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Is Immunohistochemical Screening of Cutaneous Leiomyomas for the Early Detection of Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome Justified?

Harvey, Nathan T., FRCPA*,†; Wood, Benjamin A., FRCPA*,†

The American Journal of Dermatopathology: December 2018 - Volume 40 - Issue 12 - p 939–940
doi: 10.1097/DAD.0000000000001016
Letters to the Editor
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*Dermatopathology Group, PathWest Laboratory Medicine, Perth, Western Australia, Australia

School of Biomedical Science, Faculty of Health and Medical Sciences, University of Western Australia, Perth, Western Australia, Australia

The authors declare no conflicts of interest.

To the Editor:

We have followed with interest the recent literature that advocates the use of fumurate hydratase (FH) immunohistochemistry in cutaneous leiomyomas to aid in the detection of patients with hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC).1,2 HLRCC (also known as Reed syndrome) is characterized by multiple leiomyomas, both cutaneous and uterine, with an increased risk for the development of renal cell carcinoma.3,4 The syndrome is associated with heterogenous germline mutations in the FH gene on chromosome 1, resulting in absent or reduced activity of the enzyme.5,6 As with any inherited cancer syndrome, early identification can guide potentially beneficial management, including regular screening investigations. This is particularly desirable in HLRCC, as the carcinomas which develop show an aggressive clinical course.3 The ability of FH immunohistochemistry (ie, the absence of FH staining) to identify tumours associated with this syndrome has been demonstrated by several groups,1,2,7 and routine use of FH immunohistochemistry as a triage tool to screen cutaneous leiomyomas and to identify patients who should be referred for additional follow-up has been proposed.1,2

While on the surface this approach seems attractive, we are not convinced that the currently available data support it and would like to offer a contrary view. We have tabulated some of the reported data from the aforementioned studies in Table 1. Lack of immunohistochemical positivity for FH certainly is associated with HLRCC-related lesions, with a sensitivity of 70% and a specificity of 98% in the data reported by Carter et al2 and a sensitivity of 83% and specificity of 76% in the data reported by Llamas-Velasco et al.7 However, to truly justify its routine application, it should be additive to simple clinical correlation. The retrospective and in some cases selective methodologies used in the available studies render direct comparison and evaluation difficult. However, in the study by Carter et al., 6 of 7 cases of confirmed HLRCC presented with multiple cutaneous leiomyomas (a sensitivity of 86%),2 whereas Llamas-Velasco et al7 reported that all of their confirmed and suspected cases had multiple cutaneous lesions. A similar picture emerges when examining the data of Buelow et al.1 A key point in the latter study is that the authors reported lesional FH mutations, without data regarding germline mutations. It is reasonable to assume that detection of FH mutation in a tumor is sensitive, but not necessarily specific, in the identification of patients with germline mutations, as the rate of somatic mutations in cutaneous leiomyomas is not well established. On this basis, that study would suggest that the presence of multiple lesions has a sensitivity of 85% for germline mutations, compared with a sensitivity of 50% for FH immunohistochemistry (Table 1), with the specificity for germline mutation being unestablished.

TABLE 1

TABLE 1

Carter et al note that “it could be argued that the presence of multiple cutaneous leiomyomata is sensitive enough to proceed directly to genetic testing.”2 They point out, quite correctly, that the history of multiple lesions is often not provided, and indeed the significance of this finding could easily be missed by a clinician without experience in this relatively rare condition. However, we would argue that a phone call to the referring clinician (or note in the pathology report) would allow the relevant clinical information to be obtained, as well as affording an opportunity to highlight the need for further genetic testing in patients who meet the clinical criteria. In a recent survey of over 200 practitioners' views on communication of results in dermatopathology, we found that nearly one-half of clinicians believed that a telephone call from the pathologist was appropriate for a diagnosis, which raised the possibility of an inherited cancer syndrome (Korbl et al, submitted manuscript).

Another immunohistochemical marker that has been reported to be of use in identifying patients with HLRCC is 2-succinocysteine. This is a stable chemical modification of proteins that occurs as a consequence of the intracellular accumulation of fumarate, secondary to functional loss of FH. Strong nuclear and cytoplasmic staining with antibodies directed against this moiety has been correlated with HLRCC-associated renal cell carcinomas and uterine leiomyomas.8–10 Buelow et al1 tested this marker on their cohort and found a sensitivity of 92% and specificity of 75% for the identification of FH mutation in the tumor. Llamas-Velasco et al11 reported 83% sensitivity and 67% specificity of strong immunohistochemical staining for detection of HLRCC-related lesions in their cohort. Although the data are currently limited, these figures suggest that 2-succinocysteine immunohistochemistry may be more sensitive in identifying HLRCC-related lesions than FH immunohistochemistry. The utility of this finding is limited by the lack of a commercially available antibody at this time. Nonetheless, neither seems to be better than the clinical identification of multiple lesions.

Given that multiple cutaneous leiomyomas form part of the clinical definition of HLRCC, most of the confirmed cases in the cited studies have this clinical feature, raising the risk of an element of circular reasoning. The data that are lacking are how often HLRCC can present with a solitary cutaneous leiomyoma, or conversely how often a solitary cutaneous leiomyoma represents the sentinel finding in a patient with HLRCC. Certainly most reported confirmed cases are characterized by multiple lesions, and this seems to be the most penetrant feature of the condition clinically.12–14 There may yet be a role for immunohistochemical staining if it is able to identify occult cases of HLRCC that present with only a solitary cutaneous lesion, or if somatic abnormalities other than mutations (eg, promoter rearrangements or epigenetic events) are established to be causative of the syndrome. There is clearly a need for prospective studies to evaluate these questions. However, until such time as that data are available, we should be cautious to avoid the trajectory taken with immunohistochemical screening for mismatch repair defects in cutaneous sebaceous lesions, where initial enthusiasm has now been tempered by recognition that correlation with the clinical scenario may be better and more cost-effective approach.15 As such, we would argue that, at least with the currently available data, the best (and cheapest) tool for the early identification of HLRCC may be the telephone, rather than the immunostainer.

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REFERENCES

1. Buelow B, Cohen J, Nagymanyoki Z, 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 carcinoma syndrome). Am J Surg Pathol. 2016;40:982–988.
2. Carter CS, Skala SL, Chinnaiyan AM, et al. Immunohistochemical characterization of fumarate hydratase (FH) and succinate dehydrogenase (SDH) in cutaneous leiomyomas for detection of familial cancer syndromes. Am J Surg Pathol. 2017;41:801–809.
3. Launonen V, Vierimaa O, Kiuru M, et al. Inherited susceptibility to uterine leiomyomas and renal cell cancer. Proc Natl Acad Sci U S A. 2001;98:3387–3392.
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