High Mitotic Rate Research Articles

Survival analysis in head and neck melanoma after negative sentinel lymph node biopsy: A seer-based population study.

Cutaneous malignant melanoma (CMM) is one of the most aggressive skin tumors. Sentinel lymph node biopsy (SLNB) is an important test before thorough treatment of melanoma. The aim of this study was to investigate cancer-specific survival (CSS) in patients with head and neck CMM after negative SLNB and to analyze predictors of decreased survival. Based on the Surveillance, Epidemiology and End Results (SEER) database, a study was conducted using data from patients with head and neck CMM after negative SLNB. The demographic, clinical, and pathological characteristics of the case population were analyzed. Cox univariate, Kaplan-Meier analysis, and multivariate Cox regression models were used to explore predictors of decreased survival; propensity score matching (PSM) analysis was used to reduce confounding bias, and outcomes were compared between the wide margin excision and narrow margin excision groups. A total of 1597 confirmed head and neck CMM patients with SLNB-negative were found. A Breslow>4.0mm was the highest independent risk predictor for patients (HR 3.82, 95% CI 2.04-7.16, P < .001), and significant risk independent predictors also included a high mitotic rate >4 (HR 1.54, 95% CI 1.06-2.25, P = .023). Age< 60years old was a significant survival predictor (HR 0.56, 95% CI .37-.85, P = .007), and not scalp and neck CMM were also important factors for longer survival (auricle skin: HR .51, 95% CI .29-.90, P = .02; unspecified parts of face: HR .59, 95% CI .40-.87, P = .007). After harmonizing baseline data by PSM, it was found that the extent of surgical resection did not affect patient survival. This study analyzed the risk factors affecting CSS in patients with CMM of the head and neck region with SLNB-negative and observed a statistically significant difference in the prognosis of patients with CMM in different aesthetic subunits of the head and neck region. Close clinical follow-up for this population is necessary, and periodic medical examinations should be carried out.

Ki-67 index assessment on FNA specimens of gastrointestinal stromal tumor: Correlation with mitotic rate and potential predictive value for risk stratification.

Risk assessment of gastrointestinal stromal tumor (GIST) is challenging on cytology specimens. This study aims to determine whether Ki-67 index evaluated on fine-needle aspiration (FNA) specimens can correlate with the mitotic rate of GIST in surgical specimens and provide further risk assessment. Cases with cell blocks containing adequate tumor cells and surgical resections were included. Ki-67 immunostain was retrospectively performed on cell block sections, and Ki-67 index was calculated on the "hot spot" areas. This study included 50 GIST cases from stomach (n=45; 90%), duodenum (n=4; 8%), and distal esophagus (n=1; 2%). The tumor size ranged from 1.5 cm to 21 cm (mean, 5.4 cm). Based on the mitotic count, 37 GISTs (74%) had low mitotic rate (LMR) and 13 GISTs (26%) had high mitotic rate (HMR). The spindle cell, epithelioid, and mixed types accounted for 60%, 14%, and 26%of GIST, respectively. Ki-67 index counted on cell block sections correlated well with mitotic count evaluated in surgical specimens (r=0.8031). Mean Ki-67 index was higher in HMR than LMR groups (3.5% vs. 1%, p < .001). The receiver operating characteristic curve using Ki-67 index to predict mitotic rate was further analyzed, and area under the curve was 0.839. Using a cutoff of 2.5% yielded a sensitivity of 70% at 92% specificity. This study demonstrates good correlations between Ki-67 index and mitotic count or risk stratification, suggesting that Ki-67 index evaluated on cytology specimens may offer a promising approach to preoperatively predict the mitotic rate and risk of GIST.

Solitary Fibrous Tumors of the Head and Neck: A Single-Institution Study of 52 Patients.

ObjectiveTo evaluate the clinicopathologic characteristics of head and neck solitary fibrous tumors and features that may predict tumor recurrence.Study DesignRetrospective review.SettingUniversity of California–Los Angeles Medical Center.MethodsA single-center retrospective study was conducted on pathologically confirmed cases of head and neck solitary fibrous tumors between 1996 and 2021. Patient demographics, clinical course, and histopathologic features were evaluated. Recurrence-free survival was estimated via Kaplan-Meier analysis.ResultsA total of 52 patients were reviewed. The average patient age was 54.7 years (range, 15-89). The most common subsite was the orbit (53.8%, n = 28), but other involved areas included the nasopharynx, paranasal sinuses, and scalp. The median tumor size was 2.95 cm (range, 1.3-11.2). Strong STAT6 (100%) and CD34 (97.9%) expression was observed on immunohistochemistry. Almost all patients were initially managed with wide local excision; 82% of patients (n = 14) had positive margins on pathologic review; and 15% (n = 4) had recurrence at a median 28.5 months (range, 10-113). White patient race was the only significant predictor of tumor recurrence. Patient age (≥55 years), tumor size (≥4), high mitotic rate, and disease subsite were not associated with recurrence.ConclusionHead and neck solitary fibrous tumors demonstrate a significantly larger local recurrence rate as compared with their rate of metastasis. They can recur many years following initial therapy, warranting long-term surveillance and follow-up to assess for tumor recurrence.

EPEN-29. Spatial transcriptomic analysis of ependymoma implicates unresolved wound healing as a driver of tumor progression

Abstract Ependymoma is a childhood brain tumor that remains incurable in approximately 50 percent of cases, most commonly in posterior fossa subgroup A (PFA). Uncovering how heterogeneous cell types within the tumor microenvironment (TME) interact is crucial to a complete understanding of PFA disease progression. The underlying cellular components of the PFA TME have been revealed by single-cell RNAseq (scRNAseq), identifying divergent epithelial differentiation and epithelial-mesenchymal transition (EMT) lineages. Here, we utilize spatial transcriptomics (Visium) of 14 PFA samples, integrated with scRNAseq, to chart neoplastic and immune cell architecture, with a higher resolution of cellular heterogeneity than scRNAseq alone. At a gross level, all PFA were primarily comprised of neoplastic epithelial and mesenchymal transcriptomic spatial zones, each containing a diversity of hierarchical cellular stages. In all samples we revealed spatially and transcriptomically-distinct mesenchymal zone-associated subclusters, including a quiescent undifferentiated progenitor-like subpopulation and clusters with characteristics of early and late stage EMT. Two early stage EMT clusters were distinguished by signatures of either myeloid cell interaction or hypoxia, and both were demonstrated to be EMT-initiating processes in in-vitro PFA experimental models. Myeloid cell interaction is the predominant initiating stage of EMT in PFA, occurring in zones that are spatially distinct from hypoxia induced EMT. Other mesenchymal clusters represent later EMT stages characterized by wound repair and tissue remodeling. Increased proliferation was a general characteristic of epithelial zone clusters, which included a second undifferentiated progenitor-like population that showed a particularly high mitotic rate and was associated with histologically hypercellular areas. Given the biological parallels with normal wound healing, we propose that mesenchymal and epithelial zones interact to create a cycle of persistent tissue damage response and mitogenic re-epithelialization signals. Unresolved wound repair is therefore a potential driver of PFA progression, a new concept that could provide novel targets for effective therapeutic intervention.

PEC-PRO: A new prognostic score from a series of 93 patients with localized perivascular epithelioid cell neoplasms (PEComas) treated with curative intent.

11571 Background: Perivascular Epithelioid Cell Neoplasms (PEComas) encompass a heterogeneous family of mesenchymal tumors. The current understanding of their natural history is limited. Previously described clinicopathological factors aimed to define benign or malignant variants, but there is a lack of prognostic factors associated with recurrence of surgically resected tumors, preventing the development of a prognostic score to better optimize patient’s management. Methods: This is a retrospective analysis of clinicopathological features from patients diagnosed with a localized PEComa, within all centers from the French Sarcoma network and one center in Belgium. We analyzed 12 clinicopathological factors in a Cox proportional hazard framework to derive a multivariate prognostic risk model for progression-free survival (PFS). We built the PEComa PROgnostic score (PEC-PRO) ranging from 0 to 5, based on the coefficients of the multivariate model. Three different prognostic groups were identified: low risk (score = 0), intermediate risk (score = 1) and high risk (score ≥2). Results: Ninety-three patients were analyzed with a median follow-up of 46 months (range, 3-253). At diagnosis, the median age was 54 years (range, 13-84), with female predominance (72%). Most common primary locations were uterus (n = 15;16%) and kidney (n = 15;16%). Median tumor size was 6.2 cm (range, 0.8-30). Among patients with reported surgical margins, 64 (73%) and 23 (27%) had R0 and R1-2 margins, respectively. The median PFS was 26 months (IC95, 2.9-124.4), with 1- and 5-year overall survival (OS) rates of 95.7% and 69.9%, respectively, while the median OS was not reached. Using univariate analyses, male gender, primary tumor size &gt; 5 cm, high nuclear grade and cellularity, high mitotic rate &gt; 1/50 HPF, necrosis, vascular invasion, nodal invasion, and R1-2 margins were associated with a shorter PFS. Among those, male gender (HR = 2.88; IC95 1.12-7.411, p = 0.03), vascular invasion (HR = 3.14; IC95 1.10-8.96, p = 0.034), necrosis (HR = 3.93; IC95 1.35-11.47, p = 0.015), and R1-2 margins (HR 4.47; IC95 1.60-12.46, p = 0.007) remained associated with PFS in the multivariate analysis and were included in the multivariate model. Median PFS in patients with high PEC-PRO score was 16 months as compared to 104 months and not reached for patients with intermediate and low PEC-PRO scores, respectively (p &lt; 0.001). We also confirmed the prognostic relevance of the PEC-PRO score in terms of OS. Conclusions: Using a weighted combination of clinicopathological features, the PEC-PRO score reliably predicts the post-operative recurrence risk in patients with localized PEComas. It has the potential to better improve follow-up strategies and personalize adjuvant treatments. The findings of this retrospective analysis require validation in a prospective trial.

Upregulation of Cartilage Oligomeric Matrix Protein Predicts Poor Prognosis in Urothelial Carcinoma.

PurposeCartilage oligomeric matrix protein (COMP) is known as a large pentameric glycoprotein, which interacts with various extracellular matrix proteins in tissues. COMP has been reported to play a role in multiple connective tissue disorders. Recently, elevated COMP levels have been found to be associated with increased tumor size, metastases, faster recurrence of cancer, and overall poorer survival in several cancers. However, the clinical importance of COMP in urothelial carcinoma remains unclear. We investigated the association between COMP expression and clinical outcomes in urothelial carcinoma.Patients and MethodsIn this retrospective study, we collected urothelial carcinoma (UC) tissue from 340 upper urinary tract UC (UTUC) patients and 295 urinary bladder UC (UBUC) patients. Pearson’s chi-square test, Kaplan–Meier analysis, and the multivariate Cox proportional hazards model was used to examine the relationship between COMP expression and patient characteristics, pathological findings, and patient survival, such as metastasis-free survival (MFS) and disease-specific survival (DSS).ResultsA total of 295 UBUC patients and 340 UTUC patients were recruited. The COMP mRNA level was significantly higher among invasive tumors (pT2–pT4) than in noninvasive tumors (pTa-T1) in UBUC groups (P < 0.01). COMP overexpression was associated with advanced T stage, nodal metastases, vascular invasion, perineural invasion, high histological grade, and high mitotic rate in both UBUC and UTUC cohorts. COMP overexpression was predictive of shorter DSS (hazard ratio [HR] in UBUC, 3.986, P < 0.001; in UTUC, 2.283, P = 0.027] and MFS (HR in UBUC, 6.813, P < 0.001; in UTUC, 4.070, P < 0.001). Kaplan–Meier analysis demonstrated high COMP expression associated with poor DSS and MFS in UTUC and UBUC groups (all P < 0.0001).ConclusionCOMP overexpression was linked to poor clinical prognosis and poor pathological features in UC. These results suggest COMP as a biomarker for UC.

Micromolar Concentrations of Methionine Aminopeptidase Inhibitor has Little Cytotoxic Effect on Cancerous and Non‐Cancerous Mammalian Cells

Tuberculosis (TB) is a disease of the lung caused by the bacterium, Mycobacterium tuberculosis (Mtb), and is the second leading cause of mortality from an infectious agent after SARS‐CoV‐2. Mtb is an opportunistic pathogen that benefits from a compromised immune system and is particularly deadly in HIV patients. New therapies targeting TB are necessary due to an increase in multi‐drug resistant strains. Our collaborators at Texas Southern University identified novel bacterial methionine aminopeptidase (MtMetAP1) inhibitors. Genetic knockout studies support the lethality of the deletion of MtMetAP1 in Mtb. Further studies support the existence of an ortholog in Homo sapiens (HsMetAP1) that performs similar essential functions. Although these novel inhibitors are known to be effective against Mtb, their cytotoxicity in mammalian cells has yet to be established. We hypothesize that there will be low levels of cytotoxicity in cancerous and primary lung cell lines at varying concentrations of the MetAP novel inhibitor, UST‐001. Using flow cytometry via a MUSE® Cell Count and Viability Kit, the cytotoxicity of UST‐001 was assayed in H1299 cancer cells. The H1299 cells were exposed to concentrations of UST‐001 ranging from 0.1μM to 750μM for 48 hours at 37℃and 5% CO2. Three negative controls were included in each replicate: DMSO (carrier), pure media, and Isoniazid (INH). INH is a common clinically effective TB treatment. The viability of H1299 cells was still over 60% at the highest inhibitor concentration tested. Trypan Blue Assays were performed on the same H1299 cells at each concentration and the controls, which corroborated flow cytometry results. In establishment of a dose‐response curve, our data showed that at UST‐001 concentrations below 100 μM, induced little to no cell death and cell viability of 90% or higher. Since cancerous cells have higher mitotic rates and more repair pathways, we hypothesize that we will be able to establish an IC50 curve in non‐cancerous Mlg‐2908 lung fibroblast cells at higher concentrations. Current flow cytometry testing on Mlg‐2908 cells, using the same protocol as the H1299 cells, shows cell viability of 89% or higher in 0.1 μM to 10 μM UST‐001 concentrations. Since cancerous cells have higher mitotic rates and more repair pathways, we hypothesize that we will be able to establish an IC50 curve in Mlg‐2908 cells at higher concentrations. Further studies using a Muse Annexin V apoptosis assay will focus on the UST‐001 mechanism of cell death. Our ultimate goal is to characterize the toxicity of this drug in mammalian systems, with hopes of potentially identifying a new class of antibiotics and pharmaceutical targets.

Risk stratification and outcomes in 210 gynecologic perivascular epithelioid cell tumors (PEComas) cases.

To better understand the risk stratification and outcomes of gynecologic PEComas. Clinicopathological features and outcomes of gynecologic PEComas cases reported in both English and Chinese literature before September, 2020 were evaluated. The efficacy of three proposed criteria were compared to verify their practicability in gynecologic PEComas. The Chi-square test and Cox proportional hazard model were performed for statistical analysis. A total of 210 cases were retrieved: 95 from English literature and 115 from Chinese literature. The Flope criterion achieved an accuracy of 47% for detecting malignancy of gynecologic PEComas, 64.2% for the Schoolmeester criterion, and 63.8% for the WHO criterion. Both Chi-square test and uni-variate analysis showed that tumor size ≥ 5cm, infiltrative growth pattern, mitotic rate ≥ 1/50 high per filed (HPF), high nuclear grade and cellularity, necrosis, and vascular invasion were significantly related to recurrence and/or metastasis (R/M) of gynecologic PEComas. Still only high mitotic rate (≥ 1/50 HPF), high nuclear grade and cellularity, and necrosis significantly influenced the long-term survival. Multi-variate analysis showed high nuclear grade and cellularity was an independent risk factor for R/M of gynecologic PEComas. No model was fitted for the death rate due to a small number of events. When defined malignant PEComas cases as meeting three or more out of six clinicopathologic features, the accuracy of such attempt was 62%, but the false-negative rate dropped by 37-55%. Gynecologic PEComas with three or more high-risk factors may be considered as malignant. Further efforts should be invested to look for new potential prognostic factors.

Clinicopathologic features of scrotal leiomyosarcoma: single institutional experience of ten cases

Scrotal leiomyosarcoma arises from the subcutaneous smooth muscle layer and is an exceptionally rare disease process, with only six patients in the largest reported case series. This rarity creates uncertainties regarding diagnosis, surgical management, and clinical outcomes. Our purpose was to retrospectively describe our institutional experience with scrotal leiomyosarcoma from 2010 to 2022. Slides were reviewed with case inclusion requiring both nuclear atypia and mitotic activity. Ten patients with scrotal leiomyosarcoma were identified. Clinical impression included scrotal cyst in nine cases. The median age at diagnosis was 52 years (range: 29-75 years). The mean tumor size was 1.6cm (range: 0.4-3.7cm). Margins were positive in three cases and close in one case, prompting four re-excisions. The mean mitotic rate was 2.3 per 10 high-power field (range: 1-11), with mean Ki67 of 4.6% (range: 1-15%). Nine of the tumors were grade 1, while 1 was grade 2. Four patients had disease-specific follow-up. The remaining six patients have not had disease-specific surveillance. None of the ten patients have shown evidence of recurrence (median follow-up: 75 months, range: 0-116 months). Our series demonstrates that scrotal leiomyosarcoma has a deceptive clinical presentation with a wide age range and small tumor size. With complete surgical resection, scrotal leiomyosarcoma has an excellent prognosis and rigorous follow-up or adjuvant treatment is not likely to be necessary. Cases with unusual clinical or pathologic findings, such as large tumor size or high mitotic rate, may merit more intensive disease-specific surveillance.

Risk factors for lymphatic and hematogenous metastasis after diagnosis of cutaneous Melanoma in Taiwan

Risk factors of lymphatic and hematogenous metastasis in cutaneous melanoma remained unclear in Asian population. This study aimed to identify clinical and histopathological factors to predict metastatic pathways in cutaneous melanoma in Taiwan. A total of 247 patients diagnosed as stage I and II melanoma, followed at National Taiwan University Hospital were included in this retrospective study from 1980 to 2020. Kaplan-Meier curves and Cox proportional hazards regression were utilized to identify risk factors. During a median follow-up of 143 months, 48 (19.4%) and 62 (25.1%) patients developed lymphatic and hematogenous metastasis respectively. In the univariate analysis, age> 70 years, greater Breslow thickness, ulceration, neurotropism, and NRAS mutation were significant risk factors for lymphatic metastasis in all subtypes of melanoma. Age >70 years, head and neck location, thickness, ulceration, higher mitotic rate, neurotropism, and NRAS mutation were significant predictors of hematogenous metastasis in all subtypes. In the multivariate analysis, greater thickness (HR for 2.0-4.0mm, 4.5; p=.009 and HR for >4.0mm, 5.7; p=.003) retained its significance as an independent risk factor for lymphatic metastasis in all subtypes of melanoma. Thickness (HR for >4.0mm, 5.7; p<.001) and ulceration (HR, 2.5; p=.001) were independent risk factors for hematogenous metastasis. Risk factors of metastasis not only differ between lymphatic and hematogenous pathways, but also differ between ethnics and melanoma subtypes. Better understanding the behavior of cutaneous melanoma may help guide further treatments and follow-up plans.

Residual melanoma in wide local excision specimens after 'complete' excision of primary cutaneous in situ and invasive melanomas.

Wide local excision (WLE) to achieve adequate clearance margins is the standard initial definitive treatment for patients with biopsy-proven primary cutaneous melanoma. Residual melanoma in WLE specimens after prior complete excision-biopsy (CEB) is reported in 0-6.3% of cases. However, studies evaluating the prevalence, clinicopathological features and relevance of persistent disease in WLE specimens are limited. This study sought to determine the frequency of and clinicopathological characteristics associated with residual melanoma in WLE specimens performed after a CEB of primary cutaneous or acral melanoma (in situ or invasive) with clinically and histologically tumour-free margins, and assess its relevance. A review of the research database and pathology archives of a large Australian tertiary referral melanoma treatment centre was performed. Eligible patients were those for whom a definitive WLE was performed after CEB of a primary melanoma (in situ or invasive) with negative clinical and histological margins, between May 2013 and May 2015. All partial biopsies were excluded. Of 640 eligible patients, 510 (79.7%) had invasive melanoma and 130 (20.3%) had melanoma in situ. Residual disease was identified in 20 cases (20/640, 3.1%), of which three (15%) were melanoma in situ on CEB and 17 (85%) were invasive melanoma. On univariate analysis, the presence of residual disease in WLE specimens was associated with lentigo maligna (LM)/LM melanoma (LMM) subtype [odds ratio (OR) 10.33; 95% confidence interval (CI) 2.84-37.54; p=0.004], nodular melanoma (NM) subtype (OR 4.92; 95% CI 1.53-15.85; p=0.0076) and, for invasive tumours, higher tumour mitotic rate (mean 7.7, SD 7.51 vs 3.4, SD 4.83; OR 1.11; 95% CI 1.04-1.18; p=0.0014). Breslow thickness >4 mm was associated with a higher risk of residual disease (OR 7.30; 95% CI 1.88, 28.26; p=0.004). Cases with residual disease had primary tumours with a significantly larger diameter (median 14 mm, range 4-25) than those without residual disease (median 9 mm, range 2-60), (OR 1.07; 95% CI 1.03-1.11; p≤0.001) and were also more likely to be amelanotic (38% vs 14%), (OR 3.69; 95% CI 1.17, 11.60; p=0.026). Residual disease was associated with assessment of >3 slides of tissue (OR 6.98; 95% CI 1.54-31.62; p=0.0118) and complete blocking of the scar (OR 31.69; 95% CI 3.98-252.21; p=0.0011). Residual melanoma in WLE specimens is an infrequent occurrence. Risk factors for residual disease are LM/LMM and NM melanoma subtypes, higher mitotic rate, larger lesion diameter and amelanosis. Tumours with these features warrant more extensive pathological sampling. WLE after CEB for melanoma remains an important procedure to reduce local recurrence; however, limited pathological sampling of the WLE scar is probably appropriate for cases lacking high risk features.

Prognostic factors in acinic cell carcinoma of the head and neck: The Amsterdam experience

IntroductionThe aim was to analyse prognosticators in acinic cell carcinoma (AciCC) in two head and neck referral centers in Amsterdam, the Netherlands. Materials and methodsEighty- nine cases of AciCC treated between 1979 and 2016 were retrospectively reviewed. Five, − 10 -and 20- year estimates of survival were executed as well as univariate analysis of prognosticators. ResultsThe majority of AciCC were T1-T2; 89%. Two percent had nodal disease (2%). The most affected organ was the parotid gland (84%) with a female preponderance (67%). Mean age was 52 years with most cases diagnosed in the fourth to sixth decade. The majority of patients received adjuvant radiotherapy. Elective neck dissection (END) in the N0 neck showed no metastases. High grade transformation (HGT) was found in 21% of cases. Median follow up was 101.9 months. Median time to recurrence was 26 months. Nine patients developed distant metastases (DM) of whom 6 had HGT-AciCC. Median survival with DM was 7 months. Five,- ten -and twenty- year estimates were 84%, 81% and 81% for recurrence free survival respectively. Negative clinical features were advanced stage disease and tumour size > 2.6 cm. Negative histological features were a high mitotic rate, HGT, close and involved surgical margins and necrosis. ConclusionAciCC- HGT excluded- of the head and neck has an excellent prognosis and shows acceptable long term results. END can be considered as part of the standard treatment due to the relative high incidence of HGT- AciCC and low accuracy of cytology.

Hormonal implant‐associated soft tissue sarcoma in a domestic ferret (Mustela putorius furo)

AbstractA 6‐year‐old entire female domestic ferret (Mustela putorius furo) was presented with a rapidly growing soft tissue mass between the scapulae. The mass was surgically removed and several parts of a previously placed deslorelin acetate hormonal implant were identified within the growth. Histopathological examination revealed an implant‐associated spindle cell sarcoma with a number of histological features similar to those identified in feline injection‐site sarcoma and microchip‐associated sarcomas, such as poorly differentiated spindle cells, areas of necrosis, pleomorphic elongated nuclei with a high mitotic rate and atypical mitoses. This is the first report of a soft tissue sarcoma apparently associated with a hormonal implant.

Immunohistochemical features of gastrointestinal stromal tumors and their role for differential diagnosis and prognosis

The aim. To clarify all most important immunohistochemical features of gastrointestinal stromal tumors with different histological patterns and analyze the role of expression of Ki-67, MMP-9, VEGF and p16ink4A as a predictive markers of tumor progression.&#x0D; Materials and methods. The study is based on analysis of 100 primary GISTs for description of their morphological features and 36 GISTs taken from this 100 for study of prognostic markers.&#x0D; Results. All spindle cell GISTs have shown diffuse expression of CD117 in tumor cells. The levels of CD117 expression varied from strong expression (3+) until mild expression (1+). Strong expression were seen in 75,8 % of spindle cell GISTs. Epithelioid GISTs demonstrated heterognous moderate or mild expression of CD117. All primary epithelioid GISTs from patients that had relapse of tumor in period from 1 till 3 years demonstrated focal mild expression of CD 117 in tumor cells. Expression of DOG-1 were seen in all 100 cases of GISTs, that were included in our study. The strong expression of DOG-1 (3+) were seen in all 45 GISTs that had low mitotic rate (≤5 mitoses per 50HPF) and not associated with their histological pattern. GISTs with high mitotic rate demonstrated heterogeneous expression of DOG-1 in tumors: moderate expression (2+) with patchy areas of strong expression (3+). Expression of CD56 was not found in spindle cell GISTs, but single tumor cells of epithelioid GISTs that had high mitotic rate demonstrated expression of this marker. The average expression of p16ink4A were higher in tumors that gave relapses compared with tumors without relapses (50,3 % versus 5,7 % respectively, U-test=16.5; p≤0,01).The average expression of MMP-9 also were significantly higher in GISTs that gave relapses: 63,2 % compared with 13,4 % in GISTs without relapse (U-test=16; p≤0 ,01).The strong VEGF expression was found in 66,7 % of GISTs that had relapses and only in 8,3 % of GISTs without relapses. 50 % of GISTs without relapses was negative for VEGF. Finally, the average expression of Ki-67 were 13,4 % in GISTs with relapses and 8,7 % in GISTs without them (U-test=16; p≤0,01).&#x0D; Conclusion. We highly recommend using DOG-1 for epithelioid GISTs. Additionally in epithelioid GISTs can be used CD56 that can give focal positive reaction in some tumour cells. The following minimal panel of markers for differential diagnosis of spindled GISTs from other mesenchymal tumors of gastrointestinal tract is proposed: CD117, DOG-1 and SMA, where the first too markers will demonstrated the moderate or strong diffuse expression and SMA can be occasionally positive in some tumor cells. p16ink4A, ki-67, VEGF and MMP-9 can be used as additional prognostic markers in GISTs.

Different mitotic rates are associated with different prognostic factors, relapses, and survival rates in melanoma

Mitotic rate is one of the major prognostic factors in melanoma. To investigate the significance of mitotic rate and possible impacts of clinicopathological factors on the course of all staged melanoma patients. A total number of 970 melanoma patients were analyzed. Mitotic rates were grouped for analysis as follows: 0-1, 1.1-4.9, 5-9.9, and ≥10 mitoses/mm2 . Melanomas with higher mitotic rates were more likely to be associated with nodular histology (P = 0.0001), higher Clark level (P = 0.0001), thick Breslow depth (P = 0.0001), ulceration (P = 0.0001), vertical growth pattern (P = 0.0001), neurotropism (P = 0.04), lymphovascular invasion (P = 0.01), de novo melanoma (P = 0.0001), absence of tumor infiltrating lymphocytes (P = 0.02), advanced stage (P = 0.0001), and relapse (P = 0.0001). The 5-year overall survival (OS) rate of all patients was 68.7%, and it decreased significantly from 87% in melanomas with 0-1 mitoses/mm2 to 65.2%, 56.6%, and 50.4% in melanomas with 1.1-4.9, 5-9.9, and ≥10 mitoses/mm2 , respectively (P = 0.0001). Age (P = 0.04), gender (P = 0.03), histology (P = 0.0001), Clark level (P = 0.001), T-stage (P = 0.003), ulceration (0.006), node involvement (P = 0.0001), metastasis (P = 0.005), and relapse (P = 0.0001) were correlated with OS in 0-1 mitoses/mm2 melanomas, whereas lymphovascular invasion (P = 0.0001), BRAF mutation (P = 0.01), metastasis (P = 0.0001), relapse (P = 0.0001), and relapse pattern (P = 0.005) were found significant for ≥10 mitoses/mm2 melanomas. Higher tumor mitotic rates associated with known histopathological and clinical poor prognostic factors were found to be significantly independent predictors of early relapse and unfavorable survival for cutaneous melanoma patients. Moreover, different prognostic variables were found to be affecting survivals in melanoma patients with lower and higher mitosis.

Overexpression of Pyruvate Dehydrogenase Kinase-3 Predicts Poor Prognosis in Urothelial Carcinoma.

BackgroundThe mitochondrial pyruvate dehydrogenase complex (PDC) link glycolysis to the tricarboxylic acid cycle by decarboxylating pyruvate to acetyl coenzyme A irreversibly. Cancer cells are characterized by a shift in cellular metabolism from mitochondrial respiration to glycolysis. PDC activity inhibition mediated by phosphorylation via pyruvate dehydrogenase kinase (PDK) has been linked to cancer. However, the clinical significance of PDKs in urothelial cancer prognosis is not clear. We investigated the role and prognostic value of PDK3 expression in patients with upper urinary tract urothelial carcinoma (UTUC) and urinary bladder urothelial carcinoma (UBUC).Patients and MethodsWe retrospectively analyzed clinical data and pathological features. Formalin-fixed urothelial carcinoma (UC) tissues were collected and embedded in paraffin. The correlation of PDK3 expression with clinical characteristics, pathological findings and patient outcomes, including metastasis-free survival (MFS) and disease-specific survival (DSS) were analyzed by Pearson’s chi-square test, Kaplan–Meier analysis, and the multivariate Cox proportional hazards model.ResultsData from 295 patients with UBUC and 340 patients with UTUC were evaluated. High PDK3 expression significantly correlated with several pathologic variables such as high T stage, lymph node metastases, high tumor grade, vascular invasion, and high mitotic rate (all P < 0.001). High PDK3 expression was associated with poor disease-specific survival (DSS) (P < 0.0001) and metastatic free survival (MFS) (P < 0.0001) in a Kaplan–Meier analysis. Additionally, multivariate analysis demonstrated increased PDK3 expression is a significant predictive risk factor for DSS [hazard ratio (HR) in UBUC, 2.79, P = 0.009; in UTUC, 2.561, P = 0.03] and MFS (HR in UBUC, 1.907, P = 0.024; in UTUC, 1.793, P = 0.044). The gene co-expression analysis showed abundant PDK3 co-upregulated genes were involved in the processes of DNA replication and repair through the Gene Ontology classification system.ConclusionHigh PDK3 expression has been linked to negative pathologic characteristics and poor oncological outcomes, suggesting that it could be used as a predictive biomarker for UC. PDK3 mRNA levels and its co-upregulated genes were strongly associated with DNA replication and repair. These results suggest that PDK3 may play a key role in tumor proliferation and development.

A Unique Case of Mantle Cell Lymphoma Masquerading as a Cecal Mass

Mantle cell lymphoma (MCL), a type of B-cell non-Hodgkin's lymphoma, is a rare and aggressive disease with a poor prognosis due to its advanced presentation at diagnosis. It is characterized by a translocation in the Bcl-1 gene, which results in overexpression of cyclin D1. MCL is frequently seen in the form of multiple lymphomatous polyposis (MLP) in which innumerable polyps are observed in the gastrointestinal (GI) tract. In rare instances, MCL presents a single mass. The most common presentation involves male patients in their sixties, with generalized lymphadenopathy, extranodal involvement, and B symptoms (night sweats, fever, and weight loss). Endoscopic findings of MLP include cerebroid folding of the gastric mucosa and innumerable polyps extending from the duodenum to the large intestine and are reported in approximately 9% of all GI lymphomas. Less commonly, only 2–4% of GI malignancies present as a primary GI MCL as a single mass, usually in the stomach and ileocecal region in the intestine. Radiologic findings include lymphadenopathy, splenomegaly, multiple polyposis, or wall thickening with ulceration or mass formation. In most instances, advanced disease is found at diagnosis, for which 5-year survival ranges only from 26 to 46%, even when appropriate treatment is initiated. High mitotic rate, or Ki-67 index, is of prognostic value and is associated with poor prognosis. Treatment involves conventional chemo-immunotherapy consisting of R CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) or RB (rituximab and bendamustine), with the latter being better tolerated and associated with longer progression-free survival. Surgical resection is usually limited to patients in which complications are seen such as bleeding, perforation, or bowel obstruction. We present a unique case of a 70-year-old male with nonbilious, nonbloody emesis, and symptomatic anemia who was found to have a cecal mass consistent with MCL.

Prognostic factors for in-transit metastasis in patients with malignant melanoma.

Malignant melanoma represents an aggressive and unpredictable malignancy, with high locoregional recurrence rates, regardless of tumor stage and therapeutic management. This study aims to identify the main histopathological prognostic factors involved in the development of in-transit metastasis in patients with malignant melanoma. The study includes only patients that were diagnosed with malignant melanoma and with histologically confirmed in-transit metastasis who were treated in a comprehensive cancer center between 2010-2021. Histopathological parameters were investigated, univariate and multivariate analysis was performed. A total of 26 patients were included in the analysis. On univariate and multivariate analysis, only primary cutaneous melanomas located on the thorax correlated with the risk of developing in-transit metastasis, whereas clinicopathological factors such as an increased Breslow thickness and Clark level, the presence of ulceration, positive lymph nodes, a non-brisk TIL density, a high mitotic rate, a nodular subtype, and age >50 years may represent risk factors, even though we could not find any correlations. Primary cutaneous melanomas that arise on the thorax present a high risk for the occurrence of locoregional disease, whereas other clinicopathological characteristics could not be used to predict local recurrence. However, prospective and more extensive cohort studies are needed in order to validate these important prognostic factors.

First reported case of a histiocytic sarcoma in an Armenian hamster (Cricetulus migratorius).

A 14-month-old male Armenian hamster (Cricetulus migratorius) presented with a spontaneous, subcutaneous, firm mass (4.0 × 2.0 × 1.5 cm) on the ventral neck extending towards the cheek pouch causing multifocal small oral ulcerations. This animal was immunized subcutaneously on the dorsal neck for the development of monoclonal antibodies seven months before presentation. The animal was euthanized and necropsy was performed. Histopathology of the mass showed a well demarcated, multilobulated, unencapsulated, highly cellular, neoplastic mass composed of spindle cells arranged in interlacing streams and bundles, with a moderate amount of fibrovascular stroma. The neoplastic cells exhibited indistinct cell borders and a moderate to large amount of eosinophilic, fibrillar cytoplasm, marked anisocytosis and anisokaryosis, binucleated and multinucleated cells, and high mitotic rate. Based on the histomorphologic features of the mass, and the presence of renal tubular hyaline globules and myeloid hyperplasia in the bone marrow, a diagnosis of histiocytic sarcoma was made. The presumptive diagnosis was confirmed by immunohistochemistry, upon which the neoplastic cells showed strong immunoreactivity for the histiocytic cell markers Iba1 and CD11b. Histiocytic sarcomas have been reported in Syrian (Mesocricetus auratus) and Siberian dwarf (Phodopus sungorus) hamsters but, to our knowledge, the current report represents the first case of histiocytic sarcoma described in an Armenian hamster. It is plausible to consider the animal's experimental immunization history and the development of the histiocytic sarcoma to be related. An association between adjuvanted vaccines and soft-tissue sarcomas has been described in cats and referred to as feline injection-site sarcomas.

Digit melanomas are associated with poor prognostic factors and unfavorable survivals.

The anatomic location of primary melanoma is significantly associated with outcome. To evaluate the prognostic factors and survival outcomes associated with melanomas on hand and foot digits. The data of 106 patients with digit melanomas were analyzed retrospectively. Median age of patients was 55years, and male-to-female ratio was one. Majority of the patients had skin melanomas (74.5%); and 25.5% of them had ungual melanomas. The lesions slightly more frequently affected toes (53.8%) and thumbs (55.9%); and 57.4% of the lesions were right-sided. Acral lentiginous melanoma was the major histological subtype (67.5%). Digit melanomas were associated with aggressive histological features, such as high Clark level (75%), thick Breslow depth (72.3%), presence of ulceration (74.3%), and high mitotic rate (58.3%). At admission, the rates of stage I-II, stage III, and stage IV diseases were 57.6%, 33%, and 9.4%, respectively. The recurrence and mortality rates were 41.7% and 46.2%, respectively. The 5-year RFS and OS rates were similar: 47%. Melanoma origins (skin vs. ungual), locations (finger vs. toe; first digit vs. others; and right vs. left), and histological subtypes (acral lentiginous melanoma vs. others) had no impact on survivals. The known poor prognostic histological factors, such as Clark level, Breslow thickness, mitotic rate, ulceration, and neurotropism, were found to be associated with both RFS and OS. Digit melanomas are associated with poor clinicopathological prognostic features, and they might predict unfavorable survivals.