Renal cell carcinoma with Xp11.2 translocation/TFE3 gene fusions-experience from a tertiary care hospital in Kerala, India

Renal cell Carcinoma (RCC) with Xp11.2 translocation/TFE3 (Transcription factor E3) gene fusions comprise at least one-third of the cases of pediatric RCC. The significance of identifying these cases is that, VEGFR (Vascular Endothelium derived Growth Factor)-targeted therapies and mTOR (mechanistic target of rapamycin) inhibitors seems to be active in the treatment of Xp11.2 translocation RCC. However, only few studies are available regarding this rare malignancy and as a result prognosis remains controversial. We present 2 cases of Xp11.2 RCC reported in our institute with a glimpse to the morphological patterns, ImmunoHistoChemistry (IHC) studies and cytogenetics. Conclusion: RCC with Xp11.2 translocation/TFE3 gene fusion is a rare pediatric tumour for which the treatment options are on the advancing edge, based on which the prognosis can be improved.


Case 1
A 21 yr old lady was referred to Amrita Institute of medical Sciences with history of right sided abdominal discomfort and pain. There was no history of hematuria or urinary tract infection. Abdominal Examination revealed a palpable mass in the right hypochondrium. CT scan of the abdomen & pelvis showed a large partially cystic mass of 9x8cm size, Bosniak type 3, arising from the anterior portion of right kidney. Subsequently she underwent Right open Radical Nephrectomy.

Histopathology
We received a Right Nephrectomy Specimen with perinephric fat and Hilar node. Cut surface of the kidney showed a well encapsulated, unilocular cyst, whole measuring 9x7.5x7cm, involving mid and lower pole of kidney. There were grey brown solid areas with focal areas of haemorrhage.
Microscopy: The histopathological sections showed a well encapsulated cystic neoplasm composed of cells arranged in doi: 10.7243/2055-091X-2-6 papillary pattern, and alveolar and nesting patterns. Some papillary cores showed foamy histiocytes The tumour cells had abundant clear to eosinophilic cytoplasm, discrete cell borders, vesicular chromatin and prominent nucleoli appreciable at 40x (Furhman Grade 2). Psammoma bodies were frequent. The cystic areas were lined by similar cells. Mitosis is occasional. Necrosis & hyaline nodules were also seen focally. Vascular emboli were also seen. Adjacent kidney shows cortical glomerulosclerosis. Hilar lymph node showed neoplastic infiltrate in 1/3 lymphnodes (Figure 1). Hence a diagnosis of Renal cell carcinoma, with Xp11.2 translocation like features and lymph node metastasis (1/3) was made. IHC and TFE gene mutation study/Xp11.2 Translocation studies were suggested for confirmation. TNM staging: pT2N1Mx.

Case 2
A 17year old girl, was referred to Amrita Institute of Medical Sciences with history of total painless hematuria associated with clots in urine, along with right sided abdominal pain. There was no relevant past history. Abdominal Examination was unremarkable. CTscan of the abdomen showed a well defined large lesion, of size 3x2.5x4cm at lower pole of right kidney Subsequently she underwent Laparoscopic Right Radical Nephrectomy.

Histopathology
We received "Right radical nephrectomy" specimen. Cut section showed a well encapsulated grey white to yellowish white solid and cystic lesion measuring 3x3x5cm in the mid pole. The lesion was soft and granular. Background renal parenchyma was unremarkable. No adrenals or Lymph nodes were identified.
Microscopy: The sections from the kidney show a neoplasm composed of cells arranged in papillary pattern. Some of the papillae showed central core of foamy histiocytes. The cells had abundant clear to eosinophilic cytoplasm, discrete cell borders, vesicular chromatin and prominent nucleoli. Psammoma bodies and hyaline nodules were seen. The cystic areas were lined by similar cells. Mitosis is occasional. Necrosis was absent. Adjacent kidney shows cortical glomerulosclerosis, occasional tubular red cell casts and patchy lymphocytic infiltration was seen in the interstitium (Figure 2).

ASPL-TFE3:
Microscopically a mixture of large, clear cells with granular eosinophilic cytoplasm with large nuclei vesicular chromatin, prominent nucleoli, discrete cell borders are seen. Psammoma bodies and intracytoplasmic hyaline droplets are frequent [1]. PRCC-TFE3: Cells have less abundant cytoplasm, fewer psammoma bodies, hyaline nodules with more compact and nested architecture [1].

Cytogenetics
This image shows characteristic translocation detected by cytogenetic analysis Figure 4. Following table helps to differentiate translocation associated RCC from Clear cell RCC with papillary areas and Papillary RCC with IHC studies ( Table 1).   Xp11.2 RCC. Its likely to present with tumors at higher stages and also those with hematogenous metastases seem to have a dismal prognosis [5,8,9]. However in the majority of cases, there has been no evidence of disease following resection. VEGFR-targeted therapies and mTOR inhibitors seem to be active in Xp11.2 translocation RCC [3].

Conclusion
By highlighting the significance of detecting these cases, as targeted therapy is available. More studies and data are required, especially in the Indian as well as Asian Scenario, for assessing the prognosis of this disease.