RESUMEN
a-Methylacyl coenzyme A racemase (AMACR) is traditionally considered to be a marker of papillary renal cell carcinoma. However, AMACR expression can be seen in other renal tumors. The aim of this study was to investigate AMACR immunoreactivity within the spectrum of clear cell renal cell neoplasms. Fifty-three clear cell renal epithelial tumors were used in assembling the following four cohorts: low grade (LG) clear cell renal cell carcinoma (CCRCC), high grade (HG) CCRCC, CCRCC with cystic changes, and multilocular cystic renal neoplasm of low malignant potential (MCRNLMP). Representative blocks were stained for AMACR, using two different clones (SP52 and OV-TL12/30). There were at least some AMACR immunoreactivity in 77.8 % and 68.9 % of CCRCCs (using SP52 and OV-TL12/30 clone, respectively). Moderate to strong positivity, or positivity in more than one third of the tumor (even weak in intensity) was detected in 46.7 % of CCRCCs using SP52 and in 48.9 % of CCRCC using OV-TL12/30 clone. The highest AMACR reactivity was observed in HG CCRCC (60 % by SP52 and 66.7 % by OV-TL12/30). Strong and diffuse AMACR positivity was detected in 8.9 % of all CCRCCs. AMACR immunoreactivity in MCRNLMP was 37.5 % (SP52 clone) and 25 % (OV-TL12/30 clone). We demonstrated relatively high expression rate of AMACR in CCRCC, while very variable in intensity and distribution. This finding may have diagnostic implications especially in limited samples (i.e., core biopsies), as AMACR positivity does not exclude the diagnosis of CCRCC.
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Biomarcadores de Tumor , Carcinoma de Células Renales , Neoplasias Renales , Racemasas y Epimerasas , Racemasas y Epimerasas/metabolismo , Humanos , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/diagnóstico , Neoplasias Renales/patología , Neoplasias Renales/metabolismo , Neoplasias Renales/diagnóstico , Biomarcadores de Tumor/metabolismo , Inmunohistoquímica/métodos , Masculino , Femenino , Persona de Mediana Edad , AncianoRESUMEN
AIMS: Renal cell carcinoma (RCC) with clear cells and psammoma-like calcifications would often raise suspicion for MITF family translocation RCC. However, we have rarely encountered tumours consistent with clear cell RCC that contain focal psammomatous calcifications. METHODS AND RESULTS: We identified clear cell RCCs with psammomatous calcifications from multiple institutions and performed immunohistochemistry and fluorescence and RNA in-situ hybridisation (FISH and RNA ISH). Twenty-one tumours were identified: 12 men, nine women, aged 45-83 years. Tumour size was 2.3-14.0 cm (median = 6.75 cm). Nucleolar grade was 3 (n = 14), 2 (n = 4) or 4 (n = 3). In addition to clear cell pattern, morphology included eosinophilic (n = 12), syncytial giant cell (n = 4), rhabdoid (n = 2), branched glandular (n = 1), early spindle cell (n = 1) and poorly differentiated components (n = 1). Labelling for CA9 was usually 80-100% of the tumour cells (n = 17 of 21), but was sometimes decreased in areas of eosinophilic cells (n = 4). All (19 of 19) were positive for CD10. Most (19 of 20) were positive for AMACR (variable staining = 20-100%). Staining was negative for keratin 7, although four showed rare positive cells (four of 20). Results were negative for cathepsin K (none of 19), melan A (none of 17), HMB45 (none of 17), TFE3 (none of 5), TRIM63 RNA ISH (none of 13), and TFE3 (none of 19) and TFEB rearrangements (none of 12). Seven of 19 (37%) showed chromosome 3p deletion. One (one of 19) showed trisomy 7 and 17 without papillary features. CONCLUSIONS: Psammomatous calcifications in RCC with a clear cell pattern suggests a diagnosis of MITF family translocation RCC; however, psammomatous calcifications can rarely be found in true clear cell RCC.
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Calcinosis , Carcinoma de Células Renales , Neoplasias Renales , Femenino , Humanos , Carcinoma de Células Renales/patología , Neoplasias Renales/patología , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Translocación Genética , Aberraciones Cromosómicas , Biomarcadores de Tumor/genéticaRESUMEN
Low-grade oncocytic tumour (LOT) of the kidney has recently emerged as a potential novel tumour type. Despite similarity to oncocytoma or eosinophilic chromophobe renal cell carcinoma, it shows diffuse keratin 7 immunohistochemistry (IHC) and negative KIT (CD117), which differs from both. We aimed to identify the molecular characteristics of these tumours. Seventeen tumours (one male, 16 female, nine previously published) fitting the original description of this entity (solid eosinophilic cell morphology, often with areas of tumour cells loosely stretched in oedematous stroma, and the above IHC features) were analysed with a next-generation sequencing panel of 324 cancer-associated genes from formalin-fixed, paraffin-embedded tissue. All tumours harboured at least one alteration in either TSC1 (n = 7, 41%), TSC2 (n = 2, 12%), MTOR (n = 5, 29%) or PIK3CA (n = 4, 24%). Four tumours harboured a second alteration, including two NF2, one each in conjunction with MTOR and TSC2 alterations, one PTEN with TSC1 alteration and one tumour with both MTOR and TSC1 alterations. No other renal cancer-related or recurring gene alterations were identified. In addition to the previously described IHC findings, 16 of 16 were positive for GATA3. Eleven patients with follow-up had no metastases or recurrent tumours. Recurrent tuberous sclerosis/MTOR pathway gene alterations in LOT support its consideration as a distinct morphological, immunohistochemical and genetic entity. PIK3CA is another pathway member that may be altered in these tumours. Further study will be necessary to determine whether tumour behaviour or syndromic associations differ from those of oncocytoma and chromophobe carcinoma, warranting different clinical consideration.
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Adenoma Oxifílico , Carcinoma de Células Renales , Neoplasias Renales , Humanos , Masculino , Femenino , Recurrencia Local de Neoplasia , Carcinoma de Células Renales/genética , Neoplasias Renales/genética , Mutación , Adenoma Oxifílico/genética , Riñón , Serina-Treonina Quinasas TOR/genética , Factor de Transcripción GATA3/genética , Fosfatidilinositol 3-Quinasa Clase I/genéticaRESUMEN
Background/Objective: Hormone receptor (HR) status is one of the key factors in determining the treatment of breast cancer. Previous studies suggested that HR status may change in metastatic tissue. However, available studies focused mainly on primary biopsies and there are only few trials comparing HR status in the primary tumour and the metastasis using material from complete resection. The aim of the study was to determine the frequency of HR alterations in metastatic breast cancer. Materials and methods: The study retrospectively examines a total of 50 patients who underwent brain, lung, or liver metastasectomy for metastatic breast cancer between January 2000 and January 2019. Results: HR conversion was observed in a total of 30 cases (60.0%), while HER-2/neu (human epidermal growth factor receptor 2) discrepancy surprisingly occurred only in one case (2.0%). A change in immunophenotype occurred in 28% of cases. Triple-negativity was more frequent in brain metastases (p = 0.039). Conclusions: We have confirmed that HR conversion between the primary tumour and its metastases occurs in a significant number of cases, which has important implications for further treatment decisions.
RESUMEN
The category of "oncocytic renal tumors'' includes well-recognized entities, such as renal oncocytoma (RO) and eosinophilic variant of chromophobe renal cell carcinoma (eo-ChRCC), as well as a group of "gray zone" oncocytic tumors, with overlapping features between RO and eo-ChRCC that create ongoing diagnostic and classification problems. These types of renal tumors were designated in the past as "hybrid oncocytoma-chromophobe tumors". In a recent update, the Genitourinary Pathology Society (GUPS) proposed the term "oncocytic renal neoplasm of low malignant potential, not further classified", for such solitary and sporadic, somewhat heterogeneous, but relatively indolent tumors, with equivocal RO/eo-ChRCC features. GUPS also proposed that the term "hybrid oncocytic tumor" be reserved for tumors found in a hereditary setting, typically arising as bilateral and multifocal ones (as in Birt-Hogg-Dubé syndrome). More recent developments in the "gray zone" of oncocytic renal tumors revealed that potentially distinct entities may have been "hidden" in this group. Recent studies distinguished two new entities: "Eosinophilic Vacuolated Tumor" (EVT) and "Low-grade Oncocytic Tumor" (LOT). The rapidly accumulated evidence on EVT and LOT has validated the initial findings and has expanded the knowledge on these entities. Both are uniformly benign and are typically found in a sporadic setting, but rarely can be found in patients with tuberous sclerosis complex. Both have readily distinguishable morphologic and immunohistochemical features that separate them from similar renal tumors, without a need for detailed molecular studies. These tumors very frequently harbor TSC/MTOR mutations that are however neither specific nor restricted to these two entities. In this review, we outline a proposal for a working framework on how to classify such low-grade oncocytic renal tumors. We believe that such framework will facilitate their handling in practice and will stimulate further discussions and studies to fully elucidate their spectrum.
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Adenoma Oxifílico , Carcinoma de Células Renales , Neoplasias Renales , Adenoma Oxifílico/patología , Biomarcadores de Tumor/genética , Carcinoma de Células Renales/genética , Humanos , Riñón/patología , Neoplasias Renales/genéticaRESUMEN
We evaluated the clinicopathologic and molecular characteristics of mostly incidentally detected, small, papillary renal neoplasms with reverse polarity (PRNRP). The cohort comprised 50 PRNRP from 46 patients, divided into 2 groups. The clinically undetected (<5 mm) neoplasms (n = 34; 68%) had a median size of 1.1 mm (range 0.2-4.3 mm; mean 1.4 mm), and the clinically detected (≥5 mm) neoplasms (n = 16; 32%) which had a median size of 13 mm (range 9-30 mm; mean 16 mm). Neoplasms were positive for GATA3 (n = 47; 100%) and L1CAM (n = 34/38; 89%) and were negative for vimentin (n = 0/44; 0%) and, to a lesser extent, AMACR [(n = 12/46; 26%; weak = 9, weak/moderate = 3)]. KRAS mutations were found in 44% (n = 15/34) of the clinically undetected PRNRP and 88% of the clinically detected PRNRP (n = 14/16). The two clinically detected PRNRP with wild-type KRAS gene were markedly cystic and contained microscopic intracystic tumors. In the clinically undetected PRNRP, the detected KRAS mutations rate was higher in those measuring ≥1 mm vs <1 mm [n = 14/19 (74%) vs n = 1/15 (7%)]. Overall, the KRAS mutations were present in exon 2-codon 12: c.35 G > T (n = 21), c.34 G > T (n = 3), c.35 G > A (n = 2), c.34 G > C (n = 2) resulting in p.Gly12Val, p. Gly12Asp, p.Gly12Cys and p.Gly12Arg, respectively. One PRNRP had a G12A/V/D complex mutation. Twenty-six PRNRP were concurrently present with other tumors of different histologic subtypes in the ipsilateral kidney; molecular testing of 8 of the latter showed wild-type KRAS gene despite the presence of KRAS mutations in 5 concurrent PRNRP. On follow up, no adverse pathologic events were seen (range 1-160 months; mean 44 months). In conclusion, the presence of KRAS mutations in small, clinically undetected PRNRP provides a unique finding to this entity and supports its being an early event in the development of these neoplasms.
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Neoplasias Colorrectales , Neoplasias Renales , Neoplasias Colorrectales/patología , Genes ras , Humanos , Riñón/patología , Neoplasias Renales/genética , Mutación , Proteínas Proto-Oncogénicas p21(ras)/genéticaRESUMEN
A distinct renal tumor has recently been described as "high-grade oncocytic renal tumor" and "sporadic renal cell carcinoma with eosinophilic and vacuolated cytoplasm". The Genitourinary Pathology Society (GUPS) consensus proposed a unifying name "eosinophilic vacuolated tumor" (EVT) for this emerging entity. In this multi-institutional study, we evaluated 19 EVTs, particularly their molecular features and mutation profile, using next-generation sequencing. All cases were sporadic and none of the patients had a tuberous sclerosis complex. There were 8 men and 11 women, with a mean age of 47 years (median 50; range 15-72 years). Average tumor size was 4.3 cm (median 3.8 cm; range 1.5-11.5 cm). All patients with available follow-up data (18/19) were alive and without evidence of disease recurrence or progression during the follow-up, ranging from 12 to 198 months (mean 56.3, median 41.5 months). The tumors were well circumscribed, but lacked a well-formed capsule, had nested to solid growth, focal tubular architecture, and showed ubiquitous, large intracytoplasmic vacuoles, round to oval nuclei, and prominent nucleoli. Immunohistochemically, cathepsin K, CD117, CD10, and antimitochondrial antigen were expressed in all cases. Other positive stains included: PAX8, AE1/AE3 and CK18. CK7 was typically restricted only to rare scattered cells. Vimentin, HMB45, melan-A, and TFE3 were negative in all cases. All tumors showed retained SDHB. All cases (19/19) showed non-overlapping mutations of the mTOR pathway genes: TSC1 (4), TSC2 (7), and MTOR (8); one case with MTOR mutation showed a coexistent RICTOR missense mutation. Low mutational rates were found in all samples (ranged from 0 to 6 mutations/Mbp). Microsatellite instability and copy number variations were not found in any of the 17 analyzable cases. EVT represents an emerging renal entity that shows a characteristic and readily identifiable morphology, consistent immunohistochemical profile, indolent behavior, and mutations in either TSC1, TSC2, or MTOR genes.
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Carcinoma de Células Renales , Neoplasias Renales , Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Renales/patología , Variaciones en el Número de Copia de ADN , Secuenciación de Nucleótidos de Alto Rendimiento , Riñón/patología , Neoplasias Renales/patología , Mutación , Recurrencia Local de Neoplasia , Serina-Treonina Quinasas TOR/genéticaRESUMEN
Most succinate dehydrogenase (SDH)-deficient renal cell carcinomas (RCCs) demonstrate stereotypical morphology characterized by bland eosinophilic cells with frequent intracytoplasmic inclusions. However, variant morphologic features have been increasingly recognized. We therefore sought to investigate the incidence and characteristics of SDH-deficient RCC with variant morphologies. We studied a multi-institutional cohort of 62 new SDH-deficient RCCs from 59 patients. The median age at presentation was 39 years (range 19-80), with a slight male predominance (M:F = 1.6:1). A relevant family history was reported in 9 patients (15%). Multifocal or bilateral tumors were identified radiologically in 5 patients (8%). Typical morphology was present at least focally in 59 tumors (95%). Variant morphologies were seen in 13 (21%) and included high-grade nuclear features and various combinations of papillary, solid, and tubular architecture. Necrosis was present in 13 tumors, 7 of which showed variant morphology. All 62 tumors demonstrated loss of SDHB expression by immunohistochemistry. None showed loss of SDHA expression. Germline SDH mutations were reported in all 18 patients for whom the results of testing were known. Among patients for whom follow-up data was available, metastatic disease was reported in 9 cases, 8 of whom had necrosis and/or variant morphology in their primary tumor. Three patients died of disease. In conclusion, variant morphologies and high-grade nuclear features occur in a subset of SDH-deficient RCCs and are associated with more aggressive behavior. We therefore recommend grading all SDH-deficient RCCs and emphasize the need for a low threshold for performing SDHB immunohistochemistry in any difficult to classify renal tumor, particularly if occurring at a younger age.
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Carcinoma de Células Renales , Neoplasias Renales , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Femenino , Humanos , Hiperplasia , Inmunohistoquímica , Neoplasias Renales/genética , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Necrosis , Succinato Deshidrogenasa/genética , Adulto JovenRESUMEN
AIMS: Formal depiction of granulomatous inflammation associated with renal neoplasms has mainly consisted of case reports. Herein, we investigate the clinicopathological features and potential significance of granulomas associated with renal tumours from a large multi-institutional cohort. METHODS AND RESULTS: One hundred and eleven study cases were collected from 22 institutions, including 57 partial nephrectomies and 54 radical nephrectomies. Patient ages ranged from 27 to 85 years (average = 60.1 years; male = 61%). Renal neoplasms included clear cell renal cell carcinoma (RCC; 86%), papillary RCC (8%), chromophobe RCC (3%), clear cell papillary RCC (1%), mixed epithelial stromal tumour (1%) and oncocytoma (1%). Granulomas were peritumoral in 36%, intratumoral in 24% and both in 40% of cases. Total granuloma count per case ranged from one to 300 (median = 15) with sizes ranging from 0.15 to 15 mm (mean = 1.9 mm). Necrotising granulomas were seen in 14% of cases. Histochemical stains for organisms were performed on 45% of cases (all negative). Sixteen cases (14%) had a prior biopsy/procedure performed, and eight patients had neoadjuvant immunotherapy or chemotherapy. Eleven patients (10%) had a confirmed diagnosis of sarcoidosis, including five in whom sarcoidosis was diagnosed after nephrectomy. CONCLUSION: Based on this largest case-series to date, peri-/intratumoral granulomas associated with renal neoplasms may be more common than initially perceived. The extent of granulomatous inflammation can vary widely and may or may not have necrosis with possible aetiologies, including prior procedure or immunotherapy/chemotherapy. Although a clinical association with sarcoidosis is infrequent it can still occur, and the presence of granulomas warrants mention in pathology reports.
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Carcinoma de Células Renales , Neoplasias Renales , Sarcoidosis , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Renales/patología , Femenino , Granuloma/patología , Humanos , Inflamación , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Sarcoidosis/patologíaRESUMEN
Chromophobe renal cell carcinoma (ChRCC) is the third most common renal cell carcinoma in adults. The aim of this review is to provide a comprehensive overview highlighting the broad morphologic spectrum of ChRCC, and offer a practical approach for handling cases in daily practice. For the purpose of this review, we classify ChRCC subtypes as (1) classic, (2) eosinophilic, (3) sarcomatoid, and (4) other rare patterns. The concept of eosinophilic ChRCC has significantly evolved, yet it still is one of the major diagnostic challenges pathologists face in routine practice due to its morphologic overlap with renal oncocytoma. Rare patterns of ChRCC have been described over the last few decades, showing a wide histologic spectrum including those with adenomatoid microcystic pigmented, multicystic, neuroendocrine, small cell, and papillary features. ChRCC represents a heterogenous group of neoplasms, demonstrating varied but unique morphologic and genetic profiles. Although the field of ChRCC knowledge is still evolving, rare patterns can present diagnostic challenges if they are not known to pathologists and/or clinicians. Proper and generous tumor sampling along with careful histologic examination allow for recognition of these rare morphologies. The role of routine molecular testing appears to be limited. From a clinical management standpoint, the rare patterns of ChRCC seem to have no definite clinical implications at present and likely can be managed similarly to usual ChRCC. Finally, we will discuss distinctive novel/emerging renal neoplasms previously considered under the spectrum of ChRCC, low-grade oncocytic renal tumor and eosinophilic vacuolated tumor, with regard to their current significance and implications for future classification strategies.
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Adenoma Oxifílico , Carcinoma de Células Renales , Neoplasias Renales , Adenoma Oxifílico/diagnóstico , Adenoma Oxifílico/genética , Adenoma Oxifílico/patología , Adulto , Biomarcadores de Tumor/genética , Carcinoma de Células Renales/patología , Diagnóstico Diferencial , Humanos , Neoplasias Renales/patologíaRESUMEN
Clear cell renal cell carcinoma (CCRCC) is well known for intratumor heterogeneity. An accurate mapping of the tumor is crucial for assessing prognosis, and perhaps this can be linked to potential success/failure of targeted therapies. We assembled a cohort of 7 CCRCCs with prominent vasculature and microvascular hyperplasia (ccRCCPV), resembling those seen in high grade gliomas. A control group of classic CCRCC with no variant morphologies was also included. Both groups were analyzed for clinicopathologic, morphologic, immunohistochemical, and molecular genetic features. No statistically significant differences in mRNA expression of studied genes between the two groups were found. Using NGS panel Trusight Oncology 500 (TSO500), only one clinically significant gene mutation, VHL c.263G > A, p. (Trp88Ter), was found. TMB (Tumor Mutation Burden) and MSI (MicroSatellite Instability) were low, and no copy number variations (CNVs) were detected in the study cohort. Prominent microvascular hyperplasia in CCRCC is a rare phenomenon. From molecular genetic point of view, these tumors do not appear to be different from classic CCRCC. Prognostically, they also demonstrated similar clinical behaviors.
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Carcinoma de Células Renales/patología , Neoplasias Renales/patología , Anciano , Biomarcadores de Tumor , Carcinoma de Células Renales/genética , Femenino , Humanos , Hiperplasia/genética , Hiperplasia/patología , Neoplasias Renales/genética , Masculino , Persona de Mediana Edad , Mutación , PronósticoRESUMEN
Predicting the clinical behavior and trajectory of chromophobe renal cell carcinoma (ChRCC) by histologic features has so far proven to be challenging. It is known that ChRCC represents a heterogeneous group of neoplasms demonstrating variable, yet distinctive morphologic and genetic profiles. In this international multi-institutional study, we aimed to assess the impact of histologic diversity in ChRCC (classic/eosinophilic versus rare subtypes) on survival outcome. This is an international multi-institutional matched case-control study including 14 institutions, examining the impact of histologic subtypes of ChRCC on survival outcome. The study group (cases) included 89 rare subtypes of ChRCC. The control group consisted of 70 cases of ChRCC including classic and eosinophilic features, age- and tumor size-matched. Most of the rare subtypes were adenomatoid cystic/pigmented ChRCC (66/89, 74.2%), followed by multicystic ChRCC (10/89, 11.2%), and papillary ChRCC (9/89, 10.1%). In the control group, there were 62 (88.6%) classic and 8 (11.4%) eosinophilic ChRCC. There were no statistically significant differences between the study and control groups for age at diagnosis, gender distribution, tumor size, presence of tumor necrosis, presence of sarcomatoid differentiation, and adverse outcomes. No statistically significant differences were found in clinical outcome between the rare subtypes and classic/eosinophilic groups by tumor size, necrosis, and sarcomatoid differentiation. Further, no statistically significant differences were found in clinical outcome between the two groups, stratified by tumor size, necrosis, and sarcomatoid differentiation. Our findings corroborated previous studies that both sarcomatoid differentiation and tumor necrosis were significantly associated with poor clinical outcome in classic/eosinophilic ChRCC, and this was proven to be true for ChRCC with rare histologic subtypes as well. This study suggests that rare morphologic patterns in ChRCC without other aggressive features play no role in determining the clinical behavior of the tumor.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Biomarcadores de Tumor , Carcinoma de Células Renales/patología , Estudios de Casos y Controles , Neoplasias Renales/patología , NecrosisRESUMEN
The fusion genes containing neuregulin-1 (NRG1) are newly described potentially actionable oncogenic drivers. Initial clinical trials have shown a positive response to targeted treatment in some cases of NRG1 rearranged lung adenocarcinoma, cholangiocarcinoma, and pancreatic carcinoma. The cost-effective large scale identification of NRG1 rearranged tumors is an open question. We have tested a data-drilling approach by performing a retrospective assessment of a de-identified molecular profiling database of 3263 tumors submitted for fusion testing. Gene fusion detection was performed by RNA-based targeted next-generation sequencing using the Archer Fusion Plex kits for Illumina (ArcherDX Inc., Boulder, CO). Novel fusion transcripts were confirmed by a custom-designed RT-PCR. Also, the aberrant expression of CK20 was studied immunohistochemically. The frequency of NRG1 rearranged tumors was 0.2% (7/3263). The most common histologic type was lung adenocarcinoma (n = 5). Also, renal carcinoma (n = 1) and prostatic adenocarcinoma (n = 1) were found. Identified fusion partners were of a wide range (CD74, SDC4, TNC, VAMP2, UNC5D), with CD74, SDC4 being found twice. The UNC5D is a novel fusion partner identified in prostate adenocarcinoma. There was no co-occurrence with the other tested fusions nor KRAS, BRAF, and the other gene mutations specified in the applied gene panels. Immunohistochemically, the focal expression of CK20 was present in 2 lung adenocarcinomas. We believe it should be considered as an incidental finding. In conclusion, the overall frequency of tumors with NRG1 fusion was 0.2%. All tumors were carcinomas. We confirm (invasive mucinous) lung adenocarcinoma as being the most frequent tumor presenting NRG1 fusion. Herein novel putative pathogenic gene fusion UNC5D-NRG1 is described. The potential role of immunohistochemistry in tumor identification should be further addressed.
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Adenocarcinoma/genética , Neoplasias Pulmonares/genética , Neurregulina-1/genética , Proteínas de Fusión Oncogénica/genética , Neoplasias de la Próstata/genética , Receptores de Superficie Celular/genética , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Antígenos de Diferenciación de Linfocitos B/genética , Femenino , Antígenos de Histocompatibilidad Clase II/genética , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Neoplasias de la Próstata/patología , Sindecano-4/genética , Tenascina/genética , Proteína 2 de Membrana Asociada a Vesículas/genéticaRESUMEN
The 5th edition of WHO classification of adult renal tumors introduced a couple of changes in existing, well established entities, as well as some new distinct renal tumors. Papillary renal cell carcinoma (RCC) is no longer divided into type 1 and type 2. Type 1 is now called “classic” variant and type 2 doesn´t exist anymore. There were long discussion about problematic type 2. According to WHO 2022 the correct name is papillary RCC (and subtype/variant should be mentioned in the description). Another important change came for clear cell papillary RCC. Because there is no convincing evidence that genuine clear cell papillary RCC can produce recurrences or metastases, it is now termed as clear cell papillary tumor. All previously reported aggressive cases are now considered misclassified clear cell RCC (mostly) or other entities. In less typical cases, genetic support of diagnosis with complex analysis of VHL gene should be added. New category “other oncocytic tumors” emerged for tumors from gray zone between renal oncocytoma and chromophobe RCC. Term hybrid oncocytic tumor should be reserved for those with hereditary Birth-Hogg-Dubé syndrome. Emerging entities, like eosinophilic vacuolated tumor (EVT) and oncocytic low-grade tumor (LOT) are mentioned, however, more work is needed for better establishment of the criteria. There is a new category of “molecularly defined renal carcinomas”, where MITf translocation RCCs are divided into TFE3 rearranged RCC with fusion partner dependent morphologic variability, and to TFEB rearranged RCC. In this group, indolent TFEB translocated RCCs are recognized, as well as potentionally aggressive RCC with TFEB gene amplification. In WHO 2016, ALK rearranged RCC was considered as emerging entity. In WHO 2022 it is listed among “molecularly defined RCC” as a distinct renal tumor with broad morphologic spectrum dependent partly on fusion partners. ELOC (TCEB1) mutated RCC is renal tumor composed of clear cell elements and huge fibromyomatous stroma. Diagnostic approach should be complex with support of immunohistochemistry (including CK7) and molecular genetic approach. However, there is overlap with MTOR pathway genes mutated RCC with fibromyomatous stroma. SMARCB1 deficient renal medullary carcinoma is high-grade invasive adenocarcinoma in patients with clinically proved sickle-cell trait and SMARCB1 deficiency.
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Adenoma Oxifílico , Carcinoma de Células Renales , Neoplasias Renales , Humanos , Adulto , Carcinoma de Células Renales/diagnóstico , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Neoplasias Renales/diagnóstico , Neoplasias Renales/genética , Neoplasias Renales/patología , Adenoma Oxifílico/genética , Adenoma Oxifílico/patología , Translocación Genética , Organización Mundial de la Salud , Biomarcadores de TumorRESUMEN
Compared to the WHO classification of the male genital tumors in 2016, minimal changes were introduced in the current WHO 2022. Classification of germ cell tumors remains the same as in the previous edition, dividing germ cell tumors into those derived from germ cell neoplasia in situ (GCNIS) and those independent of GCNIS. The group of GCNIS derived germ cell tumors is essentially unchanged. Most remarkable change was made to the chapter teratoma with somatic malignancy. Primitive neuroectodermal tumor (PNET), a particular type of somatic malignancy arising in the setting of teratoma, is currently termed embryonic-type neuroectodermal tumor (ENET). Diagnostic criteria for teratoma with somatic type malignancy have been mildly modified. Seminoma now belongs to the group of germinomas. There is one novel entity in the category of germ cell tumors independent of GCNIS, namely testicular neuroendocrine tumor, prepubertal type. Similar to other organ systems, the term carcinoid is no longer used. Two new entities were introduced in the category of sex cord stromal tumors: myoid gonadal stromal tumor and signet ring stromal tumor. Diagnostic criteria for malignant sex cord stromal tumors were moderately changed. Mitotic activity is now assessed according to mm2 instead of historical assessment according to the number of mitoses per high power fields. There is a new separate chapter named Genetic tumor syndromes. Intratubular large cell hyalinizing Sertoli cell neoplasia which arises exclusively in patients with Peutz-Jeghers syndrome, now belongs here. Large cell calcifying Sertoli cell tumor occurs as a hereditary tumor in patients with Carney complex as well as sporadically. Therefore, it is enlisted both in the chapter on sex cord tumors and as well as in genetic tumor syndromes. Well differentiated papillary mesothelial tumor was added as a new entity to the section of testicular adnexal tumors. Sertoliform cystadenoma, a tumor previously belonging to testicular adnexal tumors, is currently recognized as a subtype of Sertoli cell tumor.
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Neoplasias de Células Germinales y Embrionarias , Tumor de Células de Sertoli , Tumores de los Cordones Sexuales y Estroma de las Gónadas , Teratoma , Neoplasias Testiculares , Humanos , Masculino , Neoplasias Testiculares/genética , Neoplasias Testiculares/patología , Tumores de los Cordones Sexuales y Estroma de las Gónadas/patología , Organización Mundial de la SaludRESUMEN
The 5th edition of WHO classification of the urinary tract tumors is only mildly edited version of the previous WHO classification (from year 2016). The most prominent changes are represented by modifications in the structure and concept of chapters and there are minor alterations in the nomenclature of some entities. Histological characteristics are still the gold standard for classification of urothelial tract neoplasms.
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Neoplasias Urológicas , Humanos , Neoplasias Urológicas/diagnóstico , Organización Mundial de la SaludRESUMEN
Thyroid-like follicular renal cell carcinoma is an uncommon kidney tumor with no distinct molecular alteration described to date. This cohort of eight women with mean and median ages of 45 and 46 years, respectively (range 19-65 years), had unencapsulated, well-circumscribed tumors composed of tightly packed anastomosing follicle-like cysts filled with eosinophilic colloid-like material and lined by cuboidal cells with high nuclear to cytoplasmic ratios, oval to elongated nuclei with perpendicular arrangement toward the lumens, and prominent nuclear overlapping. The stroma between these was minimal with the exception of two tumors. Calcifications and necrosis were absent. Immunohistochemically, the tumors were positive for KRT19 (7/7), PAX8 (5/5), cyclin D1 (6/6), KRT7 (5/7), and AMACR (1/5; focal, weak), and were negative for WT1, TTF1 (transcription termination factor-1), and thyroglobulin. In three of three tumors tested molecularly, EWSR1-PATZ1 fusion was identified by RNA sequencing and confirmed by RT-PCR and Sanger sequencing. Over a follow-up period of 1-7 years, no evidence of recurrence or metastasis has been detected. The EWSR1-PATZ1 fusion has been recognized as a recurrent alteration in a subset of round to spindle cell sarcomas with EWSR1-non-ETS fusions (EWSR1-PATZ1 sarcoma) and in several central nervous system tumors. The finding of an EWSR1-PATZ1 fusion in all three of the thyroid-like follicular renal cell carcinomas for which sufficient tissue was available for genomic profiling provides the first distinct molecular abnormality in thyroid-like follicular renal cell carcinomas, supporting its designation as a distinct diagnostic entity.
Asunto(s)
Carcinoma de Células Renales/genética , Neoplasias Renales/genética , Factores de Transcripción de Tipo Kruppel/genética , Fusión de Oncogenes , Proteína EWS de Unión a ARN/genética , Proteínas Represoras/genética , Adulto , Anciano , Carcinoma de Células Renales/patología , Femenino , Humanos , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
The Genitourinary Pathology Society (GUPS) undertook a critical review of the recent advances in renal neoplasia, particularly focusing on the newly accumulated evidence post-2016 World Health Organization (WHO) classification. In the era of evolving histo-molecular classification of renal neoplasia, morphology is still key. However, entities (or groups of entities) are increasingly characterized by specific molecular features, often associated either with recognizable, specific morphologies or constellations of morphologies and corresponding immunohistochemical profiles. The correct diagnosis has clinical implications leading to better prognosis, potential clinical management with targeted therapies, may identify hereditary or syndromic associations, which may necessitate appropriate genetic testing. We hope that this undertaking will further facilitate the identification of these entities in practice. We also hope that this update will bring more clarity regarding the evolving classification of renal neoplasia and will further reduce the category of "unclassifiable renal carcinomas/tumors". We propose three categories of novel entities: (1) "Novel entity", validated by multiple independent studies; (2) "Emerging entity", good compelling data available from at least two or more independent studies, but additional validation is needed; and (3) "Provisional entity", limited data available from one or two studies, with more work required to validate them. For some entities initially described using different names, we propose new terminologies, to facilitate their recognition and to avoid further diagnostic dilemmas. Following these criteria, we propose as novel entities: eosinophilic solid and cystic renal cell carcinoma (ESC RCC), renal cell carcinoma with fibromyomatous stroma (RCC FMS) (formerly RCC with leiomyomatous or smooth muscle stroma), and anaplastic lymphoma kinase rearrangement-associated renal cell carcinoma (ALK-RCC). Emerging entities include: eosinophilic vacuolated tumor (EVT) and thyroid-like follicular renal cell carcinoma (TLFRCC). Finally, as provisional entities, we propose low-grade oncocytic tumor (LOT), atrophic kidney-like lesion (AKLL), and biphasic hyalinizing psammomatous renal cell carcinoma (BHP RCC).
Asunto(s)
Neoplasias Renales/clasificación , Humanos , Neoplasias Renales/diagnóstico , Neoplasias Renales/patologíaRESUMEN
The Genitourinary Pathology Society (GUPS) reviewed recent advances in renal neoplasia, particularly post-2016 World Health Organization (WHO) classification, to provide an update on existing entities, including diagnostic criteria, molecular correlates, and updated nomenclature. Key prognostic features for clear cell renal cell carcinoma (RCC) remain WHO/ISUP grade, AJCC/pTNM stage, coagulative necrosis, and rhabdoid and sarcomatoid differentiation. Accrual of subclonal genetic alterations in clear cell RCC including SETD2, PBRM1, BAP1, loss of chromosome 14q and 9p are associated with variable prognosis, patterns of metastasis, and vulnerability to therapies. Recent National Comprehensive Cancer Network (NCCN) guidelines increasingly adopt immunotherapeutic agents in advanced RCC, including RCC with rhabdoid and sarcomatoid changes. Papillary RCC subtyping is no longer recommended, as WHO/ISUP grade and tumor architecture better predict outcome. New papillary RCC variants/patterns include biphasic, solid, Warthin-like, and papillary renal neoplasm with reverse polarity. For tumors with 'borderline' features between oncocytoma and chromophobe RCC, a term "oncocytic renal neoplasm of low malignant potential, not further classified" is proposed. Clear cell papillary RCC may warrant reclassification as a tumor of low malignant potential. Tubulocystic RCC should only be diagnosed when morphologically pure. MiTF family translocation RCCs exhibit varied morphologic patterns and fusion partners. TFEB-amplified RCC occurs in older patients and is associated with more aggressive behavior. Acquired cystic disease (ACD) RCC-like cysts are likely precursors of ACD-RCC. The diagnosis of renal medullary carcinoma requires a negative SMARCB1 (INI-1) expression and sickle cell trait/disease. Mucinous tubular and spindle cell carcinoma (MTSCC) can be distinguished from papillary RCC with overlapping morphology by losses of chromosomes 1, 4, 6, 8, 9, 13, 14, 15, and 22. MTSCC with adverse histologic features shows frequent CDKN2A/2B (9p) deletions. BRAF mutations unify the metanephric family of tumors. The term "fumarate hydratase deficient RCC" ("FH-deficient RCC") is preferred over "hereditary leiomyomatosis and RCC syndrome-associated RCC". A low threshold for FH, 2SC, and SDHB immunohistochemistry is recommended in difficult to classify RCCs, particularly those with eosinophilic morphology, occurring in younger patients. Current evidence does not support existence of a unique tumor subtype occurring after chemotherapy/radiation in early childhood.
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Neoplasias Renales , Humanos , Organización Mundial de la SaludRESUMEN
Chromophobe renal cell carcinoma (ChRCC) accounts for 5% to 7% of all renal cell carcinomas. It was thought for many years that ChRCC exhibits a hypodiploid genome. Recent studies using advanced molecular genetics techniques have shown more complex and heterogenous pattern with frequent chromosomal gains. Historically, multiple losses of chromosomes 1, 2, 6, 10, 13, 17, and 21 have been considered a genetic hallmark of ChRCC, both for classic and eosinophilic ChRCC variants. In the last 2 decades, multiple chromosomal gains in ChRCCs have also been documented, depicting a considerably broader genetic spectrum than previously thought. Studies of rare morphologic variants including ChRCC with pigmented microcystic adenomatoid/multicystic growth, ChRCC with neuroendocrine differentiation, ChRCC with papillary architecture, and renal oncocytoma-like variants also showed variable chromosomal numerical aberrations, including multiple losses (common), gains (less common), or chromosomal changes overlapping with renal oncocytoma. Although not the focus of the review, The Cancer Genome Atlas (TCGA) data in ChRCC show TP53, PTEN, and CDKN2A to be the most mutated genes. Given the complexity of molecular genetic alterations in ChRCC, this review analyzed the existing published data, aiming to present a comprehensive up-to-date survey of the chromosomal abnormalities in classic ChRCC and its variants. The potential role of chromosomal numerical aberrations in the differential diagnostic evaluation may be limited, potentially owing to its high variability.