High-yield areas to grade tumor budding in colorectal cancer: A practical approach for pathologists.

BACKGROUND: Tumor budding (TB) has significant prognostic implication in stage II colorectal cancer (CRC) and is graded based on the International Tumor Budding Consensus Conference (ITBCC) protocol. In the current study, we evaluate tumor budding and its relationship to multiple histologic features in 104 tumors. METHODS: One-hundred four resected CRC cases were retrieved. Tumor bud count and TB grade were compared to the final tumor bud count/TB grade of the tumor per ITBCC protocol. The following high-yield co-features were assessed in each slide: highest T stage, presence of benign mucosa, presence of a precursor lesion, and highest tumor volume. RESULTS: Twenty-nine (28 %) cases had discrepancies between slide TB grade and final TB grade. The least discrepancies were seen in slides with benign mucosa (7 %) and precursor lesions (7 %). Among stage II patients without high-risk features, no discrepancies were observed in slides with benign mucosa. Slides with deepest invasion (rs = 1.000, p = 0.01) and benign mucosa (rs = 0.957, p < 0.001) had the strongest correlation with final tumor bud count in the same stage II subgroup. Similar relationships were observed when comparing final TB grade. Deepest invasion, tumor volume, as well as lymphovascular invasion, when present, also showed strong correlations with final TB grade in the entire cohort (rs = 0.828-0.845, p < 0.001). CONCLUSION: Our study is the first study to evaluate the relationship between TB grade and co-existing histologic features. We highlight the benefit of focusing on slides with high-yield co-features, with the strongest correlation seen in slides with adjacent benign mucosa and precursor lesions.

Predicting severity of periorbital necrotizing fasciitis.

PURPOSE: To determine whether severity of periorbital necrotizing fasciitis can be predicted based on premorbid patient characteristics. METHODS: Records of 10 consecutive patients with periorbital necrotizing fasciitis presenting at a single center, treated by one attending ophthalmic plastic surgeon, were retrospectively reviewed. Demographic information and medical history were used to determine a Charlson Comorbidity Index (CCI) score for each patient. Other variables included presenting visual acuity, number of surgical debridements performed, infectious organism (if known), and visual acuity at last follow-up. Data were compared with Mann-Whitney U test to determine correlation between variables, using p-values as outcome measures. RESULTS: Increased age at presentation correlated with worse presenting and final visual acuity, requiring more surgical debridements to control disease (each p < .0001). Worse initial visual acuity correlated with need for increased number of debridements (p = .002), but increased number of debridements did not correlate with final visual acuity (p = .101). CCI did not correlate with initial vision (p = .30), final vision (p = .72), or number of surgical debridements necessary (p = .99). Presenting visual acuity did not correlate with final visual acuity (p = .268). CONCLUSION: Older patients have more severe cases of periorbital necrotizing fasciitis, as defined by increased number of surgeries required to control disease and worse visual outcomes. CCI did not correlate with severity of disease.

Conjunctival Melanoma: Features and Outcomes Based on the Fitzpatrick Skin Type in 540 Patients at a Single Ocular Oncology Center.

PURPOSE: To determine the association of Fitzpatrick skin type (FST) with conjunctival melanoma. METHODS: Retrospective case series of 540 patients with conjunctival melanoma to assess clinical features and outcomes per FST. RESULTS: The FST was Type I (n = 126, 23%), II (n = 337, 62%), III (n = 56, 10%), IV (n = 8, 2%), V (n = 12, 2%), and VI (n = 1, <1%). A comparison (FST I vs. II vs. III, IV, V, and VI) revealed Types I and II associated with older mean patient age (63.9 vs. 60.7 vs. 51.1 years, p < 0.001), greater percentage of female patients (68% vs. 44% vs. 42%, p < 0.001), lower frequency of complexion associated melanosis (1% vs. 2% vs. 13%, p < 0.001), smaller tumor thickness (2.1 vs. 2.8 vs. 3.6 mm, p = 0.01), and less eyelid involvement (13% vs. 13% vs. 28%, p = 0.02). Kaplan-Meier estimates for 5-year risk showed no difference by Types for visual acuity loss ≥3 lines, local tumor recurrence, exenteration, metastasis, or death. CONCLUSION AND RELEVANCE: Most patients with conjunctival melanoma show FST I or II, and this demonstrated no association with 5-year rate of vision loss, tumor recurrence, exenteration, metastasis, or death.

Diffuse Carbonic Anhydrase 9 and GATA3 Expression in Fumarate Hydratase Deficient Renal Cell Carcinoma - A Case Report and Immunoprofile Review.

Fumarate hydratase deficient renal cell carcinoma (FHRCC) can exhibit a heterogenous immunoprofile. In the present case, a solitary 10.5 cm mixed cystic and solid left kidney tumor showed various growth patterns, involving renal sinus adipose tissue and the renal pelvis. Tumor cells showed prominent nucleoli and perinucleolar halos. Aberrant diffuse (>90%), strong, and membranous carbonic anhydrase 9 and variable GATA3 expression were present. Diagnostic loss of fumarate hydratase expression and 2-succinyl cysteine overexpression (cytoplasmic and nuclear) were identified. Carbonic anhydrase 9 and GATA3 expression in FHRCC is rarely reported in the literature, and may cause misdiagnosis of clear cell RCC and/or urothelial carcinoma.

Atrophic Kidney-Like Lesion-Case Report and Review of the Literature.

Atrophic kidney-like lesion (AKLL) is a rare kidney lesion, which was recently suggested by the Genitourinary Pathology Society as a provisional entity. As of now, 16 examples of AKLL have been described in the literature. Here we report a new tumor which shows similar clinicopathologic characteristics with those previously reported in AKLL. Immunohistochemical (IHC) studies in the current lesion identified a biphasic staining pattern consisting of a mixture of WT1+/KRT7-/PAX8- large dilated cysts and WT-/KRT7+/PAX8+ small atrophic cysts. Histomorphologic features of AKLL overlap with several neoplastic and non-neoplastic entities which can lead to mischaracterization. Awareness of the differentiating features is likely important when evaluating these lesions.

SEPT9 Expression in Hepatic Nodules: An Immunohistochemical Study of Hepatocellular Neoplasm and Metastasis.

The methylated SEPT9 DNA ( mSEPT9 ) in plasma is a US Food and Drug Administration (FDA)-approved screening biomarker in colorectal cancer and is emerging as a promising diagnostic and prognostic biomarker in hepatocellular carcinoma (HCC). We evaluated the SEPT9 protein expression by immunohistochemistry (IHC) in various hepatic tumors from 164 hepatectomies and explants. Cases diagnosed as HCC (n=68), hepatocellular adenoma (n=31), dysplastic nodule (n=24), and metastasis (n=41) were retrieved. SEPT9 stain was performed on representative tissue blocks showing tumor/liver interface. For HCC, archived IHC (SATB2, CK19, CDX2, CK20, and CDH17) slides were also reviewed. The findings were correlated with demographics, risk factors, tumor size, alpha fetoprotein levels at diagnosis, T stage and oncologic outcomes, with significance defined as P <0.05. Percentage of SEPT9 positivity differed significantly among hepatocellular adenoma (3%), dysplastic nodule (0%), HCC (32%), and metastasis (83%, P <0.001). Compared with patients with SEPT9- HCC, those with SEPT9+ HCC were older (70 vs. 63 y, P =0.01). The extent of SEPT9 staining correlated with age ( rs =0.31, P =0.01), tumor grade ( rs =0.30, P =0.01), and extent of SATB2 staining ( rs =0.28, P =0.02). No associations were found between SEPT9 staining and tumor size, T stage, risk factors, CK19, CDX2, CK20, or CDH17 expression, alpha fetoprotein levels at diagnosis, METAVIR fibrosis stage, and oncologic outcome in the HCC cohort. SEPT9 is likely implicated in liver carcinogenesis in a HCC subset. Similar to mSEPT9 DNA measurement in liquid biopsies, SEPT9 staining by IHC may prove helpful as an adjunct diagnostic biomarker with potential prognostic ramifications.

Multinucleated tumor cells in clear cell renal cell carcinoma.

OBJECTIVES: Multinucleated tumor cells (MTCs) in clear cell renal cell carcinoma (ccRCC) are not well understood. METHODS: Our study included ccRCC cases in a single institution between 2010 and 2019. We classified MTC as MTC with degenerative atypia (MTCD), MTC with no anaplasia (MTCNA), and MTC with anaplasia (MTCA). Clinicopathologic characteristics and outcomes were compared between MTC groups. RESULTS: In all, 92 of 256 people (36%) with ccRCC had MTC. People with ccRCC with MTCD and those with ccRCC but no MTC had similar clinicopathologic characteristics and outcomes. Also, MTCNA and MTCA were associated with larger tumor size, advanced pathologic tumor stage, higher World Health Organization/International Society of Urologic Pathologists nuclear grade, and higher metastatic potential (P < .001 for each parameter). Overall, MTCA was associated with an increased rate of recurrence (P = .004), higher metastatic potential (P < .001), and shorter time to metastasis (P = .033), regardless of tumor stage. Univariate Cox regression revealed MTCNA as a significant predictor of metastasis at 5 years (hazard ratio [HR], 4.171; 95% CI, 1.934-8.998); moreover, MTCA was a significant predictor of recurrence (HR, 5.723; 95% CI, 2.495-13.124), metastasis (HR, 12.024; 5.966-24.232), and death (HR, 5.661; 95% CI, 2.688-11.924) at 5 years. CONCLUSIONS: Although MTCD may not be relevant in tumor grading, MTCNA and MTCA are associated with adverse outcomes.

Unravelling interobserver variability in gastrointestinal glandular neoplasia: a contemporary study of US and Korean pathologists.

AIMS: Interobserver variability in the assessment of gastric neoplasia biopsies between most Western and Eastern (predominantly represented by Japanese in the literature) pathologists has been documented. It is unknown if such variability exists between the US and Korean pathologists in the current era. METHODS: Ten gastrointestinal (GI) pathologists from the USA (n=5) and South Korea (n=5) evaluated 100 scanned images of gastric (n=50) and colorectal (n=50) neoplasia biopsies and answered multiple questionnaires. Consensus was defined as the answer chosen by the majority. Cohen's (κc) and Fleiss' kappa (κf) values were calculated between the consensus of the two groups and among the raters, respectively. RESULTS: Both groups reached a consensus in the majority of cases (74%-100%) with slight to perfect intergroup (κc=0.049-1.000) and no to substantial intragroup (κf=-0.083 to 0.660) agreements. For gastric neoplasia, Korean pathologists relied heavily on cytoarchitectural atypia, whereas the US pathologists focused on stromal invasion when diagnosing adenocarcinoma. For colorectal neoplasia, the Korean pathologists identified concurrent intramucosal carcinoma when diagnosing invasive adenocarcinoma, while the presence of desmoplasia was a prerequisite for the diagnosis of invasive adenocarcinoma for the US pathologists. CONCLUSIONS: For GI neoplasia biopsy interpretation, the diagnostic approach of Korean pathologists is similar to that of Eastern/Japanese pathologists. Consensus outperformed kappa statistics in capturing the magnitude of inter-rater and intergroup reliability, highlighting the potential benefit of consensus meetings to decrease the gap between Western and Eastern diagnostic approaches.

Tumor Stroma Ratio and Its Significance in Locally Advanced Colorectal Cancer.

Colorectal cancer is the third leading cause of cancer-related death, and its incidence is rising in the younger patient population. In the past decade, research has unveiled several processes (underlying tumorigenesis, many of which involve interactions between tumor cells and the surrounding tissue or tumor microenvironment (TME). Interactions between components of the TME are mediated at a sub-microscopic level. However, the endpoint of those interactions results in morphologic changes which can be readily assessed at microscopic examination of biopsy and resection specimens. Among these morphologic changes, alteration to the tumor stroma is a new, important determinant of colorectal cancer progression. Different methodologies to estimate the proportion of tumor stroma relative to tumor cells, or tumor stroma ratio (TSR), have been developed. Subsequent validation has supported the prognostic value, reproducibility and feasibility of TSR in various subgroups of colorectal cancer. In this manuscript, we review the literature surrounding TME in colorectal cancer, with a focus on tumor stroma ratio.

A comparison of primary laser versus laser after anti-vascular endothelial growth factor for type 1 retinopathy of prematurity.

PURPOSE: To compare characteristics of laser treatment for high-risk type 1 retinopathy of prematurity (ROP) in eyes treated with primary laser versus laser after an initial treatment with intravitreal anti-vascular endothelial growth factor (anti-VEGF). METHODS: The medical records of consecutive patients at a single academic institution treated for type 1 ROP before 36 weeks' postmenstrual age with primary laser versus laser after initial treatment with anti-VEGF were reviewed retrospectively. Outcome measures were laser spot number, mean laser power, total laser energy (Joules), and retinal vascularization to the nasal ora at time of laser treatment. RESULTS: Compared with the 46 eyes treated with primary laser, the 46 eyes treated with laser after anti-VEGF required fewer spots (mean, 775 vs 1418 [P < 0.01]), less power (182 vs 223 mW [P < 0.01]), and less total energy (27 vs 61 Joules [P < 0.01]), and showed greater vascularization to the nasal ora at the time of laser treatment (47.8% vs 6.5% [P < 0.01]). CONCLUSIONS: In our study cohort, laser after initial anti-VEGF treatment may have allowed for greater retinal vascularization and been less destructive than primary laser for high-risk type 1 ROP.

Conjunctival melanoma: outcomes based on tumour origin in 629 patients at a single ocular oncology centre.

PURPOSE: To investigate clinical features and outcomes of conjunctival melanoma classified by tumour origin. METHODS: Retrospective review of conjunctival melanoma patients at a single ocular oncology centre between April 18, 1974 and September 9, 2019. Lesions were divided into three tumour origin groups (primary acquired melanosis [PAM], nevus, and de novo) and clinical features and outcomes were compared. RESULTS: There were 629 patients with conjunctival melanoma that arose from PAM (n = 476, 76%), nevus (n = 59, 9%), or de novo (n = 94, 15%). A comparison (PAM vs. nevus vs. de novo) revealed patients with tumours arising from PAM presented with older mean age (62 vs. 52 vs. 55 years, p < 0.001), worse initial logMAR visual acuity (Snellen equivalent 20/30 vs. 20/25 vs. 20/25, p = 0.03), and greater clock hour involvement (4.8 vs. 4.0 vs. 3.2, p < 0.001). Tumours arising from nevus had lower frequency of fornix (31% vs. 9% vs. 24%, p = 0.02) and tarsal involvement (29% vs. 9% vs. 26%, p = 0.046) and more frequent classification as AJCC category T1 (60% vs. 89% vs. 62%, p = 0.01). After follow-up of (57.2 vs. 68.2 vs. 51.7 months, p = 0.35), tumours arising from PAM had worse mean final visual acuity (20/50 vs. 20/40 vs. 20/40, p = 0.02) and greater frequency of visual acuity loss ≥3 lines (25% vs. 15% vs. 10%, p = 0.02). Kaplan-Meier estimates for 5-year risk showed no difference by tumour origin for visual acuity loss ≥3 lines, local tumour recurrence, exenteration, metastasis, or death. CONCLUSIONS: Conjunctival melanoma most often arose from PAM, and tumour origin did not affect clinical outcomes.

Conjunctival Melanoma: Outcomes Based on Age at Presentation in 629 Patients at a Single Ocular Oncology Center.

PURPOSE: To investigate the clinical features and outcomes for conjunctival melanoma based on patient age. METHODS: A retrospective review of patients with conjunctival melanoma managed at a single tertiary referral center from April 18, 1974, to September 9, 2019. Clinical features and outcomes were compared by patient age category at presentation (young ≤45 years, middle-aged 46-69 years, and older ≥70 years), with Kaplan-Meier and Cox proportional hazard analysis [hazard ratio (95% confidence interval)]. RESULTS: There were 629 patients categorized as young in 130 (21%), middle-aged in 278 (44%), and older in 221 (35%). A comparison by age category (young vs. middle-aged vs. older) revealed that older patients had melanoma with greater number of affected quadrants (1.7 vs. 1.8 vs. 2.0, P = 0.001) and clock hours (3.9 vs. 4.2 vs. 5.2, P = 0.001). All patients were treated with surgical excision, with no difference in requirement for additional medical or radiation therapy. By 10-year Kaplan-Meier outcomes, older patients had more frequent visual acuity loss ≥3 lines (11% vs. 28% vs. 64%, P < 0.001) and local tumor recurrence (38% vs. 46% vs. 70%, P < 0.001). Hazard ratio for the oldest age group (age ≥70) revealed a 7.76-fold (3.33-18.09) increased risk for visual acuity loss (P < 0.001), and a 2.08-fold (1.32-3.28) increased risk of local tumor recurrence (P = 0.002). There was no difference by age in risk for enucleation, exenteration, locoregional lymph node involvement, distant systemic metastasis, or death. CONCLUSIONS: Older patients with conjunctival melanoma present with more extensive disease and have increased risk for visual acuity loss and local tumor recurrence.

Conjunctival Melanoma: Outcomes based on the American Joint Committee on Cancer Clinical Classification (8th Edition) of 425 Patients at a Single Ocular Oncology Center.

PURPOSE: The aim of this study was to evaluate outcomes of conjunctiva melanoma based on the American Joint Committee on Cancer Classification (AJCC) 8th edition. DESIGN: Retrospective interventional case series. METHODS: Outcomes analysis of 425 patients. RESULTS: In this analysis of 425 patients with conjunctival melanoma, there were 266 (63%) patients classified as T1, 75 (18%) as T2, 84 (20%) as T3, and 0 (0%) as T4. A comparison (T1 vs T2 vs T3) revealed that history of primary acquired melanosis was more common in T2 (81% vs 96% vs 81%; P = 0.01) and conjunctival nevus more common in T1 (20% vs 9% vs 11%; P = 0.03). Of 381 patients with follow-up (mean of 57.6 months), comparison revealed higher T category with increasing local recurrence/new tumor (30% vs 43% vs 49%; P = 0.004), increasing exenteration (3% vs 9% vs 28%; P < 0.001), increasing melanoma-related locoregional lymph node metastasis (2% vs 7% vs 12%; P = 0.001), increasing melanoma-related systemic metastasis (9% vs 25% vs 23%; P < 0.001), and increasing melanoma-related death (4% vs 12% vs 18%; P < 0.001). A comparison at 10 years revealed visual acuity loss of >3 lines (32% vs 42% vs 63%; P < 0.001), melanoma recurrence/new tumor (47% vs 70% vs 74%; P < 0.001), exenteration (4% vs 24% vs 46%; P < 0.001), melanoma-related locoregional lymph node metastasis (3% vs 13% vs 25%; P < 0.001), melanoma-related systemic metastasis (13% vs 45% vs 40%; P < 0.001), and melanoma-related death (8% vs 22% vs 37%; P < 0.001). CONCLUSIONS: Based on the AJCC 8th edition of conjunctival melanoma, the 10-year risk per T category significantly increased for visual acuity loss of >3 lines, recurrence/new tumor, exenteration, locoregional and systemic melanoma-related metastasis, and melanoma-related death.