bubble_chart Overview

Tumorous polyps are true neoplasms resulting from the proliferation of large intestinal mucosal epithelial cells. Solitary occurrences are generally referred to as adenomas, which can be further classified into tubular, villous, and mixed types based on their histological features and biological behavior. Multiple occurrences are commonly seen in familial adenomatous polyposis, along with other conditions such as non-familial adenomatous polyposis and syndromes associated with extracolonic tumors, including Gardner syndrome and Turcot syndrome. These conditions often exhibit varying rates of malignant transformation and are considered precancerous lesions. Consequently, the diagnosis of adenomas holds significant clinical importance.

bubble_chart Etiology

The histogenesis of adenomas is not yet fully understood. Initially, Lane suggested that deep crypt cells develop increasing atypia as they migrate toward the surface. This change can not only be observed in routine vertical sections of crypts but has also been confirmed by histochemical methods. For example, adenomatous epithelium contains more sulfomucins than sialomucins, while the epithelium of the deep crypts in normal tissue also predominantly expresses sulfomucins. Additionally, the lectin DBA, which binds to N-acetylgalactosamine, shows weak staining in adenomas and the deep crypt epithelium of normal tissue. Ruggiero et al. further demonstrated that the blood group Ley antigen diffusely stains many adenomas, whereas in normal mucosa, positive reactions are only observed in the deep crypts. The consistency in histochemical reactions between adenomatous epithelium and deep crypt epithelium strongly supports the possibility that adenomas originate from the deep crypts. Another hypothesis regarding the origin of adenomas was proposed in 1986 by Urbanski et al., who described eosinophilic epithelium. They found that in such lesions, crypts contained reduced goblet cells and were lined by a layer of eosinophilic cells. Eosinophilic epithelium is often located near adenomatous epithelium, with transitional features observed between the two. However, other researchers have noted the presence of eosinophilic crypts in lesions lacking adenomatous glands. Some authors have also highlighted the role of intestinal mucosal lymphoid follicles, which are often adjacent to adenomatous epithelium. These follicles have been found to be associated with the development of adenomas in both humans and experimental animals.

bubble_chart Pathological Changes

Regardless of where the adenoma originates in the crypt, the hyperplasia of adenoma tissue mainly forms an outwardly protruding mass toward the luminal surface. Although all adenomas initially grow as sessile lesions, as they enlarge, some develop into pedunculated or subpedunculated forms. This is speculated to result from factors such as intestinal peristalsis, stool consistency, and the presence of the colonic mesentery. Literature suggests that in the descending colon and sigmoid colon, where peristalsis is stronger and stools are more formed, polyps are more likely to become pedunculated compared to other parts of the intestine.

1. Large Intestine Adenoma

1. Histological Structure of Adenoma

The histological features of adenomas are not only the basis for diagnosis but also the foundation for their classification. Histological sections of adenomas often reveal villous components, which are numerous delicate branches extending from the lesion's base, along with abundant mucus secretion. The cores of these branches consist of loose fibrous connective tissue, covered by a single or multiple layers of columnar epithelial cells. Pathologically, adenomas are classified into tubular adenomas, villous adenomas, and mixed adenomas (i.e., tubulovillous adenomas) based on the proportion of villous components. Currently, the criteria for distinguishing these three types of adenomas are inconsistent. In 1977, Appel's criteria defined adenomas with less than 5% villous components as tubular adenomas, those with 5–50% as mixed adenomas, and those with over 50% as villous adenomas. In 1979, Shinya's criteria classified adenomas with less than 25% villous components as tubular adenomas, those with 25–75% as mixed adenomas, and those with over 75% as villous adenomas. This latter standard has been largely adopted by the World Health Organization (WHO).

The distribution of villous components varies within different regions of the same adenoma, leading to potential discrepancies in histopathological diagnoses from biopsies taken at different sites. A biopsy from an area rich in villous components might be reported as a "villous adenoma," while a biopsy from an area with fewer villous components might be labeled a "tubular adenoma." However, when the entire adenoma is excised and examined, it may be diagnosed as a "mixed adenoma." Clinicians should be aware of these inconsistencies in pathological reports. Since the degree of villous components correlates with the malignancy potential of adenomas, accurately assessing the proportion of villous components can help evaluate the risk of malignant transformation.

Histologically, early-stage tubular adenomas show densely packed tall columnar cells in the crypts, with deeply stained nuclei and reduced or absent goblet cells. As the lesion progresses, the glands become markedly hyperplastic, elongated, branched, and dilated, with varying glandular lumen sizes. The epithelial cells may also proliferate, protruding into the lumen with a tendency to form papillae, and in severe cases, they may exhibit multilayered arrangements. The nuclei are hyperchromatic, with occasional mitotic figures confined to the basal layer. The stroma contains scant connective tissue, small blood vessels, and inflammatory cell infiltration.

Unlike tubular adenomas, villous adenomas typically arise from the surface epithelium of the large intestinal mucosa and grow into the lumen, forming papillary protrusions. Histologically, they exhibit a characteristic delicate villous structure, with villi often directly connected to the mucosal surface. The surface is covered by single or multiple layers of columnar epithelial cells, which vary in size but are arranged regularly. The nuclei are hyperchromatic and located basally, with frequent mitotic figures. The cores of the villi consist of fibrous connective tissue, containing varying amounts of small blood vessels and inflammatory cell infiltration.

Mixed adenomas histologically display features of tubular adenomas with admixed villous adenoma components.

2. Atypical Dysplasia in Large Intestine Adenomas

Atypical hyperplasia mainly refers to the abnormal proliferation of epithelial cells, where the size, morphology, and arrangement of the proliferating cells differ from those of normal mature cells. It is an important precancerous lesion. The grading of atypical hyperplasia in adenoma epithelial cells is significant for assessing the severity of the lesion and estimating prognosis. Currently identified factors related to the malignant transformation of large intestine adenomas, such as adenoma size, histological type, anatomical distribution, and number of adenomas, ultimately correlate with the degree of atypical hyperplasia.

There are various methods for grading the degree of atypical hyperplasia in adenomas. The most widely used classification in China is the three-tier system proposed by Morson et al., which states that all adenomas exhibit atypical hyperplasia and further divides them into mild (grade I), moderate (grade II), and severe (grade III) grades. **Grade I atypical hyperplasia (Grade I)** is primarily characterized by cytological atypia, with reduced goblet cells in the glandular tubules. The nuclei become pencil-shaped, densely packed, and stratified, but their height does not exceed half of the cell. The glandular tubules are slightly elongated. **Grade II atypical hyperplasia (Grade II)** exhibits increased cytological atypia and the emergence of histological atypia. The nuclei become stratified, occupying two-thirds of the epithelial cells, while the apical portion of the cells remains intact. The glandular tubules become elongated and twisted, varying in size, with some showing shared walls and back-to-back arrangements. **Grade III atypical hyperplasia (Grade III)** demonstrates significant cytological and histological atypia. The nuclei are stratified, occupying the entire cytoplasm of the epithelial cells, and goblet cells are rare or absent. The polarity of the epithelial cells is disordered. The glandular tubules are elongated, twisted, and vary in size, with frequent shared walls, back-to-back arrangements, and sometimes cribriform structures. According to this classification system, **grade I atypical hyperplasia adenomas account for 81.9%, grade II for 11.6%, and grade III for 6.5%**. However, practical application has shown that these grading criteria are not entirely objective and are difficult to standardize. Therefore, pathological diagnoses in China often use more ambiguous classifications such as **grade I–II or grade II–III**.

In Japan, a **five-tier grading system** is used to assess the degree of atypical hyperplasia. The extent of epithelial pseudostratification (nuclear distribution within cells) and glandular branching patterns are key criteria for grading. **Grades 0–1** correspond to **grade I atypical hyperplasia**, characterized by **grade I pseudostratification**, where nuclei shift from being parallel to perpendicular to the cell's long axis. Further progression leads to what Lev et al. termed **adenomatous tumorous changes**, equivalent to **Kozuka’s grade IV lesions**, which correspond to **grade II atypical hyperplasia** and exhibit **grade III pseudostratification**. If the luminal cytoplasm near the lumen is also filled with nuclei, it is classified as **grade V lesions**. This method of grading based on nuclear positioning within cells is simple and practical, serving as an important supplement to Morson’s three-tier classification.

Due to the lack of unified and objective standards, even experienced gastrointestinal pathologists may exhibit significant discrepancies in grading atypical hyperplasia. In recent years, **morphometric analysis** has been found to be highly useful in objectively evaluating the degree of atypical hyperplasia. Key parameters include **glandular structural atypia, nuclear-to-cytoplasmic ratio, mean nuclear area, and standard deviation of nuclear height (not absolute area or height)**. However, such morphometric methods are impractical for routine pathological diagnosis. Nevertheless, accurate grading of atypical hyperplasia is crucial because **grade III atypical hyperplasia is often regarded as carcinoma in situ or a borderline malignant lesion**.

3. **Malignant Transformation of Large Intestinal Adenomas**

Malignant transformation of adenomas is characterized by **nuclear atypia, loss of polarity, increased nuclear-to-cytoplasmic ratio, and numerous mitotic figures**. Based on invasion depth, it can be classified as **carcinoma in situ or invasive carcinoma**, with the muscularis mucosae serving as the boundary. Wolff et al. found **6.6% carcinoma in situ** among 855 endoscopically resected polyps, with no cases of metastasis. It is believed that **carcinoma in situ does not metastasize** because the intestinal lamina propria lacks lymphatic vessels. Therefore, clinically, **adenoma malignant transformation usually refers to invasive carcinoma**. Although **carcinoma in situ is a malignant change**, current pathology often classifies it as **grade III atypical hyperplasia** to: 1. Avoid misleading clinicians into performing unnecessary radical surgeries. 2. Reduce psychological burden on patients, as such lesions can be effectively treated if completely excised endoscopically.

The vast majority of colorectal cancers originate from the malignant transformation of colorectal adenomas, based on the following observations: ① The gender and age distribution of adenomas closely resemble those of colorectal cancer; ② Both adenomas and cancers share similar distribution patterns in the colon, with the rectum and sigmoid colon being the most common sites; ③ It is not uncommon to find colorectal cancers coexisting with adenomas; ④ Individuals with adenomas have a significantly higher incidence of colorectal cancer compared to those without adenomas.

The incidence of adenoma malignant transformation varies among different literature reports. The main factors influencing adenoma transformation are the degree of dysplasia, adenoma size, and the extent of villous component proliferation. Both adenoma enlargement and increased villous components can exacerbate the degree of cellular dysplasia. Adenomas with a diameter below 1 cm rarely undergo malignant transformation. Grinnell and Lane reported the malignant transformation rates of 1,352 cases of tubular adenomas, showing rates of 0.7%, 4.7%, and 10.5% for diameters of <0.9 cm, 1–1.9 cm, and >2 cm, respectively. Therefore, it is believed that the malignant transformation rate of tubular adenomas is relatively low, while that of villous adenomas is approximately five times higher than that of tubular adenomas.

II. Large Intestine Multiple Adenomas

1. Familial Multiple Adenomatous Tumor Diseases

This disease is an autosomal dominant genetic disorder with a penetrance of 50%, meaning that approximately half of the patients' offspring will develop the condition, with equal distribution between males and females. The average age of onset is 23 years, and malignant transformation often occurs before the age of 40, leading to colorectal cancer. This condition was first reported by Menzel et al. in 1721, with key data coming from Bussy et al.'s 1975 observations of over 300 familial adenoma patients at St. Mark's Hospital in London, UK. It is estimated that the incidence of this disease in the general population ranges from 1/7,000 to 1/24,000. Domestic data suggest an incidence of over 1/100,000. Zhejiang Medical University collected 13 cases over 20 years, while we detected 20 cases, including 14 males and 6 females, with the youngest being 20 years old and the oldest 68, averaging 37 years. Most cases have a family history, but a minority do not, which may be related to recessive inheritance or genetic mutations. Decosse et al. reported such cases at about 20%, while Schaffer reported 41.8%. In recent years, research on the relationship between fragile sites, cancer breakpoints, and oncogenes has gained attention. In 1991, Cao Shimin et al. from the Chinese Academy of Sciences conducted comprehensive chromosomal analyses on peripheral blood lymphocytes from 30 members of two familial multiple colorectal tumor families. They found that under low-folate culture conditions, the chromosomal structural aberration rate in most familial multiple colorectal tumor patients was significantly elevated, averaging 10%. Frequently observed fragile sites included 3P14, 1p22, and 1P32.

Endoscopically, the condition is characterized by numerous small adenomas, mostly only a few millimeters in size, with a few exceeding 1 cm, resulting in minimal size variation. Morphologically, they appear as sessile, semicircular, nodular elevations with smooth or lobulated surfaces, red and soft in texture, either pedunculated or sessile. In dense distributions, they exhibit a carpet-like structure.

Histologically, they are essentially identical to adenomas, with rare instances of hyperplastic polyps. Therefore, there is no fundamental difference from solitary adenomas, except that this disease manifests at a younger age and has a higher cancer incidence. The average age of detection in clinical patients is about 36 years, but in asymptomatic populations undergoing screening, it is around 24 years. Some believe that without treatment and with follow-up, malignant transformation will inevitably occur within 5–20 years, with the average age of malignant transformation being 39 years, often presenting as multicentric. In addition to being associated with colorectal cancer, Murphy and Sato have reported cases complicated by gastric cancer.

2. Gardner Syndrome

This condition was first reported by Divic and Bussey in 1912, but it was not until the 1950s that Gardner systematically conducted follow-up investigations into its clinical course and genetic characteristics, formally naming it Gardner syndrome. It consists of four types of lesions: ① multiple adenomas in the large intestine; ② bone tumors, commonly occurring in the jaw, skull, and long bones; ③ desmoid tumors, frequently found in the mesentery after surgery; ④ skin lesions, including sebaceous cysts and epidermoid cysts, often appearing on the head, back, face, and limbs, with some cases showing dental deformities. Cases where all the above lesions are present are termed the complete type, while those with two of the latter three lesions are called the incomplete type, and those with only one are referred to as the simple type.

It is generally believed that Gardner's syndrome shares the same hereditary traits, age of onset, number, type, distribution, and risk of malignant transformation of large intestine adenomas as typical familial adenomatous polyposis. However, some data suggest potential differences between the two. For example, children of Gardner's syndrome patients will eventually develop extracolonic manifestations, which are absent in familial adenomatous tumor diseases. Cultured skin fibroblasts and epithelial cells from both conditions revealed that tetraploidy increased to 98% in Gardner's syndrome patients, compared to only 15% in familial adenomatous tumor diseases. Clinically, compared to familial adenomatous polyposis, large intestine adenomas in Gardner's syndrome appear later in life, may manifest after extracolonic symptoms, are fewer in number, and exhibit a less "carpet-like" distribution.

3. Turcot Syndrome

This condition presents as a syndrome of multiple large intestine adenomas and central nervous system malignancies. It is also hereditary but differs from familial adenomatous tumor diseases by following an autosomal recessive inheritance pattern. Turcot first reported this syndrome in 1959, describing two siblings with large intestine adenomatous tumor diseases and central nervous system malignancies. Both died of malignant gliomas—one three months and the other eight years after diagnosis. In 1962, McKusick compiled 16 cases and named the syndrome after Turcot.

The adenomas in this syndrome are distributed throughout the large intestine but are fewer and more scattered. In children under 10 years old, the number rarely exceeds 100, while in those over 10, it may exceed 100 but generally remains below 200. Malignant transformation occurs early, typically before age 20, and is more common in females.

4. Sporadic Adenocarcinoma

This condition does not necessarily have a family history, though its incidence is notably higher in families with familial large intestine cancer or hereditary isolated adenomas. The number of adenomas ranges from a few to several dozen, rarely exceeding 50. A threshold of fewer than 100 is often used to distinguish it from familial adenomatous tumor diseases. Tubular and mixed adenomas are more common, while villous adenomas are rare. The age of onset is older, averaging 45 years, with localized or scattered distribution. Some propose that this condition is a form of familial adenomatous tumor diseases where adenomas have not fully developed and thus do not reach the 100-count threshold.

bubble_chart Clinical Manifestations

An adenoma is a protrusion of the epithelial tissue of the large intestine's mucous membrane into the intestinal lumen, appearing slightly red, which can be distinguished from the grayish-white hyperplastic polyps. However, even experienced endoscopists have a diagnostic accuracy of no more than 70%, and misdiagnosis is highly likely for adenomas smaller than 0.5 cm or hyperplastic polyps larger than 0.5 cm.

Most adenomas are tubular adenomas, and their exact incidence varies across statistical reports due to differences in data sources—some based on clinical records, others on physical examinations—as well as factors such as patient age, gender, thoroughness of the examination, diagnostic criteria, and nomenclature. Tubular adenomas commonly occur in the rectum and sigmoid colon, with pedunculated forms accounting for 85%. Their size ranges from a few millimeters to 10 cm, with diameters of 1–2 cm being most common. Adenomas detected in asymptomatic populations during screenings are often smaller than those found in clinical patients. Those with a diameter of <5 mm are termed microadenomas, primarily tubular adenomas, but they may also exhibit grade II or even grade III atypical hyperplasia, and occasionally invasive carcinoma, which warrants attention.

Adenomas typically appear spherical or hemispherical, with a smooth surface that may have shallow fissures, marked congestion, and redness, sometimes with punctate hemorrhagic spots forming a tiger-stripe-like pattern. When secondary infection occurs, the surface may be covered with mucopurulent secretions. In 5–10% of tubular adenomas, white spots may appear around the pedicle or even on the opposite side of the adenoma's apex. These white spots are round, a few millimeters in size, and clustered in small patches. Their nature is not entirely clear, but histologically they mainly represent inflammatory changes.

Villous adenomas are less common and predominantly affect adults over 50 years old. They are most frequently found in the left colon, with the rectum accounting for about 82% and the sigmoid colon for 13%, while the right colon is rarely involved. Most are sessile or semi-pedunculated, with only 17% being pedunculated. Their morphology is irregular: sessile types resemble flower beds or cauliflower, semi-pedunculated types resemble fluffy balls, and pedunculated types resemble clusters of grapes. The surface is uneven, covered with numerous fine villous projections, often coated with abundant mucus. They are fragile and frequently accompanied by erosion and bleeding, generally larger than 2 cm in diameter—bigger than tubular adenomas—and tend to grow gradually with age.

Mixed adenomas are primarily a histological term, mostly arising from the enlargement of tubular adenomas where the glandular epithelium develops villous growth, forming a mixed type. Thus, they resemble tubular adenomas. Pedunculated and semi-pedunculated forms are common, with an uneven surface that may have deep fissures, a lobulated appearance, and many villous projections.

Since adenomas lack distinctive macroscopic features, current endoscopic diagnosis and classification still involve some errors. Thompson et al. stained polyps removed endoscopically with 1% trypan blue and combined this with stereomicroscopy to accurately describe the macroscopic characteristics of adenomas. They found that the lobular structure of tubular adenomas and villous adenomas differs significantly. The degree of atypia in the mucosal surface's grooves and the presence of fissures or ulcers can also predict the level of atypical hyperplasia and the presence of invasive carcinoma.

The main symptoms of familial multiple adenomatous tumor diseases are bloody and mucous stools, increased frequency of bowel movements, loose stools, as well as varying degrees of abdominal discomfort and systemic symptoms such as weight loss and anemia. Those with cancerous changes often develop intestinal obstruction, but some may remain asymptomatic. The hallmark feature of familial adenomatous tumor diseases is the presence of multiple adenomas in the large intestine, with a diagnostic threshold of over 100 polyps. According to Bussoy's statistics, the number ranges from 104 to over 5,000, averaging around 1,000. The adenomas are predominantly distributed in the left colon, especially in the sigmoid colon and rectum. Yamada classified adenomatous tumor diseases into dense and non-dense types based on the distribution density of the polyps. The dense type refers to densely clustered adenomas with almost no normal mucosa in between, while the non-dense type retains normal mucosa between the adenomas. Generally, cases with more than 1,000 adenomas are classified as dense, and those with fewer than 1,000 as non-dense. On X-ray imaging, these appear as uniformly distributed, round filling defects throughout the large intestine, with diameters of 0.3–0.5 cm and smooth contours. In areas where polyps are densely packed, double-contrast barium enema imaging may resemble a corn-like arrangement, but traditional barium enema can easily obscure the polyps, leading to misdiagnosis as fistula disease.

bubble_chart Diagnosis

The vast majority of colorectal cancers originate from the malignant transformation of colorectal adenomas, based on the following observations: ① The gender and age distribution of adenomas are similar to those of colorectal cancer; ② The distribution of adenomas and cancers in the colon is alike, with both predominantly occurring in the rectum and sigmoid colon; ③ It is not uncommon for colorectal cancer to coexist with adenomas; ④ Individuals with adenomas have a significantly higher incidence of colorectal cancer compared to those without adenomas.

bubble_chart Treatment Measures

1. The principle for managing adenomas is to perform endoscopic removal and whole-tumor biopsy upon detection. Surgical treatment is required for the following conditions: ① presence of lymphatic infiltration; ② histological evidence of poorly differentiated cancerous tissue; ③ cancerous infiltration at or near the resection margin of the adenoma. Among adenoma specimens, infiltrative adenocarcinoma is found in approximately 2-5% of cases, and the overall rate of lymphatic metastasis does not exceed 5%. This indicates that endoscopic resection is appropriate for the vast majority of polyp malignancies, especially pedunculated ones. In pedunculated polyps, lymphatic metastasis is very rare when cancerous changes are confined to the head of the polyp.

2. The treatment principle for familial multiple adenomatous diseases is to resect the entire large intestine that may develop cancer upon diagnosis, thereby preventing the occurrence of large intestine cancer. For patients who have already developed cancer, an appropriate radical surgery should be selected.