M62 Coloproctology Course

John Northover returned to deliver a keynote lecture on multidisciplinary pelvic surgery. Updates on polyp management, oncology and IBD were among the sessions.

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Adenomatous Polyps, The Good, The Bad and The Ugly

Najib Haboubi, Trafford Healthcare NHS Trust, Manchester, UK

Professor of Liver and Gastrointestinal Pathology

The term polyp is derived from the Greek word of multiple feet (poly : many & pes : feet). It also means little nipple. The polyp is defined clinically as a circumscribed protrusion of the mucosa, stalked or sessile. ( 1).
Polyps of the large intestine may originate from mucosal or submucosal tissue and the biological behaviour of polyps are entirely related to their pathological nature, hence the importance of histological assessment. Therefore the term ‘Polyp’ has no scientific value unless its nature is qualified i.e. metaplastic, inflammatory, neoplastic, hamartomatous etc. These qualifications are entirely dependant on histological examination.

Adenomatous polyps are defined as neoplastic epithelial tumours with no evidence of malignancy. ( 2) All adenomas are dysplastic by nature.
Dysplasia is defined as ‘unequivocal neoplastic change of the epithelium limited by the basement membrane’ (3.) In other words there is no evidence of intra or submucosal invasion.

Any lesion that does not show any degree of dysplasia is NOT an adenoma . Classically adenomas show 3 grades of dysplasia, mild, moderate or sever. This is again ,strictly a histopathological assessment. The general architecture could have a tubular, villous or tubulo villous configurations.
Adenomas are very common in the colon and rectum. The prevalence vary in the literature and depends on the type of assessment, country, age range and method of detection. For example in colonoscopic surveys which included younger patients the prevalence rate was about 2% while the autopsy studies range between 30 – 35%. (4). Furthermore the traditional colonoscopy may overlook small and sessile polyps, particularly on the right side of the colon if they have not been dye spread.

Malignant or carcinomatous polyps are defined as adenomatous polyps in which the cancer has invaded by direct continuity through the muscularis mucosa into the submucosa. (5). While the risk of metastasis is extremely low if there is mucosal invasion, this risk increases substantially when there is submucosal extension. This is due to the richness, the submucosa with lymphatic and blood vessels.

It is important to realise that whilst most carcinomas arise in a pre-existing adenoma, most adenomas will not become malignant (6,7).

The risk factors of malignant transformation in polyps relates to the size, degree of dysplasia and villocity. Nusko et al who have looked into large number of biopsies, confirm the observation of Morson and added the rectal site as a significant risk factor. (8) In their paper, none of the 5,137 adenomas of 5mm diameter or less demonstrated malignant potential. The malignancy increases progressively with size to almost 80% chance in adenomas of more than 42mm. They also have shown that if there is a pure tubular adenoma the risk of malignancy is less than 4% while if there is a villous pattern the risk of malignancy rises to just under 30%.

Size has always been reported as a crucial factor. It has been estimated that the risk of carcinoma in an adenoma is less than 1% a 1 cm or less adenomas, rising to 10% in adenomas of 1-2 cm and 20-50% in adenomas larger than 2cm.(9).

Prevalence of Malignant Polyp

The chance of an adenoma to undergo malignant transformation in a person’s lifetime is between 5-10% (10).

Taking all risk factors it has been estimated that unremoved adenomas acquire the risk of malignancy at 5, 10 and 20 years are 2.5%, 8% and 24% rates respectively (11).

It has been estimated that in an average 400 bed hospital the numbers of malignant polyps coming to the department of pathology is in the region of 2 per year. We find that this is a gross underestimate as in our own department we see significantly more malignant polyps. Obviously the figures may vary from one centre to another and from geographical location to another.

Diagnosis of Malignant Polyp

It has been shown that to make a diagnosis of malignancy in an adenoma on a biopsy carries 18.5% false negative results if compared with examining the entire specimen(12). Therefore it is important to realise that to make a definitive diagnosis of an adenoma and role out malignancy, the pathologist must look at the entire specimen.

To diagnose malignant polyp and assess the degree of high risk metastasising potential to regional lymph nodes or distant metastasis, it is essential to have a high technical and processing approach (13,14).

The polyp should be fixed appropriately and given enough time for the formalin to perculate through the specimen, then embedded and sectioned, so that the relation between the head and the stalk in the pedunculated polyp is maintained. Optimum fixation is essential in processing these polyps otherwise specimens may suffer from loss of tissue during premature processing and therefore loosing some vital pieces of ‘evidence’ (15).

Once the entire specimen is received, and a malignant focus is discovered, the risk this malignancy for/ local regional recurrence or distant metastasis governs the views of how to deal with the clinical situation.

When the diagnosis of malignant polyp is made, it is important to consider the following points:

Is polypectomy alone sufficient treatment?
What are the high risk factors, which may require colonic resection?
Are there any other relevant factors?

High Risk Malignant Polyps

High risk means that there is high potential of residual or metastatic disease in the post polypectomy colectomy specimen or in 5 years follow up.

The most important criteria which are associated with failure of treatment (high risk) are:

Level of Invasion

Haggitt et al(13) devised a system based on the vertical depth of the malignancy . It appears as follows:
0 – in-situ or intramucosal severe dysplasia
1 – Carcinoma invading the area above the junction of the adenoma and the stalk (head).
2 – carcinoma invading the junction between the adenoma and the stalk (neck).
3 – carcinoma invading any other part of the polyp.
4 – invasion into the submucosa of the bowel wall below the stalk in the pedunculated polyp and in the submucosa of the sessile polyp.
Using the above description, levels 1, 2 and 3 pertain only to invasion in pedunculated polyps while level 4 pertains to invasive carcinoma in sessile polyps. Therefore all malignancy in sessile polyps and Level 4 invasion in pedunculated polyps are classified as high risk. Keyzer et el (16), showed that malignant adenomas removed from 42 patients of whom 27% had level 1, 9% level 2, 11% level 3 and 39% level 4. In 14% the level was not identified. 29 of these cases had polypectomy followed by surgical resection. None of the 14 patients with levels 1, 2 and 3 showed either residual tumour in the resection specimen or lymph node metastasis. By contrast, of the 15 patients with level 4 lesions 3 had residual mucosal disease, 1 had lymph node metastasis and 1 died of colorectal cancer. The authors concluded that only level 4 malignant colorectal adenoma are at high risk and should therefore undergo surgical excision.

2. Degree of differentiation: Malignant polyps with poorly differentiated or signet rings elements carry a bad prognosis as they have in turn a high risk. The paper from Coverlizza (17) shows that poorly differentiation of signet ring components with vascular or lymphatic invasion and/or carcinoma extending to the margin of the specimen are high risk and none of the low risk cases show any residual tumour while the high risk did so.

3. Lympho – Vascular invasion: It is important to realise that the lympho- vascular invasion may be difficult to be differentiated from ‘retraction artefact’ . In one study there was a considerable interobserver variation in such an assessment (15). Also the number of high risk polyps falling in this category is small and almost all of them are associated with other risk factors like incomplete excision and poor differentiation.

Completeness and margin of excision. The adequacy of excision has been debated whether it is 2mm or 1mm free. The paper from Cooper (18), less than 1mm is regarded as a high risk factor with unfavourable outcome.
Other high risk features have been reported are short pedicle of 3 mm or less, polypoidal carcinoma ( polyp entirely made of cancer) and residual villous adenoma

Differing View Points on Treatment Modality

For the above reasons it is obvious that the points of views expressed by some researchers suggest that there are a high risk group of people some of them who will benefit from extended surgery and there are low risk group in which polypectomy on its own is sufficient treatment.

There are on the other hand, researchers who would suggest that there are no low risk factors, indeed, whenever there is a malignancy in a polyp it has to be regarded as a high risk factor. Colacchio et al for instance (19), reported 39 patients with malignant colorectal adenoma in a series of 729 patients with pedunculated adenomatous polyps removed endoscopically. 15 patients out of the 39 were managed by polypectomy alone and 24 had colonic resection. Of the latter group, 6 (25%) had lymph node metastasis. The analysis showed that all 24 adenomas were completely excised endoscopically and the parameter of size, level of invasion, degree of differentiation, involvement of lymphovascular structures with metastasis could not predict which lesion would have nodal metastasis and therefore they suggested that all malignant adenomas should undergo further colonic resection.

A study by Chapman et al (20) found that polypectomy alone was sufficient treatment in all risk groups provided that the endoscopist was certain the polyp was completely removed, although 4 out of 45 low risk polyps in those series died of intra-abdominal malignancies.

In the recent work by Seitz et al (21) however, presented their data on 114 cases of endoscopically removed malignant adenomas have shown that non of the 54 low risk patients suffered from adverse effect related to carcinoma and of the 60 designated as high risk polyp patients have suffered a siginificant increase in adverse outcome. They also suggested that the risk of outcome should be weighed against the risk of major surgery.

In a pooled data analysis Hassan et al, (21a) looked at 31 studies including 1900 polyps and found that there is a significant unfavourable outome in malignant polyps showing positive resection margins (residual mucosal disease), poor differentiation (increased mortality) and vascular invasion (higher lymph node metastasis). The conclusion of this pooled analysis is that the presence of the above risk factors are significantly associated with clinical outcome.

The controversies of polypectomy alone or colonic resection as described above is still raging and it seems that there is no consensus of treatment although the accepted practice is that high risk malignancy carries higher risk of local regional or distant metastasis.

What other factors are relevant?

The above analysis indicates that malignant adenomas with favourable histology and endoscopic features should be managed by polypectomy alone with a negligible risk of treatment failure. By contrast, malignant polyps with an unfavourable histology carry a risk of cancer-specifc treatment failure of between 10% and 25%. What factors should be considered in the risk analysis of colonic resection for these patients? These can be expressed as a balance for or against surgical resection as follows (22):

Factors for resection

For	Against
`Cure' cancer risk	Surgical mortality
Remove other adenomas	Morbidity
Within the specimen	Risk of stoma

The arguments for resection start with the perceived risk from histological examination of the polyp of the possibility of residual cancer with the potential to progress to a cancer death. Surgical resection is the best therapy to eliminate this, but the case of the high risk polyp resection may be unnecessary in between 75% and 90% of patients. This means that 10 resections are required to save one patient. Despite this there is still a risk of cancer death after surgical resection [ 23,24].

The state of the remaining colonic mucosa is also of relevance to the decision as to whether or not to proceed to colonic resection, since colonic neoplastic change is often multifocal. The presence of multiple adenomas in the same segment as the malignant polyp might be an argument for resection, particularly if other polyps subsequently show high grade dysplasia. Similarly, the finding of a malignant adenoma in association with a strong family history of large bowel cancer would also be in favour of resection. In such cases genetic diseases such as hereditary non-polyposis colorectal cancer should be considered.

Factors against resection

Surgical resection is associated with a significant risk of mortality and morbidity. The immediate morbidity associated with resection includes cardio-respiratory complications as well as anastomotic leakage and stoma formation [25]. In addition, there is the risk of diarrhea after extensive colonic resection, particularly in the elderly. Overall mortality of resection is about 5% [26,27]. This falls to about 3% in patients between 66 and 69 years of age but rises to >9% of patients >85 years old [27]. The median age of the malignant adenoma population is about 65 years [24] and globally there is therefore about one post-operative death for every 30 surgical resections.

If one considers 100 patients having polypectomy for a malignant adenoma confirmed by histopathology, of whom 50 have an unfavourable histology, 10% of these (5% of the total) will have an adverse cancer outcome. Thus polypectomy alone will result in five patients who subsequently develop colorectal cancer. Two of these might be salvaged by surgery but three will die of cancer. If the 50 unfavourable malignant polyps had all undergone surgical resection, besides any post-operative morbidity there would have been two post-operative deaths. Furthermore, resection would not have eliminated entirely the chance of subsequent cancer death in the operation survivors [8,28]. There is therefore no evident advantage in terms of death of either course of action, and since only few patients with a malignant polyp are seen per year in a typical district general hospital it is unlikely that this question will be answered by a randomized prospective multicentre trial.

In practice the individual patient with a histologically unfavourable malignant polyp has either a 10% chance of cancer-specific treatment failure or a 3±5% risk of postoperative death. Informed consent requires discussing these risks and uncertainties with the patient and family. Only a full explanation of the alternatives with due weight being attached to the presence of other colonic risk factors and/or the patient's general condition can result in the appropriate therapeutic decision.

Conclusion

Both the histopathologist , surgeon and the endoscopist have a role in distinguishing the favourable from the unfavourable malignant adenoma. The dilemma as to which course of action, either therapeutic polypectomy alone or surgical resection, is in the best interest of the patient with the unfavourable malignant adenoma can be best resolved by a team approach, taking the patient's condition also into account.

In summary:

Adenomas are very common.
They are the natural precursors of CRC.
Malignant transformation is seen in less than 10% of adenomas in a patient’s life time.
High risk of metastasis are poorly differentiation, Haggitt level 4 invasion and incompleteness of excision.
The treatment of choice in low risk malignant polyp is polypectomy.
In high risk ones one has to weigh the adverse effect of malignancy( 10%) against the morbidity and mortality (2-8%) of the radical operation.

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