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Papillary Renal Cell Carcinoma

Chromophil renal cell carcinoma

Renal cell carcinoma (RCC) is the most common malignant neoplasm of the kidneys. The World Health Organization recognizes distinct types of RCC, e.g., papillary renal cell carcinoma (pRCC). pRCC are often diagnosed incidentally; they are unlikely to cause any symptoms until advanced stages of the disease. Diagnosis of pRCC relies on histological, immunological, and genetic tests. pRCC are highly resistant to chemotherapy and radiotherapy, so most pRCC patients undergo surgery. Surgically non-resectable tumors are associated with a very poor prognosis because efficient molecular targeted therapies are not yet available.


Presentation

Most RCC are detected incidentally when patients undergo imaging studies in order to identify the causes of urological or non-urological complaints. The symptom triad of flank pain, hematuria and a palpable abdominal mass is sometimes described as characteristic of RCC - and it should surely prompt further studies - but most patients remain asymptomatic for prolonged periods of time. pRCC are even less likely to cause clinical disease than the more common clear cell variant of RCC [1]. Thus, RCC don't usually cause specific symptoms, and even less so are there any symptoms that would allow for the distinction between subtypes of RCC.

In case of advanced disease, patients may present constitutional symptoms like fatigue, fever, night sweats, loss of appetite and weight. If metastases have formed in other organs, e.g., in lungs, liver, or bones, these may interfere with organ function. Accordingly, RCC patients may suffer from dyspnea, nausea and vomiting, and bone pain, among others.

Fatigue
  • Common treatment-related adverse events were oedema (47.8%), fatigue (47.8%), nausea (39.1%), diarrhoea (39.1%) and blurred vision (34.8%).[ncbi.nlm.nih.gov]
  • RELATED: Restoring ASPP1 May Improve Outcomes in Clear Cell RCC The most frequently observed adverse effects in patients were nausea, vomiting, fatigue, and peripheral edema.[cancertherapyadvisor.com]
  • Some common symptoms of PRCC include: blood in the urine pain in the side unexplained weight loss excessive fatigue a lump or mass in the side unexplained fever These symptoms can also be due to other conditions, however, and don’t automatically mean[healthline.com]
  • In case of advanced disease, patients may present constitutional symptoms like fatigue, fever, night sweats, loss of appetite and weight.[symptoma.com]
  • […] progression-free survival was 6.2 months (95% CI, 4.1-7.0) in MET-driven disease and 1.4 months (95% CI, 1.4-2.7) in MET-independent disease (hazard ratio, 0.33; 95% CI, 0.20-0.52; log-rank P The most common treatment-related adverse events were nausea, fatigue[oncologynurseadvisor.com]
Constitutional Symptom
  • In case of advanced disease, patients may present constitutional symptoms like fatigue, fever, night sweats, loss of appetite and weight.[symptoma.com]
Thyroid Nodule
  • The laterocervical and supraclavicular masses were considered consistent with nodal metastases from a thyroid nodule. A hemithyroidectomy was performed before the renal tumor was diagnosed. Then the patient underwent a left-side radical nefrectomy.[ncbi.nlm.nih.gov]
Aspiration
  • Both aspirates showed cytologic features characteristic for papillary renal cell carcinoma, namely papillary structures, foamy histiocytes, intracytoplasmic hemosiderin, and nuclear grooves.[ncbi.nlm.nih.gov]
  • Following the percutaneous aspiration, the patient’s symptoms initially resolved. The pathologic evaluation of the aspirate revealed dark colored fluid, with atypical cells, without any histologically noticeable pathology.[file.scirp.org]
  • Material obtained by fine needle aspiration (FNA) biopsy of the mass was felt to be suspicious for renal cell carcinoma. The patient subsequently underwent right nephrectomy, and the lesional tissue was examined microscopically.[ncbi.nlm.nih.gov]
  • To the author's knowledge, its cytomorphology on fine-needle aspiration (FNA) or touch preparations (TPs) of core needle biopsy specimens has not been well delineated in the English language literature.[ncbi.nlm.nih.gov]
  • Tissue samples may be obtained by means of fine-needle aspiration or biopsy, or during surgery.[symptoma.com]
Nausea
  • Common treatment-related adverse events were oedema (47.8%), fatigue (47.8%), nausea (39.1%), diarrhoea (39.1%) and blurred vision (34.8%).[ncbi.nlm.nih.gov]
  • RELATED: Restoring ASPP1 May Improve Outcomes in Clear Cell RCC The most frequently observed adverse effects in patients were nausea, vomiting, fatigue, and peripheral edema.[cancertherapyadvisor.com]
  • Accordingly, RCC patients may suffer from dyspnea, nausea and vomiting, and bone pain, among others. Upon diagnosis, pRCC are usually confined to the kidney.[symptoma.com]
  • Median progression-free survival was 6.2 months (95% CI, 4.1-7.0) in MET-driven disease and 1.4 months (95% CI, 1.4-2.7) in MET-independent disease (hazard ratio, 0.33; 95% CI, 0.20-0.52; log-rank P The most common treatment-related adverse events were nausea[oncologynurseadvisor.com]
  • The most common AEs (all grades) includes: nausea (39%), fatigue (27%), edema (18%) and abnormal liver function tests (“LFTs”) (17%). One death from hepatic encephalopathy was considered related to savolitinib.[chi-med.com]
Left Flank Pain
  • We incidentally observed a case of clear cell papillary renal cell carcinoma of an 81-year-old woman, presenting with intermittent left flank pain. It is a recently described rare renal parenchymal tumor.[ncbi.nlm.nih.gov]
  • A 19-year old man complained of left flank pain and pyrexia. Computerized tomography (CT) scan and urography revealed a solid mass in the left kidney.[ncbi.nlm.nih.gov]
Melena
  • We report herein a unique case of a GIST of the small intestine and bilateral papillary renal cell carcinomas in a patient presenting with melena and dizziness.[ncbi.nlm.nih.gov]
Anger
  • , Angers University Hospital, 4 rue Larrey, 49333, Angers, France. 27 Department of Urology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.[ncbi.nlm.nih.gov]
Nocturia
  • RESULTS: Prosection of a partial nephrectomy performed in a 78-year-old man for painless gross hematuria and nocturia revealed a 6.4 5 3.6-cm well-delineated orange to yellow-tan mass harboring a white-tan 1 0.9 0.9-cm mass.[ncbi.nlm.nih.gov]
Testicular Mass
  • A 33-year-old man presented with a left testicular mass and elevated tumour markers. Staging investigations revealed retroperitoneal lymphadenopathy with obstruction of the left ureter and distant metastases.[ncbi.nlm.nih.gov]

Workup

Upon diagnosis, pRCC are usually confined to the kidney. They are well-circumscribed tumors with a preference for peripheral locations, don't typically measure more than a few centimeters in diameter and have a homogeneous structure. However, larger pRCC possibly contain necrotic areas or cystic lesions that confer a more heterogeneous appearance in images. Calcifications are seen in up to one third of pRCC [1]. Most pRCC are hypointense on T2-weighted images, and this feature may help to distinguish pRCC from clear cell RCC, which correspond to hyperintense lesions on T2-weighted images. Additionally, pRCC are hypovascular neoplasms, while hypervascularity is attributed to clear cell RCC [1]. There are several other imaging features that have been proposed to indicate one or another subtype of RCC, but not a single one allows for a reliable diagnosis of pRCC. In order to obtain a reliable diagnosis, tissues samples have to be examined. Tissue samples may be obtained by means of fine-needle aspiration or biopsy, or during surgery.

Macroscopically, pRCC appear as solid but friable, yellow, yellowish-grey or brown, well-circumscribed nodules, which are frequently encapsulated by a thick fibrous capsule or pseudocapsule [1] [2] [3]. They have a papillary or tubulopapillary architecture that can be recognized histologically, but it should be noted that papillary architecture is not unique to pRCC [4]. In any case, papillae formed by pRCC may either be delimited by a single layer of cuboidal cells with scant cytoplasm, or by large cells with abundant eosinophilic cytoplasm and pseudostratified nuclei [3]. The former is characteristic of type 1 pRCC, the latter indicates type 2 pRCC. Subtype distinction is recommended because type 2 pRCC are usually associated with higher tumor grades, an advanced stage of the disease, and a worse prognosis. For tumor grading, nuclei and nucleoli have to be observed: conspicuous, eosinophilic nucleoli indicate higher tumor grades, particularly if they are visible at low magnifications. Nuclear pleomorphism, the presence of multinucleated giant cells, and rhabdoid or sarcomatoid differentiation are suggestive of grade 4 RCC [5]. Foamy macrophages are encountered independent of the type of pRCC, but necrotic foci are more commonly observed in type 2 pRCC and may be considered an indicator of advanced disease [2]. Immunohistochemical staining for CK7, a low-molecular weight-keratin, may further help to differentiate between type 1 and type 2 pRCC, since diffuse staining is to be expected only in case of type 1 pRCC. AMACR, CD10, EMA, PAX2, PAX8, and vimentin staining should yield positive results in both pRCC and clear cell RCC [2] [6].

Besides macroscopic and microscopic examinations, genetic analyses may be carried out to identify possible targets for molecular therapies. Unfortunately though, there is little evidence as to the efficacy of targeted cancer therapies in pRCC patients. Further studies and clinical trials are required to improve that situation, and data regarding the molecular background of pRCC are necessary to promote such research.

The presence of multiple pRCC, either in one or both kidneys, indicates a predisposition for the disease and is more likely to be encountered in patients with hereditary renal cancer. However, this does not apply to hereditary leiomyomatosis and renal cell cancer [7].

Anergy
  • Through the accurate assessment of monocyte-derived dendritic cells (Mo-DCs) function, we show that Mo-DCs were freed from tumor-induced maturation blockage by tumor resection surgery, while Mo-DCs-tumor induced suppression and anergy were only interrupted[ncbi.nlm.nih.gov]
Multiple Renal Cysts
  • Bilateral multiple renal cysts in a 46-year-old man were pointed out incidentally by ultrasonography. Some of the left renal lesions were considered to be RCC, and left radical nephrectomy was performed accordingly.[ncbi.nlm.nih.gov]
Liver Biopsy
  • In addition, another focal intense uptake was observed in segment VII of the liver.[ncbi.nlm.nih.gov]
  • Histopathology was consistent with pRCC type; per operative liver biopsy also showed metastatic pRCC. The tumor was vimentin positive, panCK positive, WT1 negative, Ker7 negative, and CD10 negative.[journal.sajc.org]
Foam Cell
  • Interstitial foam cells in vascular cores - key feature. Most sensitive and specific feature of PaRCC. [8] Highly vascular.[librepathology.org]

Treatment

RCC are highly resistant to both chemotherapy and radiotherapy [2]. Thus, surgery is opted for whenever the patient's general condition doesn't rule out the corresponding intervention [2] [8]:

  • Nephron-sparing surgery or partial nephrectomy is recommended for stage 1 pRCC. It should be followed by histological analyses to assure complete removal of neoplastic tissue.
  • Locally advanced or centrally located tumors require laparoscopic or open radical nephrectomy. Lymphadenectomy is recommended in case of visible or palpable adenopathy. Prophylactic lymphadenectomy has not been shown to improve survival, but may be realized to facilitate tumor staging
  • Cryotherapy, radiofrequency ablation, and embolization may be considered in patients who are unfit for surgery. In case of small pRCC, these techniques may be sufficient to achieve cure.

In case of surgically unresectable pRCC, systemic therapy may be carried out with axitinib, erlotinib, pazopanib, sorafenib, sunitinib, temsirolimus, or bevacuzimab in combination with interferon, but response rates are unsatisfactorily low [2] [7]. Most investigators pin their hopes on targeted therapies that may counteract the molecular causes of tumor growth, e.g., tyrosine kinase inhibitors to antagonize the constitutive activation of enzymes, and enzyme replacement therapy to compensate for enzyme deficiencies. Indeed, the NCCN Guidelines for Kidney Cancer explicitly recommend the enrollment in an appropriately designed clinical trial for patients with pRCC [8].

Prognosis

pRCC are slow-growing neoplasms and they are less likely to metastasize than clear cell RCC [1]. Still, no differences were found regarding long-term prognosis and five-year survival rates: Schrader and colleagues reported five-year survival rates of 78 and 77% for pRCC and clear cell RCC, respectively [9]. Rather than on tumor (sub-)types, the individual patient's prognosis depends on specific tumor characteristics such as tumor grade and tumor stage. Clinical disease hints at more aggressive renal cancer and advanced disease, but imaging and histological data have to be considered before making any favorable or unfavorable prognosis: Upon diagnosis, type 2 pRCC have often reached a higher stage. Additionally, they tend to be of higher tumor grades than type 1 pRCC and to grow more aggressively. In sum, type 2 pRCC tend to be associated with worse outcomes [10].

Etiology

Little is known about the precise causes of sporadic pRCC. Nevertheless, certain risk factors have been identified that augment the individual risk of developing this type of cancer: For instance, there is a significant correlation between cigarette smoking and pRCC [2] [11]. While obesity has been linked to clear cell RCC, such a correlation has not yet been confirmed for pRCC [2]. It is known, though, that acquired diseases like acquired cystic kidney disease considerably increase the individual risk of pRCC. Hypertension, urinary tract infection, dietary intake of fat and other food ingredients, and occupational exposure to solvents like trichloroethylene are controversially discussed as potential risk factors for pRCC [2] [11].

Hereditary pRCC is diagnosed in patients with determined chromosomal or gene aberrations. The following list shall provide an overview of hereditary disorders that may be associated with pRCC [12]:

Epidemiology

RCC accounts for about 3% of malignancies diagnosed in adult patients and is the most common type of malignant tumor originating from the kidneys. Histopathological analyses allow for the identification of pRCC in approximately 10% of those cases [10]. The majority of cases corresponds to sporadic pRCC, but individuals with certain DNA sequence anomalies are predisposed to develop this type of tumors. Hereditary renal cancer syndromes comprise hereditary papillary renal cancer and hereditary leiomyomatosis and renal cell cancer, but also Birt–Hogg–Dubé syndrome and tuberous sclerosis [10] [12].

Men are affected much more frequently than women; male-to-female ratios range between 1.8 to 1 and 3.8 to 1 [2]. The individual risk of developing RCC increases with age: This type of tumor is most commonly diagnosed in patients aged >60 years. Pediatric RCC are rare, but if a child develops RCC, the likelihood of it being pRCC is higher than in adult patients.

Sex distribution
Age distribution

Pathophysiology

Numerous chromosomal and gene aberrations have been detected in pRCC:

  • Mutations in the MET gene account for hereditary type 1 pRCC and have also been detected in sporadic type 1 pRCC [10]. MET encodes for a tyrosine kinase receptor able to bind growth factors and to regulate cell migration and survival. MET mutations favoring the development of pRCC trigger the synthesis of constitutively active tyrosine kinases. Accordingly, MET is considered a proto-oncogene.
  • Additionally, cytogenetic studies frequently show gains in chromosome 7p and 17p, loss of chromosome Y, and variable gains in chromosomes 3q, 8p, 12q, 16q and 20q in type 1 pRCC [6].
  • Even more heterogeneity has been reported for type 2 pRCC. Anomalies may affect chromosomes 1p, 3p, 5, 6, 8, 9p, 10, 11, 15, 18, and 22, with losses of chromosomes 8, 9p21, 11, and 18 being most common [2].
  • Epigenetic alterations may also contribute to pRCC development [2].

Prevention

At this time, no measures can be recommended to prevent sporadic pRCC with certainty. The individual risk of pRCC, however, may be diminished by means of lifestyle adaptations. For instance, people should be encouraged not to start or stop smoking.

Families affected by hereditary pRCC may benefit from genetic counseling. In this context, distinct recommendations may be given depending on the underlying disease.

Summary

Approximately 90% of all kidney cancers are RCC, so this type of tumor is the most common malignancy affecting the kidneys [11]. According to their histological features, several types of RCC are distinguished, namely clear cell, papillary, and chromophobe RCC. Other entities listed in the Classification of Tumors of the Urinary System, as published by the World Health Organization, comprise clear cell papillary RCC, RCC due to hereditary or non-hereditary disorders, and unclassified RCC [4]. More than 10% of RCC are pRCC [10].

In this context, "papillary" refers to the tumor's architecture as recognized upon histological examination. Other histological and immunohistochemical features allow for a further distinction of pRCC subtypes, namely subtype 1 and 2. Both subtypes are associated with certain tumor grades and stages and thus, affect the patients' prognosis.

Patient Information

Renal cell carcinoma (RCC) is the most common malignancy of the kidneys. There are distinct types of RCC, e.g., clear cell, papillary, and chromophobe RCC. Papillary RCC account for about 10% of all cases. Here, "papillary" refers to the tumor's architecture as recognized upon histological examination. Clinical presentation and diagnosis don't differ between clear cell and papillary RCC: Patients usually remain asymptomatic for prolonged periods of time, and many tumors are detected incidentally when imaging studies are realized for non-related reasons. With regards to papillary RCC, surgery is the therapy of choice and aims at a complete resection and cure of the patient. Surgically unresectable papillary RCC are associated with a poor prognosis because those molecular defects favoring tumor development cannot yet be remedied pharmacologically. Current research is focused on the characterization of molecular features inherent to this type of RCC, and on the development of drugs targeting those underlying defects.

References

Article

  1. Low G, Huang G, Fu W, Moloo Z, Girgis S. Review of renal cell carcinoma and its common subtypes in radiology. World J Radiol. 2016; 8(5):484-500.
  2. Fernandes DS, Lopes JM. Pathology, therapy and prognosis of papillary renal carcinoma. Future Oncol. 2015; 11(1):121-132.
  3. Ulamec M, Skenderi F, Trpkov K, et al. Solid papillary renal cell carcinoma: clinicopathologic, morphologic, and immunohistochemical analysis of 10 cases and review of the literature. Ann Diagn Pathol. 2016; 23:51-57.
  4. Udager AM, Mehra R. Morphologic, Molecular, and Taxonomic Evolution of Renal Cell Carcinoma: A Conceptual Perspective With Emphasis on Updates to the 2016 World Health Organization Classification. Arch Pathol Lab Med. 2016; 140(10):1026-1037.
  5. Delahunt B, Cheville JC, Martignoni G, et al. The International Society of Urological Pathology (ISUP) grading system for renal cell carcinoma and other prognostic parameters. Am J Surg Pathol. 2013; 37(10):1490-1504.
  6. Farber NJ, Kim CJ, Modi PK, Hon JD, Sadimin ET, Singer EA. Renal cell carcinoma: the search for a reliable biomarker. Transl Cancer Res. 2017; 6(3):620-632.
  7. Twardowski PW, Mack PC, Lara PN, Jr. Papillary renal cell carcinoma: current progress and future directions. Clin Genitourin Cancer. 2014; 12(2):74-79.
  8. Motzer RJ, Jonasch E, Agarwal N, et al. Kidney Cancer, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2017; 15(6):804-834.
  9. Schrader AJ, Rauer-Bruening S, Olbert PJ, et al. Incidence and long-term prognosis of papillary renal cell carcinoma. J Cancer Res Clin Oncol. 2009; 135(6):799-805.
  10. Courthod G, Tucci M, Di Maio M, Scagliotti GV. Papillary renal cell carcinoma: A review of the current therapeutic landscape. Crit Rev Oncol Hematol. 2015; 96(1):100-112.
  11. Ljungberg B, Campbell SC, Choi HY, et al. The epidemiology of renal cell carcinoma. Eur Urol. 2011; 60(4):615-621.
  12. Haas NB, Nathanson KL. Hereditary kidney cancer syndromes. Adv Chronic Kidney Dis. 2014; 21(1):81-90.

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Last updated: 2019-07-11 20:10