Definitions

Gallbladder and extrahepatic biliary tract
ICD-O-3 topography code:	C23-C24.0

/span> non-invasice, benign neoplasm arising from the epithelium. It may be encapsulated or non-encapsulated. The neoplastic epithelial cells may or may not display moderate cellular atypia or dysplasia. Representative examples are pituitary gland adenoma, follicular adenoma of the thyroid gland, and adenomas (or adenomatous polyps) of the gastrointestinal tract.

Adenoma of the gallbladder
Adenomas are benign neoplasms of glandular epithelium that are typically polypoid, single and well-demarcated. They are more common in women than in men, and most occur in adults ¹

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Albores-Saavedra J, Vardaman CJ, Vuitch F (1993)
Non-neoplastic polypoid lesions and adenomas of the gallbladder.
Pathol Annu 28 Pt 1: 145-77

²

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Wistuba II, Miquel JF, Gazdar AF, Albores-Saavedra J (1999)
Gallbladder adenomas have molecular abnormalities different from those present in gallbladder carcinomas.
Hum Pathol 30: 21-5

. They are found in 0.3?0.5% of gallbladders removed for cholelithiasis or chronic cholecystitis. Adenomas are often small, asymptomatic, and usually discovered incidentally during cholecystectomy, but they can be multiple, fill the lumen of the gallbladder and be symptomatic. Occasionally, adenomas of the gallbladder occur in association with Peutz-Jeghers syndrome ^{OMIM 3}

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Foster DR, Foster DB (1980)
Gall-bladder polyps in Peutz-Jeghers syndrome.
Postgrad Med J 56: 373-6

or Gardner syndrome ^{OMIM 4}

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Tantachamrun T, Borvonsombat S, Theetranont C (1979)
Gardner's syndrome associated with adenomatous polyp of gall bladder: report of a case.
J Med Assoc Thai 62: 441-7

⁵

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Walsh N, Qizilbash A, Banerjee R, Waugh GA (1987)
Biliary neoplasia in Gardner's syndrome.
Arch Pathol Lab Med 111: 76-7

. While a significant number of adenomas in the gallbladder are associated with lithiasis, those of the extrahepatic bile ducts are not. A small proportion of adenomas progress to invasive carcinoma ⁶

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Albores-Saavedra J, Vardaman CJ, Vuitch F (1993)
Non-neoplastic polypoid lesions and adenomas of the gallbladder.
Pathol Annu 28 Pt 1: 145-77

⁷

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Kijima H, Watanabe H, Iwafuchi M, Ishihara N (1989)
Histogenesis of gallbladder carcinoma from investigation of early carcinoma and microcarcinoma.
Acta Pathol Jpn 39: 235-44

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Colon and rectum
ICD-O-3 topography code:	C18-C20

/span> non-invasice, benign neoplasm arising from the epithelium. It may be encapsulated or non-encapsulated. The neoplastic epithelial cells may or may not display moderate cellular atypia or dysplasia. Representative examples are pituitary gland adenoma, follicular adenoma of the thyroid gland, and adenomas (or adenomatous polyps) of the gastrointestinal tract.

Adenomas of the colon and rectum
Adenomas are defined by the presence of dysplastic epithelium. This is characterized histopathologically by enlarged, hyperchromatic nuclei, varying degrees of nuclear spindling and stratification, and loss of polarity. Dysplasia can be low-grade or high-grade, depending on the degree of architectural complexity, extent of nuclear stratification, and severity of abnormal nuclear morphology. Foci in invasive growth can be encountered in an adenoma with high-grade dysplasia. For such lesions, the terms high-grade dysplasia as well as intramucosal carcinomas are used. Paneth cells, neuroendocrine cells and squamous cell aggregates may be seen in adenomas ⁸

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Bansal M, Fenoglio CM, Robboy SJ, King DW (1984)
Are metaplasias in colorectal adenomas truly metaplasias?
Am J Pathol 115: 253-65

⁹

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Iwashita A, Watanabe H, Enjoji M (1989)
Argyrophil and argentaffin cells in adenomas of the colon and rectum.
Fukuoka Igaku Zasshi 80: 114-24

¹⁰

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Wada R (2009)
Proposal of a new hypothesis on the development of colorectal epithelial neoplasia: nonspecific inflammation--colorectal Paneth cell metaplasia--colorectal epithelial neoplasia.
Digestion 79 Suppl 1: 9-12

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Macroscopically, most adenomas are polypoid with protrusion into the colorectal lumen, either sessile with broad attachment or on a stalk. A smaller number are flat or depressed ¹¹

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Lambert R, Kudo SE, Vieth M, Allen JI, Fujii H, Fujii T, Kashida H, Matsuda T, Mori M, Saito H, Shimoda T, Tanaka S, Watanabe H, Sung JJ, Feld AD, Inadomi JM, O'Brien MJ, Lieberman DA, Ransohoff DF, Soetikno RM, Zauber A, Teixeira CR, Rey JF, Jaramillo E, Rubio CA, Van Gossum A, Jung M, Jass JR, Triadafilopoulos G (2009)
Pragmatic classification of superficial neoplastic colorectal lesions.
Gastrointest Endosc 70: 1182-99

¹²

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Park DH, Kim HS, Kim WH, Kim TI, Kim YH, Park DI, Kim HJ, Yang SK, Byeon JS, Lee MS, Chung IK, Jung SA, Jeen YT, Choi JH, Choi H, Han DS (2008)
Clinicopathologic characteristics and malignant potential of colorectal flat neoplasia compared with that of polypoid neoplasia.
Dis Colon Rectum 51: 43-9; discussion 49

and often recognizable macroscopically by mucosal reddening, subtle changes in texture, or highlighting by specialized endoscopic techniques.

Most adenomas are < 1 cm in size and have tubular architecture. Some have a villous or tubulovillous architecture. Unusual histopathological patterns such as microtubular adenoma occur.

The characteristics of adenomas are associated with the occurrence of synchronous and metachronous carcinoma. Adenomas of larger size (1 cm), more extensive villous architecture, and high-grade intraepithelial neoplasia/dysplasia, termed ?advanced adenomas? ¹³

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Heitman SJ, Ronksley PE, Hilsden RJ, Manns BJ, Rostom A, Hemmelgarn BR (2009)
Prevalence of adenomas and colorectal cancer in average risk individuals: a systematic review and meta-analysis.
Clin Gastroenterol Hepatol 7: 1272-8

, and flat depressed adenomas ¹⁴

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Lambert R, Kudo SE, Vieth M, Allen JI, Fujii H, Fujii T, Kashida H, Matsuda T, Mori M, Saito H, Shimoda T, Tanaka S, Watanabe H, Sung JJ, Feld AD, Inadomi JM, O'Brien MJ, Lieberman DA, Ransohoff DF, Soetikno RM, Zauber A, Teixeira CR, Rey JF, Jaramillo E, Rubio CA, Van Gossum A, Jung M, Jass JR, Triadafilopoulos G (2009)
Pragmatic classification of superficial neoplastic colorectal lesions.
Gastrointest Endosc 70: 1182-99

have a higher frequency of malignancy, although depressed adenomas have a lower frequency of KRAS mutation than do polypoid adenomas ¹⁵

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Morita T, Tomita N, Ohue M, Sekimoto M, Yamamoto H, Ohnishi T, Tada M, Ikenaga M, Miyake Y, Sakita I, Tamaki Y, Matsuura N, Ito M, Monden M (2002)
Molecular analysis of diminutive, flat, depressed colorectal lesions: are they precursors of polypoid adenoma or early stage carcinoma?
Gastrointest Endosc 56: 663-71

. Patients who have an adenoma of 20 mm or more with tubulovillous or villous architecture in a proximal location in the colon, multiplicity of adenomas (five or more) or are male have more frequent development of a metachronous advanced adenoma or carcinoma ¹⁶

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Martínez ME, Baron JA, Lieberman DA, Schatzkin A, Lanza E, Winawer SJ, Zauber AG, Jiang R, Ahnen DJ, Bond JH, Church TR, Robertson DJ, Smith-Warner SA, Jacobs ET, Alberts DS, Greenberg ER (2009)
A pooled analysis of advanced colorectal neoplasia diagnoses after colonoscopic polypectomy.
Gastroenterology 136: 832-41

. The clinical implications of serration in adenomas and of sessile serrated adenomas/polyps are not yet well-defined¹⁷

Bosman FT, Carneiro F, Hruban RH, Theise ND (Eds.)
WHO Classification of Tumours of the Digestive System.
4th Edition
International Agency for Research on Cancer: Lyon 2010

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Stomach
ICD-O-3 topography code:	C16

/span>denoma is a non-invasive, benign neoplasm arising from the epithelium. The neoplastic cells may display moderate cellular atypia or dysplasia.

> e cells, or even Paneth cells), express intestinal markers (MUC2 and CD10), and are negative for gastric mucins (MUC5AC and MUC6) ¹⁸

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Kushima R, Vieth M, Borchard F, Stolte M, Mukaisho K, Hattori T (2006)
Gastric-type well-differentiated adenocarcinoma and pyloric gland adenoma of the stomach.
Gastric Cancer 9: 177-84

¹⁹

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Park do Y, Lauwers GY (2008)
Gastric polyps: classification and management.
Arch Pathol Lab Med 132: 633-40

. The risk of malignant transformation is related to size (>2cm) and presence of high-grade dysplasia ²⁰

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Park DI, Rhee PL, Kim JE, Hyun JG, Kim YH, Son HJ, Kim JJ, Paik SW, Rhee JC, Choi KW, Oh YL (2001)
Risk factors suggesting malignant transformation of gastric adenoma: univariate and multivariate analysis.
Endoscopy 33: 501-6

. However, the importance of the phenotype (intestinal-type versus gastric) is debated ²¹

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Abraham SC, Montgomery EA, Singh VK, Yardley JH, Wu TT (2002)
Gastric adenomas: intestinal-type and gastric-type adenomas differ in the risk of adenocarcinoma and presence of background mucosal pathology.
Am J Surg Pathol 26: 1276-85

²²

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Park do Y, Srivastava A, Kim GH, Mino-Kenudson M, Deshpande V, Zukerberg LR, Song GA, Lauwers GY (2008)
Adenomatous and foveolar gastric dysplasia: distinct patterns of mucin expression and background intestinal metaplasia.
Am J Surg Pathol 32: 524-33

. Gastric-type adenomas include:

Pyloric-gland adenoma is a rare neoplasm with gastric epithelial differentiation characterized by closely packed pyloric gland-type tubules with a monolayer of cuboidal to low columnar epithelial cells containing round nuclei and pale to eosinophilic cytoplasm ²³

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Chen ZM, Scudiere JR, Abraham SC, Montgomery E (2009)
Pyloric gland adenoma: an entity distinct from gastric foveolar type adenoma.
Am J Surg Pathol 33: 186-93

²⁴

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Kushima R, Vieth M, Borchard F, Stolte M, Mukaisho K, Hattori T (2006)
Gastric-type well-differentiated adenocarcinoma and pyloric gland adenoma of the stomach.
Gastric Cancer 9: 177-84

²⁵

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Park do Y, Lauwers GY (2008)
Gastric polyps: classification and management.
Arch Pathol Lab Med 132: 633-40

.

Foveolar-type adenomas are rare in general but more common in patients with familial adenomatous polyposis (FAP) ²⁶

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Abraham SC, Montgomery EA, Singh VK, Yardley JH, Wu TT (2002)
Gastric adenomas: intestinal-type and gastric-type adenomas differ in the risk of adenocarcinoma and presence of background mucosal pathology.
Am J Surg Pathol 26: 1276-85

²⁷

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Kushima R, Vieth M, Borchard F, Stolte M, Mukaisho K, Hattori T (2006)
Gastric-type well-differentiated adenocarcinoma and pyloric gland adenoma of the stomach.
Gastric Cancer 9: 177-84

, and predominantly express MUC5AC without MUC6 ²⁸

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Chen ZM, Scudiere JR, Abraham SC, Montgomery E (2009)
Pyloric gland adenoma: an entity distinct from gastric foveolar type adenoma.
Am J Surg Pathol 33: 186-93

. Whether they are low-risk lesions or not is debated ²⁹

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Abraham SC, Montgomery EA, Singh VK, Yardley JH, Wu TT (2002)
Gastric adenomas: intestinal-type and gastric-type adenomas differ in the risk of adenocarcinoma and presence of background mucosal pathology.
Am J Surg Pathol 26: 1276-85

³⁰

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Park do Y, Srivastava A, Kim GH, Mino-Kenudson M, Deshpande V, Zukerberg LR, Song GA, Lauwers GY (2008)
Adenomatous and foveolar gastric dysplasia: distinct patterns of mucin expression and background intestinal metaplasia.
Am J Surg Pathol 32: 524-33

Fundic-gland polyps> perplastic polyps are the second most common gastric polyps and typically arise in previously damaged gastric mucosa ⁴⁴

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Abraham SC, Singh VK, Yardley JH, Wu TT (2001)
Hyperplastic polyps of the stomach: associations with histologic patterns of gastritis and gastric atrophy.
Am J Surg Pathol 25: 500-7

⁴⁵

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Carmack SW, Genta RM, Graham DY, Lauwers GY (2009)
Management of gastric polyps: a pathology-based guide for gastroenterologists.
Nat Rev Gastroenterol Hepatol 6: 331-41

⁴⁶

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Park do Y, Lauwers GY (2008)
Gastric polyps: classification and management.
Arch Pathol Lab Med 132: 633-40

, arising in a back- ground of H. pylori gastritis or autoimmune gastritis. Malignant transformation, although rare, is well-documented ⁴⁷

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Carneiro F, David L, Seruca R, Castedo S, Nesland JM, Sobrinho-Simões M (1993)
Hyperplastic polyposis and diffuse carcinoma of the stomach. A study of a family.
Cancer 72: 323-9

⁴⁸

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Carneiro F, Sobrinho-Simóes M (1996)
Signet ring cell carcinoma in hyperplastic polyp.
Scand J Gastroenterol 31: 95-6

⁴⁹

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Stolte M (2001)
Hyperplastic polyps of the stomach: associations with histologic patterns of gastritis and gastric atrophy.
Am J Surg Pathol 25: 1342-4

⁵⁰

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Zea-Iriarte WL, Sekine I, Itsuno M, Makiyama K, Naito S, Nakayama T, Nishisawa-Takano JE, Hattori T (1996)
Carcinoma in gastric hyperplastic polyps. A phenotypic study.
Dig Dis Sci 41: 377-86

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Polyposis syndromes
Peutz-Jeghers polyps^OMIM , juvenile polyps^OMIM , and Cowden polyps^OMIM generally do not occur sporadically, but rather as part of hereditary polyposis syndromes. Some cases of juvenile polyposis may affect the stomach only ⁵¹

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Dunlop MG, , (2002)
Guidance on gastrointestinal surveillance for hereditary non-polyposis colorectal cancer, familial adenomatous polypolis, juvenile polyposis, and Peutz-Jeghers syndrome.
Gut 51 Suppl 5: V21-7

. Gastric Peutz-Jeghers polyps are characterized histologically by branching bands of smooth muscle derived from muscularis mucosae, and hyperplasia, elongation and cystic change of foveolar epithelium; the deeper glandular components tend to show atrophy. However, syndromic gastric polyps can be difficult to distinguish from hyperplastic polyps.

Small intestine
ICD-O-3 topography code:	C17

/span> non-invasice, benign neoplasm arising from the epithelium. It may be encapsulated or non-encapsulated. The neoplastic epithelial cells may or may not display moderate cellular atypia or dysplasia. Representative examples of adenomas are pituitary gland adenoma, follicular adenoma of the thyroid gland, and adenomas (or adenomatous polyps) of the gastrointestinal tract.

Intestinal adenoma
There is good evidence for an adenoma?adenocarcinoma sequence in the small intestine as for the colon ⁵²

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Kaiser A, Jurowich C, Schönekäs H, Gebhardt C, Wünsch PH (2002)
The adenoma-carcinoma sequence applies to epithelial tumours of the papilla of Vater.
Z Gastroenterol 40: 913-20

⁵³

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Sellner F (1990)
Investigations on the significance of the adenoma-carcinoma sequence in the small bowel.
Cancer 66: 702-15

⁵⁴

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Takashima M, Ueki T, Nagai E, Yao T, Yamaguchi K, Tanaka M, Tsuneyoshi M (2000)
Carcinoma of the ampulla of Vater associated with or without adenoma: a clinicopathologic analysis of 198 cases with reference to p53 and Ki-67 immunohistochemical expressions.
Mod Pathol 13: 1300-7

. Residual adenomatous tissue at the margins is seen in 42?65% of duodenal
adenocarcinomas ⁵⁵

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Kaiser A, Jurowich C, Schönekäs H, Gebhardt C, Wünsch PH (2002)
The adenoma-carcinoma sequence applies to epithelial tumours of the papilla of Vater.
Z Gastroenterol 40: 913-20

⁵⁶

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Takashima M, Ueki T, Nagai E, Yao T, Yamaguchi K, Tanaka M, Tsuneyoshi M (2000)
Carcinoma of the ampulla of Vater associated with or without adenoma: a clinicopathologic analysis of 198 cases with reference to p53 and Ki-67 immunohistochemical expressions.
Mod Pathol 13: 1300-7

. Studies performed before the advent of advanced endoscopic techniques showed a high incidence of invasive adenocarcinoma among patients with small-bowel adenomas. For example, one study performed in 1982 reported invasive adenocarcinoma in 65% of patients with small-intestinal adenomas. More recent studies, however, demonstrate a lower incidence, which is most likely related to the now common place practice of performing upper endoscopy in patients with nonspecific symptoms. In a recent study by Catalano et al., invasive adenocarcinoma was found in only 6 out of 103 patients (5.8%) with duodenal adenomas ⁵⁷

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Catalano MF, Linder JD, Chak A, Sivak MV, Raijman I, Geenen JE, Howell DA (2004)
Endoscopic management of adenoma of the major duodenal papilla.
Gastrointest Endosc 59: 225-32

. As a result of the widespread use of endoscopy, the earliest stages of neoplastic change have been identified and characterized in adenomas of the duodenum and peri-ampullary region.

In patients with familial adenomatous polyposis (FAP) ^OMIM , random biopsy specimens of ileal mucosa show foci of abnormal, dysplastic crypts resembling dysplastic aberrant crypt foci of the colon in some patients, supporting the concept that, at least in patients with FAP, oligocryptal adenomas are a step in the development of epithelial neoplasms of the small intestine ⁵⁸

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Bertoni G, Sassatelli R, Nigrisoli E, Pennazio M, Tansini P, Arrigoni A, Rossini FP, Ponz de Leon M, Bedogni G (1999)
Dysplastic changes in gastric fundic gland polyps of patients with familial adenomatous polyposis.
Ital J Gastroenterol Hepatol 31: 192-7

. Similarly, biopsy of the proximal smallintestine in a group of FAP patients showed frequent microadenomas similar to those observed in APC-knockout (Min) mice ⁵⁹

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Preston SL, Leedham SJ, Oukrif D, Deheregoda M, Goodlad RA, Poulsom R, Alison MR, Wright NA, Novelli M (2008)
The development of duodenal microadenomas in FAP patients: the human correlate of the Min mouse.
J Pathol 214: 294-301

. In patients with FAP and in patients with sporadic adenomas, increasing grades of dysplasia are identifiable adjacent to foci of early invasive adenocarcinoma ⁶⁰

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Kaiser A, Jurowich C, Schönekäs H, Gebhardt C, Wünsch PH (2002)
The adenoma-carcinoma sequence applies to epithelial tumours of the papilla of Vater.
Z Gastroenterol 40: 913-20

.

Although adenomas can occur throughout the small intestine, the commonest site is the ampullary and peri-ampullary region ⁶¹

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Schottenfeld D, Beebe-Dimmer JL, Vigneau FD (2009)
The epidemiology and pathogenesis of neoplasia in the small intestine.
Ann Epidemiol 19: 58-69

. Adenomas can be multiple, a finding that should prompt evaluation of the patient for a polyposis syndrome ⁶²

Bosman FT, Carneiro F, Hruban RH, Theise ND (Eds.)
WHO Classification of Tumours of the Digestive System.
4th Edition
International Agency for Research on Cancer: Lyon 2010

.

>

Vulva
ICD-O-3 topography code:	C51

/span> non-invasice, benign neoplasm arising from the epithelium. It may be encapsulated or non-encapsulated. The neoplastic epithelial cells may or may not display moderate cellular atypia or dysplasia.
Representative examples are pituitary gland adenoma, follicular adenoma of the thyroid gland, and adenomas (or adenomatous polyps) of the gastrointestinal tract.

In the vulva, adenomas are rare. They are composed of clusters of small, closely packed glands and tubules lined by columnar to cuboidal mucinous epithelium⁶³

Tavassoli FA, Devilee P (Eds.)
World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Breast and Female Genital Organs.
3rd Edition
IARC Press: Lyon 2003

. Two subtypes are distinguished:

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Axe S, Parmley T, Woodruff JD, Hlopak B (1986)
Adenomas in minor vestibular glands.
Obstet Gynecol 68: 16-8

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Vagina
ICD-O-3 topography code:	C52

A non-invasice, benign neoplasm arising from the epithelium. It may be encapsulated or non-encapsulated. The neoplastic epithelial cells may or may not display moderate cellular atypia or dysplasia.
Representative examples are pituitary gland adenoma, follicular adenoma of the thyroid gland, and adenomas (or adenomatous polyps) of the gastrointestinal tract.

Testis/Male genital organs
ICD-O-3 topography code:	C62-C63

A non-invasice, benign neoplasm arising from the epithelium. It may be encapsulated or non-encapsulated. The neoplastic epithelial cells may or may not display moderate cellular atypia or dysplasia.
Representative examples are pituitary gland adenoma, follicular adenoma of the thyroid gland, and adenomas (or adenomatous polyps) of the gastrointestinal tract.

Bronchus and lung
ICD-O-3 topography code:	C34

A non-invasice, benign neoplasm arising from the epithelium. It may be encapsulated or non-encapsulated. The neoplastic epithelial cells may or may not display moderate cellular atypia or dysplasia.
Representative examples are pituitary gland adenoma, follicular adenoma of the thyroid gland, and adenomas (or adenomatous polyps) of the gastrointestinal tract.

Thyroid gland
ICD-O-3 topography code:	C73

A non-invasice, benign neoplasm arising from the epithelium. It may be encapsulated or non-encapsulated. The neoplastic epithelial cells may or may not display moderate cellular atypia or dysplasia.
Representative examples are pituitary gland adenoma, follicular adenoma of the thyroid gland, and adenomas (or adenomatous polyps) of the gastrointestinal tract.