Forty‐eight‐year‐old female MUTYH carrier presenting with five concurrent primary cancers

Abstract Background MUTYH‐associated polyposis is a rare disorder resulting from mutations involved in DNA mismatch repair. This results in an increased susceptibility to colonic adenomatosis and other cancers. Studies have examined the resulting frequency of extracolonic manifestations; however, these typically occur alone, concurrently, or temporally separate from an already diagnosed colorectal cancer in individuals with a biallelic mutation. Case Reported here is a case of five distinct primary neoplasms presenting simultaneously in a patient monoallelic for an MYH mutation. These neoplasms included squamous cell carcinoma of the vulva, rectal adenocarcinoma, synchronous anal adenocarcinoma, papillary thyroid carcinoma, and ovarian serous psammocarcinoma. Throughout her course, she underwent multiple surgical procedures, neoadjuvant chemoradiation, with further adjuvant therapy, and treatment ongoing. Due to her unique presentation, she underwent genetic testing that demonstrated she was monoallelic for an MYH mutation. Conclusion The patient had a positive response to her treatment and surgical procedures with ongoing adjuvant therapy. She will continue to undergo further genetic testing, and testing for her children is being considered. This case demonstrates a unique presentation associated with a monoallelic MYH mutation that is not described in the current literature and warrants further investigation.


| INTRODUCTION
First described in 2002, MUTYH-associated polyposis (MAP) is an autosomal recessive familial colorectal cancer syndrome due to a mutation in the MYH gene. 1,2 Through its excision of misincorporated nucleotide residues caused by dihydro2 0 deoxyguanosine, a mutagenic product of oxidative DNA damage, adenine glycosylase, the enzyme encoded by this gene, functions in DNA mismatch repair. 1,3-6 When pathogenic MYH mutations occur, the phenotype expressed is typically characterized by extensive colonic adenomatosis and an increased risk of colorectal and extracolonic malignancies. Colorectal cancer risk is increased between 23-and 28-fold in biallelic individuals. The presence of an increased risk of malignancy associated with mono-allelic mutations, particularly of the G396D variant seen in our patient, remains controversial. 7 The majority of current studies surrounding this topic sought to delineate the characteristics of this disease by identifying MYH mutations in populations of patients with polyposis and without an identified familial syndrome. Concurrent extracolonic malignancies were frequently encountered 2 ; however, none as extensive as those was seen in the case reported herein. Additionally, extensive colonic adenomatosis has historically been pathognomonic for familial adenomatous polyposis.
However, although only one gastrointestinal polyp was encountered in our case, studies have positively correlated the extent of polyposis with an increased likelihood of harboring an MYH mutation. [8][9][10] Therefore, in patients with multiple primary cancers, and patients with polyposis without an associated APC mutation, further genetic testing should be strongly considered.
Due to the rarity of MAP, specific clinical screening and treatment guidelines have yet to be published. In light of this, the disparate and aggressive presentation of this case serves two educational purposes.
These are to highlight the importance of a thorough workup in patients with oncologic presentations suspicious for genetic aberration, and how variable expressivity can lead to unpredictable presentations necessitating a broad differential diagnosis.

| DISCUSSION
The case presented contains several peculiarities which merit discussion and defy the currently tenuous conclusions surrounding this rare disease. The presentation of our patient raised concern for Lynch syn- However, immunohistochemical stains for MLH1, MSH2, MSH6, and PMS2, which are used to screen for Lynch syndrome, were negative. Additionally, though the patient did not demonstrate any germline mutations associated with Cowden syndrome, the diagnosis was considered due to her medical history of colon cancer, papillary thyroid cancer, and thyroid structural disease. However, the patient did not meet diagnostic criteria based on clinical history alone. In the current literature, MAP is most commonly diagnosed within patients suspected of having FAP but without an APC mutation.
While attenuated FAP (AFAP) is characterized by a low number of polyps, absence of an APC mutation, again, excluded this diagnosis.
F I G U R E 4 CT chest/ abdomen/pelvis: Anorectal mass axial and sagittal view F I G U R E 5 MRI pelvis demonstrated a circumferential, fungating, mucinous, 15.6 cm mass within 1 cm of the anal verge, extending from above the peritoneal reflection down to the lower rectum and upper anal canal. The tumor involved the puborectalis, and internal and external anal sphincters, and was noted to have a 50-mm depth of invasion. Due to abutment of the posterior cervix, vaginal cuff, and bilateral levator muscles, the tumor was believed to invade adjacent organs and was staged as a T4b tumor. The MRI was also suspicious for local lymph node involvement; therefore, the patient was deemed to be clinical stage IIIC (T4b, N1, Mx) F I G U R E 6 Thyroid ultrasound demonstrating multiple bilateral nodules concerning for malignancy. Pictured below is a TI-RADS 5, left-sided thyroid nodule, approximately 5.4 cm in greatest dimension The finding of a p.G396D MUTYH mutation indicated the most likely diagnosis to be MAP. This disorder is genetically defined by a homozygous mutation, and therefore, our patient, by current standards, should only be carrier and should not phenotypically express this typically Mendelian autosomal recessive disorder.
The two most common MYH mutations, of the greater than 60 mutations currently identified, include Y179C and G396D mutations. 11 In the current literature, the risk of colorectal cancer due to a biallelic MYH mutation is increased between 23-and 28-fold, depending on the specific mutations. However, the presence of an increased risk of malignancy associated with monoallelic mutations, particularly of the less virulent G396D variant seen in our patient, has yet to be established. 7  11 patients had between 10 and 100 adenomas, nine had greater than 100, and five had adenomas too numerous to count. 8 This unique presentation of an MUTYH mutation raises suspicion for concurrent and undetected genetic abnormalities. However, because MAP remains rare, and consequentially, studies regarding its prevalence and natural history remain relatively inconclusive, it is possible that this case only highlights how much left there is to learn about this disease. Formal screening and management guidelines specific for this disease have yet to be developed. The importance of understanding MAP, and thus diagnosing it and treating it appropriately, lies in its clinical similarity to other well-characterized familial cancer syndromes. Its autosomal recessive nature directly contrasts the autosomal dominant nature of FAP; the diagnosis most commonly ruled out prior to its diagnostic consideration. This difference has implications regarding which family members to screen and when to screen them. Additionally, its clinical presentation is similar to, but distinct from, other familial cancer syndromes. Therefore, a distinct work-up is likely necessary, however, one has yet to be independently established. Prospective studies on MAP have not yet been conducted. They would doubtlessly be invaluable to its accurate characterization and elucidation of its proper diagnosis and management.