肛管癌

　　一、发病原因

　　肛管癌真正病因尚未明了，但有研究表明它是多因素作用下多基因失控所致，以往注意到长期慢性刺激如肛瘘、湿疣和免疫性疾患（如Crohn病）与肛管癌发生有关。近年来发现人乳头状病毒（HPV）与它有密切关系，特别是HPV-16，50％～80％的肛管癌细胞中有HPV-16。性行为异常也是肛管癌的高危因素，男性同性恋患者47％有肛管湿疣史，其肛管癌发病危险系数是正常配偶的12.4倍。女性患者中30％有肛交史。免疫抑制如肾移植术后患者，肛管癌的发病率要比正常人群高100倍。肛管癌也存在基因表达异常，67％的肛管癌可见p53基因突变，71％的肛管癌有癌基因C-myc的表达，且分布异常。此外，也有人注意到吸烟也是肛管癌的重要诱因，有吸烟史的男、女性发病率分别是正常人的9.4倍和7.7倍。

　　二、发病机制

　　1、病理学：肛管是内、外胚层交接之处，所以肿瘤组织学来源较为复杂。大致分为3大类：上皮细胞肿瘤（如鳞状上皮癌、基底细胞癌、腺癌等）、非上皮细胞肿瘤（如肉瘤、淋巴瘤等）和恶性黑色素瘤。

　　肛管癌以鳞状细胞癌最多见，约占2/3以上。按细胞分化程度分高、中和低分化癌。少数为腺癌。至于肉瘤和淋巴瘤在肛管区少见。恶性黑色素瘤在肛管直肠肿瘤中不足1％。中山医科大学肿瘤医院统计肛管直肠肿瘤574例中，仅有4例黑色素瘤，占0.7％。但其恶性度极高，生长快，迅速转移至区域淋巴结和其他脏器，预后甚差。

　　The main way of anal canal cancer spread is lymphatic metastasis, and it mainly spreads upwards along the superior rectal artery to the pararectal lymph nodes, merging into superior rectal lymph nodes, and then transferring to the peripheral arteries of the mesenteric artery. Anal canal cancer can also spread laterally to the internal iliac and common iliac lymph nodes. The downward transfer mainly passes through the subcutaneous tissue of the perineum and the inner side of the thigh to reach the superficial inguinal lymph nodes, a few move backwards along the lateral side of the buttocks through both iliac crests to enter the superficial inguinal lymph nodes, and finally all converge to the deep inguinal lymph nodes and the external and common iliac lymph nodes. It can be seen that inguinal lymph node metastasis can often become the first station lymph node metastasis, which is different from rectal cancer. Secondly, local spread of anal canal cancer can invade the anal sphincter, posterior vaginal wall, perineum, prostate, and bladder, causing anal-vaginal fistula or anal-vesical fistula, so when performing abdominal perineal resection and rectal resection to treat anal canal cancer, the resection range of the perineum should be wider than that of rectal cancer surgery. The third way of spread of anal canal cancer is through hematogenous spread to the liver, lung, bone, peritoneum, and other organs.

　　2. Staging:There are many types and complexities of clinical and pathological staging of anal canal cancer, and currently the TNM classification method (1997) of the International Union Against Cancer (UICC) is most widely used.

　　Staging criteria:

　　(1) T primary tumor.

　　(2) Tx primary tumor has not been determined.

　　(3) T0 has no primary tumor.

　　(4) Tis in situ carcinoma.

　　(5) T1 tumor maximum diameter ≤ 2cm.

　　(6) T2 tumor maximum diameter > 2cm.

　　(7) T3 tumor maximum diameter > 5cm.

　　(8) T4 tumor regardless of size, but has invaded adjacent organs such as the vagina, urethra, and bladder (invasion of the sphincter muscles alone does not belong to T4).

　　(9) N regional lymph nodes.

　　(10) Nx regional lymph nodes have not been determined.

　　(11) N0 has no regional lymph node metastasis.

　　(12) N1 rectal peripheral lymph node metastasis.

　　(13) N2 unilateral internal iliac and (or) inguinal lymph node metastasis.

　　(14) N3 rectal peripheral lymph nodes and inguinal lymph node metastasis, and (or) bilateral internal iliac and (or) bilateral inguinal lymph node metastasis.

　　(15) M has distant metastasis.

　　(16) Mx distant metastasis has not been determined.

　　(17) M0 has no distant metastasis.

　　(18) M1 has distant metastasis.

　　Anal canal cancer in the advanced stage can present many invasive symptoms, such as stubborn perineal pain radiating to the inner side of the thigh when lymph node metastasis involves the obturator nerve; tumor invasion of the sphincter muscles can lead to fecal incontinence; invasion of the vagina can form an anal-vaginal fistula with feces excreted from the vagina; invasion of the prostate can cause abnormal urination or hematuria or urinary retention; invasion of the bladder can cause an anal-vesical fistula; if hematogenous metastasis has occurred, then corresponding symptoms and signs such as liver metastasis, lung metastasis, and gastric metastasis may appear.

　　What are the typical symptoms of anal canal cancer

　　The early symptoms of anal canal cancer are not obvious, and the clinical manifestations in the advanced stage are similar to those of lower rectal cancer, mainly including the following aspects:1. Change in defecation habits:

　　Increased frequency of defecation, often accompanied by urgent need to defecate or a feeling of incomplete defecation.2. Change in stool characteristics:

　　The stool becomes thinner or deformed, often with mucus or pus.3. Anal pain:

　　Anal pain is the main symptom of anal canal cancer. Initially, there is an uncomfortable feeling in the anal area, which gradually worsens and becomes persistent pain, more obvious after defecation.4. Anal itching:

　　Accompanied by secretions due to the stimulation of anal canal cancer secretions on the perianal skin, the patient has anal itching, and the secretions have a smelly odor.5. Anal canal mass:

　　Rectal palpation or anoscopic examination can see ulcerative mass or polypoid, fungiform mass in the anal canal, or infiltrative mass with anal canal narrowing.6. Inguinal lymph node swelling:

　　How to prevent anal canal cancer

　　1. Develop good living habits, quit smoking and limit alcohol. Smoking, the World Health Organization predicts, if people stop smoking, the world's cancer rate will decrease by 1/3 in 5 years; secondly, do not drink excessively. Cigarettes and alcohol are extremely acidic substances, and those who smoke and drink for a long time are prone to acidic体质.

　　What laboratory tests are needed for anal canal cancer

　　Histopathological examination shows that anal canal cancer is mostly squamous cell carcinoma, with a few adenocarcinomas or malignant melanomas.1. Anal palpation:

　　A mass can be felt near the dentate line, and the finger glove is stained with smelly secretions.2. Anoscopic examination:

　　Dietary taboos for anal canal cancer patients

　　First, dietary therapy for anal canal cancer

　　1. Crucian carp red bean porridge

　　Materials: One large crucian carp, about 300 grams, 30 grams of red beans, 15 slices of ginger, a little oil, and salt.

　　2. Decoction for lowering gas and calming diseases

　　Ingredients: 9 grams of white peony, 6 grams of Guangmu Xiang, 6 grams of Houpu, 15 grams of Chen Xiang, 9 grams of Yuanhu, 9 grams of Sheng Pu Huang, 9 grams of Wulingzi, 6 grams of Ru Xiang (added later), and an appropriate amount of lean pork.

　　Prepare all the herbs by washing them clean, then place them with lean meat in a pot. Add 8 bowls of clear water, and boil until 2 bowls remain. Drink it after breakfast and dinner.

　　Take about 1000 grams of the bark and thorns of the cotton tree, and about 500 grams of pure lean pork without fat. Boil until extremely soft, half meat and half soup. After eating, it will cause diarrhea. Continue taking it until cured.

　　There are two types of cotton tree flowers, white and red. When choosing, the white flower should be the best, as it has a remarkable effect on gastrointestinal and cancer treatment.

　　4. Prunella vulgaris 45 grams, sugar 3 pieces (use black sugar 300 grams instead, especially effective), boil 3 bowls of water into 1 bowl, boil it thickly every day, drink it as tea, and continue until recovery.

　　5. Mushroom 30 grams, Job's tears 30 grams, and water chestnut (cut open with shell) 90 grams. Mix the above foods, add water to boil them into a concentrated juice, remove the residue, and drink the juice. Take one dose per day, boil twice a day, and take it for a month as a course of treatment.

　　6. Lean pork 60 grams, smilax root 500 grams. Soak the smilax root in 1000 milliliters of water for 1 hour, boil it with the soaking liquid over low heat for 3 hours, remove the residue, add lean pork and boil for 1 hour, and then drink the concentrated decoction, which should be about 500 milliliters. Take one dose per day, and drink the decoction multiple times a day.

　　7. Oolong tea 6 grams, black plum 12 grams, and appropriate honey. Boil the first two ingredients in water to make a decoction, add appropriate honey to the decoction, and drink it. Take one dose per day, boil twice, and drink it over the course of a day. Drink it for a long time.

　　2. What to eat for anal canal cancer

　　1. The diet should be varied and maintain smooth defecation to prevent constipation.

　　2. Eat black fungus, garlic, eggplant, luffa, carrots, konjac, sweet potatoes, figs, strawberries, apples, pears, bananas, honey, green vegetables, etc.

　　3. Eat more fresh vegetables containing vitamins and fiber.

　　3. What to avoid eating for anal canal cancer

　　1. Avoid spicy foods such as chili and pepper, as well as fried foods.

　　2. Avoid greasy foods.

　　3. Avoid high-fat, high-protein, and low-fiber diets.

　　1. Treatment

　　The treatment of anal canal cancer must be based on its pathological type, site of growth, extent of invasion, differentiation and malignancy of cancer cells, and the presence or absence of lymphatic metastasis, and different treatment methods should be adopted. Among them, surgery is part of comprehensive treatment, and it focuses more on the combined application of radiotherapy and chemotherapy. The treatment methods for squamous cell carcinoma of the anal canal are discussed mainly.

　　1. Surgical treatment

　　(1) Abdominoperineal resection (Miles procedure): Before 1974, it was generally believed that the preferred treatment for anal canal cancer was abdominoperineal resection of the anal canal, rectum, and perineum (Miles procedure), and that surgery was the only most effective method. Due to the local invasion of anal canal cancer and lymphatic metastasis in three directions, the surgical scope is greater than that of rectal cancer. The perineal resection should include a wide area of skin around the anus (not less than 3 cm), the external and internal anal sphincters, the fatty tissue of the ischiorectal fossa, the levator ani muscle, and all lymphatic drainage areas subperitoneal of the pelvic floor. Female patients often require the resection of the posterior vaginal wall. Due to the extensive resection range, the perineal incision often needs to be opened for treatment, making it difficult to suture in the first stage. The extended Miles procedure, including the extended pelvic lymph node dissection, prophylactic inguinal lymph node clearance, and partial or total resection of pelvic organs, did not show an improvement in survival rate or reduction in recurrence rate. On the contrary, it increased the incidence of surgical complications and mortality. Beck summarized the data of 1129 patients with abdominoperineal resection surgery from 19 groups of data from 1960 to 1988, and the 5-year survival rate after surgery was about 50%, the surgical mortality rate was 5.9%, the local recurrence rate was 28%, and the distant recurrence rate was 27%.

　　In recent years, the effectiveness of radiotherapy and chemotherapy in the treatment of anal canal cancer has been confirmed, and the extended Miles surgery is no longer considered the first-line treatment method, especially for early-stage anal canal cancer, where surgery is performed as adjuvant treatment. However, for T3 and T4 stage anal canal cancer, Miles surgery should still be the main treatment, with preoperative or postoperative radiotherapy and chemotherapy.

　　(2) Inguinal lymph node dissection: The first lymphatic metastasis station of anal canal cancer to the lower part is the inguinal lymph nodes, with a metastasis rate of 8.2% to 40.5%. At the time of initial diagnosis, 1/3 to 1/2 of the patients have inguinal lymph node enlargement. A considerable number of patients with anal canal cancer develop inguinal lymph node metastasis within 1 to 2 years after Miles surgery. Therefore, inguinal lymph node dissection is considered an indispensable aspect of surgical treatment for anal canal cancer, and this view has been increasingly recognized in recent years. Preventive inguinal lymph node dissection does not improve 5-year survival rates or reduce recurrence rates. Lymph node dissection can also achieve satisfactory results when inguinal lymph node metastasis is found during follow-up after Miles surgery. Therefore, it is emphasized that regular and close follow-up examinations should be conducted after radical surgery for anal canal cancer, with monthly examinations in the first year, and every two months in the first to second years. If lymph node metastasis is confirmed, inguinal lymph node dissection should be performed in a timely manner.

　　If lymph node enlargement in the inguinal area is found during the initial diagnosis but cancer metastasis is not confirmed, anti-infection treatment before and after Miles surgery is very necessary. If the lymph nodes disappear after anti-infection treatment, it is not necessary to consider immediate lymph node dissection, and close follow-up should be given; if the lymph nodes do not shrink after anti-infection treatment, it should be considered as lymph node metastasis. Lymph node biopsy should be performed before Miles surgery to confirm lymph node metastasis, and inguinal lymph node dissection can also be performed 3 to 6 weeks after Miles surgery. This staged surgery can avoid excessive trauma to the patient in one go and can also reduce the risk of flap necrosis and infection caused by the inguinal incision being close to the colostomy.

　　In addition, preventive or palliative radiotherapy may be performed according to the specific condition of the patient.

　　The extent of inguinal lymph node dissection can be determined according to the condition, generally including superficial and deep inguinal lymph nodes, as well as external iliac lymph nodes, even up to the common iliac lymph nodes. During the cleaning process, the lymph nodes at the femoral canal (Cloquet lymph nodes) are often taken for frozen section examination to determine whether to further perform iliac lymph node dissection.

　　Due to the frequent occurrence of complications such as lymph fistula, skin flap necrosis, lower limb infection edema, perineal swelling, even elephantiasis of the lower limb and external genitalia, and malignant ulcers in the inguinal area after inguinal lymph node dissection, these severely affect the quality of life of patients, so careful consideration should be given to the selection, timing, and extent of lymph node dissection.

　　(3) Local resection: Local resection can be radical or palliative. Radical local resection is used for stage I squamous cell carcinoma with the primary tumor ≤2cm, superficial location without invasion into the deep, no signs of metastasis, and pathologically confirmed good cell differentiation. The resection range should at least include 2.5cm of skin and part of the muscle outside the margin, while preserving the anal sphincter function. This type of local resection can achieve curative effects. According to a summary of seven studies from 1964 to 1985, the 5-year survival rate of local resection in 138 T1 patients was 71%, with a local recurrence rate of 28% and a distant recurrence rate of 28%. Palliative local resection is used for patients who cannot tolerate abdominal perineal resection due to systemic conditions, and for those with residual lesions after radiotherapy and chemotherapy, and sometimes for patients with local recurrence. The purpose of palliative local resection is mainly to remove the gross lesions visible to the naked eye, and radiotherapy and chemotherapy are often needed after surgery.

　　2. Radiotherapy and chemotherapy:The radiotherapy for anal canal squamous cell carcinoma began in the 1930s, but due to reasons such as equipment and irradiation techniques, complications were severe and it did not attract much attention. It was not until the 1970s, with the deepening of theoretical research, the change of concepts, and the improvement of radiotherapy equipment and irradiation techniques, that radiotherapy was once again given attention and gradually replaced the primary position of traditional surgical treatment. Papilion was an advocate for radiotherapy, summarizing that the 5-year survival rate of early anal canal cancer without inguinal lymph node metastasis after radiotherapy was 75% to 80%. Some scholars advocate for the addition of chemotherapy to enhance sensitivity, reduce the dose of radiotherapy, and have systemic therapeutic effects, eliminating small lesions. Nigro et al. (1974) reported that radiotherapy combined with chemotherapy could achieve good results, and there were no residual cancer cells in the specimens resected after radiotherapy, proving that anal canal cancer has a high sensitivity to radiotherapy. Later, he also statistically analyzed 104 cases of anal canal cancer patients who received radiotherapy from 1971 to 1983, 62 cases were re-biopsied after radiotherapy, only 1 case had residual cancer cells; 24 cases received surgery after treatment, of which 22 cases did not find residual cancer cells. These results provided sufficient evidence for radiotherapy as the primary treatment method for anal canal cancer. It is reported that there are nearly 300 cases of treatment experience worldwide. Chemotherapy uses fluorouracil (5-Fu) and mitomycin (MMC), and high-energy rays are used to irradiate the anal canal, perineum, and pelvis, even including the inguinal area. The main side effects are radioactive dermatitis, mucositis, diarrhea, bone marrow suppression, cystitis, etc. The total 5-year survival rate of radiotherapy is about 55%, with 75% for T1 and T2 patients, 40% to 70% for T3 and T4 patients, and the local recurrence rate decreased from 25% to 8%. About 50% to 80% of the patients who relapsed after radiotherapy can still achieve satisfactory results through surgery. Currently, two schemes are used more frequently:

　　(1) Nigro (1984) treatment plan: Total radiotherapy dose of 30Gy/3 weeks, with concurrent chemotherapy, 5-FU 1000mg/m2, continuous intravenous infusion for 24 hours, from the 1st to the 4th day and the 28th to the 31st day; mitomycin (MMC) 15mg/m2, intravenous injection on the 1st day. Biopsy of the primary tumor site is performed 6 weeks after treatment, and no surgery is needed if there is no cancer residue; if there is cancer residue, radical resection is performed. This method has been treated in 104 cases, with 97 cases without cancer residue, only 7 cases with incomplete tumor disappearance, but the tumor has shrunk. Among the 104 cases, 99 cases had mild stomatitis, diarrhea, and alopecia, 15 cases had moderate leukopenia, and 5 cases had severe reactions requiring hospitalization.

　　(2) UKCCCR (United Kingdom Cancer Research Collaboration Association) scheme: Use linear accelerators to irradiate the perineum, with a total dose of 45Gy/5 weeks, including the inguinal area. After a rest period of 6 weeks, external irradiation is used to enhance the dose by 15Gy/6 times or interstitial irradiation with the radioactive isotope 192Ir, with a total dose of 25Gy. Chemotherapy (fluorouracil + mitomycin) is used at the beginning and end of radiotherapy.

　　3. Comprehensive treatment:As mentioned above, the 5-year survival rate of simple perineal resection is about 50%, and there is a relatively high recurrence rate after surgery. Moreover, permanent artificial anus needs to be created, causing great physical and psychological trauma to the patients. Simple radiotherapy, according to data from 640 cases of anal canal cancer from 1980 to 1989, has a 5-year survival rate of 68% after treatment, with a local recurrence rate of 26% and a distant metastasis rate of 17%. However, the treatment effect for patients with T3 and T4 disease is poor, and some patients still have residual primary tumors after radiotherapy, which does not reach the cure. There is no series report on simple chemotherapy, and it is currently only used for patients who are not suitable for surgery or radiotherapy. It can be seen that simple surgery, radiotherapy, or chemotherapy has not achieved ideal results. Now, in clinical practice, it is generally advocated to use a comprehensive treatment of radiotherapy + chemotherapy + surgery for anal canal cancer. Nigro's scheme reflects this view. If there is still tumor residue after biopsy after radiotherapy and chemotherapy, surgical treatment should be performed in a timely manner. Early patients can undergo local resection combined with postoperative radiotherapy and chemotherapy; for patients with T3 and T4 disease, surgery can be the main treatment, with preoperative or postoperative radiotherapy and chemotherapy; for patients who are not suitable for surgery, only radiotherapy and chemotherapy can be performed. As for biological treatment, it is still in the exploratory stage at present, and it is best to apply biological treatment after a large number of cancer cells have been destroyed by surgery, radiotherapy, and chemotherapy. The commonly used methods are freeze-dried BCG, thymosin, interferon (IFN), interleukin-2 (IL-2), tumor necrosis factor (TNF), and so on.

　　II. Prognosis

　　The main factors affecting the prognosis of anal canal cancer are the stage of the tumor, especially the depth of tumor invasion, which has a great impact on the 5-year survival rate. The 5-year survival rate of T1 and T2 cases can reach 70% to 100%, while that of T3 and T4 cases is only 10% to 40%. If the tumor invades the muscle or extramuscular soft tissue outside the sphincter, the postoperative recurrence rate can reach more than 60%. Regional lymph node metastasis is an adverse factor for prognosis, especially when the inguinal lymph nodes are found simultaneously with the primary tumor, the prognosis is poor. Distant metastasis shows that the cancer has entered the late stage, and it is more common in the liver, lung, bones, brain, and other organs.

　　The degree of differentiation of tumors is related to the prognosis. Patients with good differentiation and no regional lymph node metastasis have a 5-year survival rate of 75%; while those with poor differentiation and regional lymph node metastasis have only 24%. The histological type is also obviously related to the prognosis. Anal canal cancer is mostly squamous cell cancer, which has a better prognosis than adenocarcinoma and melanoma. The latter often die within 1.5 years after surgery. Brady (1995) summarized 231 cases of anal canal rectal melanoma from 1980 to 1990, with an average survival time of 12 to 18.6 months after surgery. Anal melanoma is sensitive to radiotherapy and chemotherapy, and the Miles operation should be performed first. Brady reported that the 5-year survival rate of 71 cases of anal canal rectal melanoma after abdominal perineal resection was 27%.

　　Comprehensive treatment has a better prognosis than single treatment. The 5-year survival rate of patients after comprehensive treatment with combined radiotherapy and chemotherapy in foreign countries has increased to 65% to 80%, while that of simple surgical treatment is only 45% to 70%. The local recurrence rate of comprehensive treatment is about 20% lower than that of simple surgical treatment.