FH and 2SC Co-expression: Screening for HLRCC with Skin or Uterine Leiomyomas as Initial Symptoms

HLRCC is a rare autosomal dominant genetic disorder, with its hereditary driving molecular event being the mutation and inactivation of the fumarate hydratase (FH) gene.

Studies indicateHLRCCThe main clinical manifestations of the syndrome are cutaneous leiomyomas and early-onset uterine leiomyomas in women. It is reported that cutaneous leiomyomasthe average age of leiomyoma symptom onset isappear at an average age of 25, which is 6 years earlier than the average age of 31 for uterine fibroid symptoms. Among these, 20% to 30% of patients may further develop highly aggressiveofFH renal cell carcinoma, which is often the main cause of death. Therefore, early identification and appropriate monitoring, prevention, and treatment will benefit these patients and their families.

Patel et al. summarized theHLRCCclinical diagnostic criteriaincludesmodified by the research teams of Smit and Schmidt, which include

The major criteria are: ① Multiple cutaneous leiomyomas, especially accompanied by stinging pain; ② One or more piloleiomyomas, accompanied by characteristic stinging pain.

The minor criteria are: ① Isolated leiomyoma andHLRCCfamily history; ② Type II papillary renal cell carcinoma occurring before age 40; ③ Severe symptomatic uterine fibroids in women before age 40; ④ A first-degree relative meeting any of the above criteria, or a second-degree paternal female relative with severe symptomatic uterine fibroids before age 40.

When a patient meets the major criteria, it indicates a high probability of havingHLRCCthe likelihood of the syndrome is very high; if only meeting no less than 2 minor criteria, doctors may suspectHLRCC, but both require further pathological analysis to aid in definitive diagnosis.

Pathologically, althoughHE staining can reveal a series of common histological features of FH-deficient uterine leiomyomas: increased cellularity, multinucleation, prominent eosinophilic nucleoli, perinucleolar halos, fibrillar cytoplasm with eosinophilic granules, and staghorn-shaped vasculature. However, these features are not highly specific. In cases with widespread severe atypical cells, they can easily be misdiagnosed as smooth muscle tumors of uncertain malignant potential or leiomyosarcoma.Additionally, in cutaneous leiomyoma cells, histological features similar to those described above have not been found to date, indicating the need for furtherIHC staining to aid in diagnosis.

Currently, the commonly used IHC test is FH-negative screening. BecauseSomein patients with FH gene mutations combined with uterine leiomyomas, tumor cells mayretainFH protein expression, therefore, relying solely onusing immunohistochemistry to detectthe sensitivity and specificity of using FH protein expression status to determine the presence of FH gene mutations are not 100%.

Based on the mechanism where FH deficiency leads to high levels of fumarate accumulation in tumor cells and tissues, causing abnormal protein succination and modifying cysteine residues to 2-succinocysteine (2SC), it has been found that 2SC can be detected by immunohistochemistry.

Benjamin et al. studied22 cases of multiple cutaneous leiomyomas were studied, and next-generation sequencing was used to detect FH gene mutations. Results showed that 85% (11/13) of patients had detectable FH gene mutations. Analysis revealed a strong association between positive 2SC immunohistochemistry and the presence of FH gene mutations (P = 0.0028), but no association with the loss of FH by immunohistochemistry (P = 0.4). All 11 patients with FH gene mutations had positive 2SC staining, with 6 of them showing negative FH staining. This indicates that the presence of multiple cutaneous leiomyomas should raise suspicion for HLRCC, and FH-IHC and 2SC-IHC are helpful in detecting FH gene mutations.

Joseph et al.’s study identified fromAmong 194 uterine leiomyoma patients, 5 cases with FH abnormalities were identified. Two showed FH loss: one with an FH gene frameshift mutation and one with homozygous FH deletion; the remaining three were gene missense mutations. IHC staining revealed that all 5 cases showed strong 2SC positivity with intense and diffuse antibody labeling. Two cases had complete loss of FH staining, while the other three had FH staining scores of 1+, 2+, and 3+, respectively. The remaining 189 non-FH abnormal cases all showed 2SC negativity and mostly strong FH positivity. This indicates thatUtilizingCombined IHC staining for FH and 2SC can detect potentially missed cases of gene missense mutations, even in those without detected FH loss.

Therefore, utilizingCombined IHC staining for FH and 2SC can improve the diagnostic rate of possible HLRCC in patients with cutaneous and uterine leiomyomas, thereby enabling timely enhanced monitoring, improved treatment and prevention, and reduced mortality.

References:

[1] Zhao Zichen, Wang Wenhui, Feng Fengzhi. Research Progress on Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome[J]. Journal of Practical Obstetrics and Gynecology, 2018, v.34(04):23-26

[2] Viral M. Patel, Marc Z. Handler, Robert A. et al.Clark Lambert. Hereditary leiomyomatosis and renal cell cancer syndrome: An update and review[J]. Journal of the American Academy of Dermatology,2017,77(1)

[3] Benjamin B, Jarish C, Zoltan N, et al. Immunohistochemistry for 2-Succinocysteine (2SC) and fumarate hydratase (FH) in cutaneous leiomyomas may aid in identification of patients with HLRCC ( hereditary leiomyomatosis and renal cell carcinom) . Am J Surg Pathol, 2016, 40( 7) : 982－988．

For more information, please contact: 800-8581156 or 400-889-9853