, CDX2 loss correlated with
BRAF
mutation, whereas SATB2 loss was associated with
KRAS
mutations and decreased T-cell infiltration. Cases with concurrent loss of all three markers were found exclusively in
MLH1
-methylated MSI-H/CIMP-H CRCs. In conclusion, MSI-H and/or CIMP-H are major common correlates of decreased CDX2/SATB2/KRT20 expression in CRCs, but the specific features associated with the loss of each marker are different in CRCs.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Developments in genomic pathology have led to novel molecular classification schemes in gastric cancers. Two of these new subtypes, Epstein-Barr virus (EBV)-associated and microsatellite ...instability-high (MSI-H), are associated with a dominant T-cell-mediated immune response. The roles of the immune modulators, indoleamine 2, 3-dioxygenase 1 (IDO1) and tryptophanyl-tRNA synthetase (WARS), have not been investigated in the context of this classification.
Using in situ hybridization and immunohistochemistry we subclassified 421 primary gastric adenocarcinomas into 5 subtypes, EBV-associated, epithelial to mesenchymal transition, MSI-H, p53-aberrant, and p53-wildtype tumors. Tumor-infiltrative lymphocytes were counted and protein expression of IDO1 and WARS was graded on tissue microarrays of these 421 tumors. High tumor-infiltrative lymphocytes as well as high expression of both IDO1 and WARS was found in EBV and MSI-H tumors. The prognostic effects of IDO1 and WARS expression were tumor subtype dependent. Although high expression levels of IDO1 and WARS were associated with poor prognosis in p53-aberrant, p53-wildtype, and all cancers combined, WARS expression was associated with better prognosis in MSI tumors.
The immunomodulators, IDO1 and WARs, are upregulated and have prognostic significance in EBV-associated and MSI-H tumors. Novel therapies targeting these proteins should be considered in the treatment of these patients.
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