CASE REPORT
Dr. Aboul Hosn: A 69-year-old woman presented with recurrent episodes of fresh blood per rectum with a history of 10 kg weight loss over the past year. She also reported chronic large-volume diarrhea for 5 years, with occasional rectal prolapse. Her medical history was significant for dermatomyositis diagnosed 4 years earlier, for which the patient was taking steroids, and an episode of lower extremity deep vein thrombosis, for which the patient was on oral anticoagulation. Her surgical history was significant for a right modified radical mastectomy for breast cancer 10 years earlier. A digital rectal examination done at the time was negative, and her laboratory tests showed a normal hematocrit with some electrolyte abnormalities, including a serum potassium level of 3 mEq/L (range, 3.5–5.2), a serum sodium level of 133 mEq/L (135–147), and a chloride value of 88 mEq/L (95–107) The patient underwent colonoscopy, which showed an ulcerated, nearly obstructing rectal mass with another 2-cm polyp at the level of the sigmoid. She then underwent an endoscopic ultrasound (EUS) that showed the mass to be hyperechoic with possible invasion of the muscularis propria and no evidence of enlarged perirectal lymph nodes.
May I kindly ask Dr. Julio Garcia-Aguilar to comment on the EUS results?
Dr. Garcia-Aguilar: Endoscopic examination is considered the first-choice method for staging of most rectal tumors, especially when neoadjuvant treatment is contemplated. However, recent data have demonstrated that transrectal endoscopic ultrasonography (TEUS) correlates with pathologic staging in only ∼65% of cases, with understaging occurring in 18% of TEUS examinations, and overstaging occurring in 17%.1 Moreover, in the presence of large, nearly obstructing lesions, such as were seen in this case, or with lesions that are too distant from the anal canal to be properly assessed by normal transrectal probes, the accuracy drops further. In such instances, magnetic resonance imaging (MRI), with phased-array coil, is more accurate for presurgical patient evaluation, as it provides a panoramic view of pelvic structures, good evaluation of the villous tumor and its characteristics, and high spatial resolution for evaluating the rectal wall and perirectal extension of the lesions.2
Dr. Aboul Hosn: However, the rectal wall could not be completely assessed in the entire circumference of the rectum due to multiple shadowing artifacts, and therefore the possibility of tumor invasion could not be excluded. No lymph nodes were visualized in the mesorectum. The patient also underwent an enhanced computed tomographic (CT) scan as part of her work-up.
Dr. Antar: CT of the chest, abdomen, and pelvis was performed and showed a large, exophytic, enhancing mass in the rectosigmoid colon, with well-delineated lobular contour and central feeding arterial branches, highly suggestive of villous adenoma. The mass was also seen to extend inferiorly into the anus, along the mucosal lining. No enlarged lymph nodes or fat-streaking in the surrounding mesorectal fascia was noted (Figure 1).
Figure 1.
A CT axial and coronal single slices showing a rectal mass with no perirectal fascia invasion or lymphadenopathy.
Dr. Mukherji: Dr. El Farran, can you comment on the accuracy of current imaging modalities in differentiating between large rectal adenomas and adenocarcinoma?
Dr. El Farran: It is not always possible to differentiate between giant adenomatous polyps and malignant masses on radiologic studies. Contrast barium enema can sometimes demonstrate the lace-like reticular or granular surface pattern seen in adenomatous polyps, because villous adenomas have friable consistency and, in different series, may have a different appearance in the same barium enema examination.3 Contrast enema, however, is neither specific nor sensitive.4 Although CT colonography has been advocated for the evaluation of colon masses, conventional colonoscopy remains the best first-line modality for evaluation of colon masses and polyps, as it can provide tissues for pathologic evaluation.5 MRI has no significant superiority over the conventional CT scan; they both show these types of adenomas as pedunculated or sessile masses with similar attenuation to soft tissues. The advantage of these modalities is in their ability to evaluate extracolonic and lymph node involvement and to provide clues to the histologic nature of some tumors.6
Dr. Aboul Hosn: The patient was taken to the operating room where she underwent low anterior resection with primary anastomosis. Final pathology results showed a 12-cm rectal villous adenoma and another 5-cm sigmoid tubulovillous adenoma, with no evidence of invasive carcinoma and 23 benign pericolonic lymph nodes (Figures 2 and 3).
Figure 2.
Resected specimen showing a 12-cm rectal villous adenoma and another 5-cm sigmoid tubulovillous adenoma.
Figure 3.
Histologic sections of the (A) tubulovillous adenoma and the (B) villous adenoma.
May I ask Dr. Rida to comment on the available treatment modalities of giant villous adenomas?
Dr. Rida: Rectal villous adenomas comprise 40–66% of all tumor entities of the colorectum, making them a common surgical problem.7 On the one hand, the benign nature of these lesions requires treatment options with low morbidity and low mortality. On the other hand, the size and high malignant potential of these adenomas mandates complete excision of the lesion with safe margins to ensure full histopathologic evaluation and a low possibility of recurrence. Endoscopic mucosal resection (EMR) and endoscopic piecemeal resection (EPMR) are therapeutic options widely accepted for the treatment of colorectal adenoma, intramucosal cancer, and minimally invasive submucosal cancer.8,9 Small sessile adenomas of the rectum qualify for endoscopic snare excision, whereas large benign adenomas of the lower rectum can be resected by conventional transanal excision.10,11 Giant adenomas (>5 cm in diameter) of the upper and mid third of the rectum remain a challenge for these techniques. Radical resections, like low anterior resection with total mesorectal excision (TME) have considerable inherent morbidity (from 30% to 50%) and thus have to be well justified in this potentially benign tumor setting. The introduction of a transanal endoscopic microsurgery (TEMS) system by Buess et al12 reformed the management of these lesions. TEMS offers a secure, radical, and minimally invasive method for local tumor excision of the upper and mid third rectum, reducing the potential for bladder and sexual dysfunction and incontinence.13 It is now accepted as effective management for benign and large rectal adenomas, as well as for some early cancers.14 However, especially in the symptomatic patient presented here, it is not always effective, owing to the unfavorable size, depth, location, and nature of this secretory, giant, diffuse villous lesion. Hence, formal resection of the entire rectum and sigmoid was the safest option.
Dr. O'Reilly: What are factors that would predispose to malignant transformation in colorectal adenomas?
Dr. Al-Ahmadie: Adenomatous polyps are premalignant neoplastic lesions classified on the basis of histologic criteria as tubular, tubulovillous, and villous adenomas. Less than 5% of them progress to cancer. Studies have shown that the time for an adenoma to progress to cancer ranges between 7 and 10 years.15 Characteristics of adenomas that correlate with malignant transformation potential include larger size, villous pathology, and the degree of dysplasia within the adenoma.16 Adenomatous polyps smaller than 1 cm have a slightly greater than 1% chance of being malignant, in comparison with adenomas larger than 2 cm, which have up to a 40% likelihood of malignant transformation if left untreated.14 It has also been recognized that adenomas with a predominantly villous component can attain large dimensions without developing invasive carcinoma, with sizes up to 15 cm being reported.17 Of all adenomatous polyps, mild dysplasia is found in 70% to 86%, moderate dysplasia in 18% to 20%, severe dysplasia (carcinoma in situ) in 5% to 10%, and invasive carcinoma in 5% to 7%.18 Higher grades of dysplasia are more common in adenomas of larger size and greater villous content.
Dr. Dbouk: What are the biologic and genetic factors behind malignant transformation in colorectal adenomas?
Dr. Al-Ahmadie: It is generally accepted that most, if not all, colon cancers originate within previously benign adenomas.19 The progression from adenoma to carcinoma results from an accumulation of molecular genetic alterations involving, among other changes, activation of oncogenes, inactivation of tumor suppressor genes, and participation of stability genes.20 The adenomatous polyposis coli (APC) gene is considered the gatekeeper for the process of colon carcinogenesis. Mutation or loss of this gene is believed to be the crucial first step that confers susceptibility to colonic adenomas in patients with familial adenomatous polyposis (FAP) as well as in people with sporadic adenomas.21 Another key player is the K-ras oncogene, which commonly undergoes point mutations at particular sites within the gene, thereby endowing it with the ability to transform cells. Only 9% of small adenomas exhibit K-ras gene mutations, compared with 58% of adenomas larger than 1 cm and 47% of colon cancers.22 That a large number of adenomas and cancers do not have K-ras gene mutations indicates that other genetic events must play a role.
Dr. O'Reilly: Dr. Abdelwahab, can you comment on some of the genetic syndromes associated with colorectal cancer?
Dr. Abdelwahab: Several genetic mutations have been implicated in the development of familial colorectal cancers, such as FAP, hereditary nonpolyposis colorectal cancer (HNPCC), Peutz-Jeghers syndrome, and others.23–25 Some of those gene mutations, along with their associated syndromes, are listed in Table 1.
Table 1.
Genetic syndromes for colorectal cancer
| Gene | Syndrome | Inheritance | Manifestation |
|---|---|---|---|
| APC | FAP | Autosomal dominant | ·>100 colonic polyps with average age of polyposis at 15 years and CRC developing at the end of the 3rd decade of life, if prophylactic colectomy was not performed |
| ·Associated with gastric polyps, pigment retinal epithelium hypertrophy, jaw cysts, or desmoid tumors | |||
| Attenuated FAP | ·Fewer colonic polyps compared to FAP, with average age of polyposis onset at 30 years and CRC usually developing in the early 50s | ||
| Gardner's syndrome | ·Gastrointestinal polyposis | ||
| ·Abdominal desmoid tumor | |||
| ·Osteomas of the jaw | |||
| ·Epidermal cyst | |||
| Turcot's syndrome | Autosomal recessive | ·Colonic polyposis | |
| ·Brain tumor | |||
| MMR genes; hMSH6, hMLH1, hMLH2, hPMS2 | HNPCC | Autosomal dominant | ·Lynch I (site specific): increased risk for colon cancer only |
| ·Lynch II (family cancer syndrome): increased risk of both colon and extracolonic cancers, mainly breast, gynecologic, and urothelial | |||
| ·Diagnoses according to Amsterdam II Criteria which include both | |||
| ·Combination of cancers associated with HNPCC (eg, colorectal, gastric, small bowel, hepatobiliary tract, endometrium, ovarian, brain, ureter, renal pelvis, sebaceous gland adenomas or keratoacanthomas) and | |||
| ·⩾3 relatives with CRC. One must be a first-degree relative of the other 2, at least 2 successive generations must be involved in the family, and 1 CRC must be diagnosed before the age of 50 years. | |||
| Turcot's syndrome | Autosomal recessive | ·The same as HNPCC | |
| MutYH1 | MAP | Autosomal recessive | ·Subtype of FAP without APC gene mutation, with >10 polyps but fewer than classic FAP |
| SMAD4 | Juvenile polyposis | Autosomal dominant | ·Multiple (>10) hamartomatous polyps |
| STK11 | Peutz-Jeghers syndrome | ·Multiple GIT hamartomatous polyps | |
| ·Hyperpigmented macules on lips and oral mucosa | |||
| PTEN | Cowden syndrome | ·Multiple hamartomatous polyps | |
| ·Macrocephaly | |||
| ·Benign skin tumors: multiple trichilemmomas, papillomatous papules, and acral keratosis | |||
| ·Dysplastic gangliocytoma of the cerebellum; Lhermitte-Duclos disease | |||
| ·Other malignancies: breast cancer, follicular thyroid cancer, and endometrial cancer | |||
| GREM1 | Hereditary mixed polyposis | ·Mixed adenomatous and hamartomatous polyps | |
APC = adenomatous polyposis coli; FAP = familial adenomatous polyposis; CRC = colorectal cancer; MMR = mismatch repair; HNPCC = heriditary non-polyposis colorectal cancer; GIT = gastrointestinal tract; MAP = mutYH-associated polyposis.
Dr. Aboul Hosn: This patient's recent medical history was significant for dermatomyositis and deep vein thrombosis, both of which could be indicators of an underlying occult malignancy. What is the underlying association between dermatomyositis and cancer?
Dr. Abdel-Hafiez: Dermatomyositis is an idiopathic inflammatory myopathy with characteristic skin manifestations. It is considered to be the result of a humoral attack against the muscle capillaries and small arterioles, leading ultimately to microinfarctions in the muscle tissue. The risk of malignancy is increased to 6.5-fold in patients diagnosed with dermatomyositis after 45 years of age, with the most common reported malignancies being ovarian, gastric, lymphoma, Kaposi sarcoma, melanomas, and mycosis fungoides.26 The correlation between cancer and dermatomyositis is still unclear. Studies suggest that the link between malignancy and inflammatory myopathy relates to the expression of common autoantigens between cancer tissue and muscle and skin tissue in some patients with dermatomyositis and polymyositis.27 Recently, antibodies against transcriptional intermediary factors (TIFs), which play a role in cellular proliferation and apoptosis, have been implicated in cancer-associated dermatomyositis, further pointing toward a possible adaptive antitumor immune response directed against antigens shared with immature normal cells.28 Dermatomyositis in the setting of benign neoplasms, in particular colorectal adenomas, has been described only in case reports, and in such instances, it is expected to resolve once the neoplasm is resected.29
Dr. Garcia-Aguilar: I would like to ask Dr. El-Sawy Mohamed about the ideal follow-up strategy for this patient following resection of the adenoma.
Dr. El-Sawy Mohamed: The type, number, and size of the resected colorectal adenoma dictate the ideal follow-up strategy. The surveillance recommendations following colorectal polypectomy are listed in Table 2.30 Since the patient had two advanced adenomas with no family history suggestive of FAP or HNPCC, she should have a follow-up colonoscopy in 3 years. Also, because of her breast cancer history, annual breast examination and mammography are recommended.
Table 2.
Postcolorectal polypectomy surveillance recommendations28
| Risk group | Surveillance recommendations |
|---|---|
| Patients with hyperplastic polyps. | Follow-up as average risk. |
| Patients with 1 or 2 small (<1 cm) tubular adenomas with only low-grade dysplasia. | Follow-up colonoscopy in 5 to 10 years. Timing within this interval should be based on other clinical factors (e.g., previous colonoscopy findings, family history, patient preferences, and judgment of the physician). |
| Patients with 1 or more sessile serrated polyps <1 cm with no dysplasia. | Follow-up colonoscopy in 5 years. |
| Patients with 3 to 10 tubular adenomas or any advanced adenomas (>1 tubular adenomas >1 cm; >1 villous adenomas, adenoma with HGD, >1 sessile serrated polyps >1 cm, sessile serrated polyps with dysplasia, or traditional serrated adenoma). | Follow-up colonoscopy in 3 years, provided that adenomas are completely removed. If the follow-up colonoscopy is normal or shows only 1 or 2 small (<1 cm) tubular adenomas with low-grade dysplasia, the interval for the subsequent examination should be 5 years. |
| Patients with sessile adenomas where complete removal is uncertain. | Follow-up colonoscopy within 6 months to verify complete removal. Once complete removal has been established, subsequent surveillance should be as for advanced adenomas. |
| Patients with suspected hereditary colorectal cancer syndrome. | When the family history indicates HNPCC and FAP, colonoscopy every 1 to 2 years. |
HNPCC = heriditary non-polyposis colorectal cancer; FAP = familial adenomatous polyposis.
Dr. Aboul Hosn: Is there an indication for screening this patient's relatives for colorectal cancer?
Dr. Abdel-Wahab: Screening of a patient's family members and direct relatives is recommended when a genetic syndrome is suspected. In such instances, they are classified as moderate or high risk for colorectal cancer, and their screening strategy varies accordingly.31 The screening guidelines for relatives of patients with moderate or high risk for colorectal carcinomas are summarized in Figure 4.32
Figure 4.
Screening guidelines for patients classified as (A) moderate or (B) high risk for colorectal cancer.32
Dr. Aboul Hosn: In conclusion, colorectal adenomas are premalignant lesions with well-established and thoroughly studied molecular genetic alterations leading to malignant transformations. The risk of malignancy is especially high when adenomas are large and multiple, with a villous pathology. In some instances, however, villous adenomas may reach dramatic sizes without malignant degeneration and can instead have obstructive or hypersecretory manifestations. The biologic basis of such an erratic development remains poorly understood. Dermatomyositis in the setting of a benign adenoma is a very unusual feature, as it is usually associated with an underlying malignancy. Yet, in this case, it appeared to be related to the giant villous adenoma, since it was diagnosed around the time when this patient's gastrointestinal symptoms started. A close follow-up of the patient is therefore necessary, to examine for any latent malignancy and to check whether the dermatomyositis resolves after removal of the adenoma.
Acknowledgments
The case discussed was chosen from several presented at the Memorial Sloan-Kettering Cancer Center and the American University of Beirut Inaugural Course of Oncologic Sciences, which took place at the American University of Beirut, Beirut, Lebanon, between June 23 and 28, 2013. Dr. Aboul Hosn was awarded a grant in support of his work. The series is supported by a generous endowment from Mrs. Mamdouha El-Sayed Bobst and the Bobst Foundation and a generous contribution from the office of the Vice President of Medical Affairs and Dean of the Faculty of Medicine at the American University of Beirut.
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