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Chromophobe Renal Cell Carcinoma

Chromophobe Renal Cell Adenocarcinoma

Renal cell carcinoma (RCC) is the most common malignant neoplasm of the kidneys. The World Health Organization recognizes distinct types of RCC, e.g., chromophobe renal cell carcinoma (chRCC). chRCC are often diagnosed incidentally; they are unlikely to cause any symptoms until advanced stages of the disease. Diagnosis of chRCC mainly relies on histological studies. Most chRCC are highly resistant to chemotherapy and radiotherapy, so the majority of patients undergoes surgery. Surgically non-resectable tumors are associated with an unfavorable outcome because efficient molecular targeted therapies are not yet available. By contrast, diagnosis in early stages of the disease is related to a favorable prognosis.


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 [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 liver, lungs, or bones, these may interfere with organ function. Accordingly, RCC patients may suffer from nausea and vomiting, dyspnea, and bone pain, among others. While clear cell RCC preferentially metastasize to the lungs, chRCC patients are more likely to develop liver metastases [2].

Inguinal Lymphadenopathy
  • This tumor was found by serendipity during the evaluation of fever and inguinal lymphadenopathy, with the presumptive diagnosis of posttransplantation lymphoproliferative disorder. The patient was found to have cat-scratch disease.[ncbi.nlm.nih.gov]
  • That tumor was found by serendipity during the evaluation of fever and inguinal lymphadenopathy. [16] It is also interesting to note that the incidence of RCC in patients with a cardiac transplant is similar to the general population, suggesting that[sjkdt.org]
Constitutional Symptom
  • In case of advanced disease, patients may present constitutional symptoms like fatigue, fever, night sweats, loss of appetite and weight.[symptoma.com]
Inguinal Pain
  • A 42-year-old Japanese woman presented with hematuria and complained of inguinal pain 2 months after the initial symptoms. Radical nephrectomy and renal hilar lymphadenectomy were performed.[ncbi.nlm.nih.gov]
Cat Scratch
  • The patient was found to have cat-scratch disease. A renal cell carcinoma should be considered in the differential diagnosis of a pediatric recipient of an adult kidney with an incidental finding of a tumor in the graft.[ncbi.nlm.nih.gov]
Aspiration
  • Ultrasound guided aspiration was done and cytological features of ChRCC were noted. In addition, numerous foci of calcification were seen, which was an unusual cytological feature for ChRCC.[ncbi.nlm.nih.gov]
  • To report the fine needle aspiration (FNA) features of both a typical and an eosinophilic variant of chromophobe renal cell carcinoma.[ncbi.nlm.nih.gov]
  • Tissue samples may be obtained by means of fine-needle aspiration or biopsy, or during surgery. Macroscopically, chRCC appear as solid, well-circumscribed, highly lobulated nodules, whose cut surface is of light brown color.[symptoma.com]
  • Ultrasound-guided fine needle aspiration of the mass was performed and microscopic examination revealed loosely cohesive clusters of tumor cells that have koilocytoid appearance with abundant cytoplasm and occasional binucleation [Figure 2] a.[sjkdt.org]
  • Importantly, these molecular techniques might be performed in clinical samples obtained by non- or minimally-invasive procedures, such as urine or serum, 16 or serve as ancillary tools for fine needle aspiration cytology (FNAC), as previously shown. 40[elsevier.es]
Dyspepsia
  • A 27-year-old woman presenting with epigastric pain and dyspepsia was found to have a calcified mass in the upper-middle right kidney.[ncbi.nlm.nih.gov]
Epigastric Pain
  • A 27-year-old woman presenting with epigastric pain and dyspepsia was found to have a calcified mass in the upper-middle right kidney.[ncbi.nlm.nih.gov]
Expressive Aphasia
  • A 58-year-old man presented with stroke-like symptomatology, including expressive aphasia, right side facial weakness, headaches and vomiting. CT imaging demonstrated a 4.7 cm left frontal lobe hemorrhagic mass.[ncbi.nlm.nih.gov]
Aphasia
  • A 58-year-old man presented with stroke-like symptomatology, including expressive aphasia, right side facial weakness, headaches and vomiting. CT imaging demonstrated a 4.7 cm left frontal lobe hemorrhagic mass.[ncbi.nlm.nih.gov]

Workup

Most commonly, pathological findings in diagnostic imaging studies provide first hints as to the presence of RCC. The following observations can be made with regard to chRCC [1] [3]:

  • chRCC are usually confined to the kidney. Vascular infiltration and encroachment to surrounding healthy tissue are observed in <4% of all cases.
  • They are well-circumscribed tumors that have a homogeneous structure; cystic changes and necrotic foci are uncommon. In contrast to other types of RCC, chRCC are unlikely to contain cystic or necrotic lesions even in advanced stages of the disease.
  • Calcifications are seen in approximately one third of chRCC.
  • The median tumor size at the time of diagnosis is 6 cm.

These and other properties can be displayed using distinct imaging techniques: In sonographic images, chRCC appear as hyperechogenic lesions. Most chRCC are hypodense and hypointense on on computed tomography and T2-weighted magnetic resonance images, respectively. Furthermore, they show homogeneous enhancement contrast agent administration in either type of imaging study. Vascularity is sometimes mentioned as another, type-specific feature of RCC. In this context, clear cell RCC are described as hypervascular neoplasms, while papillary RCC are characterized as hypovascular tumors [3]. chRCC are of intermediate vascularity, but this quality can hardly be defined in any of the images mentioned above. In sum, imaging studies may raise a strong suspicion of chRCC, but 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, chRCC appear as solid, well-circumscribed, highly lobulated nodules, whose cut surface is of light brown color. They mainly consist of large, polygonal cells with a reticulated cytoplasm and prominent cell membranes. Electron microscopic examination may reveal cytoplasmic microvesicles. There may be a second type of tumor cells, namely small cells with eosinophilic cytoplasm. Their proportions vary [1]. The diagnosis of chRCC may be confirmed if a diffusely positive cytoplasmic reaction is observed upon Hale colloidal iron staining [1]. If doubts remain as to the type of the tumor, immunohistochemical staining may provide helpful clues. It is particularly recommended to distinguish chRCC and oncocytoma, a benign renal neoplasm. chRCC cells usually stain positive claudin 7, CK AE1/AE3, CK7, EMA, EpCAM, and parvalbumin.

For tumor grading, nuclei and nucleoli of tumor cells 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 [4]. Of note, this grading system has merely been transferred from studies on clear cell and papillary RCC. Due to the rarity of the disease, it has not yet been validated for chRCC. Blood vessels supplying chRCC have thick walls and are eccentrically hyalinized [3].

The presence of multiple chRCC, 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. Diagnostic criteria for Birt–Hogg–Dubé include early-onset renal cancer (patient aged <50 years) and multifocal or bilateral occurrence of tumors with chromophobe and oncocytic histology [5].

Treatment

Most RCC are highly resistant to both chemotherapy and radiotherapy. chRCC with sarcomatoid differentiation are an important exception from this rule and tend to respond to chemotherapy [1]. Otherwise, surgery is opted for whenever the patient's general condition doesn't rule out the corresponding intervention. Partial and radical nephrectomy are most commonly carried out. In this context, nephron-sparing surgery should be preferred over more radical interventions in order to maintain kidney function. Lymphadenectomy is recommended in case of visible or palpable adenopathy and needn't be done preventively. Selected patients suffering from stage 1 renal cancer may alternatively be considered for ablative therapies like cryotherapy, radiofrequency ablation, and embolization [6].

In case of surgically unresectable chRCC, 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. 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. However, therapeutic targets are yet to be defined in chRCC. Further research is urgently required to expand the limited knowledge in this regard: Overexpression of the proto-oncogenes MET and KIT has been described in chRCC and although no mutations have been detected in these genes, constitutively active tyrosine kinases may be assumed to promote tumor growth, invasiveness and the formation of metastases [7] [8]. They may also render the tumor susceptible to drugs like cabozantinib, imatinib or sunitinib [5] [7]. A similar situation is given concerning the use of mTOR inhibitors to counteract a possible overactivation of mTOR pathways [4] - no treatment recommendations will be published until clinical evidence is provided. Indeed, the NCCN Guidelines for Kidney Cancer explicitly recommend the enrollment in an appropriately designed clinical trial for patients with non-clear cell RCC [6].

Prognosis

chRCC are associated with an overall favorable prognosis, particularly because most patients are diagnosed in early stages of the disease [1]. However, large tumors may metastasize to the liver and such disease progression may drastically worsen an individual patient's prognosis. chRCC progresses to metastatic renal cell carcinoma in 6-7% of affected individuals [1]. Five-year-survival rates range between 78 and 92% [1] [3].

Etiology

chRCC may originate from the intercalated cells of cortical collecting ducts, but little is known about the precise causes of sporadic chRCC. Still, 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 chRCC. Obesity, 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 chRCC [9].

People may also develop chRCC as a symptom of inherited cancer susceptibility syndromes [5]:

  • A predisposition for chRCC has been described in patients suffering from Birt–Hogg–Dubé syndrome. Birt–Hogg–Dubé syndrome is an autosomal dominant disorder caused by mutations in the FLCN gene. It is associated with fibrofolliculomas, pulmonary cysts and spontaneous pneumothorax, and renal cancer. With regard to renal cancer in Birt–Hogg–Dubé syndrome, the most common type of neoplasm is an unusual hybrid tumor presenting features of oncocytoma and chRCC.
  • Genes SDHB, SDHC, and SDHD encode for components of the succinate dehydrogenase complex. Mutations in these genes have been related to the onset of paragangliomas, pheochromocytomas, and distinct types of RCC.

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 chRCC in approximately 5% of those cases [9]. Disease incidence peaks in the 5th and 6th decade of life. The diagnosis of chRCC in early adulthood should raise suspicion as to an underlying cancer susceptibility syndrome such as Birt–Hogg–Dubé syndrome. Contrary to other types of RCC, chRCC affects men and women almost equally [1].

Sex distribution
Age distribution

Pathophysiology

Numerous chromosomal and gene aberrations have been detected in chRCC. Loss of chromosomes 1, 2, 6, 10, 13, 17, and 21 has been described repeatedly and probably results in loss of tumor suppressor genes, thereby promoting tumor growth. In fact, loss of chromosomes 2, 10, 13, and 17 can be shown in >90% of all cases [1]. On the other hand, renal cancer may be facilitated by the overexpression of proto-oncogenes like MET and KIT as well as by mTOR upregulation [7] [8].

Prevention

At this time, no measures can be recommended to prevent sporadic chRCC with certainty. The individual risk of chRCC, 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 chRCC may benefit from genetic counseling.

Summary

Approximately 90% of all kidney cancers are RCC, so this type of tumor is the most common malignancy affecting the kidneys [9]. According to their histological features, several types of RCC are distinguished, namely clear cell, papillary, and chromophobe renal cancer. 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 [10]. About 5% of RCC are chRCC [9].

The term "chromophobe" refers to the pale aspect of most cells comprising this type of renal cancer. It should be noted, though, that chRCC may contain varying proportions of eosinophilic cells, too. Cytoplasmic Hale colloidal iron staining is considered the most reliable criterion for chRCC diagnosis. Treatment recommendations vary according to tumor grades and stages, but most patients undergo surgery because RCC don't typically respond to chemotherapy or radiotherapy. chRCC are unlikely to metastasize and while the risk of local relapse shouldn't be underestimated, this type of cancer is associated with a favorable prognosis and five-year-survival rates of up to 90% [1] [3].

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. Chromophobe RCC account for about 5% of all cases.

In this context, the term "chromophobe" refers to the pale aspect of most cells comprising this type of renal cancer. This and other features of tumor cells can only be observed microscopically. There are no specific symptoms indicating the presence of chromophobe RCC. Indeed, most patients with renal cancer are diagnosed incidentally because the tumor doesn't cause any complaints. If affected individuals experience RCC-related symptoms, these may comprise flank pain, hematuria and a palpable abdominal mass, but also fatigue, fever, night sweats, loss of appetite and weight. But, as mentioned above, chromophobe RCC are usually detected during imaging studies realized for other reasons.

The majority of patients diagnosed with chromophobe RCC undergoes surgery. This type of tumor doesn't typically respond to chemotherapy or radiotherapy, but it is generally diagnosed in early stages and can be resected completely. Chromophobe RCC are associated with a better prognosis than other types of RCC and five-year-survival rates of up to 90%.

References

Article

  1. Vera-Badillo FE, Conde E, Duran I. Chromophobe renal cell carcinoma: a review of an uncommon entity. Int J Urol. 2012; 19(10):894-900.
  2. Hoffmann NE, Gillett MD, Cheville JC, Lohse CM, Leibovich BC, Blute ML. Differences in organ system of distant metastasis by renal cell carcinoma subtype. J Urol. 2008; 179(2):474-477.
  3. 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.
  4. 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.
  5. Haas NB, Nathanson KL. Hereditary kidney cancer syndromes. Adv Chronic Kidney Dis. 2014; 21(1):81-90.
  6. 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.
  7. Erlmeier F, Ivanyi P, Hartmann A, et al. c-Met in chromophobe renal cell carcinoma. Med Oncol. 2017; 34(2):15.
  8. Zimpfer A, Janke S, Hühns M, et al. C-kit overexpression is not associated with KIT gene mutations in chromophobe renal cell carcinoma or renal oncocytoma. Pathol Res Pract. 2014; 210(8):521-525.
  9. Ljungberg B, Campbell SC, Choi HY, et al. The epidemiology of renal cell carcinoma. Eur Urol. 2011; 60(4):615-621.
  10. 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.

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Last updated: 2019-07-11 20:05