Giant cell tumors are neoplasms that usually occur in the long bones of young adults. They can rarely present in the soft tissue and may display malignant behavior. Giant cell malignancies have previously been reported as tumors primary of the uterus but are exceptionally rare. Although uncommon, it is important to consider when a neoplasm with osteoclast-like giant cells is encountered. In this report, we describe a 70-year-old female patient with an unremarkable past history who presented with an enlarged uterus. Transvaginal ultrasound demonstrated multiple fibroids and a thickened endometrium. A biopsy diagnosis of a highgrade sarcoma was rendered and further refined in the surgical resection as malignant giant cell tumor of the uterus. In this case report, we describe the findings of this case and discuss the differential diagnosis of this entity.

Leiomyosarcomas (LMSs) are malignant neoplasms of soft muscle differentiation that can be classified into five distinct groups according to site-related origin: intra-abdominal, subcutaneous or deep soft tissue of the limbs, cutaneous, external genitalia, and vascular. This distinction reflects different biological behaviors as well as molecular changes, thus reflecting different prognoses and therapeutic options. Vascular LMSs are the least frequent, arising from the walls of the blood vessels, most commonly from the inferior vena cava. Due to its deep location, symptoms are non-specific, and the disease presents at an advanced stage, sometimes with metastases. Surgery is the treatment of choice, associated with chemo- and radiotherapy. Due to its rarity, most departments have minimal experience handling this disease. This article reviews the current knowledge on vascular leiomyosarcomas, particularly the inferior vena cava leiomyosarcoma.

Extraskeletal myxoid chondrosarcoma is a rare soft tissue tumour with a high local and distant metastasis rate and limited response to chemotherapy.Meckel's diverticulum is the most frequent congenital anomaly, and it is associated with a considerable risk of malignant transformation.In this case report, we describe a 50-year-old female patient with a history of extraskeletal myxoid chondrosarcoma of the lower limb and metastasis to the forearm who went to the emergency department with abdominal pain. The investigations revealed a caecal volvulus. A lesion in the middle third of the ileum was incidentally discovered and removed during surgery.Pathology examination revealed a Meckel's diverticulum adenocarcinoma, with metastasis of extraskeletal myxoid chondrosarcoma.Resection was complete; however, the patient had diffuse metastatic pulmonary disease and died eight months later due to disease progression.This mechanism of tumour-to-tumour metastasis is described in other locations, but, regarding the Meckel's diverticulum, this is a unique situation, previously unreported in the literature.

The patient presented with a vulvar mass, which histologically was multinodular with variable cellularity and some myxoid areas. A haphazard pattern was seen, conferring a "patternless pattern" ([Figure 1][1]). The cells were epithelioid and in part spindled with indistinct borders, with pale

Introduction: Embryonal sarcoma of the liver (ESL) is a rare neoplasm of the liver occurring mainly in paediatric ages. Making the correct diagnosis can be challenging as the laboratory and radiological findings that are often nonspecific, and the tumour immunophenotype is poorly defined and even somewhat variable. Case Presentation: A large epigastric mass was detected in a computerized tomography scan of a 43-year-old woman presenting with abdominal pain and bloating. The mass was biopsied and submitted to histopathological study. Microscopically the tumour had sarcomatoid features and showed multinucleated cells with periodic acid-Schiff (PAS)-positive globules. Immunostaining revealed positivity for vimentin, CD10, glypican-3, and α1-antitrypsin and negativity for keratins, muscle, adipocytic, and melanocytic differentiation markers. The patient was then submitted to a left hepatectomy with similar histological findings. Discussion: ESL in adults is a rarity and its diagnosis requires the exclusion of other entities. While some microscopic features are very common, they remain nonspecific. The main feature is the presence of multinucleated cells with PAS-positive hyaline globules. While ancillary testing is key, the immunophenotype also lacks specificity and ESL may have variable staining for glypican-3 and epithelial or muscle differentiation markers. Although it has been described for more than 3 decades, the prognosis and optimal treatment are still not well defined, but surgery has yielded favourable results.

Objective: Abdominal wall endometriosis (AWE) is a rare form of extragenital endometriosis that usually develops in association with a prior surgical scar. The purpose of the study was to review the clinical characteristics, diagnostic methods, treatment modalities, and outcomes of patients with AWE. Methods: A descriptive cross-sectional study was performed in a Gynecology Department of a Portuguese tertiary hospital, concerning patients with histologic-proven AWE, between January 2012 and December 2020 (n = 22). Statistical analysis was performed using IBM SPSS Statistics Version 27.00, with a significance level of p < 0.05. Results: The most common locations of extrapelvic endometrial ectopic implants were cesarean delivery scar (n = 13, 59.1%) and the umbilicus (n = 5, 22.7%). The median (range) age was 36 (30-42) years old, and all patients had a history of previous surgery but one. Nineteen patients had undergone a previous cesarean section, and the mean (range) time from surgery to the onset of symptoms was 100 (32-168) months. All patients were symptomatic and presented with a palpable mass at physical examination. The majority complained of a painful abdominal mass (n = 20, 90.9%) which was associated with cyclic pain in thirteen patients (65%). Ultrasound scan was performed in all patients and the nodules had a median size of 20.5 mm (5-93 mm). One patient received hormonal therapy and surgical resection was performed in the remaining patients. The nodule’s median (range) size was 31 (12-50) mm on gross examination. Conclusion: AWE should be considered in the presence of a previous pelvic surgery history associated with abdominal scar cyclic pain and swelling. A careful history and clinical examination are essential for diagnosis to avoid unnecessary delay before surgical intervention.

Immunotherapy has paved the way for the development of solid tumor new treatments in the last decade. The approval of immune checkpoint inhibitors such as anti PD-1/PD-L1 provided a revolution with optimal results. However, a considerable proportion of patients experience adverse therapeutic effects, and up to 50% may develop secondary resistance in the first three to five years. This has prompted the need for identifying new targets for immunotherapy that have good tolerance and biosafety and, of course, good tumoral response, either alone or in combination. Two of these new targets are the Lymphocyte-activation gene 3 (LAG-3) and the T cell immunoglobulin and ITIM domain (TIGIT). They are responsible for several interactions with the immune system, prompting an immunosuppressive phenotype in the tumor microenvironment. Both LAG-3 and TIGIT can be druggable, alone or in combination with anti-PD-1/PD-L1, with rather safe profiles making them attractive. In this review, we highlight some of the immune mechanisms of TIGIT and LAG-3 and their detection by immunohistochemistry, providing some insight into their use in the clinical setting.

Sarcomas are rare lesions and encompass a wide variety of entities, depending on their nature. In recent years new entities have been described and new knowledge, especially that provided by molecular studies, has been increasing. This makes it very difficult to be updated with all the described entities, since only some of the centers have the desired ancillary studies for the correct diagnosis. Some lesions are extremely rare and may appear once or twice during the lifetime of a general pathologist. When we refer to sarcomas of the gastrointestinal tract, the gastrointestinal stromal tumor (GIST) is the most well-known lesion that the pathologist will most frequently find in daily practice. This paper aims to comprehensively review the sarcomas associated with the gastrointestinal tract, emphasizing histopathology and going beyond GIST. This review highlights the histopathology of rare types of sarcomas so it may increase awareness of common and rare lesions, prompting an easy and effective diagnosis.

Introduction: Recent studies have highlighted the presence of hepatic progenitor cells (HPCs) in metastatic liver carcinomas. We provide further evidence of this phenomenon, presenting a case of a gastrointestinal stromal tumour (GIST) liver metastasis with evidence of intra- and peritumoral HPC. Case Description: A 64-year-old man presented with a gastric mass diagnosed as a high-risk KIT-mutated GIST. The patient was treated with imatinib, recurring 5 years later with a liver mass. Liver biopsy disclosed a GIST metastasis, hallmarked by a proliferation of ductular structures without cytological atypia intermingled with the tumour cells, with a CK7/CK19/CD56-positive immunophenotype and rare CD44 positivity. The patient underwent liver resection, and the same ductular structures were present in the tumour interior and at its periphery. Conclusion: We document for the time the presence of HPC in the form of ductular structures in a GIST liver metastasis, further supporting their role in the liver metastatic niche.

Breast cancer is a major health burden, and up to one-third of patients with breast cancer develop brain metastases, which are linked to a very poor prognosis. Few biomarkers are available to predict the prognosis of patients with metastases. Assessment by immunohistochemistry may be used as a tool to predict the behavior of these tumors. A retrospective transversal study including 114 patients (diagnosed between 2000 and 2016) with breast cancer brain metastases was carried out using archival biological material from 114 patients with breast cancer brain metastases. Expression of CD44, HER2, ER, PR, CA9, PDL-1, CD133, ALDH1, PTEN, AKT, PI3K, and AR markers was assessed by immunohistochemistry. The overexpression of CD44 and AKT was associated with worse overall survival ( P =0.047 and P =0,034, respectively), on univariate analysis, in the cohort of parenchymal and bone metastases; the impact of AKT expression was also evident in the parenchymal cohort on uni ( P =0.021) and multivariate analysis ( P =0.027). The remaining markers did not exhibit a statistical correlation. Immunohistochemistry markers such as CD44 and AKT may have a prognostic impact on survival in patients with breast cancer brain metastases. The conjugation with other markers may help with the stratification of patients and therapy.

Objectives. This study aimed to explore the practical organisational aspects and difficulties in the implemen-tation of the molecular classification of endometrial carcinoma (EC), and to demonstrate its potential impact in prognostic risk group classification. Methods. We conducted a multicentre, retrospective cohort study of 230 patients with EC diagnosed between 2019 and 2022. Sample processing, clinicopathological, treatment and follow-up data were collected. Molecular classification was obtained by p53 and mismatch repair proteins immunohistochemistry, and POLE next -generation sequencing.Results. Implementation was achieved through centralization of molecular analysis. In practice, it was possible to optimise turnaround times of complete integrative reports for hysterectomy specimens to a median time of 18 workdays. If genetic study was started in endometrial biopsies before surgery, 82.0% were available at the time of multidisciplinary tumour board, compared to 8.4% if performed in hysterectomy. ECs were classified as follows: 37.8% no specific molecular profile, 31.7% p53 abnormal, 24.3% mismatch repair deficient, and 6.1% POLE mutant. Integration of these results with traditional clinicopathologic factors led to a change in prognostic risk group in 15 (6.5%) patients, most being initially allocated to high-intermediate (n = 8) and low (n = 5) risk groups. Eight patients changed to a higher risk, and 7 to a lower risk group, whereas 2 remained in the same group. Conclusions. Centralization of EC molecular classification is a feasible option for countries with limited resources. Optimization of workflows may be achieved by earlier analysis in biopsies and prioritisation of patients whose results imply changes in risk group classification. & COPY; 2023 Published by Elsevier Inc.

e17615 Background: Management of endometrial carcinoma (EC) relies on prognostic risk group classification to help to determine the individual risk of recurrence and the need for adjuvant treatment after surgery. A molecular classification with four distinct prognostic EC subtypes based on genomic abnormalities - DNA polymerase epsilon ( POLE) mutated ( POLEmut), mismatch repair deficient (MMRd), p53 abnormal (p53abn) and no specific molecular profile (NSMP) - has emerged, that raises the possibility of a more precise tailoring of adjuvant therapy. This study aimed to describe the clinicopathological and molecular characteristics of an EC Portuguese cohort, assess its potential impact in patient management and evaluate its prognostic value. Methods: Multicentre, retrospective cohort study of 230 patients with EC diagnosed between 2019 and 2022. Sample processing, clinicopathological, treatment and follow-up data was collected. Molecular classification was obtained by p53 and mismatch repair proteins immunohistochemistry, and POLE next-generation sequencing. Results: Overall, 230 patients from two institutions were included. Median age at diagnosis was 68 years. The most frequent histology was endometrioid (n=163; 70.9%) and most were low-grade (n=129, 56.1%).At diagnosis, disease was confined to the uterus in the majority of patients (FIGO stage I/II, n=153, 66.5%). Most had surgery upfront (n=196, 85.2%) and, of those, 120 (52.2%) received adjuvant treatment. 26 (11.3%) had metastatic disease. Median follow-up time was 15.4 months. Regarding molecular subgroups, the majority were classified as NSMP (n=87, 37.8%), followed by p53abn (n=73, 31.7%), MMRd (n=56, 24.3%), and POLEmut (n=14, 6.1%); 11 (4.8%) were multiple-classifier. Integration of these results led to a change in adjuvant treatment in 3 patients. Median disease-specific survival (DSS) was 108 months. Factors that significantly influenced survival included age (p=0.030), histological type (p<0.001), grade (p<0.001) and FIGO stage (p=0.006). Overall, 35 (15.2%) patients developed recurrences. Median recurrence-free survival (RFS) was 46.7 months. Kaplan-Meier survival analysis showed that molecular alterations were significantly associated both with DSS and RFS (p=0.0092 and p=0.0139, respectively). Tumours with p53abn had the worst prognosis, and patients with POLEmut tumours experienced an excellent prognosis. Comparative measures (BIC, C-index, log-likelihood) showed that considering the molecular classification in establishing risk groups for adjuvant treatment had prognostic significance. Conclusions: The molecular classification has prognostic value and should be considered in adjuvant treatment decisions. It allows for a more personalised approach, helps to reduce under and overtreatment, and therefore reduce patient morbidity associated with treatment toxicities, and healthcare related costs.

Targeting the B-cell lymphoma 2 (Bcl-2) family proteins has been the backbone for hematological malignancies with overall survival improvements. The Bcl-2 family is a major player in apoptosis regulation and, has captured the researcher's interest in the treatment of solid tumors. Sarcomas are a heterogeneous group of diseases, comprising several entities, with high morbidity and mortality and with few specific therapies available. The treatment for sarcomas is based on platinum regimens, with variable results and poor outcomes, especially in advanced lesions. The high number of different sarcoma entities makes treatment standardization as well as the performance of clinical trials difficult. The use of Bcl-2 family members modifiers has revealed promising results in in vitro and in vivo models and may be a valid option, especially when used in combination with chemotherapy. In this article, a revision of these results and possibilities for the use of Bcl-2 family members inhibitors in sarcomas was performed.

A 38yearold female with a history of abnormal uterine bleeding underwent hysterectomy. On gross examination, an incidental 3 mm myometrial based nodule was found. Histologically, this wellcircumscribed nodule was seen compressing the adjacent muscular wall (Figure 1). The tumor had an organoid and solid growth pattern and was composed of epithelioid cells with predominantly granular cytoplasm (Figure 2). There was mild nuclear atypia and prominent nucleoli. Delicate vasculature surrounded the nests of cells. An extensive panel of immunohistochemical markers was performed. The lesion was negative for pankeratins, CD10, CD117, SOX10, CD68, Oct3/4, melanA, calretinin, inhibin, synaptophysin, PAX8, SMA, desmin, SMMHC, and DOG1. There was a strong nuclear positivity for TFE3 (Figure 3), and molecular testing revealed a rearrangement of TFE3 (Xp11.2)

Colorectal cancer (CRC) is the third most prevalent type of cancer, and liver metastasis is the most common site of metastatic development. In the tumor microenvironment (TME), various innate immune cells are known to influence cancer progression and metastasis occurrence. CD274 (PD-L1) and CD206 (MRC1) are proteins that have been associated with poor prognosis and disease progression. We conducted a study on tumoral and non-tumoral biopsies from 47 patients with CRC liver metastasis, using flow cytometry to phenotypically characterize innate immune cells. Our findings showed an increase in the expression of CD274 on classical, intermediate, and non-classical monocytes when comparing tumor with non-tumor samples. Furthermore, tumor samples with a desmoplastic growth pattern exhibited a significantly decreased percentage of CD274- and CD206-positive cells in all monocyte populations compared to non-desmoplastic samples. We found a correlation between a lower expression of CD206 or CD274 on classical, intermediate, and non-classical monocytes and increased disease-free survival, which points to a better prognosis for these patients. In conclusion, our study has identified potential new targets and biomarkers that could be incorporated into a personalized medicine approach to enhance the outcome for colorectal cancer patients.

Leiomyomas of the paratesticular region are a rare entity. A subtype of leiomyomas called bizarre nuclei leiomyoma is even rarer and histologically present some interesting features that are important to recognise to make the differential diagnosis with its malignant counterpart—leiomyosarcoma. We present a case of a man in his 60s, who presented with a painless mass on the right testicle. The clinical diagnosis was of an epidermoid cyst. The mass was excised and a diagnosis of leiomyoma of bizarre nuclei was made.

Colorectal cancer (CRC) is one of the most common cancers worldwide, with liver metastasis being its main cause of death. This study harvested fresh biological material from non-tumor and tumor tissue from 47 patients with CRC liver metastasis after surgery, followed by mechanical cellular extraction and stain-lyse-wash direct immunofluorescence technique. Here, 60 different T-cell populations were characterized by flow cytometry. Tumor samples were also subdivided according to their growth pattern into desmoplastic and non-desmoplastic. When we compared tumor versus non-tumor samples, we observed a significantly lower percentage of T-lymphocyte infiltration in the tumor in which the CD4+ T-cell density increased compared to the CD8+ T cells. T regulatory cells also increased within the tumor, even with an activated phenotype (HLA-DR+). A higher percentage of IL-17-producing cells was present in tumor samples and correlated with the metastasis size. In contrast, we also observed a significant increase in CD8+ follicular-like T cells (CD185+), suggesting a cytotoxic response to cancer cells. Additionally, most infiltrated T cells exhibit an intermediate activation phenotype (CD25+). In conclusion, our results revealed potential new targets and prognostic biomarkers that could take part in an algorithm for personalized medicine approaches improving CRC patients’ outcomes.

Cervical clear cell carcinoma (CCC) is a rare human papillomavirus–independent adenocarcinoma. While recent studies have focused on gastric-type endocervical adenocarcinoma (GTA), little is known about CCC. A total of 58 (CCCs) were collected from 14 international institutions and retrospectively analyzed using univariable and multivariable methods and compared with 36 gastric-type adenocarcinomas and 173 human papillomavirus–associated (HPVA) endocervical adenocarcinoma (ECA) regarding overall survival (OS) and recurrence-free survival (RFS). Most cases were FIGO stage I (72.4%), with Silva C pattern of invasion (77.6%), and the majority were treated with radical surgery (84.5%) and adjuvant therapy (55.2%). Lymphovascular invasion was present in 31%, while lymph node metastasis was seen in 24.1%; 10.3% were associated with abdominopelvic metastases at the time of diagnosis; 32.8% had recurrences, and 19% died of disease. We did not find statistically significant differences in OS and RFS between CCC and GTA at 5 and 10 years (P=0.313 and 0.508, respectively), but there were significant differences in both OS and RFS between CCC and HPVA ECA (P=0.003 and 0.032, respectively). Also, OS and RFS in stage I clear cell and GTA were similar (P=0.632 and 0.692, respectively). Multivariate analysis showed that OS is influenced by the presence of recurrence (P=0.009), while RFS is influenced by the FIGO stage (P=0.025). Cervical CCC has poorer outcomes than HPVA ECA and similar outcomes to human papillomavirus–independent GTA. Oncologic treatment significantly influences RFS in univariate analysis but is not an independent prognostic factor in multivariate analysis suggesting that alternative therapies should be investigated.