Cirrhosis due to hepatic sarcoidosis: A rare presentation.

Key Clinical Message: Sarcoidosis, although predominantly affecting the lungs, can present with cirrhosis, posing diagnostic challenges. Elevated ACE levels and atypical liver enzyme patterns should prompt consideration of sarcoidosis in cryptogenic cirrhosis cases, necessitating comprehensive evaluation including liver biopsy and imaging for accurate diagnosis and timely management. Abstract: Sarcoidosis is a systemic disease that can affect various organs, leading to a diverse range of clinical manifestations that make diagnosis challenging. Here, we present a case of sarcoidosis in a middle-aged male who presented with cirrhosis. The cause of cirrhosis remained unknown for 4 years until the development of lymphadenopathy and ground-glass opacities on lung imaging. A liver biopsy was performed, which revealed noncaseating granulomatous inflammation, thereby identifying sarcoidosis as the cause of cirrhosis. The patient was treated with oral steroids, which slightly improved his liver function over a short period. Given the diverse presentations of sarcoidosis, it should be considered as a possible differential diagnosis in cases of cryptogenic cirrhosis.

Urachal mixed adenocarcinoma and small cell neuroendocrine carcinoma with widespread metastasis and resistance to chemotherapy: a case report.

Neuroendocrine carcinoma arising from the urachus is extremely rare. We describe a case of a 33-year-old gentleman who presented with hematuria and diagnosed to have a composite adenocarcinoma and small cell neuroendocrine carcinoma arising from the urachus. The patient also had widespread metastasis at the time of presentation, therefore, he was referred for chemotherapy. However, the disease showed progression despite treatment. Recognition of neuroendocrine carcinoma component in urachal tumors, although rare, is very essential as this histologic type carries poor prognosis with aggressive clinical outcome.

A rare case of myxoma presenting as a scrotal lump.

A myxoma is a benign intramuscular gelatinous tumor that is rarely known to arise from the scrotum. It can be confused both clinically and radiologically with other more common scrotal wall lesions such as a sebaceous cyst or an abscess. We report a case of a 54-year-old patient who presented with a scrotal wall swelling that was initially suspected to be an infected cyst or cold abscess on imaging. The final diagnosis of a myxoma was made after surgical excision and histopathological examination.

Bilateral large cell calcifying Sertoli cell tumours: A testicular preservation approach in a young male.

Testicular Large cell calcifying Sertoli cell tumours (LCCSTs) are extremely rare. The primary challenge in benign LCCSTs, which are typically multifocal and bilateral tumours affecting young males, is to confirm the diagnosis to avoid radical intervention and preserve fertility potential. Patient clinical presentation, laboratory results, diagnostic radiological tests along with confirmatory histopathological studies, are the cornerstones in such cases, nevertheless genetic testing is warranted, as LCCSTs can be part of genetic syndrome such Carney complex. We present a case of bilateral benign LCCSTs in young male managed with testicular preservation approach with characteristic clinical, radiological and histopathological features.

Primary Sarcomas of the Larynx: A Case Series of Four Different Histopathologic Types.

Primary laryngeal sarcomas are rare. Their nomenclature and classification are similar to soft tissue counterparts; however, there are notable differences between clinical presentation, behavior, treatment, and follow-up. There is sparse information regarding the clinical features, biologic behavior, and treatment modalities of laryngeal sarcomas. To increase our understanding about these tumors, we describe herein an additional series of four cases of different pathologic types of laryngeal sarcomas, including low-grade chondrosarcoma, leiomyosarcoma, well-differentiated liposarcoma, and undifferentiated pleomorphic sarcoma. Our main aim is to upsurge awareness about the morphologic variations of laryngeal sarcomas, to avoid potential pitfalls during histopathologic examination. It is essential to ensure that correct diagnosis, subclassification, and grading are achieved for proper guidance of treatment and clinical follow-up at multidisciplinary team meetings.

Cutaneous Sarcoidosis: A Differential Diagnosis to Consider in Undiagnosed Skin Lesions.

The presentation of sarcoidosis varies depending on the organs involved. Cutaneous sarcoidosis usually presents with other organ involvement, but isolated presentation is possible. However, diagnosing isolated cutaneous sarcoidosis can be challenging in resource-poor countries, particularly where sarcoidosis is relatively uncommon, since cutaneous sarcoidosis usually does not cause troublesome symptoms. We present a case of cutaneous sarcoidosis in an elderly female who had been suffering from skin lesions for nine years. The diagnosis was made after the appearance of lung involvement, which raised the suspicion of sarcoidosis and prompted a skin biopsy. The patient was then treated with systemic steroids and methotrexate, and her lesions improved shortly thereafter. This case highlights the importance of considering sarcoidosis as a possible cause of undiagnosed, refractory cutaneous lesions.

Potential pitfalls in reporting non-neoplastic gastrointestinal mucosal biopsies.

Biopsies taken from the gastrointestinal tract (GIT) comprise a significant percentage of the pathologists' routine work. The variable histology and normal components of each organ along the GIT, as well as the different ways of responding to injury among these organs, can cause morphological changes that could result in potential diagnostic pitfalls. Herein, we review the pathological conditions of the GIT that could cause these diagnostic pitfalls. Our aim was to increase awareness among pathologists and trainees regarding these conditions and provide a pragmatic approach to prevent them and achieve a correct diagnosis.

Incidence and association of high-risk HPVs and EBV in patients with advanced stages of colorectal cancer from Qatar.

High-risk Human Papillomaviruses (HPVs) and Epstein - Barr virus (EBV) are present and involved in several types of human carcinomas, including cervical and, head and neck cancers. Nevertheless, their presence and association in the pathogenesis of colorectal cancer is still nascent. The current study explored the association between the high-risk HPVs and EBV and tumor phenotype in colorectal cancers (CRCs) in the Qatari population. We found that high-risk HPVs and EBV are present in 69/100 and 21/100 cases, respectively. Additionally, 17% of the cases showed a copresence of high-risk HPVs and EBV, with a significant correlation only between the HPV45 subtype and EBV (p = .004). While the copresence did not significantly associate with clinicopathological characteristics, we identified that coinfection with more than two subtypes of HPV is a strong predictor of advanced stage CRC, and the confounding effect of the copresence of EBV in such cases strengthens this association. Our results indicate that high-risk HPVs and EBV can co-present in human CRCs in the Qatari population where they could plausibly play a specific role in human colorectal carcinogenesis. However, future studies are essential to confirm their copresence and synergistic role in developing CRCs.

Co-expression of PD-1 with TIGIT or PD-1 with TIM-3 on tumor-infiltrating CD8+ T cells showed synergistic effects on improved disease-free survival in treatment-naïve CRC patients.

Immune checkpoints (ICs) are highly expressed on tumor-infiltrating immune cells (TIICs) in different malignancies, including colorectal cancer (CRC). T cells play crucial roles in shaping CRC, and their presence in the tumor microenvironment (TME) has proven to be one of the best predictors of clinical outcomes. A crucial component of the immune system is cytotoxic CD8+ T cells (CTLs), which play decisive roles in the prognosis of CRC. In this study, we investigated associations of immune checkpoints expressed on tumor-infiltrating CD8+ T cells with disease-free survival (DFS) in 45 naïve-treatment CRC patients. First, we examined the associations of single ICs, and found that CRC patients with higher levels of T-cell immunoglobulin and ITIM-domain (TIGIT), T-cell immunoglobulin and mucin domain-3 (TIM-3) and programmed cell death-1 (PD-1) CD8+ T cells tended to have longer DFS. Interestingly, when PD-1 expression was combined with other ICs, there were more evident and stronger associations between higher levels of PD-1+ with TIGIT+ or PD-1+ with TIM-3+ tumor-infiltrating CD8+ T cells and longer DFS. Our findings for TIGIT were validated in The Cancer Genome Atlas (TCGA) CRC dataset. This study is the first to report on the association of co-expression of PD-1 with TIGIT and PD-1 with TIM-3 in CD8+ T cells and improved DFS in treatment-naïve CRC patients. This work highlights the significance of immune checkpoint expression on tumor-infiltrating CD8+ T cells as critical predictive biomarkers, especially when co-expression of different ICs is considered.

Coinfection of HPVs Is Associated with Advanced Stage in Colorectal Cancer Patients from Qatar.

High-risk human papillomaviruses (HPVs) are considered risk factors in the origin of several human malignancies, such as breast, cervical, head and neck, as well as colorectal cancers. However, there are no data reported on the HPV status in colorectal cancer in the State of Qatar. Therefore, we herein examined the presence of high-risk HPVs (16, 18, 31, 33, 35, 45, 51, 52, and 59), using polymerase chain reaction (PCR) in a cohort of 100 Qatari colorectal cancer patients, and their association with tumor phenotype. We found that high-risk HPV types 16, 18, 31, 35, 45, 51, 52, and 59 were present in 4, 36, 14, 5, 14, 6, 41, and 17% of our samples, respectively. Overall, 69 (69%) of the 100 samples were HPV positive; among these, 34/100 (34%) were positive for single HPV subtypes, while 35/100 (35%) of the samples were positive for two or more HPV subtypes. No significant association was noted between the presence of HPV and tumor grade, stage, or location. However, the presence of coinfection of HPV subtypes strongly correlated with advanced stage (stage 3 and 4) colorectal cancer, indicating that the copresence of more than one HPV subtype can significantly worsen the prognosis of colorectal cancer. The results from this study imply that coinfection with high-risk HPV subtypes is associated with the development of colorectal cancer in the Qatari population.

PD-1 expression, among other immune checkpoints, on tumor-infiltrating NK and NKT cells is associated with longer disease-free survival in treatment-naïve CRC patients.

A variety of variables, such as microsatellite instability or inflammatory mediators, are critical players in the development and progression of colorectal cancer (CRC). Natural killer (NK) and natural killer T (NKT) cells are involved in the prognoses of CRC. Immunological components of the tumor microenvironment (TME) impact cancer progression and therapeutic responses. We report that CRC patients with higher frequencies of tumor-infiltrating PD-1+ NK and NKT cells had significantly longer disease-free survival (DFS) than patients with lower frequencies. In agreement with that, patients with higher frequencies of tumor-infiltrating PD-1- NK and NKT cells showed shorter DFS. There were no significant associations between tumor-infiltrating PD-1+TIM-3+, PD-1+TIGIT+, PD-1+ICOS+, PD-1+LAG-3+ NK cells, and PD-1+TIM-3+, PD-1+TIGIT+, and PD-1+LAG-3+ NKT cells with DFS. This study highlights the significance of PD-1 expression on tumor-infiltrating NK and NKT cells and its association with disease prognoses in CRC patients.

Rifampin-induced acute kidney injury and hemolysis: A case report and literature review of a rare condition.

Rifampicin is a bactericidal drug used in various infectious diseases, including tuberculosis (TB). Nephrotoxicity is a rare side effect of intermittent Rifampin use and even less commonly continued use. We report a case of Rifampin-induced acute tubular necrosis and hemolysis in a patient with latent TB with a relevant literature review.

Correlations between Circulating and Tumor-Infiltrating CD4+ Treg Subsets with Immune Checkpoints in Colorectal Cancer Patients with Early and Advanced Stages.

The existence of various T regulatory cell (Treg) subsets in colorectal cancer (CRC) could play a variety of functions in the regulation of anti-cancer immunity. We studied correlations between CD4+ Treg subsets with the expression of immunological checkpoints on CD4+ T cells, including PD-1, TIM-3, LAG-3, and CTLA-4 in CRC patients with early and advanced TNM staging. Strong positive correlations were found between frequencies of FoxP3+ Tregs and FoxP3+Helios+ Tregs with frequencies of various immune checkpoint-expressing CD4+ T cells in the tumor microenvironment (TME). However, there were strong negative correlations between frequencies of FoxP3-Helios- T cells and these immune checkpoint-expressing CD4+ T cells. Specifically, in the TME, we found that the correlations between FoxP3+ Tregs, FoxP3+Helios+ Tregs, FoxP3+Helios- Tregs, and FoxP3-Helios- T cells with CD4+LAG-3+ T cells and CD4+CTLA-4+ T cells were higher in patients with early stages, suggesting the potential of these highly immunosuppressive cells in inhibiting inflammatory responses in the TME. However, the correlations between FoxP3+ Tregs, FoxP3+Helios+ Tregs, and FoxP3-Helios- T cells with CD4+TIM-3+ T cells were higher in patients with advanced stages. This is the first study to explore correlations of Treg subpopulations with immune checkpoint-expressing CD4+ T cells in CRC based on clinicopathological features of CRC patients. The findings of our study provide a justification for focusing on these cells that possess highly immunosuppressive features. Understanding the correlations between different immune checkpoints and Treg subsets in CRC patients has the potential to enhance our understanding of core mechanisms of Treg-mediated immunosuppression in cancer.

Extraskeletal myxoid chondrosarcoma of the penis: Description of a rare tumor arising in an unusual location.

Extraskeletal myxoid chondrosarcoma (EMC) is a rare malignant soft tissue tumor that most commonly arises in the extremities. Its occurrence in the genitourinary tract is extremely uncommon. We present an 82-year-old man who was found to have incidental pulmonary metastasis by imaging studies. The biopsy findings from the lung were in favor of metastatic EMC. The primary mass was found to be located at the penile root, which was confirmed to be EMC. This case adds to the few reported cases of EMC arising in the perineal region, and sheds light on the clinical behavior of this soft tissue tumor.

Circulating and Tumor-Infiltrating Immune Checkpoint-Expressing CD8+ Treg/T Cell Subsets and Their Associations with Disease-Free Survival in Colorectal Cancer Patients.

T cells in the tumor microenvironment (TME) have diverse roles in anti-tumor immunity, including orchestration of immune responses and anti-tumor cytotoxic attack. However, different T cell subsets may have opposing roles in tumor progression, especially in inflammation-related cancers such as colorectal cancer (CRC). In this study, we phenotypically characterized CD3+CD4- (CD8+) T cells in colorectal tumor tissues (TT), normal colon tissues (NT) and in circulation of CRC patients. We investigated the expression levels of key immune checkpoints (ICs) and Treg-related markers in CD8+ T cells. Importantly, we investigated associations between different tumor-infiltrating CD8+ T cell subpopulations and disease-free survival (DFS) in CRC patients. We found that FoxP3 expression and ICs including PD-1, CTLA-4, TIM-3, and LAG-3 were significantly increased in tumor-infiltrating CD8+ T cells compared with NT and peripheral blood. In the TME, we found that TIM-3 expression was significantly increased in patients with early stages and absent lymphovascular invasion (LVI) compared to patients with advanced stages and LVI. Importantly, we report that high levels of certain circulating CD8+ T cell subsets (TIM-3-expressing, FoxP3-Helios-TIM-3+ and FoxP3-Helios+TIM-3+ cells) in CRC patients were associated with better DFS. Moreover, in the TME, we report that elevated levels of CD25+ and TIM-3+ T cells, and FoxP3+Helios-TIM-3+ Tregs were associated with better DFS.

Associations of different immune checkpoints-expressing CD4+ Treg/ T cell subsets with disease-free survival in colorectal cancer patients.

There are different subsets of T regulatory cells (Tregs), orchestrating critical roles in the regulation of anti-tumor immunity in colorectal cancer (CRC). In this study, we report that a high frequency of circulating CD4+FoxP3+ Tregs was associated with poorer disease-free survival (DFS), while their higher frequencies in tumor-infiltrating CD4+ Tregs was associated with better DFS. We further investigated such associations with four Tregs/T cells expressing or lacking FoxP3 and Helios (FoxP3±Helios±). For the first time, we report that a high frequency of circulating CD4+FoxP3+Helios+ Tregs was associated with poorer DFS, while a high frequency of tumor-infiltrating CD4+FoxP3-Helios- T cells was associated with poorer DFS. In the four FoxP3±Helios± T cell subsets expressing any of the immune checkpoints (ICs) investigated, we found that a high frequency of CD4+FoxP3+Helios-PD-1+ Tregs in circulation was associated with worse DFS. We also found that high frequencies of FoxP3+Helios+CTLA-4+ Tregs, FoxP3+Helios-CTLA-4+ Tregs, and FoxP3-Helios+CTLA-4+ CD4+ T cells in circulation were associated with worse DFS. In contrast, high frequencies of CD4+TIM-3+ T cells, FoxP3+Helios+TIM-3+ Tregs, and FoxP3-Helios+TIM-3+ CD4+ T cells in circulation were associated with longer DFS. Our data show that certain CD4+ Treg/T cell subsets could serve as independent predictive biomarkers in CRC patients. Identification of the exact subpopulations contributing to clinical outcomes is critical for prognoses and therapeutic targeting.

Associations of Complete Blood Count Parameters with Disease-Free Survival in Right- and Left-Sided Colorectal Cancer Patients.

Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Some complete blood count (CBC) parameters are found to be associated with CRC prognosis. In this study, ninety-seven pretreated CRC patients were included, and the patients were divided into two groups: left-sided and right-sided, depending on the anatomical location of the tumor. Based on clinicopathologic features including tumor budding, disease stages, and tumor anatomical location, levels of CBC parameters were compared, and disease-free survivals (DFS) were determined. There were differences between patients with different tumor budding scores for only three parameters, including red cell distribution width (RDW), numbers of platelets, and mean platelet volume (MPV). Furthermore, numbers of WBCs, monocytes, and MPV in CRC patients with early disease stages were higher than those with advanced stages. However, levels of eosinophil in CRC patients with advanced stages were higher than those with early stages. Depending on the tumor anatomical location, we observed that numbers of red blood cells (RBCs), hemoglobin (Hgb), and hematocrit (Hct) in CRC patients with left-sided tumors were higher than those with right-sided tumors. We found that low levels of MPV were associated with shorter DFS. However, high levels of eosinophils were associated with shorter DFS in all CRC patients. When patients were divided based on the tumor anatomical location, higher levels of MPV, MCHC, and Hgb were associated with better DFS in the left-sided but not right-sided CRC patients. However, left-sided, but not right-sided, CRC patients with high levels of eosinophil and RDW had shorter DFS. Furthermore, right-sided, but not left-sided, CRC patients with high levels of platelets tended to have a shorter DFS. Our data show that MPV and eosinophils could serve as potential prognostic biomarkers in pre-treatment CRC patients, regardless of the tumor anatomical location. Additionally, lower levels of MPV, MCHC, and Hgb, and high levels of eosinophils and RDW could be negative predictive biomarkers in left-sided CRC patients.

Correlations between Circulating and Tumor-Infiltrating CD4+ T Cell Subsets with Immune Checkpoints in Colorectal Cancer.

T regulatory cells (Tregs) play different roles in the regulation of anti-tumor immunity in colorectal cancer (CRC), depending on the presence of different Treg subsets. We investigated correlations between different CD4+ Treg/T cell subsets in CRC patients with immune checkpoint-expressing CD4+ T cells. Positive correlations were observed between levels of different immune checkpoint-expressing CD4+ T cells, including PD-1, TIM-3, LAG-3, and CTLA-4 with FoxP3+ Tregs, Helios+ T cells, FoxP3+Helios+ Tregs, and FoxP3+Helios- Tregs in the tumor microenvironment (TME). However, negative correlations were observed between levels of these immune checkpoint-expressing CD4+ T with FoxP3-Helios- T cells in the TME. These correlations in the TME highlight the role of cancer cells in the upregulation of IC-expressing Tregs. Additionally, positive correlations were observed between levels of FoxP3+ Tregs, Helios+ T cells, FoxP3+Helios+ Tregs, and FoxP3+Helios- Tregs and levels of CD4+CTLA-4+ T cells and CD4+PD-1+ T cells in peripheral blood mononuclear cells (PBMCs) and normal tissue-infiltrating lymphocytes (NILs). These observations suggest that CTLA-4 and PD-1 expressions on CD4+ T cell subsets are not induced only by the TME. This is the first study to investigate the correlations of different FoxP3+/-Helios+/- T cell subsets with immune checkpoint-expressing CD4+ T cells in CRC patients. Our data demonstrated strong correlations between FoxP3+/Helios+/- Tregs but not FoxP3-Helios+/- non-Tregs and multiple immune checkpoints, especially in the TME, providing a rationale for targeting these cells with highly immunosuppressive characteristics. Understanding the correlations between different immune checkpoints and Treg/T cell subsets in cancer patients could improve our knowledge of the underlying mechanisms of Treg-mediated immunosuppression in cancer.

Well-Differentiated Liposarcoma of the Hypopharynx Exhibiting Myxoid Liposarcoma-like Morphology with MDM2 and DDIT3 Co-Amplification.

Well-differentiated liposarcoma (WDL) is one of the most common soft tissue sarcomas in adults. It has a predilection for middle-aged males and arises in deep-seated locations such as retroperitoneum, mediastinum, and spermatic cord. Its occurrence in young individuals at the hypopharyngeal region is an exceedingly rare event. Myxoid liposarcoma (ML)-like changes can seldom occur in some cases of WDL, which makes the diagnosis of WDL more challenging. Amplification of DDIT3 gene in a subset of cases of WDL has shown to be associated with such unique morphology. Herein, we present a case of a 36-year-old gentleman who presented with difficulty in breathing and swallowing for 3 months duration. CT scan of the neck revealed a lesion along the posterior wall of the hypopharynx measuring 3.5 cm. Histopathologic examination revealed a tumor composed of lobules of oval to spindle cells in a prominent myxoid stroma with delicate chicken-wire vasculature. In the vicinity, there were lobules composed of variably sized adipocytes separated by thick fibrous septa that contains atypical hyperchromatic spindle cells. By immunohistochemistry, the tumor cells in both components were immunoreactive for CDK4, but negative for MDM2. Fluorescence in-situ hybridization (FISH) confirmed the presence of MDM2 gene amplification. There was no evidence of FUS-DDIT3 gene rearrangement, however, DDIT3 gene was also amplified. The diagnosis of well-differentiated liposarcoma with prominent myxoid stroma was rendered. This is the first documentation of WDL with ML-like morphology harboring co-amplification of MDM2 and DDIT3 in the hypopharynx.