Basaloid salivary gland neoplasms are a diverse and varied group of benign and malignant tumors. The term ‘basaloid’ is broadly used in reference to cells with elevated nuclear to cytoplasmic ratio, ...sparse cytoplasm, and hyperchromatic nuclei. However, a subset may also fit within the “small round blue cell tumor” morphologic category or the “biphasic” salivary gland tumor category. Furthermore, there are no established thresholds for the proportion of basaloid tumor cells needed to consider a tumor within the basaloid spectrum. Given the implicit variability in what is considered a basaloid salivary gland tumor, one may question the inclusion of certain entities (canalicular adenoma, HMGA2::WIF1 pleomorphic adenoma, polymorphous adenocarcinoma) in this review based on classic morphologic features. However, salivary gland tumors with even minor basaloid components may appear ‘basaloid’ in small biopsy specimens and, thus, a choice was made to focus on common and uncommon diagnostic differentials with this in mind.
Entities that will be covered in this review also include basal cell adenoma and basal cell adenocarcinoma, adenoid cystic carcinoma, lymphoepithelial carcinoma, sialoblastoma, adamantinoma-like Ewing Sarcoma, NUT carcinoma, and carcinoma showing thymus-like differentiation.
With the advent of precision oncology, there is an urgent need to develop improved methods for rapidly detecting responses to targeted therapies. Here, we have developed an ultrasensitive measure of ...cell-free tumor load using targeted and whole-genome sequencing approaches to assess responses to tyrosine kinase inhibitors in patients with advanced lung cancer. Analyses of 28 patients treated with anti-EGFR or HER2 therapies revealed a bimodal distribution of cell-free circulating tumor DNA (ctDNA) after therapy initiation, with molecular responders having nearly complete elimination of ctDNA (>98%). Molecular nonresponders displayed limited changes in ctDNA levels posttreatment and experienced significantly shorter progression-free survival (median 1.6 vs. 13.7 months,
< 0.0001; HR = 66.6; 95% confidence interval, 13.0-341.7), which was detected on average 4 weeks earlier than CT imaging. ctDNA analyses of patients with radiographic stable or nonmeasurable disease improved prediction of clinical outcome compared with CT imaging. These analyses provide a rapid approach for evaluating therapeutic response to targeted therapies and have important implications for the management of patients with cancer and the development of new therapeutics.
Cell-free tumor load provides a novel approach for evaluating longitudinal changes in ctDNA during systemic treatment with tyrosine kinase inhibitors and serves an unmet clinical need for real-time, noninvasive detection of tumor response to targeted therapies before radiographic assessment.
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Human papillomavirus (HPV)-independent primary endometrial squamous cell carcinoma (PESCC) is a rare but aggressive subtype of endometrial carcinoma for which little is known about the genomic ...characteristics. Traditional criteria have restricted the diagnosis of PESCC to cases without any cervical involvement. However, given that modern ancillary techniques can detect HPV and characteristic genetic alterations that should identify the more common mimics in the differential diagnosis, including endometrial endometrioid carcinoma with extensive squamous differentiation and HPV-associated primary cervical squamous cell carcinoma, those criteria may benefit from revision. To further characterize PESCC, we identified 5 cases of pure squamous cell carcinoma dominantly involving the endometrium that had the potential to be PESCC: 1 case involving only the endometrium and 4 cases with some involvement of the cervix. Clinicopathologic features were assessed and immunohistochemical analysis (p16, estrogen receptor, progesterone receptor, and p53), HPV RNA in situ hybridization (high-risk and low-risk cocktails and targeted probes for 16 and 18), and molecular studies were performed. All tumors showed aberrant/mutation-type p53 expression, were negative for estrogen receptor, progesterone receptor, and p16, and had no detectable HPV. Per whole-exome sequencing, 4 of the 5 tumors demonstrated comutations in TP53 and CDKN2A (p16). Four patients died of disease within 20 months (range, 1 to 20 mo; mean, 9 mo), and 1 patient had no evidence of disease at 38 months. PESCC represents a unique, clinically aggressive subtype of endometrial cancer with TP53 and CDKN2A comutations. This characteristic profile, which is similar to HPV-independent squamous cell carcinoma of the vulva, is distinct from endometrioid carcinoma with extensive squamous differentiation and HPV-associated primary cervical squamous cell carcinoma and can be used to distinguish PESCC from those mimics even when cervical involvement is present. Diagnostic criteria for PESCC should be relaxed to allow for cervical involvement when other pathologic features are consistent with, and ancillary techniques are supportive of classification as such.
We report a novel NIPBL-NACC1 gene fusion in a rare primary hepatic neoplasm previously described as the "cholangioblastic variant of intrahepatic cholangiocarcinoma." The 2 index cases were ...identified within our consultation files as morphologically distinctive primary hepatic neoplasms in a 24-year-old female and a 54-year-old male. The neoplasms each demonstrated varied architecture, including trabecular, organoid, microcystic/follicular, and infiltrative glandular patterns, and biphasic cytology with large, polygonal eosinophilic cells and smaller basophilic cells. The neoplasms had a distinctive immunoprofile characterized by diffuse labeling for inhibin, and patchy labeling for neuroendocrine markers (chromogranin and synaptophysin) and biliary marker cytokeratin 19. RNA sequencing of both cases demonstrated an identical fusion of NIBPL exon 8 to NACC1 exon 2, which was further confirmed by break-apart fluorescence in situ hybridization assay for each gene. Review of a tissue microarray including 123 cases originally diagnosed as well-differentiated neuroendocrine neoplasm at one of our hospitals resulted in identification of a third case with similar morphology and immunophenotype in a 52-year-old male, and break-apart fluorescence in situ hybridization probes confirmed rearrangement of both NIPBL and NACC1. Review of The Cancer Genome Atlas (TCGA) sequencing data and digital images from 36 intrahepatic cholangiocarcinomas (http://www.cbioportal.org) revealed one additional case with the same gene fusion and the same characteristic solid, trabecular, and follicular/microcystic architectures and biphasic cytology as seen in our genetically confirmed cases. The NIPBL-NACC1 fusion represents the third type of gene fusion identified in intrahepatic cholangiocarcinoma, and correlates with a distinctive morphology described herein.
Eosinophilic solid and cystic (ESC) renal cell carcinoma (RCC) has recently been described as a potentially new subtype of RCC based upon morphologic and immunohistochemical features. These neoplasms ...typically demonstrate solid and cystic architecture, and the neoplastic cells contain voluminous eosinophilic cytoplasm with granular cytoplasmic stippling. There is frequently focal immunoreactivity for cytokeratin 20. Although the initial cases all occurred in adult females and had benign outcome, we recently expanded the proposed spectrum of this neoplasm to include pediatric cases, multifocal neoplasms, and a case with hematogenous metastasis. ESC has been postulated to be analogous to a subtype of RCC consistently identified in tuberous sclerosis complex patients, and while previous work has demonstrated loss of heterozygosity at the TSC1 locus and copy number gains at TSC2 in ESC RCC, these genes have not been sequenced in ESC RCC. Using capture-based and amplicon-based next-generation sequencing, we now demonstrate the consistent presence of either TSC1 or TSC2 gene mutations in pediatric ESC RCC (8/9 cases) and adult ESC RCC (6/6 cases). These included a metastatic ESC RCC which had a complete response to mTOR targeted therapy. We also found these mutations in some neoplasms with variant morphology and thus potentially expand the spectrum of ESC RCC. These include one of our adult cases which demonstrated dominant “type 2” papillary RCC morphology and 2 of 3 previously unclassified pediatric RCC with features of ESC RCC minus granular cytoplasmic stippling. We also demonstrate TSC mutations in a case of so-called “oncocytoid RCC after neuroblastoma” with identical morphology and immunoprofile, providing a molecular link between the latter and ESC RCC. In summary, ESC RCC consistently harbors actionable TSC1 or TSC2 mutations, which are infrequently seen in established subtypes of RCC. These findings support TSC1/2 mutation as a molecular marker of ESC RCC, and suggest expansion of the clinicopathologic spectrum to include neoplasms with papillary architecture, occasional cases lacking well-developed granular cytoplasmic stippling, and a subset of RCC with oncocytic features in patients who have survived neuroblastoma.
A novel DEK-AFF2 fusion was recently reported in 4 nonkeratinizing squamous cell carcinomas of the sinonasal region and skull base, including 1 with exceptional response to immunotherapy, but it is ...not yet clear if this rearrangement defines a unique clinicopathologic category or represents a rare event. This study aims to characterize a larger cohort of carcinomas with DEK-AFF2 fusions to assess whether they truly constitute a distinctive entity. Among 27 sinonasal and skull base nonkeratinizing squamous cell carcinoma that were negative for human papillomavirus and Epstein-Barr virus, RNA sequencing identified DEK-AFF2 fusions in 13 cases (48%). Nine were centered in the nasal cavity, 2 in the middle ear/temporal bone, 1 in the nasopharynx, and 1 in the orbit. These tumors displayed recurrent histologic features including (1) complex endophytic and exophytic, frequently papilloma-like growth, (2) transitional epithelium with eosinophilic to amphophilic cytoplasm, (3) absent or minimal keratinization with occasional compact keratin pearls, (4) monotonous nuclei, and (5) prominent tumor-infiltrating neutrophils or stromal lymphocytes. This appearance not only overlaps with high-grade basaloid sinonasal carcinomas but also with benign papillomas and tumors reported as low-grade papillary Schneiderian carcinoma. However, DEK-AFF2 carcinomas showed frequent local recurrence, cervical lymph node metastases, and distant metastasis with 2 deaths from disease, confirming they are aggressive malignancies despite relatively bland histology. Overall, the distinctive molecular, histologic, and clinical features of DEK-AFF2 carcinomas suggest they represent a unique entity in the sinonasal region. This tumor merits increased pathologic recognition to better understand its prognostic and therapeutic implications.
Antibodies targeting the programmed cell death protein 1/programmed death-ligand 1 (PD-L1) interaction have shown clinical activity in multiple cancer types. PD-L1 protein expression is a clinically ...validated predictive biomarker of response for such therapies. Prior studies evaluating the expression of PD-L1 in primary prostate cancers have reported highly variable rates of PD-L1 positivity. In addition, limited data exist on PD-L1 expression in metastatic castrate-resistant prostate cancer (mCRPC). Here, we determined PD-L1 protein expression by immunohistochemistry using a validated PD-L1–specific antibody (SP263) in a large and representative cohort of primary prostate cancers and prostate cancer metastases. The study included 539 primary prostate cancers comprising 508 acinar adenocarcinomas, 24 prostatic duct adenocarcinomas, 7 small-cell carcinomas, and a total of 57 cases of mCRPC. PD-L1 positivity was low in primary acinar adenocarcinoma, with only 7.7% of cases showing detectable PD-L1 staining. Increased levels of PD-L1 expression were noted in 42.9% of small-cell carcinomas. In mCRPC, 31.6% of cases showed PD-L1–specific immunoreactivity. In conclusion, in this comprehensive evaluation of PD-L1 expression in prostate cancer, PD-L1 expression is rare in primary prostate cancers, but increased rates of PD-L1 positivity were observed in mCRPC. These results will be important for the future clinical development of programmed cell death protein 1/PD-L1–targeting therapies in prostate cancer.
Locally relapsed prostate cancer (PCa) after radiation therapy (RT) is associated with substantial morbidity and mortality. Morphological and molecular consequences that may contribute to RT ...resistance and local recurrence remain poorly understood. Locally recurrent PCa tissue from 53 patients with clinically localized PCa who failed with primary RT and subsequently underwent salvage radical prostatectomy (RP) was analyzed for tumor focality, clinicopathological, molecular, and genomic characteristics. Targeted next-generation sequencing with full exon coverage of 1,425 cancer-related genes was performed on 10 representative radiorecurrent PCas exhibiting no RT effect with matched adjacent benign prostate tissue. At RP, 37 (70%) of PCas had no RT effect with the following characteristics: grade group (GG) ≥ 3 (70%), unifocal tumor (75%), extraprostatic disease (78%), lymph node metastasis (8%), and “cribriform” morphologies (84%) cribriform PCa (78%) or intraductal carcinoma (IDC-P) (61%) at a median percentage of approximately 80% of tumor volume. In the setting of multifocal tumors (25%) at RP, the cribriform morphologies were restricted to index tumors. Of 32 patients with available pre-RT biopsy information, 16 had GG1 PCa, none had cribriform morphologies at baseline but 81% demonstrated cribriform morphologies at RP. Notable alterations detected in the sequenced tumors included: defects in DNA damage response and repair (DDR) genes (70%) (TP53, BRCA2, PALB2, ATR, POLQ), PTEN loss (50%), loss of 8p (80%), and gain of MYC (70%). The median tumor mutational burden was 4.18 mutations/Mb with a range of 2.16 to 31.86. Our findings suggest that most radiorecurrent PCas are enriched in cribriform morphologies with potentially targetable genomic alterations. Understanding this phenotypic and genotypic diversity of radiorecurrent PCa is critically important to facilitate optimal patient management.
We report 8 cases of a distinctive, previously undescribed renal cell carcinoma associated with somatic mutations in the neurofibromin 2 (NF2) gene. All patients were adults, ranging from 51 to 78 ...years of age and of cases of known sex 6 of 7 were males. The carcinomas were predominantly unencapsulated, and all had a rounded, nodular interface with the native kidney. The neoplasms were all solid with papillary architecture evident in most cases (7/8), while 1 was only tubular. All cases were biphasic, characterized by larger and smaller carcinoma cells. The smaller cells clustered around basement membrane material similar to the characteristic pattern of the t(6;11) renal cell carcinoma associated with TFEB gene fusions. In 6 of 8 carcinomas, branching nodules of small cells clustered around basement membrane material within larger acini yielding a distinctive glomeruloid pattern. In 6 of 8 carcinomas, the small cells were focally spindle-shaped and unassociated with the basement membrane material. The stroma was sclerotic in all 8 carcinomas, and all 8 contained psammoma bodies that were abundant in 2. In some carcinomas, focal or predominant areas had a less distinctive appearance; 2 had areas that resembled clear cell renal cell carcinoma, 2 had high-grade eosinophilic areas, while 1 had branching tubular architecture that resembled mucinous tubular and spindle cell carcinoma. Two carcinomas demonstrated cellular necrosis. Although we have minimal clinical follow-up, 1 case presented with distant metastasis, progressed and resulted in patient death. While NF2 mutations may be found in other established renal cell carcinoma subtypes (often as secondary genetic alterations), they are potentially the genetic driver of this distinctive entity.
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