PD-L1 is highly expressed in ovarian cancer and associated with cancer stem cells populations expressing CD44 and other stem cell markers.

BACKGROUND: Immune checkpoint inhibitors, including PD-L1 (programmed death ligand-1) inhibitors have well documented anticancer therapeutic effect in most types of cancers but its use in the treatment of ovarian cancer is not yet proven. The aim of our study is to explore the predictive biomarkers in ovarian cancer and its association with the outcomes. We have investigated the role of PD-L1 expressions in the tumor microenvironment cells including immune cells and cancer stem cells in different types of ovarian cancer. METHODS: A total of 119 surgical archived ovarian cancer samples were collected from the pathology department at King Fahad Specialist Hospital, Dammam, Saudi Arabia that included serous carcinomas, clear cell carcinomas, mucinous carcinomas, endometrioid carcinomas, and granulosa cell tumors. Immunohistochemistry (IHC) staining was performed using (i) PD-L1 antibodies to detect PD-L1 expressions; (ii) CD8 and CD4 to detect Tumor Infiltrating Lymphocytes (TILs); and (iii) CD44, LGR5, and ALDH2 to detect stem cell markers. The clinicopathological data were collected from patients' medical record to investigate the association with PD-L1, TILs, and stem cells expressions. RESULTS: We report high PD-L1 expressions in 47.8% of ovarian cancer samples. PD-L1 expressions were detected in different types of epithelial ovarian cancer and were not associated with poor prognosis of ovarian cancer. However, determining the expression levels of TILs in the ovarian cancer tissues found that 81% (n = 97) of ovarian cancer samples have TILs that express both of CD8 and CD4 and significantly associated with high PD-L1 expressions. Interestingly, we have found that ovarian cancer tissues with high expressions of PD-L1 were associated with high expressions of stem cells expressing CD44 and LGR5. CONCLUSIONS: PD-L1 is highly expressed in the serous type of ovarian carcinomas and the overall expression of PD-L1 is not associated with poor survival rate. Furthermore, PD-L1 expressions are strongly associated with TILs and stem cell markers in ovarian cancer. Inhibiting the PD-L1 using immune checkpoint inhibitors might downregulate stem cell population that known to be associated with cancer recurrence.

Graft-versus-host disease after pediatric liver transplantation: A diagnostic challenge.

BACKGROUND: Graft-versus-host disease (GVHD) is a rare but serious complication after pediatric liver transplantation (LTx). Early diagnosis is difficult due to nonspecific presenting symptoms and non-pathognomonic skin histopathological features. The aim of this article was to describe a case of pediatric GVHD after LTx and to review available data on pediatric GVHD highlighting the diagnostic difficulty. We also propose a diagnostic algorithm to improve the diagnostic capability and increase clinical awareness about this potentially fatal condition. METHODS: We did a comprehensive literatures review on studies on GvHD following pediatric LTx between 1990 and February 2021, chimerism study by short tandem repeat (STR), HLA typing by sequence-specific oligonucleotide (SSO) method, and flowcytometry crossmatch. RESULTS: Our search yielded 23 case reports. The most common clinical manifestations were fever and rash (91%) followed by diarrhea. Mortality rate was 36.8% mainly due to sepsis and organ failure. Diagnosis was challenging and chimerism study to confirm donor engraftment was performed on only half of the cases. Prevalence of "donor dominant HLA one-way matching" typically occurs in homozygous parents-to-child transplantation was 75% in cases with HLA testing. CONCLUSION: So far, there are no available standard diagnostic criteria for GVHD following pediatric LTx. Recognition of multiple risk factors through proper laboratory assessment can predict the occurrence, and early chimerism study can confirm suggestive clinical manifestation. The strong likelihood of developing GVHD in "donor one-way HLA match" and the severe problems imposed by this complication may justify avoidance of HLA homozygous parent's donation.

Dysgerminomas: germ cell tumors exhibit high expression of PD-L1 and associated with high TILs and good prognosis.

Ovarian germ cell tumors (OVGCTs) account for 28% of all diagnosed ovarian cancers, and malignant germ cell tumors specifically account for approximately 13% of diagnosed ovarian cancers in Saudi Arabia. Although most germ cell tumor patients have a high survival rate, patients who experience tumor recurrence have a poor prognosis and present with more aggressive and chemoresistant tumors. The use of immunotherapeutic agents such as PD-L1/PD-1 inhibitors for OVGCTs remains very limited because few studies have described the immunological characteristics of these tumors. This study is the first to investigate PD-L1 expression in ovarian germ cell tumors and explore the role of PD-L1 expression in tumor microenvironment cells and genetic alterations. A total of 34 ovarian germ cell tumors were collected from pathology archives. The collected tumor tissues included ten dysgerminomas, five yolk sac tumors, five immature teratomas, and one mature teratoma, and the remaining samples were mixed germ cell tumors. The tumors were analyzed using immunohistochemical analysis to determine PD-L1 expression, immune cell infiltration and cancer stem cell populations and their correlation with clinical outcome. Furthermore, the genetic alterations in different subtypes of germ cell tumors were correlated with PD-L1 expression and clinical outcome. Datasets for testicular germ cells (TGCTs) were retrieved from The Cancer Genome Atlas (TCGA) and analyzed using cBioPortal (cbioportal.org) and Gene Expression Profiling Interactive Analysis (GEPIA). Compared with yolk sac tumors, dysgerminomas highly express PD-L1 and are associated with high levels of tumor infiltrating lymphocytes (TILs) and stem cell markers. In addition, compared with PD-L1-negative yolk sac tissue, dysgerminomas/seminomas with high PD-L1 expression are associated with more genetic alterations and a better prognosis. Our findings will contribute to the knowledge about the potential benefits of ovarian cancer immunotherapy in specific subsets of germ cell tumor patients and the risk factors for resistance mediated by tumor microenvironment cells.

P16INK4a expression in undifferentiated carcinoma of the uterus does not exclude its endometrial origin.

Undifferentiated carcinoma of the endometrium is a rare neoplasm, which, when involving the cervix, raises a question about its origin. Diffuse p16 positivity of uterine cancers is usually interpreted as a surrogate marker for high-risk human papilloma virus and favors cervical origin. In this study, we investigated the expression of cytokeratin 7 (CK7), monoclonal carcinoembryonic antigen (mCEA), estrogen receptor (ER), vimentin, and p16 in 28 cases of undifferentiated endometrial carcinoma, 20 high-grade endometrioid adenocarcinomas, and 50 cervical adenocarcinomas. Staining was considered positive when it was cytoplasmic for CK7, mCEA, and vimentin, nuclear for ER, and both nuclear and cytoplasmic for p16. Percentages of cells staining were recorded as follows: negative (0%-5%), 1+ (6%-25%), 2+ (26%-50%), 3+ (51%-75%), and 4+ (>75%). P16 was considered positive if it stained more than 75% of the tumor cells. Diffuse/strongly positive staining for p16 was seen in 40/50 (80%) cases of cervical adenocarcinoma and 14/28 (50%) cases of undifferentiated endometrial carcinoma. In high-grade endometrioid adenocarcinoma, staining was mainly patchy. CK7, mCEA, ER, progesterone receptor, and vimentin staining in undifferentiated endometrial carcinoma was as follows: 10/28 (36%), 4/28 (14%), 21/28 (75%), 23/28 (82%), and 26/28 (93%), respectively; for high-grade endometrioid carcinoma: 20/20 (100%), 1/20 (5%), 17/20 (85%), 18/20 (90%), and 19/20 (95%); for endocervical adenocarcinoma: 50/50 (100%), 45/50 (90%), 9/50 (18%), 8/50 (16%), and 6/50 (12%), respectively. Our data indicate that p16 may play a role in the tumorigenesis of a subset of undifferentiated endometrial carcinoma. In the setting of p16 positivity, undifferentiated endometrial carcinomas are more likely to be ER, progesterone receptor, and vimentin positive and mCEA negative when compared with endocervical adenocarcinomas. Distinction between undifferentiated endometrial carcinoma and endocervical adenocarcinoma, both of which can share diffuse p16 expression, should rely on detection of human papilloma virus in the latter.

Diabetic mastopathy: A rare clinicopathologic entity with considerable autoimmune potential.

INTRODUCTION AND IMPORTANCE: Diabetic mastopathy is a rare entity affecting diabetic patients. It has been previously linked to type 1 diabetes mellitus; however, due to the several accompanying conditions, a theory of autoimmune factors contributing to the origin of this condition has been on the rise. In this paper, we report a case of diabetic mastopathy associated with several autoimmune diseases to highlight the immunological potential of this condition. CASE PRESENTATION: A 25-year-old female, known to have type 1 diabetes mellitus, hypertension, hypothyroidism, adrenal insufficiency, dilated cardiomyopathy and end-stage renal disease, was referred to our clinic for a breast lump. Radiological investigations showed a dense mass with irregular borders in the retroareolar area of the left breast. A core biopsy was obtained which revealed keloid-like fibrosis along with lymphocytes infiltrated, suggestive of lymphocytic mastopathy. CLINICAL DISCUSSION: Fibrous mastopathy has been merely attributed to a long-standing use of insulin therapy by diabetic patients; recent observations, however, proved the major contribution of immunity to etiopathogenesis. Even though human leukocyte antigen (HLA) association has not been supported in the literature, the histological changes of breast lymphocytic infiltrate are seen in patients who not only have T1DM, but also thyroiditis, systemic lupus erythematosus, Sjogren's syndrome, and Addison's disease. The frequent presence of several possible autoimmune conditions has promoted the theory of an autoimmune process affecting connective tissues, however, these claims are yet to be proven by future studies. CONCLUSION: Recent observations have proved the major contribution of immunity to etiopathogenesis of diabetic mastopathy. We shed light on the role of the immune system in triggering the disease process by reporting a case of diabetic mastopathy with a cluster of autoimmune diseases. Future studies should explore the genetic background of the condition as it would potentially have several clinical implications. The discussed pathophysiologic explanations raise the possibility of autoimmunity as a key driver in pathogenesis and indicate the need to change the nomenclature of this condition.

Transduodenal resection of periampullary neuroendocrine tumor: A case report.

INTRODUCTION AND IMPORTANCE: Periampullary tumors are characterized as tumors that emerge nearby to the major papilla in the duodenum. They are rare lesions with an incidence rate of 0.4-0.48 per 100,000. Neuroendocrine tumors (NETs) constitute only 3% of all duodenal tumors. Their proximity to the major and minor papillae along with the gastric outlet raises a surgical challenge. CASE PRESENTATION: Our patient is a 40-year-old, male, medically free. He presented with history of a testicular mass. A CT scan of the abdomen and pelvis was done and showed a large retroperitoneal lymph node. A biopsy of the epididymal mass showed no evidence of malignancy. Excision of the left para-aortic mass revealed a metastatic lymph node of a well-differentiated neuroendocrine tumor. Further evaluation by gallium-68 PET-CT scan showed a periampullary neuroendocrine tumor. The decision to operate was concluded in a multidisciplinary team meeting, and intraoperatively the duodenum showed a well-defined mass between the first and second part of the duodenum which was excised via a trans-duodenal submucosal approach. A frozen section confirmed a negative margin. The final histopathology report showed a grade 2 metastatic well-differentiated neuroendocrine tumor. The latest follow-up was 3 years post-op via fluorine-18 fluorodeoxyglucose PET-CT and it showed no FDG avid disease at the duodenum or pancreases with no FDG avid lymphadenopathy or distant metastasis. CONCLUSION: Periampullary tumors that fall under certain parameters could be resected via transduodenal local resection. This procedure yields equivalent results to more invasive surgeries, such as a Whipple's procedure, with less morbidity.

Histiocytoid variant of invasive lobular breast carcinoma. A case report and literature review.

INTRODUCTION: Histiocytoid breast carcinoma (HBC) is a variant of invasive lobular carcinoma. The occurrence of HBC is rare and the natural history and clinical course of HBC is still not well known due to limited numbers of reported cases. In reality, many tumors have been misdiagnosed and reported as benign lesions. CASE PRESENTATION: A 66-year-old- postmenopausal women, who has previous personal history of right breast invasive ductal carcinoma, for which she underwent right breast wide local excision with negative sentinel lymph node biopsy and received adjuvant radiotherapy and hormonal therapy. Two years later, a new left breast suspicious lesion was detected by Imaging. Breast Ultrasound showed left breast hypo-echoic area at 12-1 o'clock with irregular spiculated lesion 3 cm away from the nipple with posterior acoustic shadowing measuring 1 × 0.7 × 0.7 cm and mild tissue distortion with thicken cortical left Axillary lymph node. Mammography of both breasts confirmed the left breast lesion at 12o'clock with necrosis and irregular margins measuring 1.1 × 1.0 cm. MRI breasts showed, left breast heterogeneously enhancing mass at 12 o'clock with no other suspicious mass in the left or right breast. Ultrasound guided left breast biopsy of the suspicious lesion seen at 12-1 o'clock which confirmed the diagnosis of invasive lobular carcinoma, histiocytoid variant She underwent wire guided left breast wide local excision with left sentinel lymph node and axillary clearance. Final histopathology showed invasive lobular carcinoma, histiocytoid variant. CLINICAL DISCUSSION: The recognition of histiocytoid breast carcinoma is often a challenge, particularly when histiocytoid tumor cells occur in a metastatic site before the primary diagnosis of breast cancer. An awareness of histological features are needed to make the accurate diagnosis. CONCLUSION: Findings that support the correct diagnosis include identifying tumor cells with more cytological atypia, the presence of cytoplasmic vacuoles and secretions. Moreover, coexistence with invasive lobular carcinoma and/or lobular neoplasia and the use of immunohistochemistry to confirm their epithelial nature. clinico-radiological correlation is essential, as any discordance should trigger further diagnostic determination.

A Diagnostic Dilemma of a Subcutaneous Hibernoma: Case Report.

BACKGROUND Subcutaneous lipomatous lesions are commonly encountered in clinical practice. Hibernoma is a rare subtype of the benign lipomatous tumor, representing 1% of all types. It poses a challenge due to the difficulty of differentiating it from atypical lipomatous lesions and liposarcomas, which may lead to possible inappropriate diagnosis and management. CASE REPORT We report a case of a 33-year-old male who presented with a right upper thigh swelling noticed some time prior to presentation that had started increasing in size prior to his presentation. The magnetic resonance imaging (MRI) was unable to rule out atypical lipomatous tumor and liposarcoma. An ultrasound-guided biopsy gave a diagnosis of hibernoma. The patient underwent a wide local excision, which confirmed the diagnosis of hibernoma. At the 3-year follow-up, there was no evidence of local recurrence. CONCLUSIONS Hibernoma has been reported in the literature to be discovered incidentally by radiological imaging done for other causes. However, hibernomas raise a diagnostic challenge because in most imaging modalities they are indistinguishable from other malignant tumors. A wide local excision with negative margins is key to resolving the diagnostic dilemma that a hibernoma presents, as it will provide a definitive diagnosis differentiating it from other lipomatous lesions and prevent any future recurrence. Caution is advised when dealing with lipomatous lesions, as they often overlap with malignancy. Furthermore, an MRI should be done for any subcutaneous lesion that is larger than 5 cm or shows recent growth. A biopsy can resolve the diagnostic dilemma with caution to the hypervascularity of such tumors.

Metastatic renal cell carcinoma to the pancreas, thyroid, & subcutaneous tissue 13 years after Radical nephrectomy: A case report.

INTRODUCTION: Renal cell carcinoma (RCC) accounts for 3% of all adult malignancies and is known for its poor prognosis. At the time of diagnosis up to 30% of patients will present with metastasis. We report multiple metastases of RCC to rare sites; twice to pancreases, thyroid, twice to subcutaneous tissue, and the other kidney- occurring years after the radical nephrectomy. CASE PRESENTATION: Our case is of a 51-year-old female who underwent a right radical nephrectomy for RCC. Upon 6 years post-operative surveillance for recurrence, multiple metastatic lesions were found in the head of the pancreas which were resected by a Whipple procedure. Four years later, she presented with a thyroid nodule and fine needle aspiration showed metastatic RCC. The patient underwent a total thyroidectomy. Months later, the patient presented with a right forearm mass. Biopsy showed metastatic RCC. Excision with negative margins was performed. A year later, a metastatic lesion was found in the tail of pancreas in addition to a recurrent metastatic mass over the right forearm. The patient underwent completion pancreatectomy and resection of the forearm mass. One year later, another metastatic lesion was found in the left kidney, for which the patient underwent left partial nephrectomy with negative margins. CONCLUSION: RCC is one of the most aggressive malignancies. A high index of sucion is crucial to detect its metastasis. As some lesions maybe missed because they lack the classical radiological findings or are found in atypical locations, in addition to the latent recurrence of RCC metastasis, a lifelong follow-up is recommended.

De Novo Psoriasis Vulgaris Diagnosed after Nivolumab Treatment for Refractory Hodgkin's Lymphoma, Completely Resolved after Autologous Hematopoietic Stem Cell Transplantation.

The programmed cell death protein-1 (PD-1) inhibitor nivolumab has been recently approved as an effective and safe treatment for patients with refractory/relapsed Hodgkin's lymphomas. Dermatological adverse events, mainly skin rash, have been reported in 1-5% of patients. We describe a case of de novo psoriasis vulgaris (PsV), diagnosed after nivolumab treatment for refractory Hodgkin's lymphoma. After administration of 6 cycles, skin lesions appeared in the right tibia, forearms, and dorsum of hands, and biopsy confirmed the diagnosis of PsV. The lesions completely resolved after autologous stem cell transplantation (ASCT) which was performed in the context of the treatment for the primary disease. PsV is an inflammatory skin disease, and it is considered to be mediated through cytotoxic T-cells. PD-1 blockage may lead to expansion of such T-cells, resulting thus in PsV appearance. The early published studies showed that nivolumab represents a safe treatment approach. PsV occurrence has not been reported so far in patients treated with nivolumab for hematological diseases, and it seems that long-term follow-up is necessary to fully clarify the entirety of PD-1 inhibitors' skin adverse events. Additionally, this clinical observation provides an evidence for a potential exploitation of ASCT in refractory and severe forms of PsV.

Screening for Lynch syndrome in young Saudi colorectal cancer patients using microsatellite instability testing and next generation sequencing.

Individuals with Lynch syndrome (LS) have germline variants in DNA mismatch repair (MMR) genes that confer a greatly increased risk of colorectal cancer (CRC), often at a young age. Identification of these individuals has been shown to increase their survival through improved surveillance. We previously identified 33 high risk cases for LS in the Saudi population by screening for microsatellite instability (MSI) in the tumor DNA of 284 young CRC patients. The aim of the present study was to identify MMR gene variants in this cohort of patients. Peripheral blood DNA was obtained from 13 individuals who were at high risk of LS due to positive MSI status and young age (<60 years at diagnosis). Next generation sequencing, Sanger sequencing and Multiplex Ligation-dependent Probe Amplification were used to screen for germline variants in the MLH1, MSH2, MSH6 and PMS2 MMR genes. These were cross-referenced against several variant databases, including the International Society for Gastrointestinal Hereditary Tumors Incorporated database. Variants with pathogenic or likely pathogenic significance were identified in 8 of the 13 high risk cases (62%), comprising 4 in MLH1 and 4 in MSH2. All carriers had a positive family history for CRC or endometrial cancer. Next generation sequencing is an effective strategy for identifying young CRC patients who are at high risk of LS because of positive MSI status. We estimate that 7% of CRC patients aged <60 years in Saudi Arabia are due to LS, potentially involving around 50 new cases per year.

Predictive Value of IHC4 Score for Pathological Response to Neoadjuvant Chemotherapy in Hormone Receptor-Positive Breast Cancer.

PURPOSE: This study aimed to explore the value of IHC4 in predicting pathological response after neoadjuvant chemotherapy in patients with hormonal receptor (HR)-positive breast cancer (BC). MATERIALS AND METHODS: In this retrospective exploratory study, data for 68 HR-positive BC patients who received neoadjuvant chemotherapy were recorded. IHC4 scores were calculated based on estrogen receptors/progesterone receptors, Ki-67 and HER2 status. Logistic and ordinal regression analyses in addition to likelihood ratio test were used to explore associations of IHC4 scores and other clinico-pathological parameters with pathological complete response (pCR) and pathological stage. RESULTS: Taking the 25th percentile as the cut-off, a lower IHC4 score was associated with an increased probability of pCR (low; 52.9% vs. High; 21.6%, OR=4.1, 95% CI= 1.28-13.16, p=0.018) and a lower pathological stage (OR =3.9, 95% CI=1.34-11.33, p=0.012). When the IHC4 score was treated as a continuous variable, a lower score was again associated with an increased probability of pCR (OR=1.010, 95% CI=1.001-1.018, p=0.025) and lower pathological stage (OR=1.009, 95% CI= 1.002-1.017, P=0.008). Lower clinical stage was associated with a better pCR rate that was of borderline significance (P=0.056). When clinical stage and IHC4 score were incorporated together in a logistic model, the likelihood ratio test gave a P-value of 0.004 after removal of the IHC4 score and 0.011 after removal of the stage, indicating a more significant predictive value of the IHC4 score for pCR. CONCLUSIONS: This study suggests that the IHC4 score can predict pathological response to neoadjuvant chemotherapy in HR-positive BC patients. This finding now needs to be validated in a larger cohort of patients.