Oncocytoid Salivary Tumors: Differential Diagnosis and Utility of Newly Described Immunohistochemistry.

BACKGROUND: Oncocytoid salivary tumors include several entities such as oncocytoma, Warthin tumor, secretory carcinoma (SC), salivary duct carcinoma (SDC), acinic cell carcinoma (AciCC), oncocytic mucoepidermoid carcinoma (OMEC), intraductal carcinoma, and epithelial myoepithelial carcinoma (EMC). This review investigates the differential diagnosis of oncocytoid salivary tumors and explore the role of newly described immunostains as valuable tools for their diagnosing and potentially guiding treatment options. METHODS: We assess the utility of incorporating new immunohistochemical markers in routine practice to aid in diagnosing oncocytoid salivary tumors and potentially provide treatment options. RESULTS: In SDC, AR and Her2 immunostains are utilized as diagnostic tools and biomarkers for selecting patients who might benefit from Androgen-deprivation therapy (ADT) and HER2-targeted therapy. Furthermore, nuclear Pan-Trk immunostaining can aid in diagnosing SC. Additionally, NR4A3 immunostaining has been shown high sensitivity and specificity in identifying AciCC in both surgical and cytologic specimens. Similarly, RAS Q61R mutant-specific immunostaining, detected in EMC, may offer a cost-effective diagnostic marker for this tumor. Although further studies are required to evaluate the role of BSND, this marker has been reported to be positive in Warthin tumor and oncocytoma, aiding in differentiating them from other oncocytoid tumors, particularly OMEC. In addition, BRAFV600E mutant-specific immunostaining can serve as a diagnostic and potentially therapeutic marker for oncocytic intraductal carcinoma in mutation positive cases. CONCLUSION: Oncocytoid salivary tumors may have overlapping morphologies, posing diagnostic challenges for pathologists. Recently described immunohistochemical markers may offer valuable tools for diagnosing and potentially guiding treatment options for these tumors.

Salivary Ductal Carcinoma: A Case Report.

ABSTRACT: Salivary ductal carcinoma is an extremely rare tumor located in the parotid gland. This case details a salivary ductal carcinoma within the parotid gland of a 59-year-old man and its management.

Relationship between Baseline [18F]FDG PET/CT Semiquantitative Parameters and BRCA Mutational Status and Their Prognostic Role in Patients with Invasive Ductal Breast Carcinoma.

AIM: To assess the relationship between [18F]FDG PET/CT, breast cancer gene (BRCA) status, and their prognostic role in patients with ductal breast cancer (DBC). METHODS: Forty-one women were included. PET/CT semiquantitative parameters such as standardized uptake value (SUV) body weight max (SUVmax), SUV body weight mean (SUVmean), SUV lean body mass (SUVlbm), SUV body surface area (SUVbsa), metabolic tumor volume (MTV), total lesion glycolysis (TLG), ratio SUVmax/blood-pool (S-BP), and ratio SUVmax/liver (S-L) were also extracted. The relationship between these parameters, BRCA, and other clinicopathological features were evaluated. Kaplan-Meier, univariate, and multivariate analyses were performed to find independent prognosticators for progression free (PFS) and overall survival (OS). RESULTS: Significant positive correlations between BRCA status and SUVmax (p-value 0.025), SUVlbm (p-value 0.016), and SUVbsa (p-value 0.018) were reported. Mean PFS was 53.90 months with relapse/progression of disease occurring in nine (22.0%) patients; mean OS was 57.48 months with death occurring in two (4.9%) patients. Survival curves revealed TLG, MTV, and BRCA status as prognosticator for PFS; BRCA was also a prognosticator for OS. Univariate and multivariate analyses did not confirm such insights. CONCLUSION: We reported a correlation between some PET/CT parameters and BRCA status; some insights on their prognostic role have been underlined.

Squamoid Eccrine Ductal Carcinoma: Treatment and Outcomes.

BACKGROUND: Squamoid eccrine ductal carcinoma (SEDC) represents a subtype of eccrine carcinomas that are diagnostically challenging for both clinicians and dermatopathologists. OBJECTIVE: To provide an updated review of SEDC and examine patient outcomes with different treatment modalities. METHODS: A review of Ovid MEDLINE was performed to review the English language medical literature of SEDC. RESULTS: A comprehensive review of clinical presentation, histologic findings, rates of lymphovascular and metastatic disease, treatment modalities and recurrence rates are reviewed. LIMITATIONS: There is a limitation on available data because of the rare incidence. CONCLUSIONS: SEDC is a rare adnexal neoplasm with a relatively high rate of local recurrence, lymphovascular invasion, perineural invasion, and metastases. Clinicians should be aware of this entity as close follow-up is essential to detect recurrence and metastatic disease. Mohs micrographic surgery seems to result in superior patient outcomes.

Pancreatic metastasis of invasive ductal breast carcinoma: A potential diagnostic pitfall.

The 42-year-old patient, diagnosed with Stage IIA breast cancer, completed the postoperative adjuvant chemotherapy and radiotherapy. At the 11th year of diagnosis, a 3 cm tumor was detected in the pancreas and pancreatectomy was performed. Although the diagnosis of primary pancreatic adenocarcinoma was made at first, then the pancreatic metastasis of breast cancer was discovered. Pancreatic metastasis of breast cancer is extremely rare, and a limited number of patients have been reported in the literature. Here, we report an additional case of this rare tumor and the problems correlating with its diagnosis.

Pulmonary tumor embolism: A retrospective study over a 30-year period.

BACKGROUND: Pulmonary tumor embolism (PTE) is difficult to detect before death, and it is unclear whether the discrepancy between antemortem clinical and postmortem diagnosis improves with the advance of the diagnostic technologies. In this study we determined the incidence of PTE and analyzed the discrepancy between antemortem clinical and postmortem diagnosis. METHODS: We performed a retrospective autopsy study on patients with the history of malignant solid tumors from 1990 to 2020 and reviewed all the slides of the patients with PTE. We also analyzed the discrepancies between antemortem clinical and postmortem diagnosis in 1999, 2009 and 2019 by using the Goldman criteria. Goldman category major 1 refers to cases in which an autopsy diagnosis was the direct cause of death and was not recognized clinically, but if it had been recognized, it may have changed treatment or prolonged survival. RESULTS: We found 20 (3%) cases with PTE out of the 658 autopsy cases with solid malignancies. Out of these 20 cases, urothelial carcinoma (30%, 6/20) and invasive ductal carcinoma of the breast (4/20, 20%) were the most common primary malignancies. Seven patients with shortness of breath died within 3-17 days (average 8.4±2.2 days) after onset of the symptoms. Pulmonary embolism was clinically suspected in seven out of twenty (35%, 7/20) patients before death, but only two patients (10, 2/20) were diagnosed by imaging studies before death. The rate of Goldman category major 1 was 13.2% (10/76) in 1999, 7.3% (4/55) in 2009 and 6.9% (8/116) in 2019. Although the rate of Goldman category major 1 appeared decreasing, the difference was not statistically significant. The autopsy rate was significantly higher in 2019 (8.4%, 116/1386) than in 2009 (4.4%, 55/1240). CONCLUSIONS: The incidence of PTE is uncommon. Despite the advances of the radiological techniques, radiological imaging studies did not detect the majority of PTEs. The discrepancy between the antemortem clinical and the postmortem diagnosis has not improved significantly over the past 30 years, emphasizing the value of autopsy.

Pancreatic collision tumor of ductal adenocarcinoma and neuroendocrine tumor-A rare case report.

A collision tumor is composed of two adjacent histological distinct neoplasms without the histological admixture of cell types in the same organ or tissue. It is rare in pancreas. Herein we report an unusual case of a mixed malignant neuroendocrine tumor (NET) and ductal adenocarcinoma of pancreas in a 24 year old male who presented with history abdomen pain. A clinicoradiological diagnosis of chronic calcific pancreatitis with carcinoma body of pancreas was made. Distal pancreaticosplenectomy specimen showed a grey white, nodular growth measuring 2 x 2 x 1.2 cm on the cut surface of pancreas. Histopathology revealed a composite tumor consisting of ductal and neuroendocrine origin. Immunohistochemistry showed complementary staining for CK7 in adenocarcinoma and chromogranin A in NET areas confirming a collision tumor. Accurate evaluation of the radiologic pointers, histomorphologic evaluation to recognize and quantitate the individual components, appropriate immunohistochemical evaluation and correlation is essential for diagnosis.

Optimizing the diagnosis and management of ductal prostate cancer.

Ductal adenocarcinoma (DAC) is the most common variant histological subtype of prostate carcinoma and has an aggressive clinical course. DAC is usually characterized and treated as high-risk prostatic acinar adenocarcinoma (PAC). However, DAC has a different biology to that of acinar disease, which often poses a challenge for both diagnosis and management. DAC can be difficult to identify using conventional diagnostic modalities such as serum PSA levels and multiparametric MRI, and the optimal management for localized DAC is unknown owing to the rarity of the disease. Following definitive therapy for localized disease with radical prostatectomy or radiotherapy, the majority of DACs recur with visceral metastases at low PSA levels. Various systemic therapies that have been shown to be effective in high-risk PAC have limited use in treating DAC. Although current understanding of the biology of DAC is limited, genomic analyses have provided insights into the pathology behind its aggressive behaviour and potential future therapeutic targets.

Parotid Salivary Duct Carcinoma With a Prominent Squamous Component: Immunohistochemical Profile, Diagnostic Pitfalls, and Therapeutic Implications.

Salivary duct carcinoma of the parotid gland is a highly aggressive epithelial malignancy morphologically resembling high-grade, invasive, and in situ breast carcinoma. It can occasionally present with variable morphology making it diagnostically challenging in cases with unusual morphological components. Ancillary testing, particularly androgen receptor (AR) positivity on immunohistochemistry, can be very helpful in cases that demonstrate extensive squamous morphology, since AR positivity is uncommon in both the primary salivary gland and metastatic squamous cell carcinomas to the parotid. In this report, we describe a case of salivary duct carcinoma that showed only a squamous cell carcinoma component on the initial primary tumor site biopsy, as well as in subsequent contralateral neck lymph node and skin metastases. Apart from the variable morphology, the typical salivary duct and squamous cell carcinoma tumor components also showed significant immunohistochemical differences, including differential staining of human epidermal growth factor receptor 2/neu. The associated diagnostic pitfalls, distinct immunoprofiles of the tumor components, helpful adjuncts for making the correct diagnosis, and associated therapeutic implications are discussed.

Small Cell-like Change in Central Zone Histology-A New Observation Mimicking Cribriform Intraductal Prostatic Adenocarcinoma.

A small cell-like change in prostate has been described in high-grade prostatic intraepithelial neoplasia (PIN), intraductal prostatic adenocarcinoma, and invasive prostate cancer. It occurs when these processes have a cribriform architecture. To date, small cell-like change has not been described in benign glands. Herein, I describe such a change in cribriform central zone histology from a radical prostatectomy with a spatially remote treatment naïve Grade Group 3 prostate cancer. The cancer did not have cribriform morphology or intraductal prostatic adenocarcinoma. The small cell-like change was positive for racemase in PIN-4 cocktail and no nuclei were highlighted by Ki-67. This is the first report of a small cell-like change in benign prostate tissue. Although rare, such finding in cribriform architecture of central zone histology can potentially be misinterpreted as a neoplastic process.

Salivary Duct Carcinoma: An Aggressive Salivary Gland Carcinoma with Morphologic Variants, Newly Identified Molecular Characteristics, and Emerging Treatment Modalities.

Salivary duct carcinoma (SDC) is a rare, aggressive salivary gland malignancy with significant mortality. Morphologically, most tumors are characterized by apocrine differentiation with a typical immunophenotype of androgen receptor positive/gross cystic disease fluid protein positive/estrogen receptor negative/progesterone receptor negative. Several morphologic variants of SDC exist, representing diagnostic pitfalls. Several differential diagnoses should be considered because prognosis, treatment, and management may be different from SDC. For SDC, current treatment strategies are aggressive and commonly include surgical excision with lymph node dissection and adjuvant radiotherapy. Continued research is examining the utility of androgen deprivation therapy and targeted molecular therapy.

PIN-like ductal carcinoma of the prostate has frequent activating RAS/RAF mutations.

AIMS: Prostatic intraepithelial neoplasia-like (PIN-like) ductal carcinoma is a rare tumour characterised by often cystically dilated glands architecturally resembling high-grade PIN, but lacking basal cells. These tumours are frequently accompanied by grade group 1 acinar cancer and behave relatively indolently. In contrast, conventional ductal adenocarcinoma of the prostate is an aggressive variant comparable to grade group 4 acinar cancer. Here, we used targeted next-generation sequencing to molecularly profile PIN-like ductal carcinoma cases at radical prostatectomy. METHODS AND RESULTS: Five PIN-like ductal carcinoma samples at radical prostatectomy with sufficient tumour tissue available were analysed for genomic alterations by targeted next-generation sequencing using the Johns Hopkins University (JHU) solid tumour panel. DNA was captured using SureSelect for 640 genes and sequenced on the Illumina HiSeq platform. Three of five (60%) of the PIN-like ductal carcinomas showed activating mutations in the RAS/RAF pathways, which are extraordinarily rare in conventional primary prostate carcinoma (<3% of cases), including an activating hot-spot BRAF mutation (p.K601E), an activating hot-spot mutation in HRAS (p.Q61K) and an in-frame activating deletion in BRAF (p.T488_Q493delinsK). An additional two cases lacked BRAF or HRAS mutations, but harboured in-frame insertions of uncertain significance in MAP2K4 and MAP3K6. One case had sufficient acinar tumour for sequencing, and showed a similar molecular profile as the concurrent PIN-like ductal carcinoma, suggesting a clonal relationship between the two components. CONCLUSIONS: PIN-like ductal carcinoma represents a molecularly unique tumour, enriched for potentially targetable oncogenic driver mutations in the RAS/RAF/MAPK pathway. This molecular profile contrasts with that of conventional ductal adenocarcinoma, which is typically enriched for pathogenic mutations in the mismatch repair (MMR) and homologous recombination (HR) DNA repair pathways.

NR4A3 Immunohistochemistry Reliably Discriminates Acinic Cell Carcinoma from Mimics.

Acinic cell carcinoma (AciCC) harbors a recurrent t(4;9)(q13;q31) translocation, which leads to upregulation of Nuclear Receptor Subfamily 4 Group A Member 3 (NR4A3). Previous work on tissue microarrays suggests that NR4A3 immunohistochemistry (IHC) may be useful in the diagnosis of AciCC. Thus far, only a single study has evaluated the utility of NR4A3 immunohistochemistry (IHC) in the diagnosis of AciCC, using a tissue microarray to assess most non-AciCC tumor types. Herein we evaluate the diagnostic performance of NR4A3 IHC for AciCC in a large cohort of 157 salivary gland tumors, using whole tissue sections. The cohort consisted of 37 AciCC (6 of them (16%) with high grade transformation), 30 secretory carcinomas (SC), and 90 additional salivary gland tumors, including mucoepidermoid carcinomas (MEC), polymorphous adenocarcinomas (PAC), pleomorphic adenomas (PA), salivary duct carcinomas (SDC), and adenoid cystic carcinomas (AdCC). NR4A3 nuclear staining by IHC was considered positive if present in more than 5% of tumor cells. Overall, 92% of AciCC (34/37) expressed NR4A3 by IHC, with strong (89%) or moderate (3%) nuclear staining, yielding a sensitivity of 92%. IHC detected NR4A3 expression in all cases of recurrent/metastatic AciCC and tumors with high grade transformation. Importantly, all SC were negative for NR4A3 IHC, with no staining in 28/30 cases and weak focal staining, in < 5% of cells, in 2/30 (7%). Similarly, all MEC (20/20), SDC (20/20) and AdCC (10/10) were negative for NR4A3 by IHC, as were most PA (18/20; 15%) and PAC (18/20; 5%). Two PA and two PAC showed multifocal expression of NR4A3 in more than 5% of cells, of weak intensity in 3 cases and moderate in 1 PAC, yielding an overall specificity of 97% for NR4A3 IHC for the diagnosis of AciCC. In conclusion, NR4A3 is a highly sensitive and specific immunohistochemical marker for AciCC; moderate to strong and/or diffuse NR4A3 expression is a consistent and diagnostic feature of AciCC.

The significance of tyrosine kinase receptor B and brain-derived neurotrophic factor expression in salivary duct carcinoma.

Salivary duct carcinoma (SDC) is a high-grade salivary gland neoplasm. It may occur de novo or secondarily from pleomorphic adenoma (ex-PA), with secondary development accounting for more than 50% of the cases. In recent years, the expression of tyrosine kinase receptor B (TrkB), which is in the same family as HER2, has been confirmed in various types of carcinomas. However, there are a few studies on SDC. In order to examine the expression and role of TrkB in SDC, we investigated it. Immunohistochemistry was used to detect the expression of TrkB and its ligands, brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT-4) in 20 patients with SDC. The mRNA levels of TrkB, BDNF, and NT-4 were analyzed using quantitative polymerase chain reaction. TrkB was negative in 10 cases and positive in 10 cases, BDNF was negative in 11 cases and positive in 9 cases, and NT-4 was positive in all cases. There was a high number of TrkB-positive cases in the pT4 group and The H-score of TrkB was also significantly higher in the stage III and IV groups. There was a high number of BDNF-positive cases in the ex-PA group and Histo-score of BDNF had a trend of high expression in ex-PA. There were no significant differences or correlations in mRNA expression. Our results suggest that TrkB may be involved in SDC tumor growth.

Oncocytic intraductal carcinoma of salivary glands: a distinct variant with TRIM33-RET fusions and BRAF V600E mutations.

AIMS: Salivary gland intraductal carcinoma (IDC) is a complex ductal neoplasm surrounded by a layer of myoepithelial cells. Recent insights have shown that there are three different types: intercalated duct-like, with frequent NCOA4-RET fusions; apocrine, with salivary duct carcinoma-like mutations; and mixed intercalated duct-like/apocrine, with RET fusions, including TRIM27-RET. In addition, an oncocytic IDC has been described, but it remains unclear whether it represents a fourth variant or simply oncocytic metaplasia of another IDC type. Our aim was to more completely characterize oncocytic IDC. METHODS AND RESULTS: Six IDCs with oncocytic changes were retrieved from the authors' archives, from three men and three women ranging in age from 45 to 75 years (mean, 63 years). Five arose in the parotid gland, with one in an accessory parotid gland. Four patients with follow-up were free of disease after 1-23 months. Several immunostains (S100, mammaglobin, androgen receptor, and p63/p40) and molecular tools (RNA sequencing, RET fluorescence in-situ hybridisation, BRAF V600E VE1 immunohistochemistry, and Sanger sequencing) were applied. Histologically, the tumours were variably cystic with solid intracystic nodules often difficult to recognise as intraductal. In all, tumour ducts were positive for S100 and mammaglobin, negative for androgen receptor, and completely surrounded by myoepithelial cells positive for p63/p40. Molecular analysis revealed TRIM33-RET in two of six cases, NCOA4-RET in one of six cases, and BRAF V600E in two of six cases. One case had no identifiable alterations. CONCLUSIONS: Oncocytic IDC shares similarities with intercalated duct-like IDC. Although additional verification is needed, the oncocytic variant appears to be sufficiently unique to be now regarded as the fourth distinct subtype of IDC. Because of its indolent nature, oncocytic IDC should be distinguished from histological mimics.

Primary De novo ductal adenocarcinoma of the lacrimal gland.

BACKGROUND: Primary ductal adenocarcinoma of the lacrimal gland is a rare and aggressive malignant epithelial lacrimal gland neoplasm, morphologically and phenotypically resembles salivary duct carcinoma, and both strongly resemble infiltrating ductal carcinoma of breast. METHOD: Retrospective Chart review of cases of malignant lacrimal gland tumors from 2013 July to 2020 July. Authors describe the clinico radiological, morphological and immunohistochemical features of primary ductal adenocarcinoma (PDA) of lacrimal gland. Extensive review of literature of PDA of lacrimal gland and salivary gland ductal carcinoma has been performed. RESULTS: Retrospective chart review of the last 7 years yielded 22 malignant lacrimal gland neoplasms of which 4 cases demonstrated features of primary ductal adenocarcinoma of lacrimal gland, 2/4 cases showed an evidence of a pre existing pleomorphic adenoma and 2 were found to be de novo ductal adenocarcinomas. PDA of lacrimal gland showed expression of CK7, CK19, AR, HER2, cyclin D1 and were negative for CK5/14, CK 20, ER, PR, PSA, TTF-1, S-100 and SMA. Expression of GCDFP-15 was noted in one case. The presence of multiple events of loco-regional recurrences and/or distant metastasis necessitated a multidisciplinary approach. CONCLUSIONS: Authors have expressed the need of clinical correlation; thorough tissue sampling and extensive immunohistochemical work up in identification of de novo PDA's and their molecular subtypes. A multi-institutional study might help in formulating the diagnostic criteria, identification of actionable targets, and thus study the role of targeted therapy in this rare and aggressive tumor which may result in better patient outcomes.

Prognostic Significance of Tumor-infiltrating Lymphocytes on Survival Outcomes of Patients With Resected Pancreatic Ductal Adenocarcinoma: A Systematic Review and Meta-Analysis.

Tumor-infiltrating lymphocytes (TILs) play an important role in mediating treatment response in pancreatic cancer. This meta-analysis investigated the prognostic significance of TIL subsets on overall survival (OS) and disease-free survival (DFS) of patients with pancreatic cancer. Studies were gathered via search of PubMed, Google Scholar, and Cochrane Library databases up to August 1, 2019. Using Review Manager version 5.3.5, pooled hazard ratios and 95% confidence intervals (CIs) were calculated using random or fixed-effects models, depending on the heterogeneity of studies. A total of 11 studies comprising 1760 patients were included in the meta-analysis. Pooled analysis revealed that high CD8 TILs were associated with improved OS [hazard ratio (HR)=0.59, 95% CI=0.51-0.69, P<0.00001] and DFS (HR=0.60, 95% CI=0.50-0.73, P<0.00001). Similarly, high CD3 TILs correlated with better OS (HR=0.64, 95% CI=0.54-0.75, P<0.00001) and DFS (HR=0.53, 95% CI=0.31-0.92, P<0.0001). In contrast, high FoxP3 TILs were associated with worse OS (HR=1.39, 95% CI=1.03-1.88, P=0.03). Finally, high CD4 TILs showed significant improvement in OS (HR=0.74, 95% CI=0.63-0.86, P=0.0001). TILs are a promising prognostic biomarker in pancreatic cancer. Prospective studies evaluating TILs are recommended as well as the establishment of standards in the assessment of TILs.

Heat Shock Protein 90 Family Isoforms as Prognostic Biomarkers and Their Correlations with Immune Infiltration in Breast Cancer.

BACKGROUND: The heat shock protein 90 (HSP90s) family is composed of molecular chaperones composed of four isoforms in humans, which has been widely reported as unregulated in various kinds of cancers. Nevertheless, the role of each HSP90s isoform in prognosis and immune infiltration in distinct subtypes of breast cancer (BRAC) remains unclear. METHODS: Public online databases including the Oncomine, UALCAN, Kaplan-Meier Plotter, Tumor IMmune Estimation Resource (TIMER), Gene Expression Profiling Interactive Analysis (GEPIA), GeneMANIA, and Database for Annotation, Visualization, and Integrated Discovery (DAVID) were integrated to perform bioinformatic analyses and to explore the possible associations among HSP90s gene expression, prognosis, and immune infiltration in BRAC. RESULTS: The mRNA expression of all HSP90s members was elevated in distinct clinical stages and subtypes of BRAC, compared with the normal breast tissue (P < 0.05). Overexpressed HSP90AA1 was associated with poor prognosis, particularly, both short overall survival (OS) and release-free survival (RFS) in Basal-like BRAC patients; overexpressed HSP90AB1 and HSP90B1 were both associated with poor RFS in Luminal A BRAC patients, while overexpressed TRAP1 was associated with favorable RFS in Luminal A BRAC patients. Moreover, HSP90s gene expression in BRAC showed correlations with the infiltration of CD8+ T cells, neutrophils, macrophages, and dendritic cells (DCs), as well as the activation of tumor-associated macrophages (TAMs), DCs, and CD4+ helper T (Th) cells. The underlying mechanisms of HSP90s modulating tumor-infiltrating immune cells (TIICs) might be related with their functions in antigen processing and presentation, major histocompatibility complex (MHC) binding, and assisting client proteins. CONCLUSION: This study demonstrated that HSP90s family genes were overexpressed and might be serve as prognostic biomarkers in subtypes of BRAC. It might be a novel breakthrough point of BRAC treatment to regulate immune infiltration in BRAC microenvironment for more effective anticancer immunity through pharmacological intervention of HSP90s.