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Renal primitive neuroectodermal tumors.

Primitive neuroectodermal tumors (PNETs), along with Askin tumor and Ewing sarcoma (ES), exist as members of the ES/PNET family of tumors, (1) which comprises 1% of all sarcomas. (2) As their name would suggest, PNETs arise from the cells of the primitive neuroectoderm. (3) Primitive neuroectodermal tumors may occur both within and outside of the central nervous system. (4) Most commonly, peripheral PNETs are found to arise in the chest wall and paraspinal regions. (5) It is less common, although still possible, to see peripheral PNETs in the genitourinary system, as case reports have documented instances of their occurrence in the uterus, (3) epididymus, (3) and bladder. (6)

To our knowledge, the first reported case of a PNET with a renal origin was in 1975, (7) although during the past decade, increasing numbers of case reports and case series have been documented, indicating that this entity may have been underreported or misdiagnosed in the past. (6,8)

In one case series of 52 patients with renal PNETs, the average age for those affected was 26, with 38% of all patients with the tumor between the ages of 20 and 29. (6) Other work has concurred and also placed the average patient age in the mid- to late 20s. (9,10) Overall, 75% of patients with renal PNETs are between the ages of 10 and 39,6 although a wide range of patients have been shown to be susceptible, including children younger than 5 years and persons older than 60 years. (6,10) Both males and females have been shown to be affected, with some work documenting a predominance in males, (10) although this has not been universally confirmed. (3) Typically, whites and Hispanics are the most commonly affected by ES/PNET family tumors, with cases in blacks and Asians occurring rarely. (1)

Renal PNETs present as very clinically aggressive tumors. (3,4,6,10) Cases of local recurrence and metastasis have been shown to comprise more than 50% of the clinical presentations in this cancer, (5) with the most common sites of metastasis shown to be the lymph nodes, lungs, and liver. (6) In a 2001 review of 25 cases of renal PNET, the mean patient survival was approximately 10 months. (11) Other work has shown the overall 5-year disease-free survival rate for peripheral PNETs to be between 45% and 55%. (6)

HISTOGENESIS

Parham et al (8) have suggested that the source of renal PNETs may be the adrenergic fibers that invest in the kidney from the celiac plexus. Additionally, they have also posited that embryonic neural crest cells may migrate into the kidney and then subsequently undergo tumorigenesis.

CLINICAL FEATURES

As previously discussed, renal PNETs typically occur in older children and young adults, (3,6,9,10) a different demographic than the more senior populations traditionally affected by clear cell renal cell carcinomas (RCCs), papillary RCCs, and chromophobe RCCs. (12) Patients with renal PNET may present with malaise, an increase in abdominal circumference, weight loss, nephric colic, fever, flank pain, hematuria, and night sweats. (3,4,6,11) Dysuria, testicular pain, and varicocele have also been reported. (4,6) Dyspnea and dizziness may also be seen if the tumor features atrial involvement. (13)

Laboratory abnormalities that may be seen in renal PNET include elevated lactate dehydrogenase, glutamicoxaloacetic transaminase, glutamic-pyruvic transaminase, and creatinine. (6)

In addition to noting the clinical features present in PNET, it is also important to note the absence of features common to the heredity cancer syndromes that may cause renal neoplasms across this same age range. This includes the ocular and central nervous system hemangioblastomas, pheochromocytomas, or pancreatic tumors indicative of Von Hippel-Lindau syndrome and the fibrofolliculomas or pulmonary cysts often seen in Birt-Hogg-Dube syndrome. (12,14) Additionally, pathologists must also keep in mind that translocation and heredity papillary RCCs may also occur within this same age range. (12)

[FIGURE 1 OMITTED]

MACROSCOPIC FEATURES

Renal PNETs may vary in appearance. Some have been reported to have a dark brown or tan-yellow coloration (3,10) (Figure 1), whereas others appear gray-white. (3,6) In this sense, their gross appearance may not allow them to be exclusively distinguished from the traditionally yellow coloration of clear cell RCCs, the tan-to-yellow variegated appearance of many papillary RCCs, or the pale tan appearance of many chromophobe RCCs. (12) It is also notable that extensive areas of necrosis or hemorrhage may be seen in renal PNETs, which may also alter their gross appearance. (1-3) Renal PNETs are often reported to have a lobular shape, (2,10) and may potentially contain a fibrous capsule or cystic components. (3,6) Many cases have been documented to feature some sort of angiolymphatic invasion, (10) with involvement of the inferior vena cava, renal vein, and tumor thrombus frequently reported. (3,6,13) Extension further up to the right atrium has also been documented. (13) Locally, the tumor itself may replace the renal parenchyma and extend into the perirenal fat. (10)

The size of renal PNETs may vary. In one series of 11 cases of renal PNET, the tumor sizes varied from 8 to 15.6 cm, with a median tumor size of 11.8 cm. (10) Despite this, case reports of renal PNETs 20 cm in size or greater have also been reported. (5,15) As both the size and coloration of these tumors features considerable overlap with more common renal neoplasms, gross examination alone cannot confer a diagnosis of renal PNET. (12)

HISTOPATHOLOGY

Histologically, renal PNETs feature primitive and poorly differentiated cells that are small, are round or ovoid, and have hyperchromatic, irregular, and potentially pleomorphic nuclei (1,3,5,6) (Figure 2, A). Minimal cytoplasm within poorly defined cytoplasmic borders are seen in the tumor cells, and mitotic figures are common. (1,3-5,10) Some cases may also feature vesicular nuclei and small nucleoli. (10)

Collectively, the cells of renal PNETs appear as broad sheets or as fingerlike projections in instances of invasion. There is no differentiation of the tumor cells into glomeruli or tubules, as would typically be seen in Wilms tumors. Additionally, PNETs do not feature cartilaginous or myogenous structures. (10) The most diagnostically useful histologic feature of these tumors is the arrangement of the tumor cells into pseudorosettes, clusters of cells with a neurofibrillary stromal core, which serve to indicate neural differentiation (4-6,8) (Figure 2, B). Additionally, tumor cells in renal PNETs may also be arranged into nests, cords, or clusters. (5,6) It is important to differentiate this histology from the solid acinar structures typical of clear cell RCC, the elongated trabecular growth patterns commonly seen in papillary RCC, or the cobblestone appearance of chromophobe RCC. Such histologic distinctions take on an especial importance when considering that the clear cell morphology common to the renal tumors seen in von Hippel-Lindau syndrome or the chromophobic or oncocytic features frequently noted in the renal tumors of Brit-Hogg-Dube syndrome may aid in distinguishing these entities from renal PNET. (12)

IMMUNOPROFILE

When a diagnosis of renal PNET is being considered, the best approach is to use a full panel of reactants, the most useful of which is CD99 (Figure 3, A). This marker stains almost all cases of PNET. (1,3-6,11) Despite this, CD99 staining has also been reported in cases of, among other tumor types, (1,16) non-Hodgkin lymphoma (5) and Wilms tumor (10); hence, its presence alone is not sufficient for a diagnosis.

In light of this, other markers may contribute to making an accurate diagnosis. CD45, which typically stains positive in non-Hodgkin lymphomas but not in PNETs, is one that may be used. (5) Wilms tumor 1 (WT-1), a common marker for Wilms tumor, may also be used to rule against a PNET diagnosis, (3,10) although in rare instances, it may also stain positive in renal PNETs. (4) In one study, Friend leukemia virus integration 1 (FLI-1) demonstrated positive staining in 5 out of 8 cases of renal PNET and 0 out of 10 cases of Wilms tumor, indicating that this marker may aid in differentiating the two as well. (10) CD56 has been suggested as a marker that frequently stains positive in Wilms tumor or neuroendocrine tumor, but is less common in PNET. (13) Although not specific, other markers demonstrating tissue differentiation have been studied. Neuron-specific enolase has been shown to stain positive in 95% of renal PNET cases. (6,11) Similarly, Leu-7, vimentin (Figure 3, B), S-100 protein, and synaptophysin stain positively in 48% to 70% of cases. (6) Pancytokeratin (AE1/ AE3) has also been found to stain positive in approximately 25% of cases. (10) The Table depicts the more commonly used stains for influencing a diagnosis of renal PNET, and contrasts their expression patterns with those observed in clear cell RCC, papillary RCC, chromophobe RCC, desmoplastic small round cell tumor, primary renal synovial sarcoma, rhabdomyosarcoma, non-Hodgkin lymphoma, and Wilms tumor. (6,17-23) Although to our knowledge, many of the traditional markers studied in renal cancer have not been formally studied in renal PNET because of the limited numbers of identified cases, some work has shown that neuron-specific enolase and synaptophysin may help distinguish renal PNET from these other, more common entities. (6,18) As the Table also illustrates, vimentin, S100 protein, and pancytokeratin may also help differentiate PNET from these other tumors. (6,17,19) As renal specific immunostaining studies for desmoplastic small round cell tumor, rhabdomyosarcoma, and non-Hodgkin lymphoma were not found after an extensive literature search, more work remains to be completed in this area.

[FIGURE 2 OMITTED]

[FIGURE 3 OMITTED]

ULTRASTRUCTURE

In renal PNET, electron microscopy may also indicate the presence of neurosecretory granules, microtubules, and peripheral microfilaments, consistent with neural differentiation. (5,6)

GENETICS

The most common genetic mutation in PNETs is t(11; 22)(q24; q12), which results in the creation of an ES breakpoint region 1 (EWS)/FLI-1 chimeric fusion transcript, which acts as an aberrant transcription factor. (1,16,24) This specific mutation is seen in 85% to 95% of cases of PNET.1,2,10,25 The second most common mutation is an EWS/Ets-related gene (ERG) mutation, t(21; 22)(q22; q12), which occurs in between 5% and 10% of PNETs. (1,25,26) Although mutations involving other members of the erythroblastosis virus-transforming sequence transcription factor family can exist, these are much less common. (1) EWS gene arrangements have been shown to be identifiable using fluorescent in situ hybridization from preparations of fresh and frozen tumor specimens, as well as from those that have already been formalin fixed and paraffin embedded. (1,25) To detect EWS gene rearrangements using fluorescent in situ hybridization, one popular technique has been to use a break-apart fluorescent probe designed to bind complementary sequences flanking each end of the EWS gene, with the probes binding noncontiguously in cases of gene translocation (25) (Figure 4).

In addition to fluorescent in situ hybridization, realtime polymerase chain reaction may also be used to aid in the diagnosis, in which primers designed to amplify fusion genes may also indicate the presence of a genetic alteration. Some have suggested using fluorescent in situ hybridization initially, with real-time polymerase chain reaction most useful to test for false negatives. (27)

DIFFERENTIAL DIAGNOSIS AND DIAGNOSTIC PITFALLS

It is believed that malignant rhabdomyosarcoma, PNET, and ES all have the same mesenchymal precursor, but with different stages of differentiation and malignant characterizations, (28) which enhances both the difficulty and the importance of ensuring that a correct diagnosis is made. In addition to these entities, the differential diagnosis for renal PNET also includes Wilms tumor, neuroblastoma, small cell neuroendocrine tumor, desmoplastic small cell round tumor, RCC, and synovial sarcoma. (2,3,10)

In order to make a diagnosis of renal PNET, one must consider the tumor's morphology, immunostaining profile, and, in some instances, genetic mutations. Perhaps the most important identifying histologic feature to diagnose renal PNET is the presence of pseudorosettes. (6) One of the diagnostic clues to differentiate PNET from ES is that the differentiation of the rosettes is typically greater in PNET than in ES. (5) As a cautionary note, pathologists should also be aware that rosettes may also be seen in neuroblastoma, (28) and hence their presence alone is not sufficient for diagnosis. Normal levels of homovanillic acid and vanillylmandelic acid support a diagnosis of PNET over neuroblastoma. (28)

[FIGURE 4 OMITTED]

CD99 is the most important immunohistochemical marker in making a diagnosis of ES/PNET. (4) As discussed above, it may also be seen in non-Hodgkin lymphomas and Wilms tumors, and has prompted suggestions to expand the immunopanel for potential PNETs. (3,10) Other tumors in which CD99 expression has been reported include synovial sarcomas, desmoplastic small cell tumors, clear cell RCC of the kidney, and rhabdomyosarcomas. (1,16) It is also notable that an EWS gene arrangement, as seen in renal PNET, may also be observed in desmoplastic small round cell tumor, clear cell sarcoma, and neuroblastoma, (25) and again, cannot be relied upon solely to make a diagnosis of PNET.

TREATMENT AND PROGNOSIS

The current treatment for renal PNET may include a combination of surgery, chemotherapy, and radiotherapy. (3,6,11) Cavotomy and thrombectomy have also been performed in cases with a tumor thrombus. (6) In addition to a nephrectomy, (4) surgical resection of other involved organs or vasculature may be necessary. (4,6) Laparoscopic surgical intervention has been shown to allow a rapid resumption of neoadjuvant chemotherapy. (15) Of interest, a case of spontaneous regression of metastatic lung nodules from renal PNET postnephrectomy has been documented. (28)

Chemotherapy recommendations to treat PNET have included alternating cycles of ifosfamide and etoposide with vincristine, doxorubicin, and d-actinomycin, although the addition of ifosfamide and etoposide has not been shown to be beneficial in patients with metastasis. (29) Radiotherapy has been suggested for locally advanced disease or when there is involvement of Gerota fascia. (9)

Patients with renal PNETs face an aggressive tumor with a poor prognosis, especially if it is diagnosed at an advanced stage, which is frequently the case. (1,3) Previous work has shown that approximately 58% of renal PNETs are diagnosed at an advanced stage. (6) In one study of 40 patients with renal PNET, 57.5% were disease free for 5 to 58 months; 42.5% died between 1 and 24 months later, with 70.5% of those patients with known metastases. (6) In another study of 16 patients, 63% had localized disease and 31% had metastatic disease; the 3- and 5-year survival rates were 60% and 42% respectively. (9) The overall 5-year survival rate for peripheral PNETs has been reported to be between 45% and 55%. (6) In addition to advanced stage, it has also been suggested that tumor palpability and the presence of synaptophysin may indicate a worse prognosis. (6)

SUMMARY AND CONCLUSION

Renal PNETs represent a rare but aggressive tumor that presents a diagnostic challenge. Renal PNET must be considered in renal tumors of all ages, but most specifically in older children and young adults. Its histologic features, immunostaining profile, and genetic mutations provide key diagnostic clues. Given its poor prognosis and often late presentation, it is important to diagnose this entity correctly.

This work was supported by the Clinical and Translational Science Institute Multidisciplinary Predoctoral Fellowship program, awarded through the Clinical and Translational Science Institute and the Institute for Clinical Research Educational Education at the University of Pittsburgh (grant 5TL1RR02415502 and grant 5TL1RR024155-05) to Tanner L. Bartholow. Additional funds were provided by the Doris Duke Charitable Foundation.

References

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(2.) Funahashi Y, Hattori R, Yamamoto T et al. Ewing's sarcoma/primitive neuroectodermal tumor of the kidney. Aktuelle Urol. 2009; 40(4):247-249.

(3.) Chu WC, Reznikov B, Lee EY, Grant RM, Cheng FW, Babyn P. Primitive neuroectodermal tumour (PNET) of the kidney:a rare renaltumour in adolescents with seemingly characteristic radiological features. Pediatr Radiol. 2008; 38(10): 1089 1094.

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(16.) Llombart-Bosch A, Navarro S. Immunohistochemical detection of EWS and FLI-1 proteins in Ewing sarcoma and primitive neuroectodermal tumors: comparative analysis with CD99 (MIC-2) expression. Appl Immunohistochem Mol Morphol. 2001; 9(3):255 260.

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(28.) Lam JS, Hensle TW, Debelenko L, Granowetter L, Tennenbaum SY. Organ-confined primitive neuroectodermal tumor arising from the kidney. J Pediatr Surg. 2003; 38(4):619 621.

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Tanner Bartholow, BS; Anil Parwani, MD, PhD

Accepted for publication July 28, 2011.

From the Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Anil Parwani, MD, PhD, Department of Pathology, UPMC Shadyside Hospital, Room WG 02.10, 5230 Centre Ave, Pittsburgh, PA 15232 (e-mail: parwaniav@upmc.edu).
Biomarkers for Renal Primitive Neuroectodermal Tumor
(PNET) in Comparison to Their Expression in Other Tumors
in the Differential Diagnosis for Renal PNET

 Renal
 Primitive Clear Cell Papillary
 Neuroecto- Renal Cell Renal Cell
 dermal Carci- Carci-
Immunostain Tumor noma noma

CD99 (4,5,10,20 22) 99% NS NS
WT-1 (3,4,10,20) Typically - NS NS
 Rarely +
FLI-1 (10) 62.5% NS NS
Neuron-specific 95% 52% 20%
 enolase (6,18,20,22,23)
Leu-7 (6) 67% NS NS
Vimentin (6,17,21 23) 70% 87% 100%
S-100 protein (6,19,21) 52% 69% 30%
Synaptophysin (6,18) 48% 1% 10%
Cytokeratin/ 25% 35% 82%
 pancytokeratin
(AE1/AE3) (10,17,20 22)

 Desmo-
 Chromo- plastic
 phobe Small Renal
 Renal Cell Round Cell Synovial
Immunostain Carcinoma Tumor Sarcoma

CD99 (4,5,10,20 22) NS 23% Typically -
WT-1 (3,4,10,20) NS 91% NS

FLI-1 (10) NS NS NS
Neuron-specific Typically - 84% NS
 enolase (6,18,20,22,23)
Leu-7 (6) NS NS NS
Vimentin (6,17,21 23) Typically - NS 89%
S-100 protein (6,19,21) 6% NS Typically -
Synaptophysin (6,18) Typically - NS NS
Cytokeratin/ 16% 87% May be +
 pancytokeratin
(AE1/AE3) (10,17,20 22)

 Non-
 Rhabdomy- Hodgkin Wilms
Immunostain osarcoma Lymphoma Tumor

CD99 (4,5,10,20 22) 16% May be + May be +
WT-1 (3,4,10,20) NS NS 78%

FLI-1 (10) NS NS Typically -
Neuron-specific 8% Typically - 63%
 enolase (6,18,20,22,23)
Leu-7 (6) NS NS NS
Vimentin (6,17,21 23) 100% NS 63%
S-100 protein (6,19,21) NS NS NS
Synaptophysin (6,18) NS NS NS
Cytokeratin/ 10% NS NS
 pancytokeratin
(AE1/AE3) (10,17,20 22)

Abbreviations: FLI-1, Friend leukemia virus integration 1;
NS, not studied; WT-1, Wilms tumor 1; +, positive; -, negative.
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Date:Jun 1, 2012
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