Renal cell carcinoma: histological classification and correlation with imaging findings (2024)

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Abstract

Renal cell carcinoma (RCC) is the seventh most common histological type of cancer inthe Western world and has shown a sustained increase in its prevalence. Thehistological classification of RCCs is of utmost importance, considering thesignificant prognostic and therapeutic implications of its histological subtypes.Imaging methods play an outstanding role in the diagnosis, staging and follow-up ofRCC. Clear cell, papillary and chromophobe are the most common histological subtypesof RCC, and their preoperative radiological characterization, either followed or notby confirmatory percutaneous biopsy, may be particularly useful in cases of poorsurgical condition, metastatic disease, central mass in a solitary kidney, and inpatients eligible for molecular targeted therapy. New strategies recently developedfor treating renal cancer, such as cryo and radiofrequency ablation, molecularlytargeted therapy and active surveillance also require appropriate preoperativecharacterization of renal masses. Less common histological types, although sharingnonspecific imaging features, may be suspected on the basis of clinical andepidemiological data. The present study is aimed at reviewing the main clinical andimaging findings of histological RCC subtypes.

Keywords: Renal cell carcinoma, Kidney cancer, Computed tomography, Magnetic resonance imaging

Abstract

Os carcinomas de células renais (CCRs) são o sétimo tipohistológico de câncer mais comum no mundo ocidental e vêmapresentando uma tendência mantida de aumento em sua prevalência. Aclassificação histológica dos CCRs é de extremaimportância, uma vez que a determinação dos subtiposhistológicos tem significativas implicações prognósticase terapêuticas. Os métodos de imagem têm destacadaimportância no diagnóstico, estadiamento e seguimento dos pacientes comCCR. As variantes histológicas mais comuns são células claras,papilífero e cromófobo. A caracterizaçãoradiológica dos subtipos de CCRs, seguida ou não de biópsiapercutânea confirmatória, é particularmente útil empacientes sem adequadas condições cirúrgicas, pacientes comdoença metastática, pacientes com rim único e lesãocentral, e em pacientes candidatos a terapia de alvo molecular. As novasestratégias, recentemente desenvolvidas, para o tratamento do câncerrenal, como crio e radiofrequência, terapia molecular alvo e vigilânciaativa também exigem adequada caracterizaçãopré-operatória das massas renais. Os subtipos histológicos menoscomuns, apesar de não terem achados de imagem específicos, podem sersuspeitados com base em dados clínicos e epidemiológicos.

INTRODUCTION

Renal cell carcinomas (RCCs) are the seventh most common histological type of cancer inthe Western world and have maintained an increasing prevalence^(1,2), representing 1% to 3% of all malignant visceral neoplasms.Approximately 40% of patients with RCC die because of the disease progression, thus thistumor is the most lethal malignant urological tumor. Currently, most RCCs areincidentally found at imaging investigations, whether for urological reasons or not.There is a clear predominance of men among patients with RCC, representing two thirds ofcases.

The histological classification of RCCs is extremely important, considering thesignificant implications of the subtypes in the prognosis and treatment of thesetumors^(3,4). As already known, with the recent developments inimmunohistochemistry, imaging-guided percutaneous biopsy became a minimally invasivemethod with relatively high accuracy (70-90%) in the preoperative histopathologicalcharacterization of renal tumors^(5,6). However, despite its minimuminvasiveness, percutaneous biopsy involves risks and limitations and currently it isonly indicated in cases where a renal tumor cannot be radiologically characterized or inspecific clinical situations.

In this context, a preoperative radiological characterization of RCCs subtypes is ofutmost importance and, depending on the clinical situation, it may be supplemented ornot by confirmatory percutaneous biopsy. Such a procedure is particularly useful incases of patients with poor surgical condition, metastatic disease, solitary kidney andtumor lesion difficult to be treated by conservative surgery, and in patients eligiblefor molecular targeted therapy^(7-10).

About two decades ago, RCCs were divided between clear cell and granular cellvariants⁽³⁾. Currently,according to the 2004 WHO classification, several histological RCC subtypes arerecognized (Table 1). The most frequenthistological subtypes include clear cell renal cell carcinomas (ccRCC), papillary renalcell carcinomas (pRCC), and chromophobe renal cell carcinomas (crRCC) (Figure 1). These three subtypes together representmore than 90% of all RCCs⁽¹¹⁾.

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Figure 1

Histology of the most common RCC subtypes. A: Clear cell RCC – cellswith lipid-rich ample cytoplasm, hence the name of the neoplasm. B:Type 1 Papillary RCC – small basophilic cells with scarce cytoplasm, organized ina spindle-shaped pattern, in a single layer of cells surrounding the basalmembrane. C: Type 2 Papillary RCC – cells organized in aspindle-shaped pattern with papillae covered by cells with abundant eosinophilicgranular cytoplasm with prominent nucleoli. D: Chromophobe RCC –large pale cells with reticulated cytoplasm and perinuclear halos. E:Collecting duct RCC – histology shows an irregular, infiltrating cells arrangementin the collecting duct walls, showing remarkable desmoplasia. F:Medullary RCC – it originates in the distal nephron, also with an irregular cellarrangement, remarkable pleomorphism and hyperchromatic nuclei.

In 2013, the International Society of Urological Pathology (ISUP) proposed a new RCCclassification including the WHO proposal, but suggesting the inclusion of five new,well-characterized types of renal neoplasm and three additional types considered as newand emerging entities⁽¹²⁾.

Imaging methods play a relevant role in the diagnosis of RCCs, determining a tendencytoward the diagnosis of tumors at earlier stages, besides being essential for stagingand therapeutic planning⁽¹³⁾.

Recently, some studies have demonstrated that imaging methods can differentiate clearcell renal cell carcinomas from the papillary and chromophobe histological types whichare respectively the second and third most common RCC types⁽¹⁴⁾. In addition to the traditional techniques withevaluation of density, signal intensity and pattern of intravenous contrast uptake bythe lesion, other techniques, particularly quantitative magnetic resonance imaging (MRI)with diffusion-weighted and perfusion imaging have been employed in the characterizationof renal epithelial neoplasms.

The present article is aimed a reviewing the main histological characteristics andimaging findings of the main histological RCC variants, correlating them with clinicalcases observed in the authors' institution.

CLEAR CELL CARCINOMA

This is the most common variant, representing between 70% and 75% of all RCCs^(3,7). Most clear cell carcinomas (95%) are sporadic, and the remaining 5%are associated with hereditary syndromes (von Hippel-Lindau disease, tuberoussclerosis). Clear cell RCC originates from the proximal convoluted tubules epithelium(renal cortex) e presents a predominantly expansile growth pattern. Macroscopically, itis a solid, yellowish lesion with variable degrees of internal necrosis, hemorrhage andcystic degeneration. Such findings are most frequently observed in large-volume,fast-growing tumors. Tumor calcifications may also be found. Histologically, suchlesions present clear cells because of their lipid- and glycogen-rich cytoplasmiccontent⁽⁴⁾. Frequently, suchtumors also present cell with eosinophil granular cytoplasm. The imaging findings arecompatible with such histopathological features, identifying hypervascularized andheterogeneous lesions due to necrosis, hemorrhage, cysts and calcifications. Necrosis ismore common in larger lesions, generally with dimensions > 4 cm. The rate ofoccurrence and degree of necrosis have also been associated with high-grade tumorhistology^(15,16). At computed tomography (CT), such tumors usuallypresent with intense contrast uptake in the corticomedullary phase (120-140 HU) andtypical washout in the nephrographic phase (90-100 HU) (Figure 2).

At MRI, signal intensity similar to the one of the renal cortex at T1-weighted images,and hypersignal at T2-weighted images. Because of the presence of intracellular lipidcontent, other finding observed in up to 60% of ccRCC is signal loss at out-of-phaseimage as the chemical shift imaging technique is employed⁽¹⁷⁾ (Figure 3). Itshould be observed that this is a nonspecific finding of ccRCC, since it may also beseen in angiomyolipoma without macroscopic fat and, more rarely, also in pRCC. ccRCC mayalso present a hypo-dense pseudocapsule in the corticomedullary phase at CT, and withhyposignal at MRI T1- and T2-weighted sequences. Discontinuity of this pseudocapsulegenerally indicates a high-grade tumor. The comparative analysis of the lesion signalintensity in the corticomedullary phase at contrast-enhanced MRI is an effective tool inthe differentiation between ccRCC and pRCC. Quantitative analysis of the contrast uptakeby tumors at multiphase examinations (corticomedullary, nephrographic and excretoryphases) demonstrated that the percentages of signal alteration in the three phases aftercontrast injection in relation to the pre-contrast phase were significantly higher inccRCC (230%, 250% and 227% for the corticomedullary, nephrographic and excretory phases,respectively) than in pRCC (49%, 92% and 88% for the corticomedullary, nephrographic andexcretory phases, respectively), or in crRCC (98%, 183% and 159% corticomedullary,nephrographic and excretory phases, respectively)⁽¹⁴⁾.

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Figure 3

Clear cell RCC variant. MRI with the chemical shift imaging technique. In phase(A) and out of phase (B) images showing expansile,solid lesion in the right kidney (arrows) presenting with subtle signal loss inthe out of phase sequence, that is difficult to be visualized, characterized onlyby the signal intensity loss índex corresponding to 11% (signal intensityloss index = in phase signal intensity – out of phase signal intensity / in phasesignal intensity × 100).

Although with still controversial results, until the present moment, the utilization ofMRI diffusion-weighted imaging has not been useful in the differentiation of RCChistological subtypes⁽¹⁸⁾.

Another relatively common finding of these lesions is extension toward the perirenalfat, renal sinus fat and into the renal vein and inferior vena cava. In the presence ofvenous invasion, perirenal collateral venous circulation is commonly observed.

Hematogenous metastases are relatively common in clear cell carcinomas and affectprincipally the lungs, liver and bones⁽¹⁹⁾. Lymph node metastases are described in up to 15% of cases. As ageneral rule, ccRCC carries a worse prognosis than the other two more commonhistological subtypes (pRCC and crRCC)^(4,11).

PAPILLARY CARCINOMA

The papillary variant of this tumor is the second most common histological RCC subtype,representing about 10% of cases in the several series in the literature^(3,4). It may also occur sporadically or as a familial condition. On itsturn, this variant presents two subtypes based on the histological appearance andbiological behavior of the lesion, with quite distinctive prognosis. However, thesesubtypes cannot be preoperatively differentiated with the current imagingtechniques⁽²⁰⁾.

Histological findings include cells organized in a spindle-shaped pattern and possibleareas of internal hemorrhage and cystic alterations, particularly in largerlesions⁽¹¹⁾.

Type 1 (basophilic) pRCC presents a single layer of basophilic cells surrounding thebasal membrane. These small cells present scarce clear cytoplasm and hyperchromaticnuclei. On its turn, the histological subtype 2 (eosinophilic) presents with papillaecovered by cells with abundant granular eosinophilic cytoplasm, with prominent nucleoliassociated with areas of necrosis. Generally, pRCCs carry a better prognosis thanccRCCs. Type 1 pRCC is typically detected at earlier stages and lower grades than type 2pRCC and therefore are associated with a better prognosis. Usually, at diagnosis, type 2pRCC appears as a high-grade tumor, frequently associated with ganglial metastasis and,in some cases, with venous invasion. Papillary RCCs tend to be solid, well defined,slow-growing lesions⁽²¹⁾. Also, theytend to be bilateral (4%) and/or multifocal (22.5%) and are associated with acquiredchronic renal disease.

At CT and MRI, such tumors tend to appear more hom*ogeneous than ccRCC and hypovascularas compared with the adjacent renal parenchyma^(15,16,22). In the corticomedullary phase at contrast-enhanced CT,these tumors tend to present a mean density ranging between 50-60 HU, and 65-75 HU inthe nephrographic phase (progressive uptake). At MRI, papillary carcinomas frequentlymanifest as peripheral lesions with intense hyposignal on T2-weighted images (Figure 4), presumably due to the intratumoralhemosiderin content⁽²³⁾ or to theirarchitectural arrangement. Lesions > 4.0 cm in diameter may be heterogeneous due tothe presence of necrosis, hemorrhage and calcification. Only rarely these tumors maypresent internal foci of macroscopic fat (interstitial macrophage with cholesterol) oreven intracytoplasmic fat and, in this case, signal loss is also observed on the out ofphase sequence at chemical shift imaging.

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Figure 4

Papillary RCC variant. A: MRI, axial, T2-weighted image showingexpansile, hom*ogeneous lesion with intense hyposignal. B:Contrast-enhanced MRI, axial, T1-weighted image showing a remarkably hypovascularlesion in relation to the adjacent cortex.

Papillary RCCs may also present as neoplastic cystic lesions, generally with hemorrhagiccontent and hypovascular mural solid papillary projections.

CHROMOPHOBE RENAL CELL CARCINOMA

Chromophobe RCC represents about 5% of all malignant renal epithelial tumors, and ismost frequent in the sixth decade of life. Such a subtype is less aggressive thanccRCC^(3,11), and carries the best prognosis amongst RCCs.Metastasis occurs in only 7% os cases. Pathologically, such a less aggressive variant isorange colored turning grey after fixation. At microscopy, these tumor present largepale cells with reticulated cytoplasm and perinuclear halos. In the presence ofsarcomatoid transformation, the lesion become more aggressive, with a considerably worseprognosis^(3,24). Some pathologists believe that there is a very closerelationship between the chromophobe variant and oncocytomas. Both would be originatedfrom collecting ducts intercalated cells and constitute common associated findings incases of Birt-Hogg-Dubé syndrome⁽²⁵⁾.

At imaging studies, chromophobe carcinomas tend to be more hom*ogeneous than clear cellcarcinomas^(13,14,21). Such lesionsare hypovascular as compared with the renal cortex, and most of times present a moderatecontrast uptake (80-100 HU in the corticomedullary phase at CT scan), and therefore lessintense than the clear cell variant, and more intense as compared with the papillaryvariant⁽²¹⁾ (Figure 5). Not rarely, however, crRCC may appear as ahom*ogeneous and remarkably vascularized lesion in the corticomedullary phase (120-140HU). At MRI, the lesion tends to present a slight hyposignal or intermediate signalintensity at T2-weighted sequences (Figure 6), andalso may present a central scar. It is important to note that findings of crRCC areindistinguishable from those of oncocytomas (benign tumors originated from intercalatedtype B cells of the cortical collecting ducts), which may also present a central scar.Necrosis may occur in the voluminous lesions.

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Figure 5

Chromophobe RCC. CT, corticomedullary (A) and nephrographic(B) phases showing expansile, solid lesion with hom*ogeneouscontrast uptake, with mean density = 92 HU and 126 HU, respectively.

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Figure 6

Chromophobe RCC. MRI, axial T2-weighted image identifying expansile, welldelimited lesion in left kidney, with intermediate signal intensity, a distinctpseudocapsule (arrow) and a central scar area.

COLLECTING DUCT CARCINOMA (BELLINI DUCT CARCINOMA)

This rare RCC variant represents less than 1% of all malignant kidney tumors, but it isimportant to highlight the high aggressiveness of this lesion^(3,9,26), whose prognosis is quite unfavorable since 30% ofpatients already present with metastasis at the diagnosis, and 60-70% of them die withina two-year period⁽²⁷⁾.

Histologically, collecting duct renal cell carcinoma (cdRCC) is characterized by anirregular, infiltrating cells arrangement in the collecting duct walls, showingremarkable desmoplasia⁽¹³⁾. A subtlemale prevalence is observed, and in general such lesions show up after the fifth decadeof life. At imaging studies, cdRCCs appear as heterogeneous lesions with extremelyvariable signal intensity on T2-weighted sequences, depending on the amount ofhemorrhage, necrosis, cystic component and calcification; and frequently presenthyposignal at those sequences (Figure 7). Ingeneral, and typically, the lesions originate in the medulla, implying a differentialdiagnosis with transitional cell carcinoma⁽²⁸⁾. Larger lesions may invade the cortex. Most of these lesions aresolid, but some of them may present as complex lesions⁽²⁶⁾. They are hypovascular at multidetector CT as well asat MRI, tending to heterogeneous or peripheral contrast uptake.

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Figure 7

Collecting duct RCC. A: MRI, coronal plane, T2-weighted image showingexpansile, irregular lesion in the upper pole of left kidney, with heterogeneoussignal intensity and predominance of hyposignal (asterisk). B:Contrast-enhanced MRI, axial, T1-weighted image. The lesion presents predominantlyperipheral, heterogeneous signal intensity, considerably less intense than therenal cortex.

MULTILOCULAR CYSTIC RENAL CELL CARCINOMA

It is a very infrequent lesion, with incidence ranging between 1-4% of allRCCs⁽²⁹⁾, with prevalence in men(male/female ratio 3:1) at mean age of 50 years. This tumor appears as a multiseptatedcystic lesion separated from the kidney by a fibrous capsule⁽¹⁶⁾. It carries an excellent prognosis and can becompletely cured. Recurrence and metastasis have not been described.

Histopathological analysis reveals serous, gelatinous or hemorrhagic cysts lined by asingle layer of small collections of epithelial cells with clear cytoplasm. Developmentof solid nodules is not observed. This finding differentiates multilocular cystic RCCfrom ccRCC with extensive cystic degeneration⁽³⁰⁾.

Calcification in septa or in the pseudocapsule occurs in up to 20% of cases. At CT andMRI, these tumors appear as complex cysts, classified as II-F to IV categories accordingto the Bosniak system⁽¹⁶⁾ (Figure 8).

MEDULLARY RENAL CELL CARCINOMA

This rare variant of RCC was first described in 1995 by Davis. Some pathologistsconsider this variant as a cdRCC subtype⁽³¹⁾. Besides being rare, it is an extremely aggressive tumor,originating in the distal nephrons, from the collecting duct cells. A remarkable featureof this histological tumor subtype is its association with sickle cell disease andsickle cell trait. Typically, as a result from such association, medullary renal cellcarcinomas affect young patients at the second and third decades of their lives.

At imaging studies, this tumor appears as infiltrating lesions causing calycealobstruction and dilatation. It is a hypovascular lesion (Figure 9) and is frequently associated with locoregionaladenopathy⁽³²⁾.

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Figure 9

Medullary RCC. Male, 25-year-old patient with sickle-cell disease.Contrast-enhanced CT image showing extensive, solid, hypovascular, predominantlymedullary and slightly heterogeneous lesion in the right kidney. Observe theinfiltrating feature of the lesion in the pyelocalyceal system (arrow) and in theproximal portion of the ureter.

RENAL MUCINOUS TUBULAR AND SPINDLE CELL CARCINOMA (MTSCC)

This recently described, very rare renal tumor originates from distal convoluted tubulecells and collecting ducts. A clear female prevalence is observed, generally withoccurrence in the fourth and fifth decades of life^(3,11). It is considered to bea low-grade neoplasm, and among the few cases described in the literature up till thismoment, none presented proliferation. At histology, this tumor is composed of denselyclustered cells intermingled with clear mucinous stroma and a well defined spindle cellcomponent⁽⁴⁾.

At imaging studies, MTSCCs do not present any typical feature, and in the few casesreported until de present moment they appear as circ*mscribed nodules or massesincidentally found at ultrasonography and CT. Typically, these tumors tend to behom*ogeneous, with low signal intensity at T1-weighted sequences and intermediate toslightly hyperintense signal at T2-weighted sequences⁽²²⁾. Some of these lesions may present with an irregularcentral scar. After intravenous contrast agent injection, it is hypovascular in relationto the adjacent cortex, and in cases where a central scar is present (Figure 10) the tumor may present variableopacification degrees⁽³³⁾.

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Figure 10

Renal mucinous tubular and spindle cell carcinoma. Female, 57-year-old patientwith hematuria. A: MRI, T2-weighted image showing expansile lesionwith intermediate signal intensity, and (B) contrast-enhancednephrographic phase showing hypovascular lesion – compare with the cortex (arrow).Observe the hyposignal of the scar (asterisk). Despite the large dimensions of thelesion, it is well delimited, with no infiltrating feature. C:Surgical specimen showing a circ*mscribed, yellowish lesion with central scar(asterisk).

RENAL CELL CARCINOMA ASSOCIATED WITH CHROMOSOME'S SHORT ARM TRANSLOCATION

This is a recently described and quite rare type of neoplasm, whose origin involves theTFE3 gene and 11 Xp11.2 chromosome's short arm translocation^(3,4). In general,this neoplasm is found in children and young adults. As regards pathological findings,macroscopically it resembles a ccRCC and appears as a well delimited mass withpseudocapsule. Histologically, however, it presents papillary projections resembling apRCC. It carries a more indolent prognosis as compared with the clear cellvariant⁽³⁴⁾. There is nocharacteristic finding for these lesions which in general may appear as heterogeneouslesions, particularly the larger and hypervascular ones⁽³⁵⁾.

RENAL CELL CARCINOMA ASSOCIATED WITH NEUROBLASTOMA

This is also an exceptionally rare. There are only few cases described in the literatureabout children who developed RCC after being treated for neuroblastoma^(3,36). It may be either uni- or bilateral and there is no predilectionfor gender. Considering that it occurs after treatment for neuroblastoma, generally itaffects young patients at a mean age of 13 years. In the rare cases described, this typeof neoplasm appears as a well delimited, hypovascular lesion, generally with a moreindolent behavior⁽³⁴⁾.

UNCLASSIFIED RENAL CARCINOMAS

Even with the classification developed in 2004, 4% to 6% of the neoplasms cannot yet behistologically characterized with accuracy^(3,5), which could be improvedwith the Vancouver classification proposed by ISUP⁽¹²⁾. Tumors in this category are histologically heterogeneous and,in most cases, rated as high-grade lesions. Some findings are useful to identify suchlesions, as follows: presence of sarcomatoid component without any recognized epithelialelements; production of mucin; presence of mixed stromal and epithelial elements; andnon-recognized cell types⁽³⁷⁾. Thiscategory includes the histological RCC subtypes with worst prognosis.

CONCLUSION

The histological classification of RCCs is of utmost importance, considering thesignificant prognostic and therapeutic implications of its histological subtype, andhence the relevance of the role played by the radiologist in the preoperative imagingrecognition of the histological RCC subtypes. Currently, better results have beenachieved in the differentiation between clear cell renal cell carcinomas and non clearcell RCCs in the daily clinical practice. It is expected that results of furtherprospective studies add new information to the current body of data about thismatter.

Footnotes

References