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Journal of Peking University (Health Sciences) ›› 2021, Vol. 53 ›› Issue (4): 640-646. doi: 10.19723/j.issn.1671-167X.2021.04.003

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Clinicopathological features and prognosis of fumarate hydratase deficient renal cell carcinoma

YU Yan-fei,HE Shi-ming,WU Yu-cai,XIONG Sheng-wei,SHEN Qi,LI Yan-yan,YANG Feng,HE Qun(),LI Xue-song()   

  1. National Urological Cancer Center, Beijing 100034, China
  • Received:2021-01-11 Online:2021-08-18 Published:2021-08-25
  • Contact: Qun HE,Xue-song LI E-mail:bdyyqhe@sina.com;pineneedle@sina.com
  • Supported by:
    Scientific Research Seed Fund of Peking University First Hospital(2020SF36)

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Abstract:

Objective: To investigate the clinicopathological features and prognosis of fumarate hydratase deficient renal cell carcinoma (FH-RCC). Methods: Immunohistochemical (IHC) staining was used to detect the expression of fumarate hydratase (FH) in tumor tissues of 109 different types of renal cell carcinoma (RCC) patients aged 60 years and younger from the Department of Urology of Peking University First Hospital from January 2013 to December 2019. The clinicopathological data and prognosis of FH-RCC were collected and analyzed. Results: There were eleven patients with FH-negative expression. Seven were males and four females. The age of onset ranged 16-53 years (mean age: 36.7 years), and four female patients all had a history of uterine leiomyoma. Only one first-degree relative of one patient had renal cancer, and none of the patients had a history or family history of cutaneous leiomyomas. The diameter of the tumor was 2.1-12.0 cm (mean: 8.83 cm). Renal sinus or perirenal fat invasion was seen in nine cases, tumor thrombus in renal vein or inferior vena cava in six cases, lymph node metastasis in seven cases, adrenal gland invasion in four cases and splenic capsule invasion in one case. The cases were initially diagnosed as type Ⅱ papillary RCC (7/49, 14.3%), collecting duct carcinoma (2/9, 22.2%) and unclassified RCC (2/51, 3.9%). Tumor histopathology mostly showed a mixture of different structures, such as papillary, tubular cystic, solid, and so on. The most common histological structures were papillary (9/11, 81.8%) and tubular (8/11, 72.7%). Three cases had sarcomatoid areas. At least focal eosinophilic nucleolus (WHO/grades Ⅲ-Ⅳ) and perinuclear halo could be seen in all cases. Immunohistochemical (IHC) stains of most tumors were negative for CA9, CD10 and CK7. The results of fluorescence in situ hybridization (FISH) showed that there was no translocation or amplification of TFE3 gene in two cases with TFE3 IHC expression. All the patients were followed up for 11-82 months. Mean survival was 24 months. Five cases died of distant metastasis 9-31 months after operation (mean: 19 months), and five of the six patients alive had became metastatic. Conclusion: Morphologically, FH-RCC overlaps with many types cell RCC. A mixture of papillary and tubular cystic arrangement is the most common growth pattern of FH-RCC. At least focally large and obvious eosinophilic nucleoli are an important histological feature of this tumor. The negative expression of FH can help to confirm the diagnosis. Young female RCC patients with uterine leiomyomas should be suspected of FH-RCC. Some FH-RCC cases lack clinical evidence. The suspicion raised by pathologists based on histological characteristics is often the key step to further genetic testing and the final diagnosis of the tumor.

Key words: Renal cell carcinoma, Fumarate hydratase, Immunohistochemistry, Prognosis

CLC Number: 

  • R737.11

Table 1

Clinical features of FH-RCC"

Patient
No.		 Gender Age/
years		 Presentation Personal history Family history Tumor
location		 Distant metastasis OS/month
1 M 39 Flank pain - Uterine leiomyomas Right Liver, thoracic
vertebrae		 11.3
2 F 35 Physical examination Uterine leiomyomas,
adrenal cortical hyperplasia		 Uterine leiomyomas Left Omentum 12.5
3 F 26 Flank pain Uterine leiomyomas RCC Right Bone 13.2
4 M 34 Physical examination - - Left Bone, diaphragm 20.0
5 M 16 Flank pain - Uterine leiomyomas Left - 9.2 (DOD)
6 M 53 Physical examination - - Right Bone 16.6 (DOD)
7 M 37 Physical examination - Uterine leiomyomas Left Rectum 32.8
8 F 40 Physical examination Multiple uterine leiomyomas Uterine leiomyomas Left - 17.2 (DOD)
9 M 48 Hematuria - - Left Unkown 17.2 (DOD)
10 F 28 Flank pain Uterine leiomyomas Uterine leiomyomas,
colorectal carcinoma		 Right - 31.5 (DOD)
11 M 48 Hematuria Cystic nephroma - Right - 82.7

Table 2

Pathologic features of FH-RCC"

Patient No. Size/cm Initial histological type Fuhrman grade pTNM stage Histological structures
Solid Papillary Tubulocystic Cribriform
1 12.0 PRCC Ⅱ G3 pT3aN1 - Yes Yes Yes
2 6.5 PRCC Ⅱ G3 pT3aN1 - Yes Yes -
3 11.0 PRCC Ⅱ G3 pT2b - Yes Yes -
4 6.5 PRCC Ⅱ G3 pT4N1 Yes Yes - -
5 8.5 PRCC Ⅱ G3 pT4N1 - Yes - -
6 10.5 CDC G3 pT4N1 Yes Yes Yes -
7 12.0 U-RCC G4 pT4N1 Yes Yes Yes Yes
8 9.0 U-RCC G3 pT3aN1 - Yes Yes Yes
9 8.0 PRCC Ⅱ G3 pT3bN2 Yes Yes Yes -
10 11.0 PRCC Ⅱ G3 T3a - Yes Yes -
11 2.1 CDC G3 pT1a - - Yes -

Figure 1

The histological features of fumarate hydratase-deficient renal cell carcinoma (HE ×40) A, papillary structure, resembling type Ⅱ papillary renal cell carcinoma; B, tubular structure, resembling collecting duct carcinoma and high magnification shows eosinophilic (viral inclusion-like) macronucleoli with perinucleolar clearing (lower left, HE ×200); C, cystic structure; D, cribriform and tubular structure; E, solid structure; F, sarcomatoid area."

Figure 2

Immunohistochemical staining (×40) A, positive FH staining of non-FH-RCC (lower right) and normal kidney tissue (upper left); B, negative FH staining of FH-RCC and positive FH staining of residual normal renal tubules (arrow); C, diffuse strong positive staining of TFE3. FH, fumarate hydratase; FH-RCC, fumarate hydratase-deficient renal cell carcinoma."

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