Pancreatic cancer

Japanese: 膵癌

Concept Pancreatic cancer is an exocrine tumor that occurs primarily in the pancreas and is most frequently seen in people in their 60s. The male to female ratio is 1.6:1, with a slight male predominance. It is the fifth leading cause of death from malignant neoplasms in men and the sixth leading cause in women by organ. The number of cases has been increasing in recent years, with approximately 23,000 people developing the disease each year. The cause is unclear, but external environmental factors such as smoking, dietary habits, and alcohol consumption, and internal environmental factors such as family history, diabetes, chronic pancreatitis, and intraductal papillary mucinous neoplasm (IPMN) are attracting attention.
Pathophysiology: When cancer obstructs the main pancreatic duct, pancreatic juice stasis occurs. In pancreatic head cancer, obstruction of the bile duct can cause obstructive jaundice, and obstruction of the pancreatic duct can cause pancreatic juice stasis. Stasis of pancreatic juice and bile can cause complaints such as upper abdominal pain, discomfort, and a feeling of heaviness. Decreased excretion of bile and pancreatic juice can cause digestive and absorption disorders, leading to malnutrition and weight loss. The function of the islets of Langerhans is often impaired, resulting in impaired glucose tolerance. The sudden onset or exacerbation of diabetes is not uncommon. Infiltration of the organs, blood vessels, and nerve plexuses surrounding the pancreas can cause a variety of symptoms. Infiltration from the pancreatic head plexus to the superior mesenteric artery plexus and celiac artery trunk plexus can cause persistent lumbar and back pain.
Important findings in blood biochemistry are abnormal liver function and elevated tumor markers such as CEA and CA19-9 (Figure 8-9-16). Concomitant pancreatitis may cause elevations in pancreatic enzymes such as serum amylase, but if the cancer progresses, obstruction of the main pancreatic duct may occur, resulting in chronic obstructive pancreatitis, and the levels may actually become low.
diagnosis
In imaging diagnosis, ultrasound examination is suitable for screening. Pancreatic cancer appears as a mass with internal low echo or uneven patchy echo. Findings of dilation of the bile duct and pancreatic duct upstream of the tumor are useful. MDCT (Figure 8-9-17), ERCP (endoscopic retrograde cholangiopancreatography) (Figure 8-9-18), MRI/MRCP, EUS (endoscopic ultrasound) (Figure 8-9-19), etc. are important for diagnosing the presence, local progression, and spread of lymph node metastasis. It is typically depicted as a low absorption area on MDCT, and focal stenosis or complete obstruction of the pancreatic duct is typically seen on ERCP. For the purpose of definitive diagnosis, pancreatic juice cytology by ERCP, scraping cytology and biopsy of the pancreatic duct stenosis or interruption, and EUS (endoscopic ultrasound)-guided biopsy and aspiration cytology are also useful. Intraoperative ultrasound (Figure 8-9-20) and other methods are used to confirm the spread of cancer with the naked eye. Distant metastasis and peritoneal dissemination are diagnosed using chest and abdominal CT and FDG-PET.
Treatment The outcome of treatment is poor. Surgery is performed as a curative treatment, but the resection rate is low at about 30%, and even in resected cases, the 5-year survival rate is only about 15-25%. This means that only a few out of 100 people survive pancreatic cancer. Therefore, cases deemed inoperable undergo chemoradiotherapy or chemotherapy. It remains true that surgical resection that completely removes the pancreatic cancer locally is a necessary condition for the treatment of pancreatic cancer in operable cases. In other words, it is important to aim for an R0 curative resection, or a surgery that does not reveal or expose the pancreatic cancer at the local resection margin. Procedures that involve extended lymph node dissection have not resulted in improved surgical outcomes for pancreatic cancer, and recent reports have not concluded that extended surgery is the best method of pancreaticoduodenectomy for pancreatic head cancer. The important mode of progression of pancreatic cancer is perineural invasion in the retropancreatic tissue, followed by lateral invasion through the I and II parts of the pancreatic head plexus, to the superior mesenteric artery plexus and the celiac artery plexus. This nerve plexus invasion is a major factor in preventing complete local resection of pancreatic cancer. It is no exaggeration to say that the surgeon's battle against pancreatic cancer is a battle against nerve plexus invasion. The fusion fascia of Treitz, which covers the posterior surface of the pancreas, covers the duodenum on the right posterior side, and extends from parts I and II of the pancreatic head plexus to the left side, covering the posterior surface of the superior mesenteric artery plexus. In other words, all important tissues such as arteries and nerve fibers are present in front of these membranes. Therefore, plexus resection is a technique that occupies an important position in the complete resection of pancreatic head cancer. The stage classification according to the Guidelines for the Treatment of the Pancreas (6th ed., edited by the Japan Pancreas Society, 2009) is shown in Table 8-9-8.
The resected specimen is examined to determine whether it is carcinoma in situ (Figure 8-9-21) or invasive cancer (Figure 8-9-22). In the case of pancreatic cancer surgery, most patients undergo adjuvant chemotherapy after surgery. The only postoperative adjuvant chemotherapy with evidence is gemcitabine therapy. There are locally advanced cases and distant metastasis cases of unresectable pancreatic cancer. Chemotherapy alone is recommended for pancreatic cancer with distant metastasis, but either chemoradiotherapy or chemotherapy alone is recommended for locally advanced unresectable pancreatic cancer. Gemcitabine was approved for insurance coverage in Japan in 2001, and chemotherapy with gemcitabine alone has become the standard treatment. Oral fluoropyrimidine preparation S-1 and gemcitabine + erlotinib therapy are also used (Figure 8-9-23). The trend in survival rates for conventional pancreatic cancer is shown in Figure 8-9-24.
Differential diagnosis includes autoimmune pancreatitis, chronic pancreatitis, and any pancreatic tumor (pancreatic endocrine tumor, serous cystic adenoma, mucinous cystic adenoma, IPMN (intraductal cystic mucinous neoplasm)). When observing a pancreatic tumor or inflammation, it is important to always keep pancreatic cancer in mind.
Tumors of the papilla of VaterThe area where the bile duct and pancreatic duct open through the duodenal wall is surrounded by the muscle of Oddi, and this area is collectively called the papilla of Vater (Figure 8-9-25). In other words, the papilla of Vater is a collective term for the papilla bile duct, papilla pancreatic duct, common duct, Brunnel's gland, and papilla duodenal mucosa. Tumors arising from these areas are called tumors of the papilla of Vater. Tumors of the papilla of Vater have a variety of differential histologies, including carcinoma, adenoma, and carcinoid. A review of 576 autopsy cases revealed that the common duct had a high level of highly dysplastic epithelium, which is thought to be the most important site for the development of cancer (Kimura et al., 1988).
A CT image of carcinoma of the papilla of Vater was constructed and shown in coronal section (Figure 8-9-26).
Cancer is subclassified into intestinal and biliary pancreatic types, with the intestinal type having a better prognosis after resection (Figure 8-9-27). In cases where the tumor is clearly considered to be benign, a papillary resection may be performed (Figure 8-9-28). In this case too, complete local resection is important (Figure 8-9-29). [Kimura Osamu]
■ References
Kimura W: Strategies for the treatment of invasive ductal carcinoma of the pancreas and how to achieve zero mortality for pancreaticoduodenectomy. J Hepatobiliary Pancreat Surg, 15: 270-277, 2008.
Kimura W, Ohtsubo K: Incidence, sites of origin, and immunohistochemical and histochemical characteristics of atypical epithelium and minute carcinoma of the papilla of Vater. Cancer, 61: 1394-1402, 1988.
Kimura W, Futakawa N, et al: Different clinico-pathologic findings in two different histologic types of carcinoma of the papilla of Vater. Jpn J Cancer Res, 85: 161-166, 1994.
Pancreatic Cancer Clinical Practice Guidelines Revision Committee: Pancreatic Cancer Clinical Practice Guidelines. Edited by the Japan Pancreas Society, Kanehara Publishing, Tokyo, 2009.

Table 8-9-8
Pancreatic cancer stage classification according to the treatment guidelines

Table 8-9-8

Fig. 8-9-16
Pancreatic cancer diagnostic algorithm

Fig.8-9-16

Fig.8-9-23
Pancreatic cancer treatment algorithm

Fig.8-9-23

Figure 8-9-24
Changes in survival rate for conventional pancreatic cancer ">

Figure 8-9-24

Fig.8-9-25
Schema of the papilla of Vater

Fig.8-9-25

Figure 8-9-27
Postoperative survival curve for cancer of the ampulla of Vater ">

Figure 8-9-27

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

Japanese:

概念
　膵癌は原発性に膵に発生する上皮性悪性腫瘍のうち，外分泌系の腫瘍に属するものである．60歳代に最も高頻度にみられる．男女比は1.6：1と男性にやや多い傾向がある．臓器別にみた悪性新生物による死因では男性で5番目，女性で6番目となる．近年増加の傾向にあり，年間約23000人に発症する．　原因は明らかではないが，外部環境因子としては喫煙，食習慣，飲酒などが，内部環境因子としては家族歴，糖尿病，慢性膵炎，膵管内乳頭粘液性腫瘍（IPMN）などが注目されている．
病態生理
　癌が主膵管を閉塞すると膵液のうっ滞が生じる．膵頭部癌では胆管閉塞による閉塞性黄疸や膵管閉塞による膵液のうっ滞が出現する．膵液・胆汁のうっ滞は上腹部の痛みや不快感，重苦感など愁訴の原因となる．また胆汁・膵液の排出減少は消化吸収障害をきたし，栄養不良や体重減少の原因となる．しばしばLangerhans島の機能が障害され耐糖能異常が現れる．急激な糖尿病の発症や増悪もまれではない．膵周囲の臓器，血管，神経叢への浸潤は多彩な症状をもたらす．膵頭神経叢から上腸間膜動脈神経叢・腹腔動脈幹神経叢への浸潤によって頑固な腰背部痛が出現する．
　血液生化学的には肝機能異常やCEAやCA19-9などの腫瘍マーカーの上昇が重要な所見である（図8-9-16）．随伴性の膵炎によって血清アミラーゼ値など膵酵素の上昇がみられることもあるが，癌が進行した場合には主膵管閉塞から閉塞性慢性膵炎となり，むしろ低値となることもある．
診断
　画像診断では，超音波検査はスクリーニングに適している．膵癌は内部低エコーないし不均一な斑状エコーを呈する腫瘤として描出される．腫瘍より上流の胆管や膵管の拡張所見は有用である．MDCT（図8-9-17），ERCP（内視鏡的逆行性胆管膵管造影）（図8-9-18），MRI/MRCP，EUS（超音波内視鏡）（図8-9-19）などは存在診断や局所進行度，リンパ節転移の有無などの広がり診断に重要である．MDCTでは低吸収域として描出され，ERCPでは膵管の限局性狭窄，あるいは完全閉塞が典型像となる．確定診断を目的としたERCPによる膵液細胞診や膵管狭窄部・途絶部の擦過細胞診・生検，およびEUS（超音波内視鏡）ガイド下の生検・吸引細胞診も有用である．術中超音波（図8-9-20）などを駆使して癌の広がりを肉眼とともに確認する．　遠隔転移や腹膜播種は胸腹部CTやFDG-PETで診断する．
治療
　治療成績は不良である．根治的治療として手術が行われるが，切除率が約30％と低く，切除された症例でも5年生存率は15～25％程度にとどまる．膵癌から生還できるのは100人のうち数人ということになる．したがって，手術不能と判断された症例は化学放射線療法や化学療法を行う．　手術可能症例では膵癌を局所的に完全にとりきる外科切除が膵癌治療の必要条件であることは現在でも間違いがない．すなわち手術としてはR0の治癒切除，膵癌を局所切離断端にあらわさない，あるいは露出させない手術を目指すことが重要になる．　リンパ節の拡大郭清を伴う術式は膵癌の手術成績を向上させる結果にはならず，最近の報告でも膵頭部癌に対する膵頭十二指腸切除術として，拡大手術がよいという結論にはなっていない．　膵癌の進展様式として重要なのは膵後方組織内の神経線維周囲浸潤から引き続き膵頭神経叢第Ⅰ部，第Ⅱ部を経て，上腸間膜動脈神経叢，腹腔動脈神経叢へと横方向に浸潤することである．この神経叢浸潤が膵癌の局所の完全切除にはだかる大きな因子になる．「外科医の膵癌との戦いは神経叢浸潤の戦いである」といっても過言ではない．膵後面を覆うTreitzの癒合筋膜は，右側後面は十二指腸を，左側に向かっては膵頭神経叢第Ⅰ部，第Ⅱ部から上腸間膜動脈神経叢後面にひろがって覆っている．つまり，これらの膜の前面にすべての動脈，神経線維などの重要な組織が存在する．したがって神経叢切除は，膵頭部癌の完全切除のための重要な位置を占める手技である．　膵臓取扱い規約（第6版，日本膵臓学会編，2009）によるステージ分類を表8-9-8に示した．
　切除標本を確認して上皮内癌（図8-9-21）か浸潤癌（図8-9-22）か確認する．膵癌手術の場合，多くは手術後に術後の補助化学療法にまわる．術後補助化学療法でエビデンスのあるものはゲムシタビン療法のみである．切除不能膵癌には局所進行症例と遠隔転移症例がある．遠隔転移を有する膵癌に対しては，化学療法単独が推奨されているが，局所進行切除不能膵癌に対しては化学放射線療法，化学療法単独どちらも推奨されている．わが国では2001年にゲムシタビンの保険適応が承認され，その単独化学療法が標準治療となっている．経口フッ化ピリミジン製剤のS-1やゲムシタビン＋エルロチニブ療法なども使われる（図8-9-23）．　通常型膵癌の生存率の推移を図8-9-24に示した．
鑑別診断
　自己免疫性膵炎，慢性膵炎，あらゆる膵の腫瘍（膵内分泌腫瘍，漿液性囊胞腺腫，粘液性囊胞腺腫，IPMN（膵管内囊胞粘液性腫瘍））などがある．膵の腫瘍，炎症をみたら膵癌を常に念頭におくことが重要である．
Vater乳頭部腫瘍
　胆管と膵管が十二指腸壁を貫いて開口する部分は，胆管と膵管がOddi筋に囲まれており，この部分を総称してVater 乳頭部という名称がつけられている（図8-9-25）．すなわち，Vater 乳頭部は，乳頭部胆管，乳頭部膵管，共通管，Brunnel 腺，乳頭部十二指腸粘膜の総称である．これらの部から発生した腫瘍をVater乳頭部腫瘍という．　Vater 乳頭部腫瘍には癌腫，腺腫，カルチノイドなどさまざまな鑑別組織が存在する．　剖検例576例の検索では共通管に異型度の高い上皮が多く，そこが癌の発生母地として最も重要と考えられている（Kimura ら， 1988）．
　Vater 乳頭部癌のCT画像を構築して冠状断で示した（図8-9-26）．
　癌は腸型と胆膵管型に亜分類され，腸型の方が切除後の予後がいい（図8-9-27）．　明らかに良性腫瘍と考えられたものは乳頭切除を行う場合がある（図8-9-28）．この場合も完全に局所の切除が重要である（図8-9-29）．［木村　理］
■文献
Kimura W: Strategies for the treatment of invasive ductal carcinoma of the pancreas and how to achieve zero mortality for pancreaticoduodenectomy. J Hepatobiliary Pancreat Surg, 15: 270-277, 2008.
Kimura W, Ohtsubo K: Incidence, sites of origin, and immunohistochemical and histochemical characteristics of atypical epithelium and minute carcinoma of the papilla of Vater. Cancer, 61: 1394-1402, 1988.
Kimura W, Futakawa N, et al: Different clinico-pathologic findings in two different histologic types of carcinoma of the papilla of Vater. Jpn J Cancer Res, 85: 161-166, 1994.
膵癌診療ガイドライン改訂委員会：膵癌診療ガイドライン．日本膵臓学会編，金原出版，東京，2009．

表8-9-8
膵癌取扱い規約によるステージ分類">

表8-9-8

図8-9-16
膵癌診断のアルゴリズム">

図8-9-16

図8-9-23
膵癌治療のアルゴリズム">

図8-9-23

図8-9-24
通常型膵癌の生存率推移">

図8-9-24

図8-9-25
Vater 乳頭部のシェーマ">

図8-9-25

図8-9-27
Vater 乳頭部癌の術後生存曲線">

図8-9-27