Discussion
MA was well recognised as a distinct entity in 1988 and was subsequently considered to be a separate entity [
3]. The concept of MA has recently been broadened to include MAs, adenofibromas and stromal tumours. There is a female preponderance and a peak age of occurrence in the fifth or sixth decade of life. MA constitutes approximately 0.2% of all adult renal epithelial neoplasms. The incidence of MA in our institution accounts for <1% of all renal tumours, similar to previous reports. Approximately 100 cases of MA have been reported in the English-language literature to date [
1]. However, most reports focused mainly on pathology; few reports on the clinical or radiological features are available.
Histogenetically, MA contains renal epithelial or stromal cells. It is postulated to be a benign counterpart of Wilms’ tumour and may be derived from remnants of metanephric blastemal or embryonic renal tissue. MA is considered to represent the most hyperdifferentiated end of the nephroblastoma spectrum and might sometimes coexist with Wilms’ tumour [
4]. The genetic profile and chromosomal abnormalities of MA are distinct from those of papillary renal cell carcinoma and Wilms’ tumour. The simultaneous presence of
BRAF gene mutation and 2p deletion plays a great role in the pathogenesis of MA [
5].
Microscopically, the tumour cells have uniformly small and indistinct nucleoli with scanty cytoplasm. Variable proportions of cells proliferate with the formation of small glomeruloid bodies. Immunohistochemical staining shows that most tumour cells are positive for MIB-1, vimentin, EMA, WT-1, and CD57; in contrast, CK7 staining exhibits weak focal positivity. In rare cases, the tumour cells have epithelial elements, lack the typical architecture of tubules and glomeruloid bodies, and show atypia and mitotic activity. Atypical MA needs to be differentiated from Wilms’ tumour, nephrogenic rests, and papillary renal cell carcinoma [
6]. MA has morphological similarities to solid papillary renal cell neoplasms; both exhibit significant similarities such as well-circumscribed tumours comprising small tightly packed cells arranged in solid sheets or ill-defined tubules. Some of the morphological features overlap; thus, the differential diagnosis is crucial. MA must also be distinguished from metastatic cancers, particularly those of the thyroid gland and lung. Despite the overlapping features, careful morphological evaluation, especially immunohistochemical staining with CD57, WT1, and CK7, may be useful for differentiation and accurate diagnosis. Meanwhile, genetic analysis may facilitate discrimination in difficult cases. The presence of cytological atypia, mitoses, and anaplastic foci favour the diagnosis of malignant MA, especially distant metastasis. Malignant MA tumours such as metanephric adenocarcinoma, mixed MA, and papillary carcinoma have also been reported [
7].
Surprisingly, tumours with typical histological characteristics of MA can present with metastatic disease [
2]. Although the natural history of these composite tumours is unknown, they theoretically exhibit aggressive behaviour and the potential for metastasis. In the present study, MA with other concomitant tumour types was determined to be composite MA. This was based on the existing literature stating that a tumour mainly comprising MA that exhibits sporadic concurrent tumours should be classified as a subtype of MA. Composite MA with a co-existing malignant component such as papillary renal cell carcinoma also has metastatic potential [
8,
9]. The features of these composite tumours are emphasised to promote a better and broader understanding of this uncommon tumour. Notably, oncocytic carcinoma, renal adenocarcinoma, and chromophobe cell carcinoma mixed with MA were reported for the first time in the present investigation. Meanwhile, the cells of two tumours had atypical epithelial elements and mitotic activities, lacked the typical architecture of tubules, and glomeruloid bodies, and were pathologically diagnosed as malignant MA; one tumour was found to be a lung metastasis 46 months postoperatively. The pathological criteria of malignant MA are not well established, and rare metastatic MA has been reported. In contrast to typical MA, malignant MA comprises hypercellular uniform cells in a solid-acini pattern; the cells are variable in size, the nucleoli are prominent, and some cells show increased numbers of mitoses with small uniform nuclei. The diagnosis of malignant MA requires the incorporation of clinical information, histopathological features, and related immunohistochemical staining markers.
Clinically, MA occurs predominantly in adult women and rarely in children,the reported age ranged from 15 months to 83 years [
10]. Most patients with MA are asymptomatic or present with nonspecific clinical manifestations such as haematuria, a palpable mass, flank pain, or chyluria [
11]. Polycythaemia, which may be associated with para-neoplastic syndrome, is frequently reported among patients with MA. Most patients in the present series were asymptomatic, and no special symptoms were noted. The regular performance of physical examinations has led to a rise in the incidental detection of asymptomatic renal masses. Additionally, MA may be multifocal or bilateral [
12,
13]. Laboratory tests would be less useful in this setting because no special tumour markers are noted. Urinalysis and renal and hepatic function tests were essentially within normal limits in our series.
Various imaging modalities may be used to characterise MAs. With respect to echogenicity, MA is a hypovascular tumour and has most often been described as a hyperechoic mass [
14]. However, the tumours in the present study were hypoechoic, isoechoic, and hyperechoic in nine, four, and five patients, respectively. Abdominal three-phase contrast-enhanced CT was performed in all 18 patients, and no obvious correlations between morphologic features and characteristic CT imaging features were found. No radiological findings were of substantial help in differentiating MA from malignant renal tumours, especially for small masses. In our series, data on the tumour-spreading patterns, lymphadenopathy, and enhancement patterns were recorded and retrospectively analysed. An enlarged lymph node was noted in one patient; the node was pathologically proven to have an inflammatory reaction, similar to a pseudometastatic lesion. The most common CT imaging characteristic was the presence of homogeneous and well-defined solid renal masses (n = 15, 83.3%), and the least common was the presence of heterogeneous or centrally located low-attenuation masses (n = 3, 16.7%). Contrast-enhanced CT revealed hypoattenuating heterogeneous masses with varying degrees of contrast enhancement in 16 (88.9%) patients, while 2 (11.2%) did not show increased attenuation. On unenhanced CT, one tumour (5.6%) showed scattered calcification with higher attenuation than the renal parenchyma. MA appears to be more commonly calcified than other neoplasm [
15], which is speculated to be related to the presence of psammomatous calcification or a high nuclear-to-cytoplasmic ratio. Less frequently reported is hypoattenuation or predominantly cystic lesions consistent with necrosis [
16]. The hypovascularity of MA seems to reflect the histological findings of mainly acinar and tubular patterns with few vessels. The magnetic resonance imaging features of MA are unspecific; limited cases showed hypointense or isointense lesions on both T1- and T2-weighted magnetic resonance images [
17].
Given the rarity of this tumour and lack of pathognomonic clinical and radiographic criteria, pathologic examination is necessary to establish a definitive diagnosis. Because of the undetermined radiological characteristics of MA, several reports recommend percutaneous fine-needle aspiration to confirm the diagnosis preoperatively [
18]. However, differentiation of MA from Wilms’ tumour based on fine-needle aspiration biopsy may be difficult [
19]. MA may be mixed with other neoplasms that may not be detected by intraoperative biopsy; thus, intraoperative frozen section is not recommended.
From a diagnostic and therapeutic viewpoint, most renal masses should be regarded as malignant and managed surgically; the exception is small renal masses with clinically benign behaviour. Accurate preoperative diagnosis could facilitate optimal management. More widespread recognition of this rare tumour and its subtypes is of great importance for appropriate management of this disease. Our initial classification of three subtypes of MA may contribute to the establishment of guidelines for the management of MA and help in selecting an appropriate surgical method.
Awareness of these subtypes may avoid diagnostic confusion, especially when percutaneous biopsy is indeterminate. When choosing a treatment modality, it might be possible to propose conservative treatment or active surveillance, especially in patients with contraindications to surgery [
20]. It should be emphasised that these tumours may not be entirely benign and that their biologic behaviour is uncertain, particularly malignant tumours and those with malignant components. Thus, careful active surveillance may be needed even for MAs of <4 cm. Continued growth or metastatic potential may be lethal; in our opinion, therefore, MA should be routinely resected. Although nephron-sparing surgery is currently the reference standard treatment for clinically localised T1a renal tumours, subjective clinical factors such as surgeon biases and tumour characteristics, including the growth pattern, more likely influence the decision-making process regarding the most appropriate treatment method. Small renal tumours, especially exophytic and peripheral tumours, are ideal candidates for nephron-sparing surgery, either open or laparoscopic partial nephrectomy [
21]. Several efficacious therapeutic procedures, such as cryoablation or radiofrequency ablation, are alternative treatment options [
22]. In our series, 14 patients underwent radical nephrectomy and only four underwent partial nephrectomy. Most of our patients underwent nephrectomy mainly because of the difficult preoperative differentiation of their lesions from malignant renal tumours. Because imaging is unable to exclude renal cell carcinoma, centrally located or anatomically complex masses should be treated by radical nephrectomy [
23].
Patients with MA treated with partial or total nephrectomy have an excellent prognosis. Only one patient in the present series developed distant metastasis 46 months after surgery. Long-term active surveillance is necessary because of the uncertainty of the biological behaviour and potentially composite malignant components of MA. Further studies on various subtypes are needed to identify the possibility or occurrence of metastasis. Metastatic MA containing foci of papillary carcinoma to local lymph nodes were reported in one study; surprisingly, however, the metastatic lesion was an MA, not a papillary carcinoma [
7]. Therefore, aggressive intervention is needed for composite MA with a coexisting malignant component.
There were several limitations in the present study. First, the retrospective design and involvement of a single centre might have introduced patient selection bias as well as treatment bias with respect to surgeon preference. Additionally, the time interval of 10 years may have changes in surgical techniques in our institute. Second, there was lack of further molecular analysis of each subtype to elucidate its histogenesis. Third, certain limitations were unavoidable considering the relatively small number of patients and the scarcity of different tumour subtype variants. Moreover, it was not possible to determine the percentage of morphological differentiation in the whole group of specimens. Because only two malignant cases were included in this study, statistical analysis and determination of significant differences were limited.
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Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
GL and TY conceived and directed the project. RZ, HS, SZ and YN analyzed data and wrote the paper. All authors read and approved the final manuscript.