Subhra Dhar1, Ashraf U Mannan2, J Jaya Singh3, Sandipan Dhar4, Swetalina Pradhan5
1 Consultant Pathologist, Kolkata Reference Lab, SRL Ltd, Kolkata, West Bengal, India
2 Basic Research Scientist, Department of Clinical Genetics and Genomics, Strand Life Science Private Limited, Bangaluru, Karnataka, India
3 Basic Research Scientist, Strand Life Science Private Limited, Bangaluru, Karnataka, India
4 Department of Pediatric Dermatology, Institute of Child Health, Kolkata, India
5 Department of Dermatology, All India Institute of Medical Sciences, Patna, Bihar, India
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|Date of Submission||03-Nov-2019|
|Date of Decision||09-Dec-2019|
|Date of Acceptance||15-Jun-2021|
|Date of Web Publication||14-Apr-2022|
Lynch syndrome or hereditary nonpolyposis colorectal cancer (HNPCC) is a type of inherited cancer syndrome with a genetic predisposition to different types of cancer. There is an increased predisposition to cancers in the endometrium, colon, stomach, ovary, uterus, skin, kidney, and brain in patients of Lynch syndrome. We are reporting a 48-year-old male who presented with a pea-sized growth in his left arm which was found to be sebaceoma on histopathology. On further detailed history, examination, and genetic study, it was proved to be a familial case of Lynch syndrome. The case is being reported to stress the importance of knowledge about clinical manifestation, associated neoplasms, and molecular genetic profile of Lynch syndrome which will enable physicians and pathologists to provide highly targeted surveillance and management for patients with high cancer risk.
Keywords: Familial cancer, genetic testing, Lynch syndrome, sebaceoma, sebaceous neoplasms
|How to cite this article:
Dhar S, Mannan AU, Singh J J, Dhar S, Pradhan S. Lynch syndrome: An unusal case of familial cancer unearthed. Indian J Pathol Microbiol 2022;65:465-7
|How to cite this URL:
Dhar S, Mannan AU, Singh J J, Dhar S, Pradhan S. Lynch syndrome: An unusal case of familial cancer unearthed. Indian J Pathol Microbiol [serial online] 2022 [cited 2022 May 3];65:465-7. Available from: https://www.ijpmonline.org/text.asp?2022/65/2/465/343205
Lynch syndrome or hereditary nonpolyposis colorectal cancer (HNPCC) is a type of inherited cancer syndrome with a genetic predisposition to different types of cancer. It is an autosomal dominant disorder and is due to defects in at least one of a family of DNA mismatch repair genes (MMR gene) like MLH 1, MLH 2, MSH 6, PMS 2, or EPCAM. Defective MMR genes lead to microsatellite instability, and accumulation of mutations in these genes leads to tumor progression. Inheritance of these genes leads to increased predisposition to cancers in the endometrium, colon, stomach, ovary, uterus, skin, kidney, and brain. More than four decades ago, Drs Muir and Torre had described the concurrent occurrence of sebaceous neoplasms and internal malignancies. Muir–Torre syndrome is a small subset (1%–3%) of Lynch syndrome where sebaceous neoplasms precede or occur simultaneously with visceral malignancies thereby establishing the importance of diligent screening/surveillance of patients following a diagnosis of sebaceous neoplasms. We present here a case of Lynch Syndrome where the patient presented to us as a case of sebaceous neoplasm.
A 48-year-old male had a pea-sized superficial cutaneous growth on his left upper arm for 3 months [Figure 1]. This growth was excised and sent to the lab for histopathological examination. On gross examination, a grayish-white nodular tissue bit measuring 1 cm in diameter was received.
Microscopy showed tumor tissue with lobular configuration and composed of basaloid cells admixed with vacuolated sebaceous cells. The surface was verrucous [Figure 2]a and [Figure 2]b. There were no areas of frank stromal invasion. Brisk mitosis was noted; however, no necrosis was seen [Figure 2]c. A diagnosis of sebaceoma was made.
|Figure 2: (a) Scanner view, H and E × 40: tumor tissue with lobular configuration and composed of basaloid cells admixed with vacuolated sebaceous cells. (b) Low power, H and E × 100: lobular configuration with basaloid cells and vacuolated sebaceous cells. (c) High power H and E, × 400: Brisk mitosis without any necrosis|
As sebaceous neoplasms are important markers of Muir–Torre syndrome where sebaceous neoplasms are associated with internal malignancy critical call-out was made to the referring clinician.
The clinician was familiar with the patient’s condition and referred the patient directly to us.
The patient came to the lab with his medical file with meticulously worked out genetic profile and clinical history of all his family members. The patient belonged to a large family comprising eight brothers and four sisters, a detailed family history has been illustrated in [Table 1].
The second brother had initially been tested and found to be a carrier of MLH1 gene mutation. This variant was detected in a heterogenous state, and it has been labeled as “pathogenic” variant. Our patient had undergone genetic counseling and testing and also tested positive for the same genetic mutation detected at the splice donor site at the junction of exon 8-intron of the MLH1 gene. The fifth brother and third sister have been tested negative for a genetic test and are disease-free.
Lynch syndrome, is an autosomal dominant multicancer disorder – Lynch syndrome-associated cancers have a high incidence of synchronous (different cancers occurring at the same time) as well as metachronous malignancies (different cancers occurring at separate times).
Individuals from the general population have a 2% lifetime risk of developing colorectal cancer, whereas the risk for patients with Lynch syndrome is over 80% with onset at a younger age and a tendency for more rapid progression., Current progress in our understanding of Lynch syndrome has redefined the rate of incidence and distribution of extracolonic malignancies namely endometrial, ovarian, gastric, urothelial or renal, biliary, pancreatic, brain, and skin.
Our patient presented to us as a sebaceous neoplasm which is a common tumor in Muir–Torre syndrome. Muir–Torre syndrome is now considered a subset of Lynch syndrome characterized by defects in the MMR gene (mismatch repair gene). It is a phenotypic variant of Lynch syndrome. Mutations in one of the DNA mismatch repair genes MLH 1, MLH 2, and MSH 6 h are found in these patients., Our patient who had undergone genetic testing has tested positive for a mutation in the MLH 1gene.
Relation between Muir–Torre and Lynch syndrome: Muir–Torre syndrome is also a genodermatoses with affected individuals presenting with skin neoplasms that either precede or occur concomitantly with internal malignancies. Some sebaceous neoplasms may represent cutaneous markers for MTS. Sebaceous hyperplasia, sebaceous adenomas, sebaceomas or sebaceous epitheliomas, and sebaceous carcinomas represent the benign to malignant spectrum of sebaceous neoplasms of which the latter three are considered to have a more specific association with MTS. Sebaceous adenomas have 25% to 60% and sebaceous carcinomas have 66% to 100% associations with MTs. Besides, one study has shown that extra facial site is more commonly associated with MTS. In our patient, the site of sebaceoma was the lower part of the upper arm. The common germline mutations in MTS is MSH 2 (more than 90%) followed by MSH 1 (less than 10%). MSH 6 mutations are also implicated in MTS. Many studies have shown that patients with MTS have the same spectrum of internal malignancies as Lynch syndrome; therefore, MTS is now considered as a phenotypic variant of Lynch syndrome.
A patient with a family history of colorectal cancer, endometrial cancer, skin tumors, or any other type of cancer associated with Lynch syndrome should be investigated for Lynch syndrome. After confirmation of diagnosis by genetic testing, other members of the family should be screened for the presence of a particular gene mutation present in the index case. Specific testing for a particular MMR gene mutation cannot only expedite the diagnosis, but it can also prove to be cost-effective. There have been attempts to establish a diagnostic criteria to aid in deciding who is at risk which includes modified Amsterdam criteria (1998) and the Bethesda criteria (2002). Currently, several web-based algorithms are available to analyze the type of cancer, age at onset, and the relationships of family members to estimate the chance of an individual to manifest Lynch syndrome. The web-based algorithms can be used to decide whether to go for microsatellite in MS1 or immunohistochemistry (IHC) testing of tumor tissue or directly subject the patient to genetic testing.
A diagnosis of sebaceoma on a skin tumor biopsy led us to this rare familial case of Lynch syndrome which has afflicted multiple members of the same family. Knowledge about clinical manifestation, associated neoplasms, and molecular genetic profile of Lynch syndrome is important as it enables physicians to provide highly targeted surveillance and management for patients with high cancer risk. Genetic counseling can prove lifesaving. Screening for neoplasms in carriers can significantly reduce cancer-related morbidity and mortality and improve outcome and quality of life for patients and his/her family members.
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The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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