Adenocarcinoma

Sanjana Mullangi; Manidhar Reddy Lekkala

Adenocarcinoma

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Continuing Education Activity

Adenocarcinomas are malignant tumors formed from glandular structures in epithelial tissue. They can arise from a variety of tissues. This activity reviews the etiology, epidemiology, pathology, evaluation, and management of adenocarcinomas of different organs and highlights the role of the interprofessional team in managing patients with this condition.

Objectives:

Identify the most common organs in which adenocarcinomas develop.
Review the evaluation of adenocarcinoma.
Outline the management options available for adenocarcinomas.

Introduction

Adenocarcinoma is a malignant neoplasm arising from epithelial cells of the glands or glandular like structures. Adenocarcinoma can arise in multiple sites of the body. Some of the common sites that develop adenocarcinoma are the breast, lung, prostate, and gastrointestinal tract, like the colon, rectum, pancreas, stomach, and esophagus. Adenocarcinomas also make up 70 percent of cancer of unknown origin.[1]

Etiology

A number of environmental as well as lifestyle risk factors are associated with the development of cancers. Different sites have different carcinogens and risk factors. Tobacco smoking, by far, seems to play a major role in most of them.

Adenocarcinoma of Lung

Smoking is a significant risk factor associated with lung cancer, with more than 90 percent of cases related to it.[2] Other risk factors include exposure to radiation, environmental toxins like arsenic, chromium, nickel, and polycarbonate, pulmonary fibrosis, scarring of the lung, and genetic causes.[2][3]

Adenocarcinoma of Breast

Breast cancer is the most common cancer diagnosis in the world and the United States. Female gender, excess estrogen exposure states like nulliparity, late pregnancy, early menarche, late menopause, external estrogen exposure, and alcohol are some of the risk factors for breast cancer.[4] Genetic factors with mutations in the BRCA1/2, p53, PTEN, PALB2, etc, and family history increase the risk of breast adenocarcinoma.[5]

Adenocarcinoma of Prostate

The most important risk factor for prostate adenocarcinoma is age. Patients clinically diagnosed with prostate cancer before age 40 are very rare.[6] Other risk factors include cigarette smoking, family history of prostate cancer as well as germline mutations like BRCA2/1 and ATM.[7]

Adenocarcinoma of the Colon/Rectum

Environmental and genetic factors increase the risk of colorectal cancer. Many hereditary colorectal cancer syndromes like the familial adenomatous polyposis, Lynch syndrome, and other non-Lynch syndromes like the biallelic MUTYH, BRCA1/2, PALB2, CDKN2A, TP53, FAP increases the risk of colorectal cancer.[8][9][10] Other risk factors include personal or family history, inflammatory bowel disease, red and processed meat, tobacco use, and alcohol also increase the risk.

Adenocarcinoma of the Pancreas

Environmental risk factors contributing to pancreatic adenocarcinoma include smoking, high fasting plasma glucose, high body mass index, western diet, and alcohol consumption, prolonged use of aspirin.[11] Hereditary risk factors also contribute to the risk, with up to 10 percent of individuals with pancreatic cancer having a family history.[12][13] ABO blood type has been associated with several gastrointestinal cancers, including pancreatic cancer as well as cystic fibrosis, with 2 to 5-fold higher risk in patients who have undergone a lung transplant.[14][15][16][17][18] The amount of cigarette smoking significantly increases

the risk of adenocarcinoma of the pancreas, [19][20][21][22][23] a population-attributable fraction of deaths due to pancreatic cancer associated with smoking is 11% to 32%.[24]

Other important risk factors include H. pylori in gastric adenocarcinoma[25], gastroesophageal reflux disease (GERD), and alcohol in esophageal adenocarcinoma.[26]

Epidemiology

Adenocarcinoma of Lung

Lung cancer is the most common cause of cancer, the leading cause of death in men in the world, and the second leading cause in women.[4] Forty percent of lung cancers are secondary to adenocarcinoma. There are significant differences in the incidence of lung cancer from one country to another, mostly attributed to the prevalence of smoking. Tobacco control efforts are going to reduce the incidence of lung cancer in the future.[27]

Adenocarcinoma of Breast

Breast Cancer is the second most common cause of cancer worldwide and the most common cancer in women.[28] The incidence of breast cancer is higher in the white countries compared to the Asian and African nations.[29] Breast cancer mortality has been in decline, largely attributed to screening measures and adjuvant therapy.[30][31]

Adenocarcinoma of Prostate

Adenocarcinoma of the prostate is the second most common cancer in men worldwide. It is the third leading cause of death in the United States.[32][4] Prostate cancer mortality is on a decline, especially in the United States, which is attributed to increased screening as well as adjuvant therapies.[32][4]

Adenocarcinoma of Colon/Rectum

Colorectal cancers are the third most common cancer in males and second in females.[4] In the United States, the annual incidence, as well as mortality, is slowly decreasing.[33] The incidence of colorectal cancers varies globally, with the highest incidence rates in Australia, New Zealand, Europe, and North America, whereas the lowest is seen in Africa and Southcentral Asia. People with low socioeconomic status also tend to have an increase in the incidence of colorectal cancer.

Adenocarcinoma of Pancreas

Pancreatic cancer is the fourth leading cause of oncologic related death in both men and women. More than 85% of the cases comprise of adenocarcinoma. Incidence increases with age and is rare before the age of 45. It peaks at age 65 to 69 in men and 75 to 79 in women.[34] It has been mostly reported in the Western world, with the highest incidence in high-income groups living in North America and Western and Central Europe. The lowest incidence was reported in South Asia and Central and Eastern Sub-Saharan Africa.[34] In the United States, incidence seems to be higher in males and predominantly seen in African Americans.

Histopathology

Adenocarcinomas are easily diagnosed and distinguished from other cancer histologies by a light microscopy examination. The diagnosis is usually based on the identification of glandular structures under light microscopy. As these features are shared by all types of adenocarcinomas, it is impossible to diagnose the primary site of origin of these tumors, especially in a metastatic setting. Also, with poorly differentiated adenocarcinomas, where minimal glandular formation is seen on light microscopy or no glandular formation but stain for mucin, immunohistochemistry (IHC) is an important tool to help further diagnose the type of adenocarcinoma.[35]

Positive staining for CK-7 along with TTF-1 (+/- napsin), which is a pneumocyte marker expressor, is highly suggestive of adenocarcinoma of the lung. Adenocarcinoma of the lung also tends to have mutations in the epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and c-ROS oncogene 1(ROS-1), which are important to diagnose, as targeted therapies are available for treatment. PD-L1 IHC assays are also performed in advanced lung cancers to help with treatment selection with immunotherapy. The College of American Pathologists recommends obtaining the above testing on all patients with advanced adenocarcinoma of the lung.[36]

Positive staining for CK-7, GATA -3 ( GATA-binding protein 3), and gross cystic fluid protein 15 is suggestive of breast adenocarcinoma.
Positive staining for prostate-specific antigen (PSA) is specific for adenocarcinoma of the prostate. P63, a nuclear basal protein, helps to differentiate from normal prostatic tissue and adenocarcinoma of the prostate.
Positive CDX-2 or cytokeratin-20 (CK-20) positive with CK-7 negative, is suggestive of colorectal adenocarcinoma.
Positive staining for CK-7, PAX 8, and WT-1 is suggestive of ovarian adenocarcinoma.
Positive staining for thyroglobulin and thyroid transcription factor-1 is suggestive of adenocarcinoma of the thyroid.

History and Physical

The clinical presentation of patients with adenocarcinoma will vary according to the primary site of involvement by the tumor and the extent of other organs involved. Obtaining a family history from the patient plays a significant role, as some of the cancers are inherited. Patients can be asymptomatic or have nonspecific symptoms like unintended weight loss and other symptoms depending on the organ's involvement with metastasis. The most commonly involved sites include the bones, lungs, liver, and lymph nodes, which represent nearly 60 percent of the cases. The most common type of adenocarcinomas comprises breast, lung, prostate, colorectal, and pancreatic.

Adenocarcinoma of the breast may present with common symptoms like sudden onset of pain or after trauma, nipple discharge/inversion, new persistent skin changes, and palpable breast mass, which could be found as an incidental finding or at a routine wellness exam.[37][38]

Adenocarcinoma of the lung can present with a chronic dry cough, dyspnea, hemoptysis, weight loss, or as an incidental finding on routine imaging. Lung adenocarcinoma is associated with extrapulmonary features like hypertrophic osteoarthropathy, which manifests as clubbing, periostitis of long bones, and arthritis.

Adenocarcinoma of prostate patients may present with difficulty urination, weak stream, incomplete emptying of the bladder, occasionally hematuria, and chronic back pain. On exam, enlarged prostate, abnormal DRE exam, although this has low sensitivity and specificity.[39]

Adenocarcinoma of the colon and rectum can present as unintentional weight loss, fatigue, generalized weakness, hematochezia, abdominal pain, and bowel obstruction. Adenocarcinoma of the pancreas can present as chronic epigastric pain, nausea, vomiting, jaundice, weight loss, anorexia, asthenia, steatorrhea, hepatosplenomegaly, and thrombophlebitis.[40]

Evaluation

Initial evaluation for a diagnosis of adenocarcinoma starts with a thorough, complete history and a physical exam. Lab work should include complete blood counts, a comprehensive metabolic panel, and urinalysis. Imaging studies are usually obtained depending on the suspicion of the primary site of adenocarcinoma as well as metastatic disease.

Computed tomography (CT) scan of the chest, abdomen, and pelvis with contrast and, in some instances, magnetic resonance imaging (MRI) are usually helpful in evaluation for a primary site of cancer. Gender-specific screening, for example, prostate exam as well as levels of PSA levels in a patient suspicious for prostatic adenocarcinoma and a complete breast and pelvis exam, including a pap smear and mammogram in females suspicious for breast cancer. Positron emission tomography (PET) scan can be helpful in identifying a primary site in 40 percent of the cases in a retrospective study and is also used for appropriate staging.[41][42] However, the use of PET scans was not found to be superior to CT scans in a prospective study.[43]

Patients with concern for a gastrointestinal tumor should be evaluated with a colonoscopy, upper endoscopy with endoscopic ultrasound (EUS), and endoscopic retrograde cholangiopancreatography(ERCP), depending on the suspicion for the origin of the primary tumor. Colonoscopy is also recommended for a colorectal origin tumor when an intra-abdominal metastasis has CK20/ CK7 negative on the IHC staining pattern. Once a biopsy is obtained, further microscopic examination, as well as IHC staining, will help accurately diagnose the type of adenocarcinoma.

Biomarkers like the CEA, CA 19-9, CA 125, etc, are not sensitive for diagnostic purposes but can be used to monitor response to therapy as well as an indicator of the activity of disease at the time of diagnosis.[44][45][46][47][48] CA 15-3 and CA 27.29 are commonly used in metastatic breast cancer to monitor disease status for patients undergoing treatment.[49]

Treatment / Management

Adenocarcinomas are diverse and can involve any part of the body. The management and treatment of adenocarcinoma differ depending on the primary site of disease as well as the stage of cancer. Prior to the initiation of any treatment, it is very important first to characterize the site and type of adenocarcinoma. Interprofessional care is of utmost importance, with the involvement of pathology, radiology, surgical oncology, radiation oncology, and medical oncology, along with other allied health professionals. In the earlier stages of cancer, where surgical resection is feasible, surgery offers the best opportunity for long-term survival. Depending on the location, type, stage, as well as performance status of the patient, different types of treatments are proposed.

Curative intent treatments usually include surgery, neoadjuvant or adjuvant systemic chemotherapy, radiation therapy, or a combination of concurrent radiation and chemotherapy, hormonal therapy in breast and prostate cancer. Management also involves close follow up of these patients with repeat blood work, surveillance scans, and long term symptom and survivorship care. Palliative treatment is proposed in the incurable setting and usually involves systemic chemotherapy, immunotherapy, and targeted therapies to prolong the survival of the patient. There is a role for palliative radiation and surgery for symptom control.

Differential Diagnosis

Differential diagnosis can be broad depending on the site of adenocarcinoma.

Adenocarcinoma of the lung: Benign lung tumors, infection, small cell lung cancer, metastasis from another primary cancer, tuberculosis.
Adenocarcinoma of the breast: Fibroadenoma, breast abscess, traumatic fat necrosis, breast lymphoma, metastasis from another primary cancer.
Adenocarcinoma of the prostate: Prostatitis, prostatic abscess, benign prostatic hyperplasia, sarcoma of the prostate, metastasis from another primary cancer.
Adenocarcinoma of colon and rectum: Crohn disease, ulcerative colitis, diverticulosis, intestinal lymphoma, metastatic cancer from another primary site, carcinoid.

Prognosis

The prognosis of adenocarcinoma depends on the type of adenocarcinoma as well as the stage of cancer at diagnosis. The tumor, node, and metastasis (TNM) staging has the greatest impact on prognosis. Other independent factors that determine prognosis are the performance status of the patient, site of metastasis, tumor burden, eligibility, and tolerance of treatment.[50][51][52][53]

Below are the SEER data on survival on different sites of adenocarcinoma, where a significant survival difference is noted between different adenocarcinomas depending on the site of origin.

Adenocarcinoma of the lung: the 5-year survival rate: Localized: 59%Regional: 31.7%Distant: 5.8%

Adenocarcinoma of the breast: the 5-year survival rateLocalized: 98.9%Regional: 85.7%Distant: 28.1%
Adenocarcinoma of the prostate: the 5-year survival rateLocalized: 100%Regional: 100%Distant: 30.2%
Adenocarcinoma of colorectal origin: the 5-year survival Localized: 90.2%Regional: 71.8%Distant: 14.3%

Complications

Complications of adenocarcinoma are primarily related to the cancer site, the extent of the tumor, metastatic area. Other complications associated with adenocarcinoma are related to the management options.

Tumor complications: Pain, generalized weakness, failure to thrive, weight loss and death
Surgery complications: Postoperative infections, perforation, bleeding risk, anesthetic complications
Chemotherapy complications: Pancytopenia, life-threatening complications secondary to immunocompromised state, kidney and liver dysfunction, neuropathy, anaphylaxis
Immunotherapy complications: Colitis, skin rash, thyroiditis, pneumonitis, psoriasis, pneumonitis, pericarditis
Radiation complications: Inflammation of surrounding organs, skin rash, neuropathies, mucositis, the progression of coronary artery disease

Deterrence and Patient Education

Patient education should be considered an important aspect when it comes to better management of any disease. In the context of adenocarcinoma, patient education regarding the importance of recognition of any concerning symptoms is of utmost importance. Clinicians need to maintain a good doctor-patient relationship, allowing them to covey their concerns freely.

The patient should receive education regarding the following:

Type of adenocarcinoma
Importance of staging in adenocarcinoma
Availability of tests and procedures for the diagnosis of adenocarcinoma
Risks and benefits associated with available treatments and side effects associated with specific treatments
Importance of interdisciplinary care in the management of adenocarcinoma and surveillance

Enhancing Healthcare Team Outcomes

Adenocarcinoma is a common diagnosis, and the management of these invasive cancers is complex depending on the primary site, stage of cancer, and performance status of the patient. Various healthcare providers are involved in the management of adenocarcinoma, including pathologists, surgical oncologists, radiation oncologists, medical oncologists, primary care physicians, radiologists, nurses, and pharmacists.

Effective management of the disease requires excellent interpersonal communication and collaboration between team members to provide improved patient-centered care. An interdisciplinary tumor board discussion is recommended in the management of these patients, which helps with effective communication, timely treatment planning, and good outcomes. Involving the patients and their families in treatment decisions improves outcomes in these patient populations. Most importantly, screening and management guidelines exist as a result of various conferences and exhaustive research (clinical trials, meta-analysis, systematic reviews) where healthcare providers come and work together towards common goals and share their ideas.

Revision of guidelines is critical to incorporate better, practical, and more feasible methods. In situations where enough data isn't available, expert opinion from a specialist may be taken to help better guide management. All this is possible with effective communication and coordination of care amongst different healthcare providers.[54]

Details

References

[1]

Pentheroudakis G, Golfinopoulos V, Pavlidis N. Switching benchmarks in cancer of unknown primary: from autopsy to microarray. European journal of cancer (Oxford, England : 1990). 2007 Sep:43(14):2026-36 [PubMed PMID: 17698346]

[2]

Alberg AJ, Samet JM. Epidemiology of lung cancer. Chest. 2003 Jan:123(1 Suppl):21S-49S [PubMed PMID: 12527563]

[3]

Hubbard R, Venn A, Lewis S, Britton J. Lung cancer and cryptogenic fibrosing alveolitis. A population-based cohort study. American journal of respiratory and critical care medicine. 2000 Jan:161(1):5-8 [PubMed PMID: 10619790]

[4]

Siegel RL,Miller KD,Jemal A, Cancer statistics, 2020. CA: a cancer journal for clinicians. 2020 Jan; [PubMed PMID: 31912902]

[5]

Lu HM, Li S, Black MH, Lee S, Hoiness R, Wu S, Mu W, Huether R, Chen J, Sridhar S, Tian Y, McFarland R, Dolinsky J, Tippin Davis B, Mexal S, Dunlop C, Elliott A. Association of Breast and Ovarian Cancers With Predisposition Genes Identified by Large-Scale Sequencing. JAMA oncology. 2019 Jan 1:5(1):51-57. doi: 10.1001/jamaoncol.2018.2956. Epub [PubMed PMID: 30128536]

[6]

Delongchamps NB, Singh A, Haas GP. The role of prevalence in the diagnosis of prostate cancer. Cancer control : journal of the Moffitt Cancer Center. 2006 Jul:13(3):158-68 [PubMed PMID: 16885911]

[7]

Nicolosi P, Ledet E, Yang S, Michalski S, Freschi B, O'Leary E, Esplin ED, Nussbaum RL, Sartor O. Prevalence of Germline Variants in Prostate Cancer and Implications for Current Genetic Testing Guidelines. JAMA oncology. 2019 Apr 1:5(4):523-528. doi: 10.1001/jamaoncol.2018.6760. Epub [PubMed PMID: 30730552]

[8]

Burt RW,DiSario JA,Cannon-Albright L, Genetics of colon cancer: impact of inheritance on colon cancer risk. Annual review of medicine. 1995; [PubMed PMID: 7598472]

[9]

Lynch HT, Smyrk TC, Watson P, Lanspa SJ, Lynch JF, Lynch PM, Cavalieri RJ, Boland CR. Genetics, natural history, tumor spectrum, and pathology of hereditary nonpolyposis colorectal cancer: an updated review. Gastroenterology. 1993 May:104(5):1535-49 [PubMed PMID: 8482467]

[10]

Yurgelun MB, Kulke MH, Fuchs CS, Allen BA, Uno H, Hornick JL, Ukaegbu CI, Brais LK, McNamara PG, Mayer RJ, Schrag D, Meyerhardt JA, Ng K, Kidd J, Singh N, Hartman AR, Wenstrup RJ, Syngal S. Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2017 Apr 1:35(10):1086-1095. doi: 10.1200/JCO.2016.71.0012. Epub 2017 Jan 30 [PubMed PMID: 28135145]

[11]

Schernhammer ES, Kang JH, Chan AT, Michaud DS, Skinner HG, Giovannucci E, Colditz GA, Fuchs CS. A prospective study of aspirin use and the risk of pancreatic cancer in women. Journal of the National Cancer Institute. 2004 Jan 7:96(1):22-8 [PubMed PMID: 14709735]

[12]

Klein AP,Hruban RH,Brune KA,Petersen GM,Goggins M, Familial pancreatic cancer. Cancer journal (Sudbury, Mass.). 2001 Jul-Aug; [PubMed PMID: 11561603]

[13]

Olson SH, Kurtz RC. Epidemiology of pancreatic cancer and the role of family history. Journal of surgical oncology. 2013 Jan:107(1):1-7. doi: 10.1002/jso.23149. Epub 2012 May 15 [PubMed PMID: 22589078]

[14]

Wolpin BM, Chan AT, Hartge P, Chanock SJ, Kraft P, Hunter DJ, Giovannucci EL, Fuchs CS. ABO blood group and the risk of pancreatic cancer. Journal of the National Cancer Institute. 2009 Mar 18:101(6):424-31. doi: 10.1093/jnci/djp020. Epub 2009 Mar 10 [PubMed PMID: 19276450]

[15]

Annese V, Minervini M, Gabbrielli A, Gambassi G, Manna R. ABO blood groups and cancer of the pancreas. International journal of pancreatology : official journal of the International Association of Pancreatology. 1990 Mar:6(2):81-8 [PubMed PMID: 2230362]

[16]

Risch HA, Yu H, Lu L, Kidd MS. ABO blood group, Helicobacter pylori seropositivity, and risk of pancreatic cancer: a case-control study. Journal of the National Cancer Institute. 2010 Apr 7:102(7):502-5. doi: 10.1093/jnci/djq007. Epub 2010 Feb 24 [PubMed PMID: 20181960]

Level 2 (mid-level) evidence

[17]

Wolpin BM,Kraft P,Gross M,Helzlsouer K,Bueno-de-Mesquita HB,Steplowski E,Stolzenberg-Solomon RZ,Arslan AA,Jacobs EJ,Lacroix A,Petersen G,Zheng W,Albanes D,Allen NE,Amundadottir L,Anderson G,Boutron-Ruault MC,Buring JE,Canzian F,Chanock SJ,Clipp S,Gaziano JM,Giovannucci EL,Hallmans G,Hankinson SE,Hoover RN,Hunter DJ,Hutchinson A,Jacobs K,Kooperberg C,Lynch SM,Mendelsohn JB,Michaud DS,Overvad K,Patel AV,Rajkovic A,Sanchéz MJ,Shu XO,Slimani N,Thomas G,Tobias GS,Trichopoulos D,Vineis P,Virtamo J,Wactawski-Wende J,Yu K,Zeleniuch-Jacquotte A,Hartge P,Fuchs CS, Pancreatic cancer risk and ABO blood group alleles: results from the pancreatic cancer cohort consortium. Cancer research. 2010 Feb 1; [PubMed PMID: 20103627]

[18]

Yamada A, Komaki Y, Komaki F, Micic D, Zullow S, Sakuraba A. Risk of gastrointestinal cancers in patients with cystic fibrosis: a systematic review and meta-analysis. The Lancet. Oncology. 2018 Jun:19(6):758-767. doi: 10.1016/S1470-2045(18)30188-8. Epub 2018 Apr 26 [PubMed PMID: 29706374]

Level 1 (high-level) evidence

[19]

Rebours V, Lévy P, Ruszniewski P. An overview of hereditary pancreatitis. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 2012 Jan:44(1):8-15. doi: 10.1016/j.dld.2011.08.003. Epub 2011 Sep 9 [PubMed PMID: 21907651]

Level 3 (low-level) evidence

[20]

Lowenfels AB, Maisonneuve P, Whitcomb DC. Risk factors for cancer in hereditary pancreatitis. International Hereditary Pancreatitis Study Group. The Medical clinics of North America. 2000 May:84(3):565-73 [PubMed PMID: 10872414]

[21]

Lynch SM,Vrieling A,Lubin JH,Kraft P,Mendelsohn JB,Hartge P,Canzian F,Steplowski E,Arslan AA,Gross M,Helzlsouer K,Jacobs EJ,LaCroix A,Petersen G,Zheng W,Albanes D,Amundadottir L,Bingham SA,Boffetta P,Boutron-Ruault MC,Chanock SJ,Clipp S,Hoover RN,Jacobs K,Johnson KC,Kooperberg C,Luo J,Messina C,Palli D,Patel AV,Riboli E,Shu XO,Rodriguez Suarez L,Thomas G,Tjønneland A,Tobias GS,Tong E,Trichopoulos D,Virtamo J,Ye W,Yu K,Zeleniuch-Jacquette A,Bueno-de-Mesquita HB,Stolzenberg-Solomon RZ, Cigarette smoking and pancreatic cancer: a pooled analysis from the pancreatic cancer cohort consortium. American journal of epidemiology. 2009 Aug 15; [PubMed PMID: 19561064]

[22]

Nöthlings U, Wilkens LR, Murphy SP, Hankin JH, Henderson BE, Kolonel LN. Meat and fat intake as risk factors for pancreatic cancer: the multiethnic cohort study. Journal of the National Cancer Institute. 2005 Oct 5:97(19):1458-65 [PubMed PMID: 16204695]

[23]

Bosetti C, Lucenteforte E, Silverman DT, Petersen G, Bracci PM, Ji BT, Negri E, Li D, Risch HA, Olson SH, Gallinger S, Miller AB, Bueno-de-Mesquita HB, Talamini R, Polesel J, Ghadirian P, Baghurst PA, Zatonski W, Fontham E, Bamlet WR, Holly EA, Bertuccio P, Gao YT, Hassan M, Yu H, Kurtz RC, Cotterchio M, Su J, Maisonneuve P, Duell EJ, Boffetta P, La Vecchia C. Cigarette smoking and pancreatic cancer: an analysis from the International Pancreatic Cancer Case-Control Consortium (Panc4). Annals of oncology : official journal of the European Society for Medical Oncology. 2012 Jul:23(7):1880-8. doi: 10.1093/annonc/mdr541. Epub 2011 Nov 21 [PubMed PMID: 22104574]

Level 2 (mid-level) evidence

[24]

Maisonneuve P, Lowenfels AB. Risk factors for pancreatic cancer: a summary review of meta-analytical studies. International journal of epidemiology. 2015 Feb:44(1):186-98. doi: 10.1093/ije/dyu240. Epub 2014 Dec 14 [PubMed PMID: 25502106]

[25]

Wroblewski LE,Peek RM Jr, Helicobacter pylori, Cancer, and the Gastric Microbiota. Advances in experimental medicine and biology. 2016; [PubMed PMID: 27573782]

Level 3 (low-level) evidence

[26]

Xie SH, Lagergren J. Risk factors for oesophageal cancer. Best practice & research. Clinical gastroenterology. 2018 Oct-Dec:36-37():3-8. doi: 10.1016/j.bpg.2018.11.008. Epub 2018 Nov 22 [PubMed PMID: 30551854]

[27]

Jeon J, Holford TR, Levy DT, Feuer EJ, Cao P, Tam J, Clarke L, Clarke J, Kong CY, Meza R. Smoking and Lung Cancer Mortality in the United States From 2015 to 2065: A Comparative Modeling Approach. Annals of internal medicine. 2018 Nov 20:169(10):684-693. doi: 10.7326/M18-1250. Epub 2018 Oct 9 [PubMed PMID: 30304504]

Level 2 (mid-level) evidence

[28]

Anderson BO, Yip CH, Smith RA, Shyyan R, Sener SF, Eniu A, Carlson RW, Azavedo E, Harford J. Guideline implementation for breast healthcare in low-income and middle-income countries: overview of the Breast Health Global Initiative Global Summit 2007. Cancer. 2008 Oct 15:113(8 Suppl):2221-43. doi: 10.1002/cncr.23844. Epub [PubMed PMID: 18816619]

Level 3 (low-level) evidence

[29]

Torre LA,Bray F,Siegel RL,Ferlay J,Lortet-Tieulent J,Jemal A, Global cancer statistics, 2012. CA: a cancer journal for clinicians. 2015 Mar; [PubMed PMID: 25651787]

[30]

de Gelder R, Heijnsdijk EA, Fracheboud J, Draisma G, de Koning HJ. The effects of population-based mammography screening starting between age 40 and 50 in the presence of adjuvant systemic therapy. International journal of cancer. 2015 Jul 1:137(1):165-72. doi: 10.1002/ijc.29364. Epub 2014 Dec 13 [PubMed PMID: 25430053]

[31]

Munoz D, Near AM, van Ravesteyn NT, Lee SJ, Schechter CB, Alagoz O, Berry DA, Burnside ES, Chang Y, Chisholm G, de Koning HJ, Ali Ergun M, Heijnsdijk EA, Huang H, Stout NK, Sprague BL, Trentham-Dietz A, Mandelblatt JS, Plevritis SK. Effects of screening and systemic adjuvant therapy on ER-specific US breast cancer mortality. Journal of the National Cancer Institute. 2014 Nov:106(11):. pii: dju289. doi: 10.1093/jnci/dju289. Epub 2014 Sep 24 [PubMed PMID: 25255803]

[32]

Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a cancer journal for clinicians. 2018 Nov:68(6):394-424. doi: 10.3322/caac.21492. Epub 2018 Sep 12 [PubMed PMID: 30207593]

[33]

Ward EM,Sherman RL,Henley SJ,Jemal A,Siegel DA,Feuer EJ,Firth AU,Kohler BA,Scott S,Ma J,Anderson RN,Benard V,Cronin KA, Annual Report to the Nation on the Status of Cancer, Featuring Cancer in Men and Women Age 20-49 Years. Journal of the National Cancer Institute. 2019 Dec 1; [PubMed PMID: 31145458]

[34]

GBD 2017 Pancreatic Cancer Collaborators. The global, regional, and national burden of pancreatic cancer and its attributable risk factors in 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. The lancet. Gastroenterology & hepatology. 2019 Dec:4(12):934-947. doi: 10.1016/S2468-1253(19)30347-4. Epub 2019 Oct 21 [PubMed PMID: 31648972]

Level 1 (high-level) evidence

[35]

Greco FA, Lennington WJ, Spigel DR, Hainsworth JD. Poorly differentiated neoplasms of unknown primary site: diagnostic usefulness of a molecular cancer classifier assay. Molecular diagnosis & therapy. 2015 Apr:19(2):91-7. doi: 10.1007/s40291-015-0133-8. Epub [PubMed PMID: 25758902]

[36]

Lindeman NI, Cagle PT, Beasley MB, Chitale DA, Dacic S, Giaccone G, Jenkins RB, Kwiatkowski DJ, Saldivar JS, Squire J, Thunnissen E, Ladanyi M. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2013 Jul:8(7):823-59. doi: 10.1097/JTO.0b013e318290868f. Epub [PubMed PMID: 23552377]

[37]

Morrow M, The evaluation of common breast problems. American family physician. 2000 Apr 15; [PubMed PMID: 10794579]

[38]

Santen RJ, Mansel R. Benign breast disorders. The New England journal of medicine. 2005 Jul 21:353(3):275-85 [PubMed PMID: 16034013]

[39]

Naji L, Randhawa H, Sohani Z, Dennis B, Lautenbach D, Kavanagh O, Bawor M, Banfield L, Profetto J. Digital Rectal Examination for Prostate Cancer Screening in Primary Care: A Systematic Review and Meta-Analysis. Annals of family medicine. 2018 Mar:16(2):149-154. doi: 10.1370/afm.2205. Epub [PubMed PMID: 29531107]

Level 1 (high-level) evidence

[40]

Porta M, Fabregat X, Malats N, Guarner L, Carrato A, de Miguel A, Ruiz L, Jariod M, Costafreda S, Coll S, Alguacil J, Corominas JM, Solà R, Salas A, Real FX. Exocrine pancreatic cancer: symptoms at presentation and their relation to tumour site and stage. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico. 2005 Jun:7(5):189-97 [PubMed PMID: 15960930]

[41]

Sève P, Billotey C, Broussolle C, Dumontet C, Mackey JR. The role of 2-deoxy-2-[F-18]fluoro-D-glucose positron emission tomography in disseminated carcinoma of unknown primary site. Cancer. 2007 Jan 15:109(2):292-9 [PubMed PMID: 17167760]

[42]

Moller AK, Loft A, Berthelsen AK, Damgaard Pedersen K, Graff J, Christensen CB, Perell K, Petersen BL, Daugaard G. 18F-FDG PET/CT as a diagnostic tool in patients with extracervical carcinoma of unknown primary site: a literature review. The oncologist. 2011:16(4):445-51. doi: 10.1634/theoncologist.2010-0189. Epub 2011 Mar 22 [PubMed PMID: 21427201]

[43]

Møller AK,Loft A,Berthelsen AK,Pedersen KD,Graff J,Christensen CB,Costa JC,Skovgaard LT,Perell K,Petersen BL,Daugaard G, A prospective comparison of 18F-FDG PET/CT and CT as diagnostic tools to identify the primary tumor site in patients with extracervical carcinoma of unknown primary site. The oncologist. 2012; [PubMed PMID: 22711751]

[44]

Maisey NR, Norman AR, Hill A, Massey A, Oates J, Cunningham D. CA19-9 as a prognostic factor in inoperable pancreatic cancer: the implication for clinical trials. British journal of cancer. 2005 Oct 3:93(7):740-3 [PubMed PMID: 16175188]

[45]

Berger AC, Garcia M Jr, Hoffman JP, Regine WF, Abrams RA, Safran H, Konski A, Benson AB 3rd, MacDonald J, Willett CG. Postresection CA 19-9 predicts overall survival in patients with pancreatic cancer treated with adjuvant chemoradiation: a prospective validation by RTOG 9704. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2008 Dec 20:26(36):5918-22. doi: 10.1200/JCO.2008.18.6288. Epub 2008 Nov 24 [PubMed PMID: 19029412]

Level 1 (high-level) evidence

[46]

Liu Z, Zhang Y, Niu Y, Li K, Liu X, Chen H, Gao C. A systematic review and meta-analysis of diagnostic and prognostic serum biomarkers of colorectal cancer. PloS one. 2014:9(8):e103910. doi: 10.1371/journal.pone.0103910. Epub 2014 Aug 8 [PubMed PMID: 25105762]

Level 1 (high-level) evidence

[47]

Konishi T,Shimada Y,Hsu M,Tufts L,Jimenez-Rodriguez R,Cercek A,Yaeger R,Saltz L,Smith JJ,Nash GM,Guillem JG,Paty PB,Garcia-Aguilar J,Gonen M,Weiser MR, Association of Preoperative and Postoperative Serum Carcinoembryonic Antigen and Colon Cancer Outcome. JAMA oncology. 2018 Mar 1; [PubMed PMID: 29270608]

[48]

Niederau C, Grendell JH. Diagnosis of pancreatic carcinoma. Imaging techniques and tumor markers. Pancreas. 1992:7(1):66-86 [PubMed PMID: 1557348]

[49]

Van Poznak C, Somerfield MR, Bast RC, Cristofanilli M, Goetz MP, Gonzalez-Angulo AM, Hicks DG, Hill EG, Liu MC, Lucas W, Mayer IA, Mennel RG, Symmans WF, Hayes DF, Harris LN. Use of Biomarkers to Guide Decisions on Systemic Therapy for Women With Metastatic Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2015 Aug 20:33(24):2695-704. doi: 10.1200/JCO.2015.61.1459. Epub 2015 Jul 20 [PubMed PMID: 26195705]

Level 1 (high-level) evidence

[50]

Sjoquist KM, Renfro LA, Simes RJ, Tebbutt NC, Clarke S, Seymour MT, Adams R, Maughan TS, Saltz L, Goldberg RM, Schmoll HJ, Van Cutsem E, Douillard JY, Hoff PM, Hecht JR, Tournigand C, Punt CJA, Koopman M, Hurwitz H, Heinemann V, Falcone A, Porschen R, Fuchs C, Diaz-Rubio E, Aranda E, Bokemeyer C, Souglakos I, Kabbinavar FF, Chibaudel B, Meyers JP, Sargent DJ, de Gramont A, Zalcberg JR, Fondation Aide et Recherche en Cancerologie Digestive Group (ARCAD). Personalizing Survival Predictions in Advanced Colorectal Cancer: The ARCAD Nomogram Project. Journal of the National Cancer Institute. 2018 Jun 1:110(6):638-648. doi: 10.1093/jnci/djx253. Epub [PubMed PMID: 29267900]

[51]

Hoang T,Xu R,Schiller JH,Bonomi P,Johnson DH, Clinical model to predict survival in chemonaive patients with advanced non-small-cell lung cancer treated with third-generation chemotherapy regimens based on eastern cooperative oncology group data. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2005 Jan 1 [PubMed PMID: 15625371]

[52]

Blackstock AW, Herndon JE 2nd, Paskett ED, Perry MC, Graziano SL, Muscato JJ, Kosty MP, Akerley WL, Holland J, Fleishman S, Green MR. Outcomes among African-American/non-African-American patients with advanced non-small-cell lung carcinoma: report from the Cancer and Leukemia Group B. Journal of the National Cancer Institute. 2002 Feb 20:94(4):284-90 [PubMed PMID: 11854390]

[53]

Stanley KE. Prognostic factors for survival in patients with inoperable lung cancer. Journal of the National Cancer Institute. 1980 Jul:65(1):25-32 [PubMed PMID: 6930515]

[54]

Kesson EM, Allardice GM, George WD, Burns HJ, Morrison DS. Effects of multidisciplinary team working on breast cancer survival: retrospective, comparative, interventional cohort study of 13 722 women. BMJ (Clinical research ed.). 2012 Apr 26:344():e2718. doi: 10.1136/bmj.e2718. Epub 2012 Apr 26 [PubMed PMID: 22539013]

Level 2 (mid-level) evidence