Muir-Torre Syndrome Research Articles

Sebaceous carcinoma in solid organ transplant recipients.

Though a rare tumor, sebaceous carcinoma is relatively well-described in immunocompetent patients, in whom it often occurs in a periorbital distribution where it has an overall poor prognosis with a high metastasis rate. The effect of transplant-related immunosuppression on the development of sebaceous carcinoma and its outcomes has not been characterized. We collected 9 cases from a single institution of patients developing sebaceous carcinoma after solid organ transplantation. We analyzed clinicopathologic features. We estimate the prevalence of sebaceous carcinoma post-solid organ transplantation to be 0.09%. The mean age at diagnosis was 66.1 years (std 7.0 years). The mean time between transplantation and sebaceous carcinoma diagnosis was 7.1 years (std 5.1 years). All tumors occurred in extra-ocular distribution. Two patients likely had Muir-Torre syndrome, of whom 1 died from metastatic sebaceous carcinoma. No other patients developed metastatic disease or had disease-related death. Mohs micrographic surgery and wide local excision were equally effective and there were no recurrences with either procedure. Our study found that sebaceous carcinoma in solid organ transplant recipients occurs in in an extraorbital distribution with only 1 patient developing metastatic disease. Both Mohs micrographic surgery and wide local excision are acceptable treatment modalities for sebaceous carcinoma in transplant recipients.

Sebaceous Carcinoma Treated With Mohs Micrographic Surgery.

Sebaceous carcinoma is a rare and potentially aggressive adnexal neoplasm with historic data indicating high rates of recurrence, metastasis, and cancer-specific mortality. To evaluate the incidence of local recurrence, metastasis, disease-specific mortality, and all-cause mortality and to identify work-up approaches. Retrospective review of patients with sebaceous carcinoma treated with Mohs micrographic surgery between 2001 and 2013 at one institution. Thirty-seven patients had 45 sebaceous carcinomas located on the periocular region (13%), non-periocular face (47%), scalp (7%), neck (4%), trunk (9%), and extremities (20%). The mean age was 66.1 years, and 24 (65%) patients were male. Five patients had Muir-Torre syndrome (MTS) or Lynch syndrome. Seven of 12 tumors showed loss of expression of ≥1 mismatch repair gene. The most common work-up involved taking a detailed personal and family medical history. No local recurrences, metastases, or disease-specific deaths occurred during an average follow-up of 3.6 years. Mohs micrographic surgery is an effective treatment for sebaceous carcinoma. Detailed history taking, age-appropriate cancer screening, and immunohistochemical staining with MLH1, MSH2, or MSH6 is helpful in identifying which patients should be referred to a geneticist for work-up of MTS.

An Overview of Autosomal Dominant Tumour Syndromes with Prominent Features in the Oral and Maxillofacial Region.

Several autosomal dominant inherited tumour syndromes demonstrate prominent features in the oral and maxillofacial region. Although multiple organ systems are frequently involved, the target organs more frequently affected are the skin (nevoid basal cell carcinoma syndrome, Brooke-Spiegler syndrome, Birt-Hogg-Dube syndrome and Muir-Torre syndrome), gastrointestinal tract (Peutz-Jegher syndrome and Gardner syndrome) or endocrine system (multiple endocrine neoplasia type 2b and hyperparathyroidism-jaw tumour syndrome). In some syndromes, the disease is multisystem with skin index lesions presenting in the head and neck (Cowden syndrome and tuberous sclerosis complex). The pertinent features of these syndromes are reviewed with a systems-based approach, emphasising their clinical impact and diagnosis.

Lynch Syndrome and Muir-Torre Syndrome: An update and review on the genetics, epidemiology, and management of two related disorders

Hereditary Nonpolyposis Colorectal Cancer (HNPCC), also known as Lynch Syndrome, is an autosomal dominant, tumor predisposing disorder usuallycaused by germline mutations in mismatch repair (MMR) genes. A subset of HNPCC, Muir-Torre Syndrome (MTS) also involves MMR gene defects and is generally accepted as a variant of HNPCC. MTS is typicallycharacterized by at least one visceral malignancy and one cutaneous neoplasm of sebaceous differentiation, with or without keratoacanthomas. In either version of the disorder, nonfunctional MMR systems lead tothe loss of genomic integrity, marked commonly by mismatches in repetitive DNA sequences, resulting in microsatellite instabilities. Deleterious nucleotide alterations ultimately drive the process of tumorigenesis in both HNPCC and MTS. The following article reviews the epidemiology, genetics, clinical presentation, and management of HNPCC and its MTS variant.

Upper tract urothelial carcinomas: frequency of association with mismatch repair protein loss and lynch syndrome

Increased risk for upper tract urothelial carcinoma is described in patients with Lynch syndrome, caused by germline mutations in mismatch repair genes. We aimed to identify the frequency of mismatch repair protein loss in upper tract urothelial carcinoma and its potential for identifying an association with Lynch syndrome. We queried our database to identify upper tract urothelial carcinomas. Patients were cross-referenced for history of colorectal carcinoma or other common Lynch syndrome-associated neoplasms to enrich for potential Lynch syndrome cases. Tumor histopathologic characteristics were reviewed and each case was analyzed for loss of mismatch repair proteins, MLH1, MSH2, MSH6, and PMS2, by immunohistochemistry. Of 444 patients with upper tract urothelial carcinoma, a subset of 215 (encompassing 30 with upper tract urothelial carcinoma and another common Lynch syndrome-associated neoplasm) was analyzed for loss of mismatch repair protein expression. Of 30 patients with Lynch syndrome-associated neoplasms, six had documented Lynch syndrome, including two with Muir–Torre syndrome. Mismatch repair protein loss was identified in 7% of total upper tract urothelial carcinomas and 30% of patients with Lynch syndrome-associated neoplasms (including all patients with Lynch syndrome/Muir–Torre syndrome). Of patients without history of Lynch syndrome-associated neoplasms, 5 of 184 (2.7%) had loss of mismatch repair protein expression. Twelve cases with mismatch repair protein loss demonstrated loss of MSH2 and MSH6, and 2 had isolated loss of MSH6. MLH1 and PMS2 expression were consistently retained. Although increased intratumoral lymphocytes, inverted growth, pushing tumor-stromal interface, and lack of nuclear pleomorphism were more commonly seen in cases with mismatch repair protein loss, only intratumoral lymphocytes and presence of pushing borders were statistically significant. MLH1 and PMS2 testing appear to have little utility in upper tract urothelial carcinoma; however, mismatch repair protein loss of MSH2 and/or MSH6 by immunohistochemistry seems relatively sensitive and specific for identifying patients with potential Lynch syndrome.

Dermatopathologic emergencies part I

In dermatopathology, there are several conditions which must be addressed emergently. While some conditions necessitate emergent intervention because of the pathology of the cutaneous manifestations, others require recognition of the underlying serious systemic conditions represented by the cutaneous signs and symptoms. We describe the desquamating disorders (Staphylococcal scalded skin syndrome, Stevens–Johnson syndrome/toxic epidermal necrolysis, and edema-related desquamation), erythema multiforme, cutaneous aspergillosis, tinea/Candida overlying fractures, rickettsial infections, and eczema herpeticum as diseases which should be addressed immediately upon presentation because of the seriousness and rapidity of progression of their pathology. Moreover, porphyria cutanea tarda, Birt-Hogg-Dube syndrome, Muir-Torre syndrome, and acquired ochronosis may exemplify conditions where the cutaneous signs serve as warnings for severe systemic disease that may not be emergencies in isolation, but can indicate rapid occult development of destructive and sometimes deadly noncutaneous pathology. The literature review was conducted using searches in Pubmed and references to textbooks on the subjects.

Muir-Torre Syndrome: the implications of sebaceous neoplasms

Muir-Torre Syndrome: the implications of sebaceous neoplasms

Superficial epithelioma with sebaceous differentiation: a case report with literature review

Superficial epithelioma with sebaceous differentiation is the original name for a rare benign tumor that lacks consensus in the literature, both in nomenclature and in diagnostic criteria. We report the case of a 68-year-old male with a white papule on the left lower eyelid, fully excised. On histology, the lesion was a superficial, lobulated, plate-like epithelial proliferation, with small mature clusters of sebocytes and ductal structures. Mismatch repair proteins MLH-1, MSH-2, MSH-6, and PMS-2 were retained in the immunohistochemistry study. We reviewed the literature and added our case, which we believe contributes to better characterization of superficial epithelioma with sebaceous differentiation. It usually presents as a solitary papule or nodule on the face of middle-aged males. Histologically, besides the hallmark of a superficial plate-like epithelial proliferation, some variations are occasionally reported: the presence of randomly scattered keratin-filled cysts, squamous eddies, minimal peripheral palisading, marked verruciform architecture, and a reticulated pattern with elongated strands of keratinocytes. The mitotic activity can be high, but no cytological atypia or necrosis is seen. If properly removed, there is no evidence of local recurrence or distant spread. The association with Muir-Torre syndrome remains unclear.

Clinicopathological study of 47 cases of sebaceoma

Sebaceoma is a rare and poorly understood form of sebaceous tumour, and it is of great significance since it may reveal Muir-Torre syndrome (MTS). Herein, we present a series of cases with details of the histopathological appearance. We examined records of cases labelled as sebaceous tumour recorded at the Strasbourg Dermatopathology Laboratory between 1991 and 2015. We include cases of benign sebaceous tumour predominantly involving immature basophilic cells. The clinical and histological data were collected as well as screening for a history of MTS. We studied 47 cases of sebaceomas (26 men), in patients of mean age 67.6years, located primarily in the head or neck (32 cases). Of the 17 patients followed up, 6 had MTS. Different types of architecture were seen: dermal nodule (9 cases) or cystic nodule (9 cases), multiple dermal nodules (22 cases), exophytic tumour (4 cases) and an appearance intermediate with sebaceous adenoma (3 cases). The cells involved were basophilic, with the presence of round ducts exhibiting an eosinophilic cuticle and, in rare cases, mature sebocytes. Mitoses were observed: mean 6.6/10 fields (0 to 19). In all cases, there was expression of CK17, EMA and androgen receptors, but not of BerEP4. Sebaceoma is a small benign tumour but identification is imperative due to association with MTS. A knowledge of the associated cytological and architectural elements-particularly cysts and labyrinthine patterns-and immunolabelling enable differential diagnosis with respect to other tumours. The extra-facial and cystic forms in particular require screening for MTS. If there is any doubt, immunolabelling of androgen receptors provides a precious tool.

Syndrome de Muir-Torre chez un patient atteint de maladie de Waldenström

Muir-Torre syndrome (MTS), a cutaneous variant of Lynch syndrome, consists of hereditary predisposition to cutaneous tumours and gastrointestinal and gynaecological neoplasms, with autosomal dominant transmission. It is associated with mutations in genes coding for proteins in the DNA mismatch repair system. Herein, we report a case of a male patient presenting Waldenstrom's macroglobulinemia since the age of 50 and which, after the age of 65 years, developed into sebaceous tumours (5 sebaceous adenomas, 1 sebaceoma, 1 sebaceous carcinoma) and colonic lesions (4 adenomas). The clinical phenotype was consistent with MTS. Somatic analysis carried out on one sebaceous tumour showed instability of the microsatellites with loss of expression of MSH2 and MSH6 although constitutional genetic analysis showed no germline mutations known to be harmful. This noteworthy case raises a number of questions, including the possibility of association between STM and Waldenstrom's macroglobulinemia, which is discussed herein.

Colon Cancer in a Young Adult: Thereʼs Muir to Know

Colon cancer is the third most common cancer in men and in women and the second leading cause of cancer death in the United States. While up to 90% of these cancers are diagnosed in people over age 50, the remaining 10% are diagnosed in younger patients and can be related to cancer syndromes (such as Lynch), which carry increased risk of extra-colonic cancers. Here we present a patient with cutaneous sebaceous adenomas and adenocarcinoma of the colon who was found to have adenocarcinoma of the small bowel. This constellation of tumors led to the diagnosis of Muir-Torre syndrome. Our patient is a 56 year-old Caucasian man who was diagnosed with multiple cutaneous sebaceous adenomas beginning at age 27. At age 30, he was diagnosed with adenocarcinoma of the transverse colon and underwent partial colectomy. One year later, he was found to have adenocarcinoma at the splenic flexure with subsequent subtotal colectomy. He underwent colonoscopy every 6 months thereafter and EGD every 2-3 years. This year, he presented with fatigue and was found to have iron deficiency anemia (Hgb 6g/dL, ferritin 5). After unrevealing, EGD and colonoscopy, subsequent capsule endoscopy followed demonstrated a large circumferential, ulcerated mass in the proximal jejunum. Push enteroscopy with biopsy revealed adenocarcinoma of small bowel. The patient underwent small bowel resection. He was referred for genetic testing which showed a genetic variant of uncertain clinical significance in the MSH6 gene (gene associated with Muir-Torre). Muir-Torre syndrome is a variant of Lynch that includes a predisposition to certain skin tumors. Based on diagnostic criteria published by Torre in 1995, a diagnosis of Muir-Torre should be suspected in patients with at least one cutaneous malignancy and at least one visceral malignancy (colon, stomach, small bowel, among others). Gastroenterologists must think about Muir Torre in the appropriate patient population and help coordinate appropriate cancer screening. The National Comprehensive Cancer Network (NCCN) 2013 screening guidelines include colonoscopy, EGD, and other screening tests are varying intervals. The NCCN does not recommend specific screening for small bowel cancer. A recently published study did not support screening for small bowel neoplasia in Lynch patients with capsule endoscopy. However, as demonstrated in this case, capsule endoscopy can be a useful tool in evaluating patients at increased risk for small bowel neoplasms. The Revised Bethesda Guidelines for testing colorectal tumors for microsatellite instability (MSI) Tumors from individuals should be tested for MSI in the following situations: 1. Colorectal cancer diagnosed in a patient who is less than 50 years of age. 2. Presence of synchronous, metachronous colorectal, or other HNPCC-associated tumors, regardless of age. 3. Colorectal cancer with the MSI-H histology diagnosed in a patient who is less than 60 years of age. 4. Colorectal cancer diagnosed in one or more first-degree relatives with an HNPCC-related tumor, with one of the cancers being diagnosed under age 50 years.

P-230 Muir-Torre Syndrome diagnostic and screening. a single center experience

P-230 Muir-Torre Syndrome diagnostic and screening. a single center experience

Desmoplastic trichilemmoma arising on scrotum of patient with suspected Muir–Torre syndrome

Desmoplastic trichilemmoma arising on scrotum of patient with suspected Muir–Torre syndrome

Role of microsatellite instability, immunohistochemistry and mismatch repair germline aberrations in immunosuppressed transplant patients: a phenocopy dilemma in Muir-Torre syndrome.

Sebaceous tumours and keratoacanthomas are uncommon neoplasms that constitute important clinical criteria for Muir-Torre syndrome (MTS) diagnosis. In MTS patients, the increased risk of developing synchronous or metachronous visceral malignancies is characterised by autosomal dominant inheritance. However, there are further conditions, other than MTS, that increase the risk of sebaceous neoplasms, e.g. iatrogenic immunosuppression. In this latter scenario, the sebaceous tumours can present microsatellite instability (MSI) and loss of mismatch repair (MMR) proteins, characteristic of hereditary syndromes, even in the absence of MMR germline mutations. In this article, we examine transplant probands in which the immunosuppressive therapies unmask the MTS cutaneous phenotypes, showing MSI and loss of MMR protein expression, as demonstrated by immunohistochemistry (IHC). Furthermore, MMR genes sequencing analysis identified the presence of germline mutations in MTS-suspected individuals, in the absence of a visceral MTS phenotype. It is well known that immunosuppression plays a central role in the development of sebaceous tumours in both MTS and in non-syndromic settings. Sebaceous skin tumours' MSI status and IHC profiles can be influenced by epigenetic or iatrogenic factors; however, they constitute valuable tools and a cost-effective approach to screen individuals who otherways should undergo MMR genes direct sequencing in the context of immunosuppression. In this complex setting, the choice of the immunosuppressive drug becomes a critical decision for the management of both MTS and sporadic transplant patients, which may benefit from the administration of immunosuppressive drugs, resulting in a low impact on skin cancerogenesis.

Generational Expression of Muir-Torre Syndrome in a Canadian Family.

Muir-Torre syndrome (MTS) is a rare autosomal dominant inherited genodermatosis that is considered to be a phenotypic subtype of hereditary nonpolyposis colorectal cancer (HNPCC), commonly referred to as Lynch syndrome. We describe the clinical course of a 57-year-old female patient with MTS. She has a confirmed HMSH2 mutation. Recently she presented with two nodular lesions. Histologic examination confirmed these lesions to be sebaceous neoplasms. The patient has a history of endometrial and colorectal adenocarcinoma as well as several nonspecific sebaceous lesions throughout her life. She has a confirmed extensive family history of MTS with both male and female family members harbouring either HMLH1 or HSMH2 mutations. Affected relatives have presented at different ages throughout their lives with cutaneous neoplasms and visceral malignancies, including malignancies rarely associated with MTS. MTS presents a diagnostic challenge for clinicians. The case demonstrates that the management of MTS, a potentially underreported syndrome, requires a multiprofessional approach incorporating vigilance, screening, and expert knowledge for successful diagnosis and potentially improved prognosis for patients and their families. The case also demonstrates the varied heritability of MTS and prompts the question of how MTS is expressed in succeeding generations.

Urothelial Carcinoma Recurrence in an Ileal Neobladder Nine Years after Primary Surgery with Muir-Torre Syndrome.

We report a patient who presented with a urothelial carcinoma recurrence developed nine years after radical cystoprostatectomy, related to Muir-Torre syndrome.

A Case of Eyelid Sebaceoma Mimicking Chalazion

Purpose: To report a rare case of sebaceoma misdiagnosed as chalazion. Case summary: A 42-year-old female presented with a visible mass in her right lower eyelid. An elevated, hard mass was located at the margin of the right lower eyelid, and she had a history of incision and curettage under the clinical impression of chalazion. On eversion of the lower eyelid, the tarsal portion of the mass was visible as a white-yellowish lesion. The mass was excised under local anesthesia. A sebaceoma was diagnosed based on histopathological examinations. Immunohistochemical studies showed positive staining results for mutator L homologue 1 (MLH1), mutator S homologue 2 (MSH2), and mutator S homologue 6 (MSH6), and she had no past medical history or family history of internal malignancy, suggesting a low possibility of Muir-Torre syndrome. Conclusions: Eyelid sebaceoma should be considered as a differential diagnosis for refractory chalazion. J Korean Ophthalmol Soc 2016;57(8):1303-1306

Importance of universal mismatch repair protein immunohistochemistry in patients with sebaceous neoplasia as an initial screening tool for Muir-Torre syndrome

Muir-Torre syndrome, a Lynch syndrome variant, is characterized by sebaceous neoplasia plus one or more malignancies, typically colon cancer. The significance of DNA mismatch repair (MMR) deficiency detection by immunohistochemistry (IHC) in colorectal carcinomas is well established and is recommended as a screening tool for Lynch syndrome in newly diagnosed colorectal carcinomas. In comparison, literature on IHC application to detect MMR proteins (MLH1, MSH2, MSH6, and PMS2) in sebaceous neoplasia has been less studied and has been derived almost exclusively from tertiary care centers. Herein we describe the largest series to date characterizing MMR deficiency in sebaceous neoplasms, as well as the relative frequencies of each deficiency. Two hundred sixteen consecutive sebaceous neoplasms (216 patients) were analyzed from a community practice setting (133 sebaceous adenomas, 68 sebaceomas, 15 sebaceous carcinomas). One hundred forty-three were MMR deficient (66%), of which 90 were MSH2/MSH6 deficient (63%), 27 MLH1/PMS2 deficient (19%), 22 MSH6 deficient (15%), and 4 PMS2 deficient (3%). MMR deficiency was significantly associated with site, with tumors off of the head and neck more likely to be MMR deficient (specificity 96%). In contrast to prior reports, no significant trend in MMR-deficient versus -nondeficient tumors was seen in age at presentation (median age, 68 versus 66), tumor-infiltrating lymphocytes, or tumor type. Given the low sensitivity of age < 60 years (30%), location off of the head and neck (41%), or presence of tumor-infiltrating lymphocytes (29%) in MMR deficiency detection, IHC screening programs should test all sebaceous neoplasms for MMR deficiency, regardless of their clinicopathological features.

Distinct pathways in the pathogenesis of sebaceous carcinomas implicated by differentially expressed microRNAs.

The molecular-genetic alterations contributing to the pathogenesis of sebaceous carcinoma and sebaceous adenoma remain poorly understood. Given that sebaceous carcinoma is associated with substantial morbidity and mortality, there is a critical need to delineate the pathways driving sebaceous carcinoma and candidate molecules for targeted therapy. To describe differentially expressed microRNAs (miRNAs) in a series of periocular sebaceous carcinomas compared with sebaceous adenomas in order to identify pathways driving the pathogenesis of sebaceous carcinoma. Thirty sebaceous carcinomas and 23 sebaceous adenomas (including 11 that were confirmed to be related to Muir-Torre syndrome and 6 that were confirmed to be sporadic) were obtained from archives (from 48 patients) of 2 institutions (University of Texas MD Anderson Cancer Center, Houston, and Siriraj Hospital, Mahidol University, Bangkok, Thailand) and profiled. Expression of miRNAs was determined using total RNA from formalin-fixed, paraffin-embedded tissue and real-time reverse transcription-polymerase chain reaction performed in a microfluidics card containing 378 unique miRNAs. Fold change was determined using the ΔΔCt method (reference probe, RNU48). Median centering was used to normalize the data. Two-sample t tests were used to identify differentially expressed miRNAs. The false discovery rate was assessed by β-uniform mixture analysis of P values from the t statistics. Significance was defined by this estimated false discovery rate. Serial testing and validation confirmed overexpression of 2 miRNAs previously reported to be oncogenic, miR-486-5p (4.4-fold; P = 2.4 × 10-8) and miR-184 (3.5-fold; P = 1.7 × 10-6), in sebaceous carcinoma compared with sebaceous adenoma and downregulation of 2 miRNAs previously reported to have tumor-suppressive properties, miR-211 (-5.8-fold; P = 2.3 × 10-9) and miR-518d (-4.5-fold; 6.7 × 10-5), in sebaceous carcinoma compared with sebaceous adenoma. Sebaceous carcinoma exhibits an miRNA expression profile distinct from that of sebaceous adenoma, implicating dysregulation of NF-κB and PTEN (targets of miR-486-5p) and TGF-β signaling (target of miR-211) in the pathogenesis of sebaceous carcinoma. The identification of miRNAs whose expression is altered in sebaceous carcinoma compared with sebaceous adenoma provides a novel entry point for a more comprehensive understanding of the molecular-genetic alterations pivotal to the development of sebaceous carcinoma.

Syndrome de Muir-Torre. À propos d’un cas diagnostiqué suite à l’apparition d’un sébacéome mimant un cancer ulcéré du sein gauche

On the basis of a case report, we conducted a search through the literature concerning Muir-Torre syndrome. This syndrome is considered to be a phenotypic variant of Lynch syndrome (or Human Non Polyposis Colorectal Cancer). Muir-Torre syndrome is a familial cancer syndrome defined as the association of an internal malignancy with cutaneous sebaceous tumors. It is a rare disease. In our knowledge, this case is the first reported skin lesion related to Muir-Torre syndrome, located on the breast and mimicking ulcerated breast cancer. Genetic counselling obviously has an important place in the management of this pathology.