Sebaceous adenoma arising within an ovarian mature cysticteratoma in Muir-Torre syndrome
Jason Smith, FRACGPa,⁎, Karen Crowe, MScb,Julie McGaughran, FRACPc, Thomas Robertson, FRCPAa
aPathology Queensland, Royal Brisbane and Women's Hospital, Herston QLD 4029, AustraliabGenetic Health Queensland, Nambour QLD 4560, AustraliacGenetic Health Queensland, Herston QLD 4029, Australia
Abstract This is the first reported case of a sebaceous adenoma arising within an ovarian mature cystic
⁎ Corresponding aE-mail addresses:
(J. Smith).
1092-9134/$ – see frohttp://dx.doi.org/10.10
teratoma in a patient with Muir-Torre syndrome. The pathologic findings and a literature review arepresented, including the importance and possible benefits of an early diagnosis of Muir-Torresyndrome. It is proposed that the presence of a sebaceous adenoma in an ovarian cystic teratoma mayserve as a useful trigger to consider further history and investigations, with the goal of identifying animportant genetic cancer predisposition syndrome.
The association of cutaneous sebaceous adenoma andMuir-Torre syndrome is well described. This is, to ourknowledge, the first reported case of sebaceous adenomaarising within an ovarian mature cystic teratoma (dermoidcyst) in a patient with documented Muir-Torre syndrome.The pathologic findings are described, and a briefliterature review is presented. In addition to being aninteresting case, the apparent association of sebaceousadenoma in a dermoid cyst with Muir-Torre syndromemay be of use in helping to diagnose others with Muir-Torre syndrome at an early stage. Just as with cutaneoussebaceous adenomas, the presence of a sebaceousadenoma in a dermoid cyst may be a useful trigger toconsider further investigations such as immunohistochem-istry for mismatch repair (MMR) proteins (MLH1, MSH2,MSH6, and PMS2) and exploration of personal andfamily history to potentially identify a clinically importantgenetic cancer predisposition syndrome.
A 52-year-old woman had a cutaneous lesion biopsiedfrom the right nasolabial fold in January 2010, which wasdiagnosed as a sebaceous adenoma. This was tested for thepresence of MMR proteins by immunohistochemistry, whichshowed loss of nuclear reactivity for the MMR proteinsMSH2 and MSH6. There was positive (retained) nuclearreactivity for MLH1 and PMS2.
The patient had a history of multiple different malignan-cies. In 2006, she was diagnosed with invasive ductalcarcinoma and ductal carcinoma in situ in her left breast,which was treated with surgery, radiotherapy, and oraltamoxifen. In addition to the cutaneous sebaceous adenoma,she had a history of several basal cell carcinomas, akeratoacanthoma, and 2 intraepidermal carcinomas. In1995, the patient had bilateral ovarian cystectomies formature cystic teratomas. On reviewing her family history, itis possible that her father may have had Lynch and/or Muir-Torre syndrome as he had had esophageal and bladder cancerand had had multiple skin lesions removed, although thedetails of the cutaneous pathology are not known.
She attended for genetic counseling, and subsequentmutation screening of theMSH2 gene was undertaken, whichrevealed that she had an MSH2 mutation (heterozygous
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mutation MSH2:c.803CNA). This mutation is predicted toresult in either premature termination of translationproducing a truncated protein or nonsense-mediatedmessenger RNA decay. The patient's history of sebaceousadenoma and heterozygous MSH2 mutation are consistentwith Muir-Torre syndrome [1]. It is interesting to note thatwhen immunohistochemistry for MMR proteins wasretrospectively performed on her previous breast cancer,there was no loss of normal staining. This suggests that herbreast cancer is coincidental rather than a manifestation ofher Muir-Torre syndrome.
Given the associated risk of ovarian and endometrialcancers in Muir-Torre syndrome, as well as the risk oftamoxifen-associated endometrial cancer, the patient wasoffered and opted for prophylactic hysterectomy andbilateral salpingo-oophorectomy. Unexpectedly, a routinepreoperative pelvic ultrasound showed a large left adnexalmass measuring up to 110 mm in diameter, with regions ofhyperechogenicity and hypoechogenicity. At surgery, the
Fig. 1. (A) Sebaceous adenoma within mature cystic ovarian teratoma (medium ppower). (C) Loss of nuclear reactivity for MSH2 MMR protein by immunohistocprotein by immunohistochemistry (medium power).
large left adnexal mass was resected and intraoperative frozen-section consultation indicated a mature cystic teratoma(dermoid cyst). The uterus and right adnexa were alsoremoved. The patient had an unremarkable postoperativecourse and was discharged home on the fourth day. In additionto postoperative follow-up with the gynecologic surgeons, thepatient has also been referred to a gastroenterologist forgastrointestinal surveillance, and her family have been offeredgenetic counseling and testing.
3. Materials and methods
The surgical specimen was initially sampled for frozen-section assessment. The specimen was then fixed in 10%neutral-buffered formalin. Representative sections wereprocessed with standard paraffin technique and stained withhematoxylin and eosin. Immunohistochemistry was per-formed using a polymer-based method in a Leica Bond-Max
ower). (B) Sebaceous adenoma within mature cystic ovarian teratoma (highhemistry (medium power). (D) Positive nuclear reactivity for MLH1 MMR
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automatic immunohistochemical stainer, with the MMRprotein antibodies (MLH1, MSH2, MSH6, and PMS2).(Leica Microsystems, Wetzlar, Germany).
4. Results
Macroscopically, the left adnexal tumor measured 130 ×100 × 90 mm and weighed 571 g. The external surface wassmooth, and dissection revealed a unilocular cyst containingbrown-yellow liquid, hair, and white paste. The inner liningof the cyst was cream and predominantly smooth.
Microscopy confirmed the frozen-section diagnosis of anovarian mature cystic teratoma. The various tissue typespresent included skin and skin adnexa, as well as respiratory-type epithelium. Part of the cyst showed an abnormalproliferation of sebaceous lobules with features similar to acystic sebaceous adenoma of the skin (Fig. 1A, B). Noinvasion was identified.
Mismatch repair immunohistochemistry showed loss ofnuclear reactivity for the MMR proteins MSH2 (Fig. 1C) andMSH6 within the sebaceous tumor cells. There was positivenuclear reactivity for MLH1 (Fig. 1D) and PMS2.
5. Discussion
Muir-Torre syndrome is now considered to be a variant ofLynch syndrome, which has also been known as hereditarynonpolyposis colorectal cancer (HNPCC). Lynch syndromeis the most common hereditary colorectal cancer predispo-sition syndrome and accounts for approximately 3% ofcolorectal cancers worldwide. It is also associated with anincreased risk of other cancers such as endometrial, gastric,ovarian, and urothelial cancers [2]. Lynch syndrome isgenetically defined by a germline mutation in an MMR geneand is inherited in an autosomal dominant fashion. The DNAMMR genes (MLH1, MSH2, MSH6, and PMS2) encodeproteins involved in the identification and repair of DNAmismatch errors during replication.
The most common mutations seen in Muir-Torresyndrome involve the MMR genes MSH2 and lesscommonly MLH1 [3]. These 2 “major” MMR genes(MSH2 and MLH1) are stabilized by interactions betweenany of several “minor” MMR genes (including MSH6 andPMS2). The “minor” DNA MMR genes are dependent ontheir binding partners for expression at the protein level [2].In this way, when a tumor loses expression ofMSH2, there isconcomitant loss of MSH6 expression, as seen in this case.
Patients with Muir-Torre syndrome have an increased riskof developing Lynch syndrome–associated cancers such ascolorectal, endometrial, gastric, ovarian, and urothelialcancers [2]. Some also consider Muir-Torre syndrome tobe associated with other cancers such as breast, parotid,laryngeal cancers and hematological malignant disease[1,3,4].
The association of cutaneous sebaceous adenoma andMuir-Torre syndrome is well described and has recentlybeen reviewed [5]. Cutaneous sebaceous adenomas are themost common neoplasm associated with and the mostspecific marker of Muir-Torre syndrome, appearing in atleast 68% of patients [4,6]. Furthermore, a single sebaceousneoplasm can be a marker of Muir-Torre syndrome [4].
It is now common practice for patients with cutaneoussebaceous neoplasms to have immunohistochemistry per-formed for MMR proteins and a review of personal andfamily history with genetic counseling where indicated [1,7].The goal is to identify patients who may have Muir-Torresyndrome at the earliest possible stage, because surveillanceand/or prophylactic surgery have been shown to minimizethe impact of associated visceral malignancies [3,8]. In 2different studies, 57% and 60% of patients with Muir-Torresyndrome, respectively, were diagnosed with a skin lesionbefore a visceral malignancy was diagnosed [9].
Retrospective studies have shown a significant reductionin the risk of ovarian and endometrial cancers in women withMuir-Torre syndrome who elect to have prophylactichysterectomy and bilateral salpingo-oophorectomy [1]. Inone study involving 315 women with Lynch syndrome, therewere no occurrences of endometrial or ovarian cancer inwomen who underwent prophylactic surgery (hysterectomyand bilateral salpingo-oophorectomy), compared with endo-metrial and ovarian cancer developing in 33% and 5%,respectively, of women who did not have prophylacticsurgery [8].
A review of the literature reveals a small number of casereports of sebaceous adenomas and sebaceous carcinomas inovarian dermoid cysts; however, none describe an associa-tion with Muir-Torre syndrome [10-15]. Some of these casereports do predate Muir and Torre's first independentdescriptions of cases in 1967 and 1968, respectively,which later became known as the Muir-Torre syndrome[16,17]. Interestingly, however, one previously describeddermoid cyst containing both sebaceous adenoma andsquamous cell carcinoma occurred in a patient withcoexistent endometrial cancer, raising the possibility ofMuir-Torre syndrome, although it is not detailed in thepublished report if this association was considered in thiscase [10]. To our knowledge, this is the first reported case ofsebaceous adenoma arising within a benign dermoid cyst in apatient with documented Muir-Torre syndrome.
It is not known whether all sebaceous adenomas indermoid cysts are associated with Muir-Torre syndrome.However, given the strong association between cutaneoussebaceous adenoma and Muir-Torre syndrome, and this caseof sebaceous adenoma in a dermoid cyst in a patient withdocumented Muir-Torre syndrome, an association appearslikely. This could be investigated further by immunohisto-chemistry testing for MMR proteins in the previouslydescribed cases.
Given the important benefits of early diagnosis ofMuir-Torre syndrome, it is suggested that, although rare,
488 J. Smith et al. / Annals of Diagnostic Pathology 16 (2012) 485–488
the presence of a sebaceous adenoma in a dermoid cystmay be a useful trigger for further investigations, in thesame way that patients with cutaneous sebaceousadenomas are investigated.
In summary, this is, to our knowledge, the first reportedcase of sebaceous adenoma arising within a benign ovarianmature cystic teratoma in a patient with documented Muir-Torre syndrome. The importance of diagnosing Muir-Torresyndrome in cases of cutaneous sebaceous adenomas iswell established. Similarly, further history and investiga-tions for Muir-Torre syndrome should be undertaken in thepresence of a sebaceous adenoma in an ovarian maturecystic teratoma.
References
[1] Eisen DB, Michael DJ. Sebaceous lesions and their associatedsyndromes: part II. J Am Acad Dermatol 2009;61:563-78.
[2] Lynch HT, Lynch PM, Lanspa SJ, et al. Review of the Lynchsyndrome: history, molecular genetics, screening, differential diagno-sis, and medicolegal ramifications. Clin Genet 2009;76:1-18.
[3] Ponti G, Ponz de Leon M. Muir-Torre syndrome. Lancet Oncol2005;6:980-7.
[4] Lazar AJ, Lyle S, Calonje E. Sebaceous neoplasia and Torre-Muirsyndrome. Curr Diagn Pathol 2007;13:301-19.
[5] Shalin SC, Lyle S, Calonje E, et al. Sebaceous neoplasia and the Muir-Torre syndrome: important connections with clinical implications.Histopathology 2010;56:133-47.
[6] Eisen DB, Michael DJ. Sebaceous lesions and their associatedsyndromes: part I. J Am Acad Dermatol 2009;61:549-60.
[7] Ponti G, Losi L, Di Gregorio C, et al. Identification of Muir-Torresyndrome among patients with sebaceous tumors and keratoacantho-mas: role of clinical features, microsatellite instability, and Immuno-histochemistry. Cancer 2005;103:1018-25.
[8] Schmeler KM, Lynch HT, Chen L-M, et al. Prophylactic surgery toreduce the risk of gynecologic cancers in the Lynch syndrome. N EnglJ Med 2006;354:261-9.
[9] South CD, Hampel H, Comeras I, et al. The frequency of Muir-Torresyndrome among Lynch syndrome families. J Natl Cancer Inst 2008;100:277-81.
[10] Chumas JC, Scully RE. Sebaceous tumors arising in ovarian dermoidcysts. Int J Gynecol Pathol 1991;10:356-63.
[12] Ribeiro-Silva A, Chang D, Bisson FW, et al. Clinicopathological andimmunohistochemical features of a sebaceous carcinoma arisingwithin a benign dermoid cyst of the ovary. Virchows Arch 2003;443:574-8.
[13] Strauss AF, Gates HS. Giant sebaceous gland tumor of the ovary. Am JClin Pathol 1964;41:78-83.
[14] Vartanian RK, McRae B, Hessler RB. Sebaceous carcinoma arising ina mature cystic teratoma of the ovary. Int J Gynecol Pathol2002;21:418-21.
[15] Venizelos ID, Tatsiou ZA, Roussos D, et al. A case of sebaceouscarcinoma arising within a benign ovarian cystic teratoma. Onkologie2009;32:353-5.
[16] Muir EG, Bell AJY, Barlow KA. Multiple primary carcinomata of thecolon, duodenum and larynx associated with Keratoacanthoma of theface. Br J Surg 1967;54:191-5.
[17] Torre D. Multiple sebaceous tumors. Arch Dermatol 1968;98:549-51.
