Diagnostic Approaches to Adult Cystic Nephroma: Insights From Two Cases

Introduction

Mixed epithelial and stromal tumors encompass a group of neoplasms ranging from predominantly cystic masses to lesions with a variable solid component. According to the World Health Organization (WHO) classification, this group includes adult cystic nephroma and mixed epithelial and stromal tumor (MEST) [1]. Such tumors are more common in middle-aged women, with a male-to-female ratio of 1: 7 [2,3]. In most cases, patients are asymptomatic; however, some may present with hematuria, lumbar or abdominal pain, urinary tract infections, or a palpable mass [4].

Adult cystic nephroma is a well-circumscribed, solitary tumor composed of numerous non-communicating cysts lined by flat to columnar or hobnail epithelium. The intercystic septa consist of fibrous stroma, often with areas of cellular condensation resembling ovarian-type stroma. This entity has been associated with hormonal imbalances or other hormonal factors [1,5]. Several etiologic theories have been proposed in the literature, ranging from a Müllerian origin to developmental defects [6].

The particular features of cases presented here – diagnosis outside the peak incidence age range (in 1 case), involvement of the mid-renal portion, and compression of the renal hilum – demonstrate that, although adult cystic nephroma constitutes a benign tumor, its clinical manifestations and radiologic features may be misleading and preclude definitive diagnosis preoperatively.

Case Reports

CASE 1:

A 37-year-old woman presented with left lumbar pain and a sensation of heaviness in the affected region. Blood tests revealed no abnormalities. Ultrasound examination identified a well-demarcated multicystic lesion with a maximum diameter of 13 cm involving the upper two-thirds of the kidney. Contrast-enhanced computed tomography (CT) demonstrated a multicystic renal mass with parietal enhancement. No free fluid or lymph node involvement was identified in the abdominal cavity (Figure 1). The initial presumptive diagnosis was a renal hydatid cyst, partly because the patient reported having a pet at home. Preoperatively, she completed a full course of antiparasitic therapy. Surgical management was subsequently performed. Total nephrectomy was selected due to intraoperative findings of renal hilum compression by the lesion. To prevent contamination, the kidney and cystic lesion were covered with compresses soaked in a scolicidal agent, followed by aspiration of the cystic contents and instillation of a scolicidal solution. The choice of total nephrectomy was based on lesion size, hilar involvement, and suspicion of a Bosniak III cyst.

The postoperative course was favorable, without complications. Imaging at the 6-month follow-up showed no additional pathological findings.

Gross pathological examination revealed a left kidney weighing 1100 g and measuring 17×13×6 cm. The upper pole exhibited a nodular, well-circumscribed mass measuring 14×13×6 cm, with involvement of the pyelocaliceal system and compression of the renal hilum. After sectioning, the lesion appeared pseudo-encapsulated and multicystic. The cysts varied in diameter from 0.5 to 1.2 cm and contained clear yellowish fluid.

Microscopically, the cysts were lined by flat to columnar, cuboidal, or hobnail epithelium. The intercystic septa were paucicellular and fibrotic, with diffuse and focal hyalinization (corpus-albicans-like), smooth muscle fibers, and abortive tubular structures. Hyperemia, hemorrhage, and a mild lymphocytic inflammatory infiltrate were also present. The pyelocaliceal system was not infiltrated by the lesion (Figure 2).

To confirm the diagnosis, immunohistochemical staining was performed for estrogen receptor (ER), progesterone receptor (PR), cytokeratin 7 (CK7), paired box gene 8 (PAX8), melanoma antigen A (Melan-A), and Ki-67. The results are summarized in Table 1. The final diagnosis was multilocular cystic nephroma (Figure 3).

CASE 2:

A 54-year-old woman presented with a 2-week history of right lumbar pain and hematuria. Paraclinical investigations and urinalysis revealed no pathological abnormalities. Ultrasound examination identified a well-demarcated multicystic lesion with a maximum diameter of 3 cm, involving the middle third of the kidney. Contrast-enhanced CT demonstrated a 3.5-cm multicystic lesion with parietal enhancement, in contact with the renal hilum. The initial presumptive diagnosis was multicystic renal carcinoma. Given the lesion’s location, hilar involvement, suspicion of a Bosniak III cyst, and the inability to exclude malignancy preoperatively, total nephrectomy was performed. The postoperative course was favorable, without complications. Imaging at the 6-month follow-up showed no additional pathological findings.

Gross pathological examination confirmed the imaging findings, whereby the lesion compressed the adjacent renal parenchyma. Microscopically, cysts of variable diameters were observed, containing hemorrhagic or eosinophilic material and lined by monostratified and focally stratified cuboidal, attenuated, hobnail, or clear cell epithelium. The stroma showed variable cellularity and was fibrocollagenous; it contained areas of edema and zonal hyalinization featuring polycyclic, corpus-albicans-like structures. Areas of ovarian-type stromal condensation were also identified (Figure 4). These findings supported the diagnosis of multilocular cystic nephroma; thus, an immunohistochemical panel was performed to confirm the diagnosis (Table 2). The results validated the final diagnosis of multilocular cystic nephroma (Figure 5).

In both cases, immunohistochemical markers contributed to the differential diagnosis as follows: MEST was excluded based on the typical architecture, specifically the absence of solid expansile stromal areas, although some immunohistochemical overlap was observed. Angiomyolipoma with epithelial cysts was excluded by a negative melanoma antigen A (Melan-A) reaction. Multilocular cystic renal neoplasia of low malignant potential, multilocular cystic renal cell carcinoma, and tubulocystic carcinoma show negative PR immunoreactivity, whereas adult cystic nephroma demonstrates PR positivity.

Molecular testing was not performed in these cases because there was no clinical indication, the associated costs are high, no specific genetic mutations are consistently identified, and endonuclease DICER1 mutations generally are not implicated in the development of this tumor.

Discussion

Adult cystic nephroma is a rare, benign, nonfamilial renal tumor that represents 1% to 2% of all renal tumors [7,8]. First described in 1892 as a cystic adenoma [9], it exhibits a bimodal age distribution. The first peak occurs in early childhood, most commonly in boys aged 2 to 4 years, with a male-to-female ratio of 3: 1. The second peak occurs between the fifth and seventh decades of life, with a clear female predominance (male-to-female ratio of 1: 8 [10]; some authors report a male-to-female ratio of 1: 7 [2,3]). Only 5% of cases occur between 5 and 30 years of age [10]. These tumors may be congenital or acquired; congenital forms are more common in children younger than 2 years [5,11].

The etiology remains controversial. One proposed theory suggests a Müllerian origin, based on the presence of ovarian-type stroma, raising concerns regarding potential malignant transformation [7]. Malignant transformation of the stromal component has been reported in the literature, most commonly as synovial sarcoma, rhabdomyosarcoma, chondrosarcoma, or unclassified sarcoma. The epithelial component may also undergo malignant transformation into undifferentiated large cell carcinoma, borderline mucinous tumor, or endometrioid adenocarcinoma [12]. Another theory proposes a developmental defect with possible neoplastic origin, potentially arising from the ureteric bud [9]. Electron microscopy studies have demonstrated the presence of microvilli and cilia, supporting resemblance to collecting tubules. Mukhopadhyay et al reported that nephroma cells express several immunohistochemical markers of distal and collecting tubules, including epithelial membrane antigen (EMA), cytokeratin 19 (CK19), and the cytokeratin cocktail AE1/AE3, as well as markers of proximal tubules such as cluster of differentiation (CD) 10, CD15, lysozyme, and alpha-1 antitrypsin, suggesting tubular differentiation of nephroma cells [13]. There is no established association with cysts in other organs; only sporadic links to other congenital anomalies have been reported [14].

Clinical manifestations are nonspecific; they may include flank pain, macroscopic or microscopic hematuria, and, less commonly, a painless abdominal mass, urinary tract infection, or arterial hypertension [9,15]. The tumor may also be detected incidentally in asymptomatic patients during routine clinical or imaging evaluations [7].

Imaging evaluation may be performed using ultrasound, CT, or magnetic resonance imaging; however, none of these modalities demonstrates multicystic-nephroma-specific features [9]. CT and magnetic resonance imaging are useful for assessing morphologic characteristics, multilocularity, and lesion circumscription [10]. On ultrasound, hypoechoic cysts separated by hyperechoic septa are observed [9]. CT imaging reveals a well-circumscribed, encapsulated, multicystic mass with septa showing variable contrast enhancement and no contrast excretion into the cysts. Cystic contents demonstrate attenuation similar to or slightly higher than that of simple fluid. When the cysts are very small, the lesion may appear solid [16]. Magnetic resonance imaging demonstrates an encapsulated multicystic mass; the septa are hypointense regardless of the sequence used, and the capsule appears hypointense on T2-weighted images. Cystic contents are hyperintense on T2-weighted images and show variable intensity on T1-weighted images. The septa become enhanced after gadolinium administration [15,16]. Although the lower renal pole is the most common location, any portion of the renal parenchyma may be involved. The average tumor diameter is 10 cm [5,7].

According to the Bosniak classification, cystic nephroma is categorized as Bosniak III; surgical excision is recommended due to the increased risk of malignancy and lack of specific imaging features. Histopathologic examination is required to differentiate it from cystic renal cell carcinoma [17]. In addition to cystic nephroma, this category includes multilocular cysts, hemorrhagic and infected cysts, and cystic renal cell carcinoma, particularly the clear cell and tubulocystic subtypes (Table 3) [17–20].

In the present report, the case 1 tumor measured 14 cm in maximum diameter, raising suspicion of a hydatid cyst on imaging. To our knowledge, only 1 similar case involving a differential diagnosis with a hydatid cyst has been reported in the literature to date [8]. The diagnosis was clarified beginning with gross examination, which revealed a multicystic lesion containing serous fluid, without evidence of a proliferative membrane, pericyst, or clear, water-like fluid characteristic of a hydatid cyst [8]. Microscopic evaluation subsequently established the final diagnosis by confirming diagnostic criteria for multicystic nephroma and the absence of daughter cysts and scolices.

The first diagnostic criteria were proposed by Boggs and Kimmelstiel, then modified by Joshi and Beckwith [7]. These criteria include: a lesion entirely composed of cysts of variable sizes separated by septa; clear demarcation from the surrounding renal parenchyma; the absence of solid components other than fibrous septa; cyst walls lined by flattened, cuboidal, or hobnail epithelium; and septa composed of fibrous tissue that may contain well-differentiated tubules.

Powell et al later formulated 8 diagnostic criteria: unilateral location; solitary mass; multilocular architecture; cysts that do not communicate with the renal pelvis or with each other; epithelial lining of the cysts; absence of normal renal parenchyma within the septa; and normal residual renal tissue adjacent to the tumor [21–23]. Two additional criteria were introduced to differentiate multicystic nephroma from Wilms tumor via cystic changes: the cystic tissue must be completely differentiated, and no embryonal or immature elements should be present [14].

The main entities to consider in the differential diagnosis include MEST, angiomyolipoma with epithelial cysts, multilocular cystic renal neoplasia of low malignant potential, cystic renal cell carcinoma, and tubulocystic carcinoma. In cases with a predominant solid component, adult nephroblastoma, mesoblastic nephroma, sarcomatoid renal cell carcinoma, and metanephric adenofibroma should also be excluded. In certain situations, infectious conditions such as renal abscess, aspergillosis, and echinococcosis may be suspected; these require appropriate diagnostic testing [12,24,25].

Unlike cystic nephroma, MEST demonstrates a more complex architecture, with thicker septa that may expand and form solid areas [5]. It is characterized by a tubulocystic epithelial component associated with a stroma comprising benign spindle cells. Immunohistochemically, the epithelial component expresses cytokeratins, particularly CK7, whereas the stromal component displays vimentin, smooth muscle actin, caldesmon, and desmin. Expression of ER, PR, CD10, calretinin, and inhibin may also be observed [26]. Because the immunohistochemical profiles of MEST and cystic nephroma overlap, differentiation primarily relies on architectural features: MEST contains expansile solid stromal areas, whereas cystic nephroma exhibits a strictly cystic architecture.

Angiomyolipoma with epithelial cysts – a subtype of perivascular epithelioid cell tumor – represents an angiomyolipoma variant with minimal adipose tissue [27,28]. Histopathologically, the tumor consists of cysts lined by flattened, cuboidal, columnar, or hobnail epithelium, supported by a “cambium-type” stroma. The remaining stroma is predominantly composed of smooth muscle fibers [27]. Immunohistochemically, the epithelial component displays cytokeratin positivity. The stromal component expresses human melanoma black 45 (HMB45), Melan-A, CD10, ER, and PR, with stronger staining around the cysts. In contrast, smooth muscle actin and desmin show more intense expression at a distance from the epithelial component [28].

Multilocular cystic renal neoplasia of low malignant potential is characterized by a multilocular cystic architecture. The cysts are lined by uni- or stratified epithelium with clear cytoplasm and low-grade nuclei (WHO grade 1 or 2). Within the capsule or intercystic fibrous septa, small clusters of tumor cells may be present but should not exceed a single 20× (1 mm) microscopic field. Immunohistochemically, this tumor expresses carbonic anhydrase IX (CAIX), EMA, cytokeratin monoclonal antibody CAM5.2, PAX8, and PAX2 [1].

Multilocular cystic renal cell carcinoma is composed entirely of cysts separated by septa containing clear cells arranged singly or in small clusters. The cysts are lined by epithelium with clear cytoplasm and small nuclei lacking prominent nucleoli. Stratified epithelium with granular cytoplasm and small intracystic papillary projections may rarely be observed [1]. Immunohistochemically, this neoplasm displays CAIX, CD10, renal cell carcinoma marker, vimentin, and pan-cytokeratin. High-molecular-weight cytokeratins and CK7 are usually absent [29].

Tubulocystic carcinoma is a rare epithelial tumor with a strictly tubulocystic architecture. Microscopically, it consists of small- to intermediate-sized tubules associated with larger cysts, lined by flattened, cuboidal, columnar, or hobnail unistratified epithelium. Nuclei are large and irregular, and nucleoli are intermediate to large. The cytoplasm is abundant and eosinophilic, whereas the stroma is fibrotic or desmoplastic [1]. Immunohistochemically, this tumor expresses alpha-methylacyl-CoA racemase (AMACR), PAX8, vimentin, keratin, and multiple cytokeratins (CK7, CK8/18, and CK19) [30,31].

In our cases, all of the above entities were excluded based on the identified microscopic features: cystic spaces lined by flattened, cuboidal, columnar, or hobnail epithelium, associated with stroma composed of spindle cells and areas resembling ovarian-type stroma, without pericystic condensation. Concurrent immunohistochemical analysis excluded alternative diagnoses and confirmed cystic nephroma.

For cystic lesions classified as Bosniak III, therapeutic options depend on tumor size and include active surveillance, partial nephrectomy, or radiofrequency ablation, when feasible, with preference for nephron-sparing approaches from an oncologic perspective [32,33]. According to the European Association of Urology, approximately half of such cases undergo excessive surgical treatment, mainly because imaging cannot reliably distinguish benign from malignant lesions [34,35]. The cases presented here illustrate the inherent risk of overtreatment when radiologic classification, lesion location, and tumor size are considered without the ability to preoperatively exclude malignancy.

Nephrectomy is considered appropriate treatment; neither radiotherapy nor chemotherapy is needed [36]. Laparoscopic partial nephrectomy is recommended in patients with preserved renal function, given the benign nature of the tumor, if the renal vasculature has been clearly delineated and lesion margins are well defined [9]. Nephron-sparing surgery is a therapeutic option in children with sufficient renal reserve and has been recommended by Okada et al [9,36,37]. In our cases, nephron-sparing surgery was not pursued. In case 1, the lesion was large and involved more than half of the renal parenchyma. In case 2, the lesion was located in the mid-renal region, in close proximity to the renal hilum.

Moreover, in our case 1, total nephrectomy was selected due to the large tumor size (14 cm), involvement of the pyelocaliceal system, compression of the renal hilum, and classification as Bosniak III, for which surgical treatment is recommended. In case 2, total nephrectomy was performed due to the clinical suspicion of multicystic renal carcinoma, clinical and imaging features that overlapped with malignant lesions reported in the literature, proximity to the renal hilum, and the aim of minimizing recurrence risk or avoiding positive surgical margins.

According to published studies, the long-term prognosis of patients with cystic nephroma is favorable; no recurrences or metastases have been reported after complete tumor excision [38]. These findings are consistent with our cases, in which the tumors were completely resected, the postoperative course was uneventful, and the patients demonstrated normal renal function at the 6-month follow-up, without evidence of recurrence or metastasis.

The limitations of this study include the absence of ultrasound images in both cases and CT images in case 2, which would have facilitated understanding of therapeutic decisions; the small sample size; the retrospective design; and the lack of molecular confirmation.

Conclusions

Cystic nephroma is a rare benign renal tumor, and accurate diagnosis is critical for appropriate management, beginning with imaging evaluation and confirmed by microscopic examination. Immunohistochemical analysis plays an important role not only in confirming the diagnosis but also in differentiating this entity from other cystic renal neoplasms. Nephrectomy alone is effective and usually ensures an excellent prognosis in cases where simple tumor excision or nephron-sparing surgery is not feasible.

The 2 cases presented reinforce these observations through their particular features, including location, size, imaging characteristics, and initial clinical suspicion. Although advanced imaging modalities are widely available and cystic nephroma is a benign tumor with a favorable prognosis, definitive diagnosis may, in some cases, be established only after histopathologic and immunohistochemical evaluation. Thus, an interdisciplinary therapeutic approach is essential to maximize patient benefit while minimizing risk. Genetic studies involving larger patient cohorts may help clarify the etiopathogenesis of this tumor and facilitate earlier diagnosis.