PD-L1 expression in sebaceous carcinomas.

BACKGROUND: Traditional systemic treatments for unresectable, recurrent, and/or advanced sebaceous carcinoma (SC) are ineffective. Tumoral immune microenvironment characterization is essential for considering immune checkpoint inhibitors as a treatment option. METHODS: A total of 173 resected SCs were reviewed. Clinical information, lesion size, and location were collected. Microscopic examination documented histopathologic features and expression of immunohistochemical markers PD-L1 and CD8. PD-L1 percentage was assessed amongst tumor (PD-L1 + Tu) and immune infiltrating cells (PD-L1 + Inf). Each case was attributed a combined positive score (CPS) following Head and Neck squamous cell carcinoma recommendations. PD-L1 expression was evaluated according to clinicopathologic parameters. Human Papilloma Virus presence (HPV) was analyzed using PCR microarray scanning. RESULTS: A therapeutically relevant CPS was seen in 51.4% of cases. Higher PD-L1 + Tu, PD-L1 + Inf, and CPSs were positively associated with greater lesion size and an extraocular location. No association was seen with patient age or gender. 9.2% of SCs showed PD-L1 + Tu ≥ 1, while 52.0% showed PD-L1 + Inf ≥ 1. A higher CD8 + T-lymphocyte density was significantly associated with a higher CPS, PD-L1 + Tu, and PD-L1 + Inf. Tumor-associated T-cell infiltrate's density was higher along tumor periphery. HPV-16, HPV-43, HPV-52, and HPV-66 were detected in 8.4% of SCs. There was no significant association between HPV status, PD-L1 expression, and CPS. A significant number of SCs express PD-L1 at therapeutic levels. Nevertheless, PD-L1 expression shows a higher intertumoral heterogeneity, in extraocular than in biologically distinct periocular cases. CONCLUSION: Our data support the need for large-scale prospective studies evaluating anti-PD-L1 immunotherapy mainly in extraocular SC treatment.

IgM and C3 Deposition in Primary Focal Segmental Glomerulosclerosis (FSGS): A Clinical and Histopathological Spectrum.

Focal segmental glomerulosclerosis (FSGS) is a common renal disorder, characterized by progressive segmental sclerosis of renal glomeruli and clinical symptoms corresponding to proteinuria. Classically, it is not considered to be an antibody-mediated disease, however, IgM and C3 deposition may be seen in a subset of cases of FSGS. The impact of this immune deposition on histopathological features in renal core biopsies, on the urinary biochemical parameters, and the clinical outcomes, has not been previously investigated in our population. The aim of this study is to analyze the aforementioned parameters in patients with primary FSGS having antibody deposition as compared to those who do not have any antibody deposition. Some 155 patients diagnosed with FSGS were retrospectively enrolled in our study. The renal biopsies were reviewed for histopathological features and immunofluorescence (IF) findings of IgM and C3 glomerular deposition. These histological features were then compared with the biochemical parameters as well as the clinical outcomes of patients. The patients were assigned to Groups 1 and 2 based on the IF findings. The IgM and/or C3 glomerular deposition had a low incidence in patients with primary FSGS in our study (28.3%). Patients having IgM and C3 co-deposition had a significantly longer time duration since the onset of their clinical symptoms; active disease duration (42 months vs 22 months, p=0.049). The mean pre-treatment serum creatinine of patients with IgM and C3 co-deposition was 6.00 mg/dL as compared to 3.29 mg/dL in patients with no immune deposition (p=0.037). The immune deposition was associated with higher rates of segmental and global glomerulosclerosis, but this finding along with other evaluated histological parameters did not show statistical significance. The number of patients having IgM and/or C3 deposition and with active steroid use/renal dialysis was similar to patients having no IgM and/or C3 deposition. The IgM and/or C3 deposition in FSGS has a low incidence within and is not associated with any significant differences in histological parameters on renal core biopsies of patients from the Pakistani population. IgM and/or C3 deposition is also associated with a significantly longer duration of active disease and these patients may present with higher pre-treatment serum creatinine. Other biochemical parameters and clinical outcomes appear comparable between the groups based on the available clinical data.

PD-L1 is Fascinating but IDO Needs Attention in Non-HCV and Non-HBV-Associated Hepatocellular Carcinoma Patients.

Background/Aim: Hepatocellular carcinoma (HCC) is one of the most common forms of liver cancer that is modulated by the immune system. Programmed cell death ligand-1 (PD-L1) has emerged as a novel therapeutic target in various cancers. Indoleamine 2,3-dioxygenase (IDO) is an immunosuppressive enzyme that is associated with poor prognoses in various cancer types. The aim of this study was to investigate the PD-L1 expression, and clinicopathological features of non-HCV and non-HBV-associated HCC patients, including IDO expression. Patients and Methods: In this study, immunohistochemical analysis was performed to analyze the expression of PD-L1 and IDO. Formalin-fixed paraffin-embedded HCC tumor tissues (n=50) were obtained from the pathology department, at Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH&RC) in Lahore, Pakistan between 2005 and 2022. All the patients were HBV and HCV negative. Furthermore, it was a rare group of patients with no previous history of any viral hepatitis. In addition, for categorical and continuous variables chi-square or Fisher exact test and Mann-Whitney U-test was performed. Results: Of 50 tissue specimens, PD-L1+ was observed in 21 [high: 12 (24%), low: 9 (18%)] and PD-L1- was observed in 29 HCC patients. IDO+ was observed in all 50 specimens [high: 42 (84%), low: 8 (16%)]. Additionally, both PD-L1 and IDO had high expression in 11 (22%) patients. While both PD-L1 and IDO had low expression in 2 (4%) patients. Furthermore, in IDO+/PD-L1- group, 20 (69%) out of 29 patients died while in the IDO+/PD-L1+ group, 9 (43%) out of 21 patients died. Conclusion: Evaluation of IDO and PD-L1 expression may add therapeutic advantage in non-HCV and non-HBV-associated HCC patients that overexpress IDO. Further validation in a larger cohort is warranted.

Angiomatoid Fibrous Histiocytoma: A Tumor With Uncertain Behavior and Various Clinicopathological Presentations.

Background Angiomatoid fibrous histiocytoma (AFH) is a rare soft tissue neoplasm of uncertain differentiation, which has various clinical and morphological presentations. Although it behaves in a benign manner, it has malignant potential. Aim To share various histological patterns and survival data in our population of this rare entity. Materials and methods We studied 25 patients who reported AFH from January 2011 to December 2021. Clinical information, gross and histological features, immunohistochemical results, and survival data were compiled and analyzed. Results Among 25 cases reported as AFH, the majority (68%) were males with a mean age of 31.8 years at the time of diagnosis. The most common location was the lower extremity, especially the thigh (56%), and the mean size of the lesion was 55 mm. Most of the lesions were superficial (84%). Grossly, the majority of lesions (76%) had a solid appearance. Microscopically, classic spindle cell morphology was the most common (76%) with a lymphoid cuff and intralesional hemorrhage. Mild cellular atypia was seen in most (92%) of the cases, while some biopsies (8%) had a high-grade morphology. The majority of patients were alive, while one patient died of the disease. Conclusion AFH is an under-recognized entity with various clinical and histological presentations and a low malignant potential.

Microsatellite Instability in Near East Sebaceous Neoplasms: Toward Improved Prediction.

Sebaceous neoplasms (SN) comprise a heterogeneous spectrum of tumors with different biological behaviors. In the Near-East Region (NER), microsatellite instability (MSI) in SN's development, and its correlation with the clinicopathologic features of tumors is not well elucidated. A cohort of 225 SN patients (40 benign SNs and 185 sebaceous carcinomas) from the NER was retrospectively reviewed. Clinical variables and available follow-up information were recorded. MSI proteins (MLH1, MSH2, MSH6, and PMS2) as well as P53, P16, EMA, CD8, and PDL-1 expressions were examined by immunohistochemistry. Detection of human papilloma virus was determined by polymerase chain reaction. Microscopic features such as mitotic count and tumor-infiltrating lymphocytes were documented. A minority of SNs from benign (n=2) or malignant (n=3) tumors in the NER exhibit MSI (2.2%). MSI is exclusively found in patients with extraocular lesions (back, n=5) and presented a poor outcome. Among these, PMS2 protein was mostly lost (average=80%, n=4). SN with MSI exhibited a significant increase in p53 expression, (average=62.10%, P=0.002). There was no significant correlation between MSI status and any of the following: PD-L1, CD8, p16, and human papilloma virus infection. Microscopically, SN with MSI show significantly higher mitotic count, cystic changes and increased tumor-infiltrating lymphocytes. MSI is rarely found in NER's SN. When detected, it is exclusively in extraocular SNs with minimal predicative microscopic features and worse outcome.

C4d at Crossroads Between Post-Infectious Glomerulonephritis and C3 Glomerulopathy.

BACKGROUND: Post-infectious glomerulonephritis (PIGN) (immune complex-mediated glomerulonephritis) and C3 glomerulopathy are sub-types of glomerulonephritis (GN) with hypercellularity. Both have overlapping clinical and morphologic features on a kidney biopsy, however, the treatment and prognosis of these diseases are quite different making their distinction of utmost importance. Immune complex-mediated glomerulonephritis arises from glomerular deposition of immune-complexes (Igs) and C3 as a result of activation of classical (CP) and lectin pathways (LP). C4d is produced as a result of activation of the CP/LP. On the other hand, C3 glomerulopathy results from activation of alternative pathway of complement. AIM: To distinguish between PIGN and C3 glomerulopathy with the help of C4d IHC stain. MATERIALS AND METHODS: We studied 28 biopsies reported as GN with hypercellularity from January 2015 to January 2020. Clinical information, histological features and immunofluorescence patterns were analyzed. C4d IHC was performed on all the biopsies. Six known cases of immune complex-mediated GN were selected to act as a positive control for C4d staining. RESULTS: Amongst 28 cases originally reported as GN with hypercellularity, 18 were labeled as post-infectious GN and 10 as C3 glomerulopathy based on clinical information and serological findings. 13 of 18 (72.2%) cases of PIGN had mild to moderate (1-2+) C4d staining, 2 (11.1%) had strong (3+) staining and 3 (16.7%) cases were negative for C4d staining. In the 10 biopsies of C3 glomerulopathy, mild (1+) C4d staining was noted only in 3 (30%) biopsies. C4d had moderate to strong (2-3+) staining in the control group. CONCLUSION: C4d IHC stain can be helpful in distinguishing PIGN from C3 glomerulopathy.

Müllerian Adenosarcoma: A Single-Centre Experience of 59 Cases of This Rare Entity.

Background and objective Müllerian adenosarcomas (MA) are rare biphasic tumors with benign epithelial and sarcomatous stromal components. There is very limited cohort study data on MA in the South Asian countries and no such study has been attempted in Pakistan. Our aim was to evaluate the clinicopathological characteristics of MA and to review the published literature on the condition. Additionally, we also analyzed the impact of various prognostic factors on the overall survival (OS) of patients with MA. Materials and methods This was a retrospective observational study performed at the Shaukat Khanum Memorial Hospital and Research Centre, Lahore from 2003 to 2020. A total of 59 histologically confirmed cases of MA were included in the study and critically reviewed. Results The mean age of the patients was 54 ±16 years, and the most common tumor location was the uterine corpus (48, 81.4%), followed by the cervix (eight, 13.6%), ovary (two, 3.4%), and vagina (one, 1.7%). Sarcomatous overgrowth (SO) was seen in 22 (37.3%) patients, and high-grade cytology was observed in 18 (30.5%) patients. Furthermore, lymphovascular invasion (LVI) was present in six (10.2%) patients, and myometrial invasion was noted in 25 (42.4%) patients. The follow-up details of 29 patients were available, and death was recorded in 13 (44.8%) patients with a median OS of three years. Conclusion MA is a rare and diagnostically challenging entity due to its wide differential diagnosis. It is essential to take note of different morphological features such as SO, cytological features, LVI, and heterologous differentiation because of their significant prognostic impact.

Sebaceous neoplasms: prevalence of HPV infection and relation to immunohistochemical surrogate markers.

BACKGROUND: Sebaceous neoplasms (SNs) and carcinomas (SCs) represent rare skin adnexal tumours. OBJECTIVES: To establish the prevalence of HPV in SNs, assess the relationship between HPV, p16 and p53 expression, and further elucidate the carcinogenetic course of SCs. MATERIALS & METHODS: A total of 113 resected SNs (five sebaceous adenomas, 10 sebaceomas and 98 SCs) from the Near-East were reviewed. Clinical information (age, gender, size and anatomical location), microscopic variables, and expression of several immunohistochemical markers (EMA, CK5/6, p63, p40, AR, p16 and p53) were documented. Cases were evaluated by fluorescently labelled PCR for HPV detection, followed by DNA microarray hybridization for subtype detection. RESULTS: HPV infection was detected in 9.4% of SNs: 28.6% sebaceous adenomas (HPV-16 and HPV-66), 9.1% sebaceomas (HPV-18) and 8.1% SCs. High-risk HPV types (HPV-16, -18, -52 and -66) constituted 90.9% of HPV infections. Histologically, HPV-positive SCs showed significantly milder cytologic atypia and patchy cellular necrosis. p16 was expressed in SNs irrespective of HPV status (20.0%, 33.3% and 65.5% of HPV-negative sebaceous adenomas, sebaceomas, and SCs, respectively), and p53 was abnormally expressed in 95.5% of HPV-negative SCs and all HPV-positive SCs. CONCLUSION: HPV infection is significantly present in benign and malignant SNs. HPV-positive SCs exhibit less cytologic atypia and necrosis than HPV-negative cases. p16 is not a surrogate marker of HPV infection in the SN setting. Further elucidation of various carcinogenic mechanisms in SCs will allow clinicians to single out the various populations at risk, optimize possible preventive strategies and develop targeted therapies.

Renal Transplant Pathology: Demographic Features and Histopathological Analysis of the Causes of Graft Dysfunction.

BACKGROUND: Renal transplant has emerged as a preferred treatment modality in cases of end-stage renal disease; however, a small percentage of cases suffer from graft dysfunction. AIM: To evaluate the renal transplant biopsies and analyze the various causes of graft dysfunction. MATERIALS AND METHODS: 163 renal transplant biopsies, reported between 2014 and 2019 and who fulfilled the inclusion criteria, were evaluated with respect to demographics, clinical, histological, and immunohistochemical features. RESULTS: Of 163 patients, 26 (16%) were females and 137 (84%) were males with a mean age of 34 ± 7 years. 53 (32.5%) cases were of rejection (ABMR and TCMR), 1 (0.6%) was borderline, 15 were of IFTA, and rest of 94 cases (57.7%) belonged to the others category. SCr (serum creatinine) in cases of rejection was 3.85 ± 0.55 mg/dl. Causes of early graft dysfunction included active ABMR (7.1 ± 4.7 months), acute TCMR (5.5 months), and acute tubular necrosis (after 6 ± 2.2 months of transplant) while the causes of late rejection were CNIT and IFTA (34 ± 4.7 and 35 ± 7.8 months, respectively). CONCLUSION: Renal graft dysfunction still remains a concerning area for both clinicians and patients. Biopsy remains the gold standard for diagnosing the exact cause of graft dysfunction and in planning further management.