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Abstract

Renal tumors in the pediatric age group are a unique group of tumors that are generally quite distinct from tumors arising in the adult kidney. This review covers benign and malignant renal tumors commonly presenting in the pediatric population. Pertinent clinical, epidemiologic, macroscopic, and microscopic features are included. Key histologic differential diagnoses are addressed. Diagnostic evaluation, including immunohistochemical staining and molecular analysis, is presented.

Keywords

Wilms tumor cystic nephroma congenital mesoblastic nephroma rhabdoid tumor renal medullary carcinoma DICER1-associated renal sarcoma clear cell sarcoma of the kidney metanephric stromal tumor metanephric adenofibroma

INTRODUCTION

Primary kidney tumors in the pediatric population are a diverse group of benign and malignant entities, generally quite distinct from tumor types found in the adult kidney [1–3]. This review is intended to provide a general approach to the pathologic evaluation of pediatric renal tumors.

MACROSCOPIC CONSIDERATIONS

A pediatric kidney tumor is typically received by pathologists as an intact resection specimen resulting from a complete or partial nephrectomy. This is because performing needle biopsy or other incisional biopsy could theoretically cause “tumor spillage,” and in the event of malignancy, this would upstage the patient, perhaps resulting in a requirement for more intensive chemotherapy. Depending on the location of the tumor, additional tissue may be resected, for example, the ipsilateral adrenal gland and variable lengths of ureter or renal vein. In the United States and Canada, pediatric renal tumors that are amenable to resection generally are not treated with chemotherapy until after the resection, once a tissue diagnosis has been confirmed. In Europe and other countries, the practice is typically to give chemotherapy preoperatively for presumed Wilms tumor (since this is the most common pediatric renal tumor). This can result in shrinkage of Wilms tumors, which is thought to lower the risk of intraoperative rupture. Postoperatively, further therapy is then tailored based on pathologic findings. In both scenarios, the pathologists’ work on a renal tumor typically involves identifying the specific tumor type, and in the case of malignancy, providing information about macroscopic extent of disease (staging).

During macroscopic prosection, the pathologist (or assistant) examines the resected tumor for signs of rupture (preoperative or intraoperative), inspects the renal vein for tumor/thrombus, and applies ink to key margin sites. Specimen weight is also assessed. Because Wilms tumors are particularly soft and prone to disruption (Fig. 1a), it is advisable to make limited cuts into the tumor and then allow time for formalin fixation before more detailed sectioning. Minimizing manipulation of the specimen prior to fixation can help prevent tumor from artifactually being squeezed into hilar blood vessels and lymphatic channels, or from being smeared along surgical margins in a manner that can interfere with histologic interpretation of staging parameters. Tissue from the unfixed cut surface of tumor and uninvolved kidney can be gently removed and frozen for potential ancillary studies. Samples for histologic examination typically include at least one section per centimeter of tumor (focusing on relationships to adjacent nonneoplastic hilar and capsular tissue, as well as uninvolved kidney for identification of nephrogenic rests), hilar lymph nodes, and selected surgical margins. Molecular studies are becoming increasingly important in tumor risk stratification and treatment; freezing of tumor and uninvolved kidney, as well as nephrogenic rests if present, is advisable in case they are needed for this purpose. Specific recommendations for macroscopic handling of pediatric renal tumors are provided in greater detail elsewhere [4–6].

Figure 1.

Wilms tumor occupying the lower pole and midportion of a nephrectomy specimen from a 3-year-old male. The mass is bulging, tan-white, and soft, with sharply demarcated borders (a).Cystic nephroma in a nephrectomy specimen from a 12-year-old female. Thin-walled cysts lined by bland epithelial cells that are flat to “hobnailed.” There is no substantial stromal cellularity (b). Metanephric adenofibroma, in a partial nephrectomy specimen from a 16-year-old male. Uniform bland round primitive epithelial cells comprise the epithelial component (lower half), and spindle cells in a collagenous stroma comprise the stromal component (upper half) (c).Wilms tumor (nephroblastoma) in a radical nephrectomy specimen from a 2-year-old female. The tumor shows triphasic morphology, including undifferentiated blastemal components (lower left), and intermixed tubular and stromal components (upper right). Multiple perilobar nephrogenic rests were present (not shown) (d).Congenital mesoblastic nephroma, cellular variant, in a radical nephrectomy specimen from a one-month-old female. Fascicles of plump spindle cells with occasional mitotic figures (e).Clear cell sarcoma of the kidney in a radical nephrectomy specimen from a 19-year-old male. Nests of ovoid cells with varying amounts of pale cytoplasm are separated by a network of delicate “chicken-wire” vasculature. Abundant clear cytoplasm imparting a “clear cell” appearance may not always be readily apparent (f).

STAGING CONSIDERATIONS

In the United States and Canada, tumor extent is reported using the Children’s Oncology Group (COG) staging system [7], summarized in Table 1. This staging system is recommended for all pediatric renal tumors except for renal cell carcinoma [4]. In stage I, tumor is limited to the kidney and completely resected with an intact capsule, without renal vein involvement. The tumor cannot have been biopsied or ruptured prior to removal. In stage II, tumor extends beyond the kidney with regional extension (i.e., vascular invasion outside the renal parenchyma, invasion into the renal sinus, or invasion through the capsule) but is completely resected. Stage III includes tumors with intra-abdominal lymph node metastasis, incompletely resected tumor, tumor spill, or piecemeal excision. In stage IV, hematogenous metastasis or metastasis to lymph nodes outside the abdomen is present. Stage V indicates bilateral disease.

Table 1.

Children’s Oncology Group staging system for pediatric renal tumors other than renal cell carcinoma.

Stage I	- Tumor limited to kidney and completely resected - Renal capsule intact and no tumor present in perirenal fat or adrenal gland - Tumor not ruptured - Tumor not biopsied before removal (applies to pretreatment specimens only) - No residual tumor apparent beyond margins of resection - Renal vein and renal sinus vessels contain no viable tumor - No infiltration of the renal pelvis or ureteral walls - No lymph node involvement by viable or non-viable tumor or distant metastases
Stage II	- Viable tumor extends beyond the kidney but is completely resected with negative margins - Regional extension of tumor (vascular invasion outside the renal parenchyma or within the renal sinus, extensive renal sinus soft tissue invasion, invasion of the renal pelvis or ureteral walls, and/or capsular penetration or extracapsular tumor with negative excision margin)
Stage III	- Nonhematogenous metastases confined to the abdomen (e.g., tumor in regional lymph nodes) - Abdominal tumor implants on or penetrating the peritoneum - Macroscopic or microscopic tumor remains postoperatively (tumor at margins of resection) - Tumor rupture/spill before or during surgery - Piecemeal excision of the tumor (removal in more than 1 piece) - Tumor biopsy before surgery and therapy (does not apply when staging post-therapy specimens)
Stage IV	- Hematogenous metastases or lymph node metastases outside the abdomino-pelvic region (beyond renal drainage system, e.g., lung, liver)
Stage V	- Bilateral renal involvement at diagnosis

In Europe and other countries where preoperative chemotherapy is routine (see section on Macroscopic Considerations), the International Society of Pediatric Oncology (SIOP) staging system may be applied [5, 8]. The two staging systems are fairly similar, although a substantial difference is that in the SIOP system stage I tumors may have undergone prior sampling by fine needle aspiration or core needle biopsy.

BENIGN TUMORS

Cystic nephroma

Pediatric cystic nephromas are benign tumors that usually occur early in life, with a median age of 16 months, although they can be found in children of any age. They are most commonly identified incidentally or may present as a palpable abdominal mass. They are associated with germline or somatic mutations in the DICER1 gene [9–10]. Cystic nephromas in the pediatric population are distinct clinically, histologically, and genetically from the lesion termed “adult-type cystic nephroma,”which is considered to be in the spectrum of mixed epithelial and stromal tumor.

Macroscopic examination of a cystic nephroma usually reveals a well-circumscribed cystic mass consisting of thin-walled cysts containing serous fluid. Histologic examination reveals variably sized simple cysts lined by a single layer of histologically bland epithelial cells that are flat to cuboidal, often with a hobnail appearance (Fig. 1b). Fibrous septa dividing the cysts have sparse cellularity without cytologic atypia; they can contain inflammation and benign epithelium-lined tubules [11]. Although cystic nephromas are benign lesions, patients with cystic nephroma, and potentially their family members, are at risk of developing other conditions associated with DICER1 mutation. This includes nodular hyperplastic thyroid, thyroid carcinoma, pleuropulmonary blastoma, Sertoli-Leydig cell tumor, cervicovaginal rhabdomyosarcoma, and other types of neoplasia.

Clinically and histologically, the differential diagnosis of cystic nephroma includes nonneoplastic pediatric cystic renal disease, including polycystic kidney disease and renal cystic dysplasia. In addition, cystic nephroma can be distinguished from adult-type cystic nephroma based on the lack of ovarian-type stroma, stromal hypercellularity, and epithelial complexity. Furthermore, cystic partially differentiated nephroblastoma (described in detail below) may enter the differential diagnosis.

Metanephric stromal tumor/metanephric adenofibroma

Metanephric stromal tumor (MST) and metanephric adenofibroma (MAF) are benign primary renal tumors that consists of metanephric type stroma with (MAF) or without (MST) accompanying epithelial elements. Both tumors occur in young children, at a median age of 2 years. They are usually found incidentally, but children may present with hematuria or hypertension (the latter as a result of juxtaglomerular cell hyperplasia) in some cases [12–14].

Macroscopic examination usually demonstrates a solitary solid lesion, which is unencapsulated, with a yellow-tan to fibrous surface [12, 13]. They can vary widely in size, ranging up to 12 cm [14]. Histologically, both show stroma composed of paucicellular spindled to stellate cells, which can surround or “entrap” underlying renal tubules and blood vessels (Fig. 1c). Some distinctive histologic features, seen in a subset of cases, include the presence of stromal myoid collarettes around entrapped elements (“onion skinning”), heterologous elements (including glial, fatty, or cartilaginous tissue), and angiodysplasia. The angiodysplasia, which consists of epithelioid transformation of arteriolar smooth muscle, can be associated with extratumoral vasculopathy with bleeding complications. Entrapped tubules may show juxtaglomerular hypertrophy, particularly in MST [12, 13]. MAF is distinguished from MST by the presence of epithelial elements that are identical to the epithelium seen in metanephric adenoma.

MST and MAF generally show patchy CD34 immunostaining in stromal elements. Both frequently harbor BRAF V600E mutations (present in stromal and epithelial elements in MAF) [15–17]. Thus, immunohistochemical and/or molecular analysis for BRAF V600E may be a helpful diagnostic tool as needed.

Histologically, an important differential diagnostic consideration includes congenital mesoblastic nephroma (discussed below), another spindle cell proliferation that can entrap renal tubules. However, congenital mesoblastic nephroma lacks some of the distinctive histologic features described above (collarettes, heterologous elements, angiodyspasia, and juxtaglomerular cell hyperplasia), and is furthermore immunohistochemically and molecularly distinct from MST and MAF.

Angiomyolipoma

Angiomyolipomas are benign renal tumors that most commonly arise in adults but may arise in pediatric patients, especially in the setting of tuberous sclerosis complex [18], and should be considered in the differential diagnosis of pediatric renal tumors. As they are more common in adults, they are covered in detail elsewhere in this issue [19].

MALIGNANT TUMORS

Wilms tumor

Wilms tumor, also known as nephroblastoma, is the most common renal tumor of childhood, accounting for >90% of malignant renal tumors in children 7 years of age or less. However, it is still quite rare, with only approximately 650 new diagnoses per year in the United States [1]. It occurs at an average age of 3–4 years, and demonstrates a slight female predominance [20]. The most common presentation is with an abdominal mass, but in some cases the child may present with hematuria, abdominal pain, anemia, or hypertension due to elevated renin production.

Although Wilms tumor is usually unilateral, there may be bilateral and/or multifocal disease in up to 10% of cases, particularly when associated with a cancer predisposition syndrome. Other clues of a possible underlying predisposition syndrome, which accounts for 10–15% of Wilms tumors [21], include presence of multicentric disease, early onset (less than 2 years of age), presence of multiple nephrogenic rests, or clinical features of specific predisposition syndromes. Some of the more common germline conditions that predispose to Wilms tumor include WT1-associated syndromes (including WAGR syndrome and Denys-Drash syndrome), familial Wilms tumor, childhood overgrowth syndromes (including Beckwith-Wiedemann syndrome, among others), and a number of other tumor predisposition syndromes [1, 21].

Macroscopic examination most commonly demonstrates a solid, occasionally cystic, grey-tan, well-demarcated mass, which is soft and friable in texture. Tumors subjected to preoperative chemotherapy often show prominent hemorrhage and necrosis.

Wilms tumor classically demonstrates “triphasic” histology on microscopic examination, consisting of blastemal, epithelial, and stromal components (Fig. 1d). Blastemal elements consist of densely packed undifferentiated small cells with scant cytoplasm and brisk mitotic activity. Epithelial elements range from primitive rosette-like structures to varying degrees of tubular and glomeruloid differentiation. Stromal components usually consist of primitive appearing loose, fibroblastic stroma, but may differentiate towards skeletal muscle or other mesenchymal line.

Nephrogenic rests are conceptualized as precursor lesions to Wilms tumor. Nephrogenic rests consist of groups of persistent nephrogenic cells that resemble developing kidney. The identification of nephrogenic rests in a kidney harboring Wilms tumor is significant because their presence, whether perilobar (located at the periphery of the renal lobule, usually multiple) or intralobar (located within the renal lobule, often singular), is associated with high rates of synchronous bilateral disease [22], and requires clinical monitoring. Young children (<1 year) with nephrogenic rests, particularly perilobar, appear to be at higher risk of developing contralateral disease [23]. However, all children with nephrogenic rests identified, regardless of age or location, will receive similar clinical follow-up.

In Wilms tumor, the most important histologic feature correlating with prognosis is the presence or absence of anaplasia; this refers to large tumor cells (at least 3 times the size of surrounding tumor cells) with nuclear hyperchromasia and atypical mitotic figures. Focal anaplasia, which refers to one or more sharply demarcated intrarenal foci of anaplasia, has a similar prognosis to Wilms tumor without anaplasia; diffuse anaplasia indicates a worse prognosis with decreased survival [24].

Treatment for Wilms tumor ideally occurs in the context of a clinical trial, such as those offered by COG and SIOP. Specific approaches are discussed in detail elsewhere [1, 25, 26]. Fortunately, with modern treatment approaches, overall survival is high (90%) [27].

Mesoblastic nephroma/congenital mesoblastic nephroma

Mesoblastic nephroma, also known as congenital mesoblastic nephroma (CMN), is a renal tumor of mesenchymal cells with fibroblastic differentiation [28]. Although rare, it is the most common renal tumor presenting in the first month of life [29]; 90% present within the first 9 months of life and 10–15% are detected prenatally [30].

CMN are categorized by their histologic appearance as either classic (approximately 25% of CMN), cellular (approximately 65%), or mixed (approximately 10%) variants, with classic variant presenting at a median age of 7 days and the cellular variant presenting at a median age of 4.6 months [31]. The classic variant shows intersecting fascicles of bland, uniform fibroblastic spindled cells without prominent mitotic activity. They often have an irregular border, with “finger-like’ projections of the tumor into the surrounding kidney. Islands of hyaline cartilage and entrapped renal structures may also be seen. The cellular variant displays greater cellular density, increased mitoses, and pushing borders (Fig. 1e). The subtypes are both morphologically and molecularly distinct, with EGFR internal tandem duplication in the classic variant [31] and ETV6::NTRK3 or variant fusions in the cellular variant [1, 32–34]. The mixed variant can show either molecular finding. Infantile fibrosarcoma is a low-grade malignant neoplasm that arises within soft tissue and has overlapping features with the cellular variant of CMN, including morphologic appearance, age of presentation, and prognosis. Furthermore, they share the same molecular driver, ETV6::NTRK3 or variant fusions. For these reasons, cellular CMN is considered the renal counterpart to infantile fibrosarcoma.

Other considerations in the differential diagnosis of CMN may include metanephric adenofibroma, clear cell sarcoma of the kidney, particularly the spindle cell variant, or occasionally blastemal-predominant Wilms tumor, although the latter would not be expected to demonstrate the infiltrative borders of CMN and would be rare in very young infants. Each of these tumors is molecularly distinct from CMN.

CMN is considered a tumor of low malignant potential, with an extremely small risk of metastasis. Surgical resection is nearly always curative, although recurrences may occur if resection is incomplete [35]. Outcomes are excellent, with 5-year overall survival of over 95% [30].

Clear cell sarcoma of the kidney

Clear cell sarcoma of the kidney (CCSK) is a rare malignant renal neoplasm that arises during childhood, most commonly between the ages of 2–3 years [36], and composes approximately 3–5% of pediatric renal tumors. Macroscopic examination most frequently reveals a large (mean size 11 cm) solitary mass centered in the renal medulla. They are usually described as tan-grey and fleshy. Necrosis and prominent cyst formation may be seen [36, 37].

CCSK may demonstrate a variety of histologic patterns on microscopic examination. However, the classic pattern is almost always present in some amount, characterized by nests of cords of ovoid cells with round vesicular nuclei and pale cytoplasm within a characteristic arborizing “chicken wire” vascularized septal network (Fig. 1f). Other histologic patterns include myxoid, sclerosing, cellular, epithelioid, palisading, spindle, storiform, and anaplastic; multiple patterns are typically present in one tumor. Tumor necrosis is the only histologic factor known to indicate a less favorable prognosis [37].

Molecularly, the majority (greater than 90%) of CCSKs have BCOR in-frame internal tandem duplications [38, 39]. Less common molecular drivers include BCOR::CCNB3 gene fusion [39, 40] or YWHAE::NUTM2 gene fusion [41]. Each of these molecular events results in upregulation of BCOR.

When the classic pattern is not present or is scant, several other tumor types may enter the differential diagnosis, including stromal-predominant Wilms tumor or congenital mesoblastic nephroma, particularly if the spindled pattern of CCSK predominates. Positive BCOR and cyclinD1 [42–44] immunostains are diagnostically useful, as is molecular confirmation of a characteristic gene alteration.

Accurate diagnosis of CCSK is important to ensure appropriate treatment, as they are aggressive tumors (overall survival 69%) which are commonly present in regional lymph nodes at the time of presentation and are prone to metastasizing to bone, lungs, brain, and other organs, but have improved outcomes when treated with doxorubicin [36].

Rhabdoid tumor

Rhabdoid tumors are rare (1–2% of pediatric renal tumors), aggressive, malignant tumors that arise in young children, with a median age at presentation of approximately 1 year [45–47]. They most often present with abdominal mass or hematuria, and approximately 20% present with hypercalcemia due to production of parathyroid hormone-related protein [48]. They were originally described in the kidney, but arise in other locations including soft tissue, liver, and in the brain as atypical teratoid/rhabdoid tumor (AT/RT).

Histologic examination reveals sheets of discohesive tumor cells with characteristic “rhabdoid” morphology, which refers to abundant eosinophilic cytoplasm with inclusions (composed of intermediate filaments) and eccentrically placed large nuclei with prominent nucleoli (Fig. 2a). Histologic patterns include sclerosing, epithelioid, spindled, lymphomatoid, vascular, pseudopapillary, and cystic [47]. The tumor’s line of differentiation (“cell of origin”) is unknown.

Figure 2.

Rhabdoid tumor in a nephrectomy specimen from an eight-month-old male. Sheets of highly atypical cells show irregular nuclei, vesicular chromatin, prominent nucleoli, and frequent eosinophilic cytoplasmic inclusions, imparting a classic “rhabdoid” morphology (a).Primary DICER1-associated renal sarcoma in post-chemotherapy nephrectomy specimen from a 2-year-old male. Immature, round cell component, with adjacent rhabdomyosarcomatous elements. Elsewhere, there were primitive cartilage nodules, adipose tissue, and mucinous epithelium (not shown) (b).Cystic partially differentiated nephroblastoma, identified incidentally in a 1-year-old female with bilateral nephrectomy undertaken due to germline WT1 variant and end-stage renal failure. Cystic spaces are lined by bland epithelium, with subjacent primitive tubular structures. Given the genetic milieu, the tumor might be best viewed as an “incipient Wilms tumor” (c). Renal cell carcinoma with TFE3 translocation in a partial nephrectomy specimen from a 20-year-old female. Tubulopapillary architecture, with papillary cores lined by large cells showing abundant clear cytoplasm and discrete cell borders (d). Renal medullary carcinoma in a 13-year-old female with a mass arising in an allograft kidney from a donor with sickle cell trait. Cells show large round nuclei with open chromatin and nucleoli; cytoplasm is eosinophilic. Neutrophilic inflammation is prominent (e). ALK-rearranged renal cell carcinoma in a 6-year-old male with sickle cell trait. Polygonal cells show abundant eosinophilic cytoplasm with frequent clear cytoplasmic valuoles. Photo courtesy of Antonio Perez-Atayde, M.D., Ph.D. (f).

Molecularly, rhabdoid tumors are characterized by SMARCB1 loss-of-function alterations, and thus exhibit loss of INI-1 staining by immunohistochemistry [49, 50]. A small number (5%) instead have loss-of-function variants in SMARCA4 with BRG1 loss by immunohistochemistry [51]. Up to one third of patients with rhabdoid tumor harbor germline alterations in one of these genes, constituting rhabdoid tumor predisposition syndrome [47].

Loss of INI-1 staining by immunohistochemistry has high specificity for rhabdoid tumor in an infant kidney, and it can be useful in ruling out other tumors that may have similar morphology, such as Wilms tumor with rhabdoid features, which shows retained INI-1 staining. However, it is important to note that renal medullary carcinoma may also show loss of INI-1 staining (see separate section on primary carcinoma of the kidney), but is typically associated with sickle cell trait.

Rhabdoid tumors of the kidney behave aggressively with significantly worse prognosis that other pediatric renal tumors discussed thus far, with 5-year survival of approximately 25% [52, 53]. Metastases, particularly to lungs, liver, and brain, are frequent, and widespread hematogenous and lymphatic spread is common. Presentation at a younger age is associated with worse prognosis [46, 52].

DICER1-associated renal sarcoma

DICER1-associated sarcomas of the kidney have been reported under several other names, including “anaplastic sarcoma of the kidney”, “dedifferentiated cystic nephroma”, or “embryonal sarcoma of the kidney” [54–56]. It is debatable whether “Wilms tumors” harboring DICER1 variants might also belong in this category. Tumors often show areas resembling cystic nephroma along with solid malignant components (Fig. 2b); fully solid tumors have also been described, often showing anaplasia [55]. It is an unresolved matter whether tumors showing epithelial differentiation are better termed DICER1-associated Wilms tumor versus DICER1-associated renal sarcoma. In the appropriate clinical scenario, the differential diagnosis can include metastasis from pleuropulmonary blastoma or other malignant extra-renal DICER1-associated sarcoma; molecular analysis may be helpful in discerning this.

Cystic partially differentiated nephroblastoma

When a pediatric renal tumor that otherwise has the histologic appearance of cystic nephroma shows primitive cells with high nucleus-to-cytoplasm ratio within the cyst lining (Fig. 2c), the diagnosis of cystic partially differentiated nephroblastoma (CPDN) is considered. When these are associated with DICER1 mutations, they can be conceived of as analogous to pleuropulmonary blastoma in the lung, which is thought to exist along a spectrum of benign to malignant based on the degree and nature of the accompanying solid component. In the kidney, when a solid proliferation is benign or of uncertain malignant potential, the term cystic partially differentiated nephroblastoma may be appropriate. When frank malignancy is evident, the term DICER1-associated renal sarcoma (or DICER1-associated anaplastic sarcoma, as appropriate) is preferred. (See separate section below.) CPDN is not well-defined in the current edition of the Pediatric World Health Organization classification of tumors [2], although in the Genitourinary World Health Organization classification of tumors it is listed as a distinct entity [57]. It remains unresolved whether the term is appropriate for largely cystic Wilms tumors with areas resembling cystic nephroma and variably cellular stromal elements, from which it historically takes the name cystic partially differentiated “nephroblastoma” [58]. Genetic testing can make this distinction, and we advocate for the use of diagnostic terminology that clarifies whether an individual “CPDN” is part of the DICER1 spectrum of renal tumors or whether it is better viewed as falling within the spectrum of Wilms tumor, since currently the term CPDN is ambiguous.

Primary carcinoma of the kidney

Primary carcinomas of the kidney are uncommon in children; renal cell carcinomas (RCC) account for less than 5% of pediatric renal neoplasms. Most RCC arising in the pediatric kidney are characterized by known molecular alterations. Some of the most common are discussed below.

RCC with MiT family translocations

Tumors with translocations in the MiT family of genes (which include TFE3, TFEB, MITF, and TFEC) comprise 40% of pediatric RCC. To date; only TFE3- and TFEB-rearranged RCC have been reported in pediatric patients; MITF-rearranged RCC is an emerging subtype that to date is confined to adults, and TFEC-rearranged RCC has never been reported. Within the pediatric age group, TFE3- and TFEB-rearranged RCC most commonly affect older children and teenagers; in the population as a whole, they are most common in adults (mean age 25) [59, 60]. Exposure to cytotoxic chemotherapy is a risk factor for the development of these tumors, and a subset of pediatric patients with MiT family translocation RCC have sickle cell trait or disease [61].

Histologically, RCC with MiT family translocations generally have papillary or nested architecture, cells with voluminous clear to eosinophilic cytoplasm, psammoma bodies, and variably hyalinized stroma. Specifically, TFE3-rearranged RCC (also known as Xp11.2 translocation RCC) usually shows papillary architecture and epithelioid cells with abundant clear to eosinophilic cytoplasm and discrete cell borders (Fig. 2d), although the morphologic spectrum varies widely. Psammomatous calcifications are often observed. TFEB-rearranged RCC (also known as t(6;11) RCC) often displays biphasic morphology, with nests of small cells clustered around basement membrane material, and surrounding larger epithelioid cells with abundant clear cytoplasm and distinct cell borders [62]. The two tumor types can show significant overlap with each other and with other renal neoplasms, including MITF-rearranged RCC, clear cell RCC and papillary RCC, among others.

Immunohistochemistry may help differentiate MiT family translocation-associated renal cell carcinomas from histologic mimics. In particular, immunohistochemical markers for TFE3 [63] and TFEB [64] are sensitive and specific markers for the presence of their respective fusions. In the absence of demonstrations of TFE3 or TFEB staining by immunohistochemistry, molecular confirmation is required to make the diagnosis of renal cell carcinoma with MiT translocation by FISH break-apart probe or RNA sequencing [65]. Of note, some perivascular epithelioid cell tumors (PEComa) may also harbor TFE3 fusions [66]; TFE3-rearranged RCC may be distinguished from PEComa by the presence of definitive epithelial differentiation and PAX8 staining in RCC.

Understanding of the outcomes of MiT translocation RCCs in the pediatric population is limited, but in adult patients TFE3-rearranged RCC appears to have a somewhat aggressive clinical course with outcomes similar to clear cell RCCs [67, 68]. In the pediatric population, it appears to behave more indolently, perhaps related to lower number of copy number alterations present in pediatric patients compared to adults, which has been shown to be associated with better outcomes [69]. Late recurrences (20–30 years after initial presentation) are known to occur. Although there are only a limited number of reported cases, TFEB-rearranged RCC appears to have a good prognosis, with only four reported patients demonstrating metastases of approximately 50 cases reported in the literature [65].

SMARCB1-deficient renal medullary carcinoma

SMARCB1-deficient renal medullary carcinoma is a rare primary carcinoma that has an even stronger association with sickle cell trait and disease than MiT family translocation RCC. SMARCB1-deficient renal medullary carcinoma occurs more commonly in males (M:F approximately 2 : 1) at a median age of 21 years [70]. Most patients present with flank or abdominal pain, hematuria, dysuria, or abdominal mass [71]. It is proposed that the hypoxic environment in sickling hemoglobinopathy promotes DNA damage which leads to inactivating SMARCB1 alterations. SMARCB1-deficient renal medullary carcinoma occurs more frequently in the right kidney, which may be due to differing blood flow leading to a more hypoxic environment in the right kidney [72].

As the name implies, SMARCB1-deficient renal medullary carcinoma most commonly arises within the renal medulla. Macroscopically, it consists of a grey-white mass with infiltrative borders. Histologically, tumors may display a variety of patterns, with malignant epithelial cells growing in cords, tubules, microcysts, or nests and sheets of cells within a prominent desmoplastic stroma. Individual tumor cells are often pleomorphic and highly atypical, occasionally with a “rhabdoid” appearance characterized by eccentric nuclei with eosinophilic cytoplasmic inclusions, as are common in other SMARCB1-deficient tumors (Fig. 2e). Sickled red blood cells can be seen in susceptible patients. Loss of nuclear INI-1 expression by immunohistochemistry supports the diagnosis, as does molecular testing demonstrating an inactivating SMARCB1 alteration. In children, the differential diagnosis includes rhabdoid tumor (see separate section) which also show loss of INI-1 expression but may be differentiated, somewhat arbitrarily, by history of hemoglobinopathy, older age of presentation in medullary carcinoma, and medullary location. Another diagnostic consideration includes ALK-rearranged RCC (discussed below).

Renal medullary carcinoma has a universally poor prognosis. Patients usually present with advanced disease; over 90% of patients have metastatic disease at the time of diagnosis. Overall survival is 4 months in patients presenting with metastatic disease, and 17 months in patients without metastatic disease [70]. However, recent clinical trials have demonstrated some improvements, showing partial responses or stable disease with newer chemotherapeutic regimens [73, 74].

ALK-rearranged RCC

ALK-rearranged RCC is another rare tumor type, with only approximately 40 reported cases. Specifically, tumors with VCL::ALK gene fusion distinctively present in young patients with sickle cell trait or disease [75–78]. Macroscopically, they are well-circumscribed masses. Histologically, the neoplastic epithelial cells show abundant eosinophilic cytoplasm and prominent clear cytoplasmic vacuoles (Fig. 2f). Similarly to medullary carcinomas, sickled red blood cells may be identified. Positive ALK immunohistochemistry is helpful in supporting the diagnosis, although molecular testing confirming the presence of ALK fusion is recommended for definitive diagnosis. There are too few reported cases to definitely understand the prognosis of renal carcinomas with VCL::ALK gene fusion. For unresectable primary tumors or metastases, targeted ALK inhibitor therapy may be an effective treatment option.

CONCLUSION

To summarize, pediatric renal tumors represent a diverse group of entities with distinctive pathologic features. Diagnostic considerations and differential diagnoses in this age group differ substantially from those in adult renal tumors.

Footnotes

ACKNOWLEDGMENTS

The authors have no acknowledgments.

FUNDING

The authors report no funding.

AUTHOR CONTRIBUTIONS

Both authors contributed to the writing and editing of the manuscript.

CONFLICTS Of INTEREST

Dr. Vargas reports Advisory Board/Consulting income from Millipore Sigma, Vertex Pharmaceuticals, and various medicolegal entities; she reports grant support from the Chan-Zuckerberg Initiative. Dr. Alston declares no potential conflicts of interest with respect to the research, authorship, and/or publication of this project.

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Pathology of Pediatric Renal Tumors

Abstract

Keywords

INTRODUCTION

MACROSCOPIC CONSIDERATIONS

STAGING CONSIDERATIONS

BENIGN TUMORS

Cystic nephroma

Metanephric stromal tumor/metanephric adenofibroma

Angiomyolipoma

MALIGNANT TUMORS

Wilms tumor

Mesoblastic nephroma/congenital mesoblastic nephroma

Clear cell sarcoma of the kidney

Rhabdoid tumor

DICER1-associated renal sarcoma

Cystic partially differentiated nephroblastoma

Primary carcinoma of the kidney

RCC with MiT family translocations

SMARCB1-deficient renal medullary carcinoma

ALK-rearranged RCC

CONCLUSION

Footnotes

ACKNOWLEDGMENTS

FUNDING

AUTHOR CONTRIBUTIONS

CONFLICTS Of INTEREST

References