Digital Pathology During the COVID-19 Outbreak in Italy: Survey Study.

BACKGROUND: Transition to digital pathology usually takes months or years to be completed. We were familiarizing ourselves with digital pathology solutions at the time when the COVID-19 outbreak forced us to embark on an abrupt transition to digital pathology. OBJECTIVE: The aim of this study was to quantitatively describe how the abrupt transition to digital pathology might affect the quality of diagnoses, model possible causes by probabilistic modeling, and qualitatively gauge the perception of this abrupt transition. METHODS: A total of 17 pathologists and residents participated in this study; these participants reviewed 25 additional test cases from the archives and completed a final psychologic survey. For each case, participants performed several different diagnostic tasks, and their results were recorded and compared with the original diagnoses performed using the gold standard method (ie, conventional microscopy). We performed Bayesian data analysis with probabilistic modeling. RESULTS: The overall analysis, comprising 1345 different items, resulted in a 9% (117/1345) error rate in using digital slides. The task of differentiating a neoplastic process from a nonneoplastic one accounted for an error rate of 10.7% (42/392), whereas the distinction of a malignant process from a benign one accounted for an error rate of 4.2% (11/258). Apart from residents, senior pathologists generated most discrepancies (7.9%, 13/164). Our model showed that these differences among career levels persisted even after adjusting for other factors. CONCLUSIONS: Our findings are in line with previous findings, emphasizing that the duration of transition (ie, lengthy or abrupt) might not influence the diagnostic performance. Moreover, our findings highlight that senior pathologists may be limited by a digital gap, which may negatively affect their performance with digital pathology. These results can guide the process of digital transition in the field of pathology.

Breast metastasis two years after pelvic surgery and adjuvant chemotherapy for serous ovarian cancer.

Ovarian cancer is considered the leading cause of death among gynecologic neoplasias. Breast metastases from primary ovarian cancer have been reported in only 0.03-0.6% of all breast cancers. A 38-year-old female, multipara, affected by advanced ovarian cancer and undergone a total abdominal hysterectomy with bilateral salpingo-oophorectomy, omentectomy, and pelvic peritonectomy two years earlier, was discovered to have a breast metastasis. She underwent a quadrantectomy (QSI) with an open biopsy of nodularity attached to the pectoral muscle fascia: on definitive histological characterization the breast lesions showed a high-grade invasive carcinoma, with papillary serum differentiation, and the immunohistochemistry study of breast lesion showed positivity for cytokeratin 7 and an extensive positivity for Wilm's tumor (WT)-1 and paired box 8 (PAX8). These aspects are indicative of mammary metastasis from carcinoma of ovarian origin. Despite their rarity, metastases to breast from ovarian cancer should be considered possible because their recognition and differentiation compared to primary tumors are crucial for prognosis. Future clinical studies on MOCB should be performed to discover new specific markers for a more accurate histopathological diagnosis and to establish the real need of surgical treatment.

Prospective Validation of the ROL System in Substaging pT1 High-Grade Urothelial Carcinoma: Results from a Mono-Institutional Confirmatory Analysis in BCG Treated Patients.

Patients with pT1 high-grade (HG) urothelial carcinoma (UC) and a very high risk of progression might benefit from immediate radical cystectomy (RC), but this option remains controversial. Validation of a standardized method to evaluate the extent of lamina propria (LP) invasion (with recognized prognostic value) in transurethral resection (TURBT) specimens is still needed. The Rete Oncologica Lombarda (ROL) system showed a high predictive value for progression after TURBT in recent retrospective studies. The ROL system was supposed to be validated on a large prospective series of primary urothelial carcinomas from a single institution. From 2016 to 2020, we adopted ROL for all patients with pT1 HG UC on TURBT. We employed a 1.0-mm threshold to stratify tumors in ROL1 and ROL2. A total of 222 pT1 HG UC were analyzed. The median age was 74 years, with a predominance of men (73.8%). ROL was feasible in all cases: 91 cases were ROL1 (41%), and 131 were ROL2 (59%). At a median follow-up of 26.9 months (IQR 13.8-40.6), we registered 81 recurrences and 40 progressions. ROL was a significant predictor of tumor progression in both univariable (HR 3.53; CI 95% 1.56-7.99; p < 0.01) and multivariable (HR 2.88; CI 95% 1.24-6.66; p = 0.01) Cox regression analyses. At Kaplan-Meier estimates, ROL showed a correlation with both PFS (p = 0.0012) and RFS (p = 0.0167). Our results confirmed the strong predictive value of ROL for progression in a large prospective series. We encourage the application of ROL for reporting the extent of LP invasion, substaging T1 HG UC, and improving risk tables for urological decision-making.

Non-muscle invasive bladder cancer biomarkers beyond morphology.

Non-muscle invasive bladder cancer (NMIBC) still represents a challenge in decision-making and clinical management since prognostic and predictive biomarkers of response to treatment are still under investigation. In addition to the risk factors defined by EORTC guidelines, histological features have also been considered key variables able to impact on recurrence and progression in bladder cancer. Conversely, the role of genomic rearrangements or expression of specific proteins at tissue level need further assessment in NMIBC. As with muscle-invasive cancer, NMIBC is a heterogeneous disease, characterized by genomic instability, varying rates of mutation and a wide range of protein tissue expression. In this Review, we summarized the recent evidence on prognostic and predictive tissue biomarkers in NMIBC, beyond morphological parameters, outlining how they could affect tumor biology and consequently its behavior during clinical care. Our aim was to facilitate clinical evaluation of promising biomarkers that may be employed to better stratify patients. We described the most common molecular events and immunohistochemical protein expressions linked to recurrence and progression. Moreover, we discussed the link between available treatments and molecular drivers that could be predictive of clinical response. In conclusion, we foster further investigations with particular focus on immunohistochemical evaluation of tissue biomarkers, a promising and cost-effective tool for daily practice.

Case Report: Unclassified Renal Cell Carcinoma With Medullary Phenotype and SMARCB1/INI1 Deficiency, Broadening the Spectrum of Medullary Carcinoma.

Renal medullary carcinoma (RMC) is a rare entity with poor prognosis bearing inactivating genomic alterations in SMARCB1/INI1 resulting in the loss of expression of INI1 and occurring in young patients with sickle cell trait or sickle cell disease. Recently, rare examples with histological characteristics of RMC have been described in older patients without hemoglobinopathies and provisionally termed "Renal cell carcinoma unclassified with medullary phenotype" (RCCU-MP). Fluorescence in situ Hybridization (FISH) can detect alterations in SMARCB1/INI1 consisting mostly in inactivating translocation of one allele and deletion of the second. To date, only seven further cases of RCCU-MP have been described in the literature. Here we report the second Italian case of RCCU-MP, a 62-year-old man presenting with persistent dull back pain and incidentally discovering a 13 cm mass in the right kidney. The nomenclature of this entity is still debated and might be updated as a variant of medullary carcinoma in the upcoming WHO classification. In the meantime, we encourage awareness of these extraordinarily rare neoplasms with poor outcomes.

Case report: Primary Ewing sarcoma of the ureter, an exceptional finding of unique manifestation of disease.

Ewing sarcoma (ES) is the second most common malignant bone tumor in children and has also been described in adults with highly aggressive behavior. ES belongs to the small round blue cell tumor family and presents the distinctive translocation of FET-ETS family genes (85% with EWSR1), generating gene fusions. Extraskeletal ES mainly occurs in soft tissues; the urogenital tract is rarely affected, and ureteral localization is an exceptional event with only 4 cases described in the literature. Here we report the first Italian case of primary ES of the ureter, a 24-year-old young man with lower back pain and a narrowed left ureteral lumen on CT scan. ES of the urogenital tract is an almost unique condition with a nonspecific clinical presentation and a challenging diagnosis for pathologists. We encourage awareness of these exceptional events in the differential diagnosis of ureteral lesions in young patients.

Intratumoral Switch of Molecular Phenotype and Overall Survival in Muscle Invasive Bladder Cancer.

In recent years, immunohistochemical protein expression was studied as a surrogate to the molecular classification of bladder cancer, although no tissue biomarkers are available for clinical use to predict survival or the response to neoadjuvant chemotherapy (CT) in UC, as the literature produced conflicting results. This retrospective study included TURB specimens harboring foci of HG pT2 muscle-invasive bladder carcinoma (MIBC) from 251 patients who subsequently underwent radical cystectomy. We performed immunohistochemical analysis on tumor samples, for relevant gene-expression-based markers for basal type (CD44, CK5/6) and luminal type (CK20 and pPARγ). Piescore, investigated in both non-muscle-invasive (NMI) and muscle-invasive (MI) components of the tumor, divided basal and luminal UC-types when at least three of the four markers were consistent with a specific phenotype, mixed types if one/two luminal and basal markers were present simultaneously, and neu-like types when all four markers investigated were negative. Eighteen selected cases were also investigated with RT-PCR to validate, and to increase the specificity of, the immunohistochemical results. We observe an immunophenotypical difference in the NMI and MI components in 96/251 UC patients (38.25%): half of tumors (44/96 cases) have a transition to basal, 36.46% (35/96 cases) to neu-like, 12.5% (12/96 cases) to mixed, and 5.2% (5/96 cases) to luminal phenotypes. Mixed tumors in the NMI component are more likely to change phenotype than other groups, particularly compared with basal tumors, which demonstrate greater stability (only 8/96 cases, p < 0.00001). The transition of luminal tumors to basal display a better OS compared with the transition toward neu-like tumors (p = 0.027). Overall, the phenotypical switch does not affect lymphovascular invasion, pT, DFS, or OS compared with non-switched cases. In the MI component, the presence of CD44 expression, irrespective of score-related phenotype, shows a protective effect in papillary-type UC (OS p = 0.008, HR 0.453, PFS p = 0.07, HR 0.599), and in UC naïve for CT (p = 0.0479). Piescore immunophenotyping reveals an intratumoral phenotypical transition between the NMI and MI components of the same tumor. The molecular change is a common event in the mixed and luminal categories, but not in basal tumors, which show better phenotypical stability. This phenomenon could partially explain the sensitivity of a subset of luminal UC to chemotherapy: good responders could be "non-real" luminal UC, which acquire nasal markers, such as CD44.

Exceptional Symbiosis Between Tumors: A Case of Gastric Signet Ring Cell Metastasis in Chromophobe Carcinoma of the Kidney.

Tumor-to-tumor metastasis is the presence of a metastatic deposit within a second malignant primary, and its identification could be challenging, particularly when the latter malignancy has not yet been discovered. Renal cell carcinoma is one of the known recipients. Here we present a 52 years old woman who presented with a small nodule in the left kidney, which had a biphasic cell proliferation, chromophobe type, and signet-ring cell type for which we suggested to investigate the presence of a second tumor of gastrointestinal origin. We present this case for the rarity of its presentation, for the peculiar histological symbiosis we found between the two tumor entities, and for the challenging diagnosis due to the presence of an occult aggressive primary tumor.

Delayed Diagnosis of a Testicular Mass During COVID-19 Pandemic in Lombardy: A Case Report.

Signs and symptoms associated with testicular and paratesticular structures should not be underestimated because they may hide diseases requiring immediate evaluation and treatment, such as germline tumors or sarcomas, with the latter histotypes being more common among elderly patients. Unfortunately, the COVID-19 pandemic in Italy has led to a diagnostic delay of several malignancies and the impact of this delay has likely been underestimated. Paratesticular leiomyosarcoma represents a very rare subtype of sarcoma. Here we describe a 57-year-old man who presented to the emergency department with dyspnea and a voluminous mass in the right paratesticular region. At the appearance of the scrotal mass 9 months prior, he had refused to undergo a urological evaluation due to fear of contracting COVID-19. We present this case for its histological rarity and to document a case of diagnostic and therapeutic delay during the pandemic in Lombardy.

How Are We Facing It? Dispatches From Pathology Residents in a COVID-19 Lombardy Hospital.

At the end of February, the Italian National Health Service reported a hot spot of Coronavirus disease in the Lombardy region. COVID-19 is a highly pathogenic viral infection which poses some challenges for healthcare workers. Indeed, Pathology Departments are involved in reorganizing samples' management, from their delivery until their processing, according to National and WHO guidelines. Since Lombardy has been declared COVID-19 hot spot, due to decreasing number of surgical procedures, our Department adopted a policy to reduce personnel, allowing pathologists to work remotely during the outbreak. Lacking clear information about viral load on tissue samples, all human specimens must be considered potentially infectious, as well as patients during post-mortem examinations, and clinical information on COVID-19 status is mandatory. It is also important that Pathology staff receive an adequate training, and adherence to rules should be always accompanied by common sense.

A case of incidentally discovered solitary fibrous tumor of the kidney: A case study.

Solitary fibrous tumor (SFT) is a rare neoplasm of mesenchymal origin. The kidney represents an unusual location for SFT and the diagnosis and treatment of renal SFT remains challenging. The present study reports the case of a right kidney SFT incidentally discovered in a 52-year old woman. Radiological findings from computed tomography and magnetic resonance imaging were not specific but highly suspect for a malignant neoplasm. The definitive diagnosis relied on histological examination and immunohistochemical staining for CD34 and signal transducer and activator of transcription 6.

Diagnostic and prognostic value of ARID1A in endometrial hyperplasia: a novel marker of occult cancer.

AT-rich interaction domain 1A (ARID1A) is a tumor suppressor protein involved in endometrioid carcinogenesis. The expression of ARID1A may be lost in the premalignant phase. Our aim was to assess ARID1A as: (i) diagnostic marker to differentiate premalignant endometrial hyperplasia (EH) form benign EH; (ii) prognostic marker for the risk of occult cancer in premalignant EH. A systematic review and meta-analysis were performed by searching electronic databases from their inception to October 2018 for all studies assessing ARID1A in EH by immunohistochemistry. Sensitivity, specificity, positive and negative likelihood ratios (LR+ and LR-), and diagnostic odds ratio (DOR) were calculated for both diagnostic and prognostic accuracy. LR+ > 5, LR- < 0.2, DOR > 25 defined good accuracy; LR+ > 10, LR- < 0.1, DOR > 100 defined excellent accuracy. Seven studies with 467 EH were included. As diagnostic marker, ARID1A showed sensitivity = 0.12, specificity = 0.99, LR+ = 4.34, LR- = 0.85, DOR = 5.12. As prognostic marker for occult cancer, ARID1A showed sensitivity = 0.33, specificity = 0.99, LR+ = 20.70, LR- = 0.49, DOR = 49.59. In conclusion, ARID1A loss is highly specific, but little accurate as diagnostic marker of premalignant EH. Instead, ARID1A loss in premalignant EH is an accurate and almost perfectly specific prognostic marker for coexistent cancer.

EGFR exon 19 deletion switch and development of p.L792Q mutation as a new resistance mechanism to osimertinib: a case report and literature review.

Epidermal growth factor receptor (EGFR) gene mutations play an important role in the treatment management of non-small cell lung cancer (NSCLC) patients. After a first- or second-generation EGFR tyrosine kinase inhibitor (TKI) therapy, the most common resistance mechanism involves the selection of a resistant clone carrying the exon 20 p.T790M point mutation. However, also for these patients, treated with a third-generation TKI (osimertinib) several mechanisms of acquired resistance are described. Here we report the case of a 68-year-old man with an EGFR exon 19 deletion treated with gefitinib in first line and osimertinib in second line besides on the presence of a p.T790M mutation, who developed an uncommon EGFR exon 20 p.L792Q point mutation at the progression to osimertinib, with the concomitant modification of the original sensitizing EGFR exon 19 deletion and the loss of p.T790M mutation.