Colorectal cancer

Japanese: 大腸癌

(1) Colorectal carcinoma
Definition and Concept Colorectal cancer is a malignant tumor that originates from the colonic mucosal epithelium. The large intestine is composed of the cecum, colon, rectosigmoid portion, and rectum, but may also include the appendix and anal canal. The large intestine is sometimes divided into two parts, with the cecum, ascending colon, and transverse colon being called the right colon, and the descending colon, sigmoid colon, rectosigmoid portion, and rectum being called the left colon.
Classification
1) Macroscopic classification:
Colon cancer is classified into the following macroscopic types: superficial (type 0), elevated tumor type (type 1), localized ulcerative type (type 2), ulcerative infiltrative type (type 3), diffuse infiltrative type (type 4), and unclassifiable type (type 5). Of these, type 2 is the most common. Superficial types are further subclassified into elevated types (Is/Isp/Ip types) and superficial types (IIaIIb/IIc types) (Figure 8-5-25).
2) Histological classification:
It is classified as adenocarcinoma, endocrine cell carcinoma, adenosquamous carcinoma, squamous cell carcinoma, or other cancers. Adenocarcinoma is subclassified into papillary adenocarcinoma, tubular adenocarcinoma (well-differentiated/moderately differentiated), poorly differentiated adenocarcinoma (solid/non-solid), mucinous carcinoma, and signet ring cell carcinoma. Most colorectal cancers are well- or moderately differentiated tubular adenocarcinoma.
3) Progression (stage):
It is classified according to the depth of invasion into the wall, the degree of lymph node metastasis, and the presence or absence of distant metastasis. In Japan, the stage of progression in the colon cancer treatment guidelines is used (Table 8-5-14). Other classifications include the TNM classification and the Dukes classification.
Causes and etiologyColorectal cancer can be broadly classified into three types based on the mechanism of development:
1) Sporadic colorectal cancer:
Most colorectal cancers are non-hereditary and are primarily caused by exposure to environmental factors. They develop as a result of the accumulation of genetic mutations in colonic mucosal epithelial cells. The incidence rate increases with age. Proposed mechanisms of carcinogenesis include the adenoma-carcinoma sequence, de novo carcinogenesis, and serrated neoplasia pathway.
a) Adenoma-carcinoma sequence: This is the pathway by which benign tumors called adenomas develop into carcinomas. Mutations in the APC gene in mucosal epithelial cells cause low-grade adenomas, which become high-grade adenomas through mutations in the K-ras gene, and cancer through mutations in the p53 gene. This is a stepwise mechanism of carcinogenesis in which the DCC gene mutates further, resulting in cancer that invades and metastasizes.
b) De novo carcinogenesis: This is a mechanism of carcinogenesis in which cancer develops directly from normal mucosa without the involvement of precancerous lesions. The basis for this is the existence of small depressed cancers that do not involve adenomatous components.
c) Serrated neoplasia pathway: This is a carcinogenesis mechanism that originates from serrated lesions such as hyperplastic polyps and sessile serrated adenomas/polyps, or serrated adenomas.
2) Hereditary colorectal cancer:
A disease in which genetic factors have a decisive influence on the development of colorectal cancer is called hereditary colorectal cancer. Compared to sporadic colorectal cancer, hereditary colorectal cancer tends to occur at a younger age, and is characterized by a high incidence of multiple colorectal cancers and cancers in other organs. Common hereditary colorectal cancers include Lynch syndrome (hereditary non-polyposis colorectal cancer: HNPCC) and familial adenomatous polyposis (FAP).
Lynch syndrome is an autosomal dominant genetic disorder caused by mutations in the mismatch repair genes (MLH1, MSH2, MSH6, PMS2). Lynch syndrome and HNPCC are the same disease. The diagnostic criteria are shown in Table 8-5-15.
FAP is a syndrome characterized by multiple colonic adenomas due to mutations in the APC gene on the long arm of chromosome 5 (5q21-22). The incidence of colon cancer has been reported in people in their teens, but about 50% of cases occur in people in their 40s, and if left untreated, the incidence reaches nearly 100% by the age of 60.
3) Colitic cancer:
This is a pathway by which cancer develops against the background of inflammatory mucosa in cases of long-term inflammatory bowel disease (IBD), and a typical example is colon cancer occurring in ulcerative colitis (UC). In UC, colon cancer is likely to occur in 1) cases with a history of more than 10 years, and 2) cases with pancolitis. Atypical ductal glands (dysplasia), which are precancerous lesions, are classified into low grade dysplasia and high grade dysplasia, and when high grade dysplasia is found, surgery is indicated as there is a high incidence of carcinoma. Colon cancer associated with UC is characterized by a tendency for early-onset and multiple occurrence, with diffuse infiltrative types, poorly differentiated adenocarcinoma, and mucinous carcinoma being relatively common. Atypical ductal glands are present in the periphery.
Epidemiology: The incidence and mortality rates of colorectal cancer in Japan are increasing significantly. According to vital statistics from 2008, colorectal cancer is the most common cause of death among women of all malignant neoplasms, and is the third most common cause of death among men after lung cancer and stomach cancer, and the number of deaths from colorectal cancer has increased approximately fivefold over the past 30 years. The most common age for both men and women is the 60s, followed by the 50s and 70s, with the disease being more common in men than women.
Clinical manifestations
1) Symptoms:
In the early stages, there are often no symptoms, but as the disease progresses, symptoms appear. Symptoms vary depending on the location of the tumor. Cancer of the rectum or left colon is characterized by bloody stools, abnormal bowel movements (constipation, diarrhea, thin stool column, tenesmus), and intestinal obstruction. If the cancer progresses further and invades other organs around the rectum, symptoms such as hematuria, frequent urination, genital bleeding, and sacral pain may also appear. On the other hand, in the right colon, the intestinal contents are liquid and the intestinal lumen is wide, so stenosis symptoms are less likely to appear. Common chief complaints are vague abdominal complaints, mild abdominal pain, anemia, and palpable masses.
2) Objective symptoms:
Inspection and palpation of the abdomen are performed to check for abdominal distension, tenderness, and masses, and digital rectal examination is performed to check for the nature of the mass and the state of bleeding. In addition, the presence or absence of Virchow metastasis (metastasis to the left supraclavicular lymph nodes) and Schnitzler metastasis (metastasis to the Douglas cavity) is also confirmed.
Test results
1) Immunological fecal occult blood reaction:
It detects the presence or absence of blood in stool by reacting specifically to human hemoglobin. It is used for screening of colorectal cancer.
2) Tumor markers:
Tumor markers used for colon cancer include serum CEA (carcinoembryonic antigen) and CA19-9 (carbohydrate antigen 19-9). They are used to predict the stage of progression and to monitor recurrence and the effectiveness of chemotherapy. The positive rate is low in early-stage cancer, so they are not suitable for screening.
3) Barium enema examination:
The location, shape, and presence or absence of stenosis of the lesion are diagnosed. In advanced cancer, the characteristic apple claw sign may be seen. The lateral image of the tumor allows the depth of invasion into the colon wall to be estimated from the degree of deformation of the wall. The lateral image of the rectum clearly shows its position in relation to the sacrum, making it possible to diagnose the location.
4) Lower gastrointestinal endoscopy:
The morphology and location of the tumor are diagnosed. Observation of the surface fine structure (pit pattern) using a magnifying endoscope is useful for distinguishing between tumors and non-tumor and diagnosing the depth of invasion of early cancer. Treatment is also possible by endoscopic removal (polypectomy, endoscopic mucosal resection (EMR), or endoscopic submucosal dissection (ESD)).
5) Other tests:
CT and MRI can show whether or not there is distant metastasis, whether or not there is infiltration into other organs, and whether or not there is swelling in the lymph nodes.
Differential diagnosis includes colorectal adenoma, carcinoid tumor, malignant lymphoma, colorectal non-epithelial tumors (smooth muscle tumors, neurogenic tumors, gastrointestinal stromal tumors (GIST), lipomas, etc.), mucosal prolapse syndrome, radiation colitis, endometriosis, and mesenteric panniculitis.
Treatment
1) Treatment policy for stage 0 to Ⅲ colon cancer:
a) Endoscopic treatment: Endoscopic treatment is indicated for mucosal (M) cancer or mildly invasive submucosal (SM) cancer, and lesions less than 2 cm in size. Endoscopic treatment is an excision biopsy, and treatment is completed if the pathology test shows negative resection margins and the depth of invasion is M. Intestinal resection with lymph node dissection is recommended as additional treatment if the pathology test shows positive vertical margins (cancer exposed at the submucosal margin), the SM invasion distance is 1000 μm or more, vascular invasion is positive, the histological type is poorly differentiated adenocarcinoma, signet ring cell carcinoma, or mucinous carcinoma, or there is severe budding at the front of the invasion.
b) Surgical treatment: The basic surgical procedure is intestinal resection and lymph node dissection. The extent of lymph node dissection varies depending on the depth of invasion into the wall.
2) Stage IV colon cancer treatment plan:
Treatment for staged colorectal cancer depends on whether the primary tumor and metastatic tumors are resectable. If both the primary tumor and metastatic tumors are resectable, then both are resected. If the primary tumor is unresectable, then neither is resected, and chemotherapy or radiation therapy is performed. If the metastatic tumors are unresectable, resection of the primary tumor may be considered depending on the symptoms caused by the primary tumor, the state of distant metastasis, and the patient's overall condition.
3) Chemotherapy:
a) Adjuvant chemotherapy: In stage III colon cancer, postoperative adjuvant chemotherapy has been shown to suppress recurrence and extend survival. Recommended therapies include 5-FU + leucovorin (LV) therapy, UFT + LV therapy, capecitabine therapy, and FOLFOX therapy (continuous intravenous administration of oxaliplatin, levofolinate, and fluorouracil). The treatment period is six months.
b) Chemotherapy for unresectable, advanced, recurrent colorectal cancer: Recent advances in chemotherapy have extended the median survival time to approximately 2 years. Furthermore, chemotherapy for unresectable, advanced, recurrent colorectal cancer can be effective, making radical resection possible. Among the treatments that have been shown to extend survival time in clinical trials, Figure 8-5-26 shows the first-line treatment regimens and second-line and subsequent treatment regimens available in Japan. Anti-EGFR antibody drugs (cetuximab, panitumumab) have been shown to be effective in KRAS wild-type patients.
4) Radiation therapy:
Radiation therapy includes adjuvant radiation therapy for rectal cancer, which is used to prevent postoperative recurrence, reduce tumor volume before surgery, and preserve the anus, and palliative radiation therapy for unresectable, advanced, recurrent colorectal cancer, which is used to relieve symptoms and prolong life. [Takatoshi Matsuyama and Kenichi Sugihara]

Table 8-5-14
Stages of colon cancer (Colon cancer treatment guidelines) ">

Table 8-5-14

Table 8-5-15
Diagnostic criteria for Lynch syndrome (Amsterdam diagnostic criteria, revised version)

Table 8-5-15

Figure 8-5-26
Chemotherapy for unresectable, advanced, or recurrent colorectal cancer

Figure 8-5-26

Source : Internal Medicine, 10th Edition About Internal Medicine, 10th Edition Information

Japanese:

（1）大腸癌（colorectal carcinoma）
定義・概念
　大腸癌は大腸粘膜上皮から発生した悪性腫瘍である．大腸は，盲腸，結腸，直腸S状部，直腸から構成されているが，虫垂，肛門管を含めて扱う場合がある．大腸を二分して，盲腸，上行結腸，横行結腸を右側大腸，下行結腸，S状結腸，直腸S状部，直腸を左側大腸とよぶこともある．
分類
1）肉眼型分類：
大腸癌の肉眼型分類は，表在型（0型），隆起腫瘤型（1型），潰瘍限局型（2型），潰瘍浸潤型（3型），びまん浸潤型（4型），分類不能型（5型）に分類される．このうち2型が最も多い．表在型はさらに隆起型（Is /Isp/Ip型），表面型（ⅡaⅡb/Ⅱc型）に亜分類される（図8-5-25）．
2）組織型分類：
腺癌，内分泌細胞癌，腺扁平上皮癌，扁平上皮癌，その他の癌に分類される．腺癌は乳頭腺癌，管状腺癌（高分化/中分化），低分化腺癌（充実型/非充実型），粘液癌，印環細胞癌に亜分類される．大腸癌の多くは高分化ないしは中分化管状腺癌である．
3）進行度（ステージ）：
壁深達度，リンパ節転移の程度，遠隔転移の有無によって分類する．わが国では大腸癌取扱い規約の進行度が用いられている（表8-5-14）．ほかにTNM分類，Dukes分類などがある．
原因・病因
　大腸癌発生の機序から，次の３つに大別される．
1）散発性大腸癌：
大部分の大腸癌は非遺伝性であり，環境因子の暴露が主因とされる．大腸粘膜上皮細胞に遺伝子変異が蓄積して発生する．加齢とともに罹患率が上昇する．発癌機序としてadenoma-carcinoma sequence，de novo発癌，serrated neoplasia pathwayが提唱されている．
　a）adenoma-carcinoma sequence：良性腫瘍である「腺腫」から発癌する経路である．粘膜上皮細胞のAPC遺伝子の変異により低異型度腺腫が発生し，K-ras遺伝子の変異で高異型度腺腫となり，p53遺伝子変異で癌となる．さらに，DCC遺伝子が変異して浸潤，転移する癌となるという段階的な発癌機転である．
　b）de novo発癌：前癌病変を介さず正常粘膜から直接癌が発生する発癌機序である．その根拠として，腺腫成分を伴わない小さな陥凹型癌の存在があげられる．
　c）serrated neoplasia pathway：過形成性ポリープやsessile serrated adenoma/polypなどの鋸歯状病変や鋸歯状腺腫を母地とする発癌機序である．
2）遺伝性大腸癌：
遺伝的要素が大腸癌発生に決定的影響を及ぼしている疾患を遺伝性大腸癌という．散発性大腸癌と比べ，若年発症の傾向があり，大腸癌の多発や他臓器の癌を高率に合併する特徴を有する．遺伝性大腸癌のなかで頻度が高い疾患として，Lynch症候群（遺伝性非ポリポーシス大腸癌：hereditary non-polyposis colorectal cancer： HNPCC）と家族性大腸腺腫症（familial adenomatous polyposis： FAP）とがある．
　Lynch症候群は，ミスマッチ修復遺伝子（MLH1，MSH2，MSH6，PMS2）の変異を原因とする常染色体優性遺伝性疾患である．なお，Lynch症候群とHNPCCは同一疾患である．その診断基準を表8-5-15に示す．
　FAPは，第5染色体長腕上（5q21-22）のAPC遺伝子変異を原因とする大腸の多発性腺腫を主徴とする症候群である．大腸癌の発生は10歳代での報告もあるが，40歳代で約50％，放置すれば60歳頃にはほぼ100％に達する．
3）colitic cancer：
炎症性腸疾患（inflammatory bowel disease： IBD）の長期経過例で炎症性粘膜を背景に癌が発生する経路であり，潰瘍性大腸炎（ulcerative colitis： UC）に発生する大腸癌が典型例である．UCでは，①10年以上の経過例，②全大腸炎型に大腸癌が合併しやすい．前癌病変である異型腺管（ディスプラジア，dysplasia）は，low grade dysplasiaとhigh grade dysplasiaに分類され，high grade dysplasiaが発見された場合には発癌の頻度が高いことから，手術適応となる．UCに合併する大腸癌の特徴は，若年発症で，多発傾向にあり，びまん浸潤型や低分化腺癌，粘液癌が比較的多い．周辺に異型腺管を伴う．
疫学
　わが国の大腸癌罹患率および死亡率は著しく増加している．2008年の人口動態統計によれば，女性では大腸癌による死亡は全悪性新生物のなかで最多であり，男性では肺癌，胃癌に次いで多く，過去30年間におよそ5倍となった．好発年齢は男女ともに60歳代が最も多く，次いで50歳代，70歳代が続き，女性より男性に多い．
臨床症状
1）自覚症状：
初期には無症状のことが多く，進行すると症状が出現する．症状は腫瘍の占居部位により異なる．直腸や左側結腸の癌は，血便，便通異常（便秘，下痢，細い便柱，テネスムス），腸閉塞症状，などが特徴である．さらに進行して直腸周囲の他臓器に浸潤すると血尿や頻尿，性器出血，仙骨部疼痛なども出現する．一方，右側結腸は腸内容が液状であり，腸管腔も広いため，狭窄症状は出現しにくい．主訴としては不定の腹部愁訴，軽度の腹痛，貧血や腫瘤触知が多い．
2）他覚症状：
腹部の視診や触診により腹部膨満や圧痛，腫瘤，また直腸指診にて腫瘤の性状や出血の状況を診る．また，Virchow転移（左鎖骨上窩リンパ節への転移）やSchnitzler転移（Douglas窩への転移）の有無も確認する．
検査成績
1）免疫学的便潜血反応：
ヒトヘモグロビンに特異的に反応にて便中の血液の有無を調べる．大腸癌検診のスクリーニングに用いられている．
2）腫瘍マーカー：
大腸癌で用いられる腫瘍マーカーには，血清CEA（carcinoembryonic antigen）とCA19-9（carbohydrate antigen 19-9）とがある．進行度の予測，再発や化学療法の治療効果のモニタリングとして用いられている．早期癌では陽性率が低く，スクリーニングには適していない．
3）注腸造影検査：
病変の存在部位，形態，狭窄の有無などを診断する．進行癌では特有のアップルコアサインがみられることもある．腫瘍の側面像で大腸壁の変形の程度から壁深達度を推定できる．直腸の側面像では仙骨との位置関係がよくわかり，占居部位が診断できる．
4）下部消化管内視鏡検査：
腫瘍の形態や存在部位を診断する．腫瘍と非腫瘍の鑑別，早期癌の深達度診断には，拡大内視鏡による表面微細構造（ピットパターン）の観察が有用である．内視鏡的摘除（ポリペクトミーや，内視鏡的粘膜切除（endoscopic mucosal resection：EMR），内視鏡的粘膜下層剥離（endoscopic submucosal dissection：ESD））による治療も可能である．
5）その他の検査：
CTやMRIでは遠隔転移の有無や他臓器への浸潤の有無，リンパ節の腫脹の有無がわかる．
鑑別診断
　大腸腺腫，カルチノイド腫瘍，悪性リンパ腫，大腸非上皮性腫瘍（平滑筋性腫瘍，神経原性腫瘍，消化管間質腫瘍（gastrointestinal stromal tumor：GIST），脂肪腫など），粘膜脱症候群，放射線照射性大腸炎，子宮内膜症，腸間膜脂肪織炎などがある．
治療
1）ステージ0〜Ⅲ大腸癌の治療方針：
　a）内視鏡治療：内視鏡治療の適応は粘膜（M）癌または粘膜下層（SM）軽度浸潤癌で，大きさが2 cm未満の病変である．内視鏡治療は摘除生検であり病理検査にて切除断端陰性，深達度がMであれば治療終了となる．病理検査で垂直断端陽性（癌が粘膜下層断端に露出しているもの）， SM浸潤距離が1000 μm以上，脈管侵襲陽性，組織型が低分化腺癌・印環細胞癌・粘液癌，浸潤先進部の簇出（budding）高度の場合は追加治療としてリンパ節郭清を伴う腸切除が推奨される．
　b）手術治療：基本術式は腸管切除＋リンパ節郭清である．リンパ節郭清の程度は壁深達度によって異なる．
2）ステージⅣ大腸癌の治療方針：
ステージ大腸癌の治療は原発巣と転移巣それぞれが切除可能か否かによって異なる．原発巣，転移巣とも切除可能であれば，いずれも切除する．原発巣が切除不能であれば，いずれも切除せず化学療法，または放射線療法を行う．転移巣が切除不能であれば，原発巣による症状，遠隔転移の状態，全身状態などに応じて原発巣の切除を検討する．
3）化学療法：
　a）補助化学療法：ステージⅢ大腸癌では術後補助化学療法の再発抑制効果と生存期間の延長が示されている．推奨される療法には5-FU＋ロイコボリン（LV）療法，UFT＋LV療法，カペシタビン療法，FOLFOX療法（オキサリプラチン，レボホリナートおよびフルオロウラシルの静脈内持続投与法）がある．投与期間は６カ月である．
　b）切除不能進行再発大腸癌に対する化学療法：最近の化学療法の進歩により生存期間の中央値は約2年に延長してきている．また，切除不能進行再発大腸癌に対する化学療法が奏効して根治切除可能となることがある．臨床試験により，生存期間の延長が検証されている治療法の中で，国内で使用可能な一次治療レジメン，二次治療以降のレジメンを図8-5-26に示す．抗EGFR抗体薬（セツキシマブ，パニツブマブ）はKRAS野生型において有効性が示されている．
4）放射線療法：
放射線療法には，直腸癌において術後の再発抑制や術前の腫瘍量減量，肛門温存を目的とした補助放射線療法と切除不能進行再発大腸癌の症状緩和や延命を目的とした緩和的放射線療法とがある．［松山貴俊・杉原健一］

表8-5-14
大腸癌の進行度（大腸癌取り扱い規約）">

表8-5-14

表8-5-15
Lynch 症候群の診断基準（アムステルダム診断基準，改訂版）">

表8-5-15

図8-5-26
切除不能進行再発大腸癌に対する化学療法">

図8-5-26

出典　内科学第10版内科学第10版について　情報

<<: E. coli - Daichokin

>>: Colitis - daichouen (English spelling) colitis