Tuberous sclerosis complex (TSC) is an autosomal dominant disorder with characteristic tumors involving multiple organ systems. Whereas renal angiomyolipoma (AML) is common in TSC, renal cell ...carcinoma (RCC) is rarely reported. Fifty-seven RCCs from 13 female and 5 male TSC patients were reviewed. Age at surgery ranged from 7 to 65 years (mean: 42 y). Nine patients (50%) had multiple synchronous and/or metachronous RCCs (range of 2 to 20 RCCs) and 5 had bilateral RCCs (28%). Seventeen patients (94%) had histologically confirmed concurrent renal AMLs, including 15 with multiple AMLs (88%) and 9 (50%) with AMLs with epithelial cysts. None of the 15 patients with available clinical follow-up information had evidence of distant metastatic disease from 6 to 198 months after their initial surgery (mean: 52 mo). The 57 RCCs exhibited 3 major distinct morphologies: (1) 17 RCCs (30%) had features similar to tumors previously described as "renal angiomyoadenomatous tumor" or "RCC with smooth muscle stroma"; (2) 34 RCCs (59%) showed features similar to chromophobe RCC; and (3) 6 RCCs (11%) showed a granular eosinophilic-macrocystic morphology. Distinct histologic changes were also commonly present in the background kidney parenchyma and included cysts or renal tubules lined by epithelial cells with prominent eosinophilic cytoplasm, nucleomegaly, and nucleoli. Immunohistochemically, all RCCs tested showed strong nuclear reactivity for PAX8 and HMB45 negativity. Compared with sporadic RCCs, TSC-associated RCCs have unique clinicopathologic features including female predominance, younger age at diagnosis, multiplicity, association with AMLs, 3 recurring histologic patterns, and an indolent clinical course. Awareness of the morphologic and clinicopathologic spectrum of RCC in this setting will allow surgical pathologists to better recognize clinically unsuspected TSC patients.
Noninvasive papillary urothelial carcinomas (PUCs) comprise most urinary bladder tumors. Distinction between low-grade (LG-PUC) and high-grade (HG-PUC) PUCs is pivotal for determining prognosis and ...subsequent treatment.
To investigate the histologic characteristics of tumors with borderline features between LG-PUC and HG-PUC, focusing on the risk of recurrence and progression.
We reviewed the clinicopathologic parameters of noninvasive PUC. Tumors with borderline features were subcategorized as follows: tumors that look like LG-PUC but have occasional pleomorphic nuclei (1-BORD-NUP) or elevated mitotic count (2-BORD-MIT), and tumors with side-by-side distinct LG-PUC and less than 50% HG-PUC (3-BORD-MIXED). Recurrence-free, total progression-free, and specific invasion-free survival curves were derived from the Kaplan-Meier method, and Cox regression analysis was performed.
A total of 138 patients with noninvasive PUC were included, with the following distribution: LG-PUC (n = 52; 38%), HG-PUC (n = 34; 25%), BORD-NUP (n = 21; 15%), BORD-MIT (n = 14; 10%), and BORD-MIXED (n = 17; 12%). Median (interquartile range) follow-up was 44.2 months (29.9-73.1 months). Invasion-free survival was different between the 5 groups (P = .004), and pairwise comparison showed that HG-PUC had a worse prognosis compared with LG-PUC (P ≤ .001). On univariate Cox analysis, HG-PUC and BORD-NUP were 10.5 times (95% CI, 2.3-48.3; P = .003) and 5.9 times (95% CI, 1.1-31.9; P = .04) more likely to invade, respectively, when compared to LG-PUC.
Our findings confirm a continuous spectrum of histologic changes in PUC. Approximately a third of noninvasive PUCs show borderline features between LG-PUC and HG-PUC. Compared with LG-PUC, BORD-NUP and HG-PUC were more likely to invade on follow-up. BORD-MIXED tumors did not statistically behave differently from LG-PUC.
Abstract Background Bladder cancer with divergent differentiation (BCDD) comprises a heterogenous group of tumors with a poor prognosis, and differential expression of nectin‐4 and programmed death ...ligand‐1 (PD‐L1) has been reported in BCDD. Importantly, nectin‐4 expression in bladder cancer is associated with response to enfortumab vedotin, and PD‐L1 expression is associated with responses to immune checkpoint inhibitors (ICIs). Methods The authors conducted a retrospective review identifying 117 patients with advanced or metastatic BCDD who were treated at Winship Cancer Institute from 2011 to 2021. They performed immunohistochemistry staining for nectin‐4 and PD‐L1 expression by histologic subtype as well as genomic analysis of these patients, including RNA sequencing, whole‐exome sequencing, and fusion detection analysis as well as a subgroup genomic analysis of patients with BCDD who received ICIs. Results The results indicated that nectin‐4 expression was highest in the groups who had the squamous and plasmacytoid subtypes, whereas the group that had the sarcomatoid subtype (70.8%) had the highest proportion of PD‐L1–positive patients. Genomic analysis yielded several key findings, including a 50% RB1 mutation rate in patients who had small cell BCDD, targetable PIK3CA mutations across multiple subtypes of BCDD, and significantly higher expression of TEC in responders to ICIs. Conclusions In this study, the authors identified clinically relevant data on nectin‐4 and PD‐L1 expression in patients with rare bladder tumors. They also identified several novel findings in the genomic analysis that highlight the role of precision medicine in this population of patients. Larger, prospective studies are needed to validate these hypothesis‐generating data.
In this study, the authors performed a retrospective analysis focused on the histologic and genomic characterization of bladder cancer with divergent differentiation. The results indicated that nectin‐4 expression was highest in patients with squamous and plasmacytoid differentiation, whereas patients who had sarcomatoid differentiation (70.8%) had the highest proportion of programmed death ligand‐1–positive disease, and several novel findings were identified in the genomic analysis that have potential clinical implications for these patients with rare tumors.
Solitary fibrous tumour (SFT) is a mesenchymal neoplasm with variable behaviour, very rarely involving the genitourinary (GU) tract. Most reported cases correspond to isolated case reports. STAT6 ...immunohistochemistry is a more recent and reliable diagnostic marker. The pathology database of two tertiary institutes was searched for SFTs involving the GU tract. STAT6 strong diffuse nuclear staining confirmed the diagnosis in all four cases, and the
NAB2::STAT6
fusion was demonstrated by NGS in one case. Two cases were diagnosed in needle biopsy, one involving the prostate and the other involving the seminal vesicle. One case corresponded to a pelvic mass inseparable from and infiltrating the prostate and bladder. The remainder represented an exceedingly rare involvement of the spermatic cord. Involvement by a SFT should be considered in the differential diagnosis of spindle cell lesions involving GU organs. STAT6 strong diffuse nuclear staining is an important ancillary tool, particularly in a biopsy.
Extrarenal clear cell renal cell carcinoma (eccRCC) is a rare type of RCC that arises in areas other than the kidney. Given its rarity, consensus guidelines for optimal treatment of eccRCC have not ...been established, and the literature is lacking any reports of patient response to systemic therapy and any reports of administration of immunotherapy to patients with ecRCC. Here, we present the case of a patient in their 60s with eccRCC arising in the spleen. The patient underwent splenic resection and then received systemic therapy, due to disease recurrence, with a combination of immunotherapy (IO) and tyrosine kinase inhibitor targeted therapy (VEGF-TKI). The patient had an excellent and durable response to this therapeutic regimen with minimal adverse effects, completing 2 years of therapy of nivolumab and cabozantinib. At the time of this report, the disease remains stable. This case demonstrates that combination therapy with IO+VEGF-TKI represents a reasonable and well-tolerated treatment option with activity in eccRCC and reveals interesting correlative data, including nests of stem-like CD8+T-cell infiltration in tumor tissue, which provide important biological context to this patient's exceptional therapeutic response.
Aims
The distinction of high‐grade prostate cancer (PCa) from poorly differentiated urothelial carcinoma (UC) can be somewhat challenging on clinical and morphological grounds alone, yet it is of ...great importance for prognostication and choice of treatment. GATA3 is a useful immunohistochemical marker to confirm urothelial origin. However, recent works report strong GATA3 immunoexpression in primary high‐grade PCa. The aim of this study was to explore GATA3 expression specifically in metastatic PCa.
Methods and results
The pathology databases of four tertiary institutions were queried for cases of metastatic PCa. Available slides and clinical records were reviewed by experienced genitourinary pathologists. Prostatic markers (PSA, PSAP, NKX3.1) and GATA3 immunohistochemistry were performed. A total of 163 metastatic PCa cases were included. At least one prostate marker was positive in each case of non‐regional distant metastasis, confirming prostatic origin. GATA3 strong staining was found in four (2.5%) cases: two liver, one bone and one non‐regional lymph‐node metastases. All four patients had Grade Group 5 PCa at the initial diagnosis. The metastatic prostatic adenocarcinomas were solid, either with no gland formation (n = 3) or with only focal cribriforming (n = 1).
Conclusions
To our knowledge, this is the first study exploring GATA3 expression specifically in metastatic PCa. Despite being infrequent, GATA3 positivity in high‐grade PCa may lead to misdiagnosis, with clinical implications. We recommend a panel of immunohistochemical markers, both prostatic and urothelial, for ruling out UC, either in primary tumour samples or in the event of metastases of unknown primary, when a genitourinary origin is suspected.
Accurate discrimination of metastatic prostate cancer from urothelial cancer is important for prognostication and therapy. GATA3 positivity occurred in 2.5% of metastatic prostate cancer cases (all being predominantly solid), constituting an important pitfall. Combined panels of immunohistochemistry (prostatic and urothelial markers) are recommended for accurate diagnosis.
Genetic profiling data of prostatic adenocarcinoma are derived from predominantly White patients. In African Americans, prostatic adenocarcinoma has a poorer prognosis, raising the possibility of ...distinct genetic alterations.
To investigate the genomic alterations of prostatic adenocarcinoma metastatic to regional lymph nodes in African American patients, with an emphasis on SPOP mutation.
We retrospectively reviewed African American patients with pN1 prostatic adenocarcinoma managed with radical prostatectomy and lymph node dissection. Comprehensive molecular profiling was performed, and androgen receptor signaling scores were calculated.
Nineteen patients were included. The most frequent genetic alteration was SPOP mutations (5 of 17; 29.4% 95% CI: 10.3-56.0). While most alterations were associated with a high androgen receptor signaling score, mutant SPOP was exclusively associated with a low median and interquartile range (IQR) androgen receptor signaling score (0.788 IQR 0.765-0.791 versus 0.835 IQR 0.828-0.842, P = .003). In mutant SPOP, mRNA expression of SPOP inhibitor G3BP1 and SPOP substrates showed a significantly decreased expression of AR (33.40 IQR 28.45-36.30 versus 59.53 IQR 53.10-72.83, P = .01), TRIM24 (3.95 IQR 3.28-5.03 versus 9.80 IQR 7.39-11.70, P = .008), and NCOA3 (15.19 IQR 10.59-15.93 versus 21.88 IQR 18.41-28.33, P = .046).
African American patients with metastatic prostate adenocarcinoma might have a higher prevalence of mutant SPOP (30%), compared to ∼10% in unselected cohorts with lower expressions of SPOP substrates. In our study, in patients with mutant SPOP, the mutation was associated with decreased SPOP substrate expression and androgen receptor signaling, raising concern for suboptimal efficacy of androgen deprivation therapy in this subset of patients.
The pathologic nodal staging of prostatic adenocarcinoma is binary for regional lymph nodes. Stages pN0 and pN1 indicate the absence or presence of regional nodal metastasis, respectively, whereas ...patients with metastasis to nonregional lymph nodes are staged as pM1a.
To determine the risk of recurrence of pN1 prostatic adenocarcinoma patients based on the extent of nodal tumor burden.
We retrospectively reviewed pN1 patients with prostatic adenocarcinoma managed with radical prostatectomy seen between 2011 and 2019. Kaplan-Meier and Cox regression analyses were performed to compare disease-free survival.
Ninety-six patients were included (median interquartile range age, 62 years 57-67 years; 70 of 96 73% white). On univariate analysis, age >65 years (P = .008), ≥2 positive regional lymph nodes (P < .001), and a maximum size of the tumor deposit ≥2 mm (P = .004) were significantly associated with an unfavorable outcome. Controlling for age, stage, metastatic deposit size, margin status, and the presence of extranodal extension, patients with ≥2 positive regional lymph nodes were 3.03 times more likely (95% confidence interval, 1.39-6.60; P = .005) to have an unfavorable outcome. Patients with pN1M1a stage showed a disease-free survival similar to that of pN1M0 patients, after controlling for the number of positive regional lymph nodes (P = .36).
Overall, pN1 patients with ≥2 positive regional lymph nodes are 3 times more likely to have an unfavorable outcome. The results suggest a benefit in further stratifying patients with metastatic prostatic adenocarcinoma to the lymph nodes into prognostically significant risk categories that could help the treating clinicians tailor subsequent patient follow-up and therapy.
Recent data suggests that HER2-targeted treatment is efficacious in urothelial carcinoma (UC). We investigated the genomic, transcriptomic, and immune landscapes and clinical outcomes in UC segmented ...by
expression.
NextGen DNA/RNA sequencing was performed for 4743 UC tumors. A total of 3% (124/4125) of tumors had HER2 IHC and whole transcriptome sequencing (WTS) data.
-high and -low tumors were defined by ≥75th and <25th percentiles of
expression, respectively. PD-L1 (SP142) positive staining was defined as ≥2+ and ≥5%. HER2 (4B5) positive staining was defined as ≥3+ and >10% or 2+ and >10% with positive HER2 in situ hybridization (ISH).
Of the patients who were
-high, 79% (61/77) were HER2 positive via IHC. Tumors from lower tract UC had higher
expression compared to upper tract UC (50 v 40 median TPM (mTPM),
< 0.001).
expression was similar between primary and metastatic tumors (47 v 47 mTPM,
= 0.95).
-high tumors had a higher prevalence of pathogenic mutations in
,
, and
versus
-low tumors,
< 0.001.
-high tumors had higher expressions of ADC target genes
(12 v 8 mTPM) and
(366 v 74 mTPM) versus
-low (
< 0.001), as well as better overall survival from time of tissue sampling than
-low (HR 1.71,
< 0.001).
Our study demonstrated a high concordance between HER2 expression by IHC and
gene expression by WTS in UC. Differences in ADC target expression between
-high vs.
-low UC may provide a rationale for combination treatment strategies with HER2-ADC. The association between high
expression and survival advantage warrants further investigation.
Most (up to 71%) of renal cell neoplasms occurring in patients with end-stage renal disease (ESRD), particularly with acquired cystic disease of the kidney (ACDK), have been reported to be papillary ...renal cell carcinoma (RCC). Our initial experience with tumors in such a setting indicated that many tumors were histologically difficult to classify into the known subtypes of RCC or had features that were different from those in sporadically occurring RCCs. In this study on 66 ESRD kidneys (52 of which showed features of ACDK) removed because tumors were detected in them, we found two major groups of RCC. Overall, there were 261 grossly identified tumors in these kidneys, and many additional tumors were observed on microscopic evaluation in some. Of the two major groups of RCCs, one consisted of tumors similar to those seen in sporadic settings (ie, clear-cell, papillary, and chromophobe RCC), and these formed the dominant mass in 12 (18%), 10 (15%), and 5 (8%) of the 66 kidneys, respectively. The other group consisted of two subtypes of RCC that appear quite unique to ESRD. The more common tumor that we have designated as "acquired cystic disease-associated RCC" was seen as the dominant mass in 24 (36%) of 66 of the kidneys, and it formed the most common tumor type among the smaller nondominant masses, as well. It was characterized by a typical microcystic architecture, eosinophilic cytoplasm with Fuhrman's grade 3 nuclei, and frequent association with intratumoral oxalate crystals. Additionally, these tumors frequently, but usually focally, exhibited papillary architecture, and clear cytoplasm. These tumors occurred only in kidneys with ACDK, and not in noncystic ESRD. The other category was "clear-cell papillary RCC of the end-stage kidneys," present as the dominant mass in 15 (23%) of the 66 kidneys and occurring in both the ACDK and noncystic ESRD. These predominantly cystic tumors showed prominent papillary architecture with purely clear-cell cytology. Immunohistochemical studies in tumors with histology similar to the known subtypes of sporadic RCC showed immunoprofiles similar to that reported in sporadically occurring tumors. The two subtypes of RCC unique to ESRD had distinctive immunoprofiles supporting their separate morphologic subcategorization. Only the acquired cystic disease-associated RCC showed lymph node metastases in 2 cases and sarcomatoid features in 2 more cases. One of the latter 2 died with widespread metastatic disease within 34 months of nephrectomy. Thus, a broad spectrum of renal cell tumors exist in ESRD, only some of which resemble the sporadic RCCs. Acquired cystic disease-associated RCC is the commonest tumor subtype in ESRD, and biologically it appears to be more aggressive than the other tumor subtypes in ESRD.
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