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Etiologic factors

ETIOLOGIC FACTORS

Recent investigations have identified a number of factors that may contribute to the pathogenesis of pancreatic cancer. These factors can be organized into general areas of risk that include environmental factors, associated medical or surgical factors, heritable genetic factors (familial pancreatic cancer), and occupational exposures.

ENVIRONMENTAL FACTORS

A number of important environmental risk factors have been investigated for their role in the etiology of pancreatic cancer.

Cigarette Smoking.

Cigarette smoking is the most firmly established risk factor associated with pancreatic cancer. Pancreatic malignancies can be induced in animals through long-term administration of tobacco-specific N-nitrosamines or by parenteral administration of other N-nitroso compounds. These carcinogens are metabolized to electrophiles that readily react with DNA, leading to miscoding and activation of specific oncogenes such as K- ras. Induction of pancreatic cancer in these systems can be modulated by additional factors, including changes in bile acid composition, cholecystokinin (CCK) levels, and diet.

At the clinical level, numerous case-control and cohort studies have reported an increased risk of pancreatic cancer for smokers in both the United States and Europe, and current estimates suggest that approximately 30% of pancreatic cancer cases are due to cigarette smoking. Recent studies that have explored the dose-response relationship have shown that the risk of pancreatic cancer increases as the amount and duration of smoking increase and that long-term smoking cessation (more than 10 years) reduces risk by approximately 30% relative to the risk of current smokers. Application of molecular epidemiologic techniques that are being developed for lung cancer may provide greater specificity in linking tobacco exposure with the development of pancreatic cancer and may facilitate the study of chemopreventive strategies.

Dietary Factors

Over the past 10 years, numerous dietary factors have been implicated in pancreatic cancer development. Generally, high intakes of fat or meat increase risk, and diets high in fruits and vegetables reduce risk. When the available studies are analyzed in greater detail, the associations between dietary intake and pancreatic cancer become more complex. For example, high fat intake, usually in the form of high meat intake, increases risk. However, a recent study has suggested that the effect may vary by source of fat and by patient population. Investigators found that large amounts of fat from any source increase the risk of pancreatic cancer in men but that only fat from nonmeat or nondairy sources increases the risk in women. Other studies have reported an increased risk of pancreatic cancer with high total energy intake, high total cholesterol intake, or high ingestion of carbohydrates. These clinical observations are supported by laboratory studies in animal models in which high-fat and high-cholesterol diets have been shown to promote pancreatic carcinogenesis.

Decreased rates for pancreatic cancer have been associated with high consumption of vegetables, citrus fruits, fiber, and vitamin C. The association of diets high in citrus with a reduced risk of pancreatic cancer is particularly interesting given the recent observation that limonene, a natural product found in citrus fruits, is a potent inhibitor of the K- ras oncoprotein.

Data regarding the effect of coffee consumption and excessive alcohol consumption appear conflicting. For each of these factors, a few studies have suggested an increased risk of pancreatic cancer (coffee, alcohol), but most studies conducted over the past 10 years have failed to consistently demonstrate such a risk (coffee, alcohol). In some cases, significant methodologic problems may have confounded interpretation of the data, leading to erroneous conclusions.

New Treatments for Pancreatic Cancer

Pancreatic cancer accounts for approximately 27,000 deaths per year in the United States and 50,000 deaths per year in Europe (excluding the former USSR). Only 1% to 4% of patients with adenocarcinoma of the pancreas will be alive 5 years after diagnosis. Thus, incidence rates are virtually identical to mortality rates. In the United States in 1995, pancreatic cancer was be the fifth leading cause of adult deaths from cancer (after lung, colorectal, breast, and prostate cancers) and was responsible for close to 5% of all cancer-related deaths.

EPIDEMIOLOGY

The incidence of pancreatic cancer declined slightly from 1973 to 1991, with 26,300 new cases (2% of all cancer diagnoses) estimated in 2006. Studies evaluating this trend suggest that the decreased incidence is due to a steady decline in the rate for white men, which peaked during the period 1970 to 1974. By contrast, rates for white women, black men, and black women have not fallen. In Japan, the incidence of cancer of the pancreas has increased sharply from 1.8/100,000 in 1960 to 5.3 in 100,000 in 1985. Overall, incidence in mortality statistics are very similar for the United States and Western Europe. Between 1989 and 1991, mortality rates for pancreatic cancer in the United States were 10 in 100,000 for men, and 7.2 in 100,000 for women. Although overall mortality rates in industrialized societies appear similar, geographically and ethnically dissimilar populations show considerable differences in mortality rates from pancreatic cancer.
The risk of developing pancreatic cancer is low in the first three to four decades of life but increases sharply after age 50, with most patients between ages 65 and 80 at diagnosis. The male to female ratio has ranged from 1.7:1.0 in older series to 1.3:1.0 in a more contemporary series. Historically, the male to female ratio was reported to decrease with age; however, this trend was not observed in a recent series from Memorial Sloan-Kettering Cancer Center. Interestingly, in several animal models of pancreatic cancer, tumors are more reproducibly induced in male animals.
Racial differences in mortality rates for pancreatic cancer have also been observed. Pancreatic cancer mortality rates for American blacks are higher than for any other ethnic group in the United States and are considerably higher than the rates observed for African blacks, suggesting an environmental contribution to this increased risk.

These broad epidemiologic categories do little to identify persons at high risk for pancreatic cancer. To define high-risk groups, we must consider the contribution of specific etiologic factors.

MANAGEMENT OF CLINICAL STAGE II (LOW TUMOR BURDEN)

SEMINOMA

Low tumor burden stage II seminoma includes all patients with retroperitoneal metastases measuring 5 cm or smaller in maximum transverse diameter. This encompasses both clinical stages IIA and IIB. Radiation therapy is the treatment of choice for most patients with these stages of disease. The radiation portal is fundamentally the same as that of patients with clinical stage I disease. Fractionation is the same except that a boost of approximately 500 to 750 rad is administered to involved lymph nodes. Relapses occur in from 5% to 15%, and death from seminoma is rare. Prophylactic mediastinal radiation therapy is not indicated, because relapses solely in the anterior or posterior mediastinum are infrequent. The combination of supradiaphragmatic and infradiaphragmatic radiation therapy results in chemotherapy intolerance, a high rate of treatment-related mortality due to chemotherapy, and a greater than expected death rate from disease due to the inability to administer adequate doses of chemotherapy.
There are exceptions to the need for radiation therapy for clinical stage I and nonbulky clinical stage II seminoma:
A horseshoe kidney is a contraindication to retroperitoneal radiation therapy due to the high likelihood of radiation-induced renal failure. Observation is preferred in clinical stage I, and primary chemotherapy is the treatment of choice for clinical stage II.
Patients who develop a second metachronous testicular germ cell tumor and who have undergone a prior RPLND or received radiation therapy should be observed frequently if clinical stage I disease is present, and undergo primary chemotherapy in the unlikely event that the disease is confined to residual retroperitoneal lymph nodes.
Inflammatory bowel disease may also be a contraindication to radiation therapy. Discussions with an experienced radiation oncologist would be indicated under such circumstances. If the decision is not to administer radiation therapy, then the management policies noted earlier for patients with a horseshoe kidney should be followed.

NONSEMINOMATOUS GERM CELL TUMORS

Low tumor burden clinical stage II nonseminomatous GCT encompasses disease ipsilateral to the primary tumor, at or below the renal hilum, not associated with tumor-related back pain, and limited to the primary landing zone. The presence of suprahilar or retrocrural lymphadenopathy, bilateral retroperitoneal nodal metastases, back pain, or contralateral lymph nodes (even if the ipsilateral lymph nodes do not appear to be involved) generally implies unresectable disease (e.g., tumor-associated back pain) or a higher likelihood of metastatic disease (suprahilar and retrocrural adenopathy), and initial chemotherapy is preferred. Ipsilateral solitary lymph nodes smaller than 3 cm are best handled by RPLND. Lymph nodes between 3 and 5 cm, even if solitary, may be associated with more extensive disease than can be detected on abdominal CT scan.

Retroperitoneal Lymph Node Dissection

The standard approach to patients with clinical stage IIA and some IIB tumors has been RPLND. The priority is to perform a definitive therapeutic operation, following which there is a minimum likelihood of infield recurrence. Margins of resection should not be compromised in an attempt to maintain ejaculatory function. Nerve-sparing dissection may be possible, depending on the location of disease.

Observation. Chemotherapy

Observation

The driving forces for early observation studies in clinical stage I patients were the infertility resulting from RPLND (due to retrograde ejaculation) and the apparent absence of therapeutic benefit (i.e., orchiectomy was a curative procedure or systemic disease occurred in the absence of retroperitoneal disease). The ability of cisplatin-based chemotherapy to cure systemic disease directly permitted observation studies, because cure of low-burden disease was more than 95% and treatment of relapse would not compromise survival. Relapse occurs in 25% to 30% of patients who are observed. A higher likelihood of retroperitoneal or systemic relapse was associated with T2-4 tumors and lymphatic or vascular invasion in T1 tumors. Some studies suggested that a high percentage of embryonal carcinoma and other histologic features also predicted a higher likelihood of relapse. However, the correlation between lymphatic-vascular invasion and the presence of embryonal carcinoma is high, and general agreement on histologic criteria for relapse independent of vascular or lymphatic invasion does not exist. Therefore, vascular-lymphatic invasion is the critical pathologic predictor for relapse in tumors confined to the testis. The retroperitoneum is the site of relapse in approximately two thirds of patients; the lungs or markers alone, in approximately one third; and other visceral sites, much less frequently. There is a slightly higher likelihood that both chemotherapy and modified bilateral RPLND ( not nerve sparing) are needed in order to achieve the same cure rate.

Patients with clinical stage I nonseminomatous GCT with a T1 tumor without vascular-lymphatic invasion and serum tumor markers that are normal or declining at half-life should be offered both surgical and observation options. If RPLND is chosen, it should be of the nerve-sparing type, thereby preserving ejaculatory capacity in the majority of patients. Frequent CT scans of the abdomen are unnecessary once an RPLND has been performed. If surveillance is chosen, then a possibly unnecessary RPLND is avoided, limiting therapy to orchiectomy alone in at least 70% of the patients (i.e., those who never relapse). Patient compliance cannot be overemphasized. A physical examination, chest x-ray, and determinations of AFP and hCG levels are required at monthly intervals in the first year, every other month in the second year, quarterly in the third year, and less frequently thereafter. An abdominal CT scan is required quarterly in the first year, every 4 months in the second year, and every 6 months beginning in the third year. Visits and evaluations should be annual in the fifth year and beyond. In both situations, relapses are extremely uncommon after 2 years and have only very rarely been observed after 5 years, in contrast to seminoma.

Chemotherapy

There are few data regarding chemotherapy as initial treatment of clinical stage I disease when the risk of retroperitoneal disease is high. In three reports of patients receiving two cycles of cisplatin-based chemotherapy, fewer than 5% relapsed and about 1% died of GCT. Although this approach avoids RPLND and the duration of therapy is brief, a majority of these patients would be exposed to the transient (e.g., myelosuppression), permanent (e.g., neuropathy), and delayed (e.g., Raynaud’s phenomenon, acute leukemia) toxicities of chemotherapy. The data are not yet mature and follow-up is short; this approach should be considered investigational.

Rarely, patients with clinical stage I disease are found to have persistently elevated serum concentrations of AFP or hCG after orchiectomy. If these markers increase or plateau at an elevated level after a period of observation (4 weeks or less), metastatic disease is present. This group of patients should receive initial systemic chemotherapy, because the disease is often not limited to the retroperitoneum. An RPLND should be done only if clinical studies at the conclusion of therapy demonstrate new disease.

Management of clinical stage 1 disease

MANAGEMENT OF CLINICAL STAGE I DISEASE
SEMINOMA

Radiation Therapy

The management of clinical stage I seminoma has not changed significantly in the last 20 years. Radiation therapy remains the treatment of choice. The ipsilateral hemiscrotum does not require therapy unless gross tumor spillage has taken place. Conventional fractionation for clinical stage I disease is 150 to 180 cGy/d for five sessions per week using high-energy linear accelerator beams to a total dose of 2500 to 3000 cGy. Elective, prophylactic radiation therapy to the mediastinum is contraindicated. The contralateral testis should be shielded during treatment. Proper shielding will result in an exposure 1% or less of the total dose. The relapse rate within the irradiated portal after adequate radiation therapy is negligible. The systemic relapse rate, usually presenting as a supraclavicular mass, ranges from 2% to 9%, and the death rate is under 2%. CT scanning of the abdomen and pelvis is required and has replaced intravenous pyelography. LAG may have two purposes. Small nodal metastases that distort architecture but do not increase nodal size may be identified, and the field size may be smaller than those planned on the basis of CT alone. The smaller field may reduce the long-term effects of abdominal radiotherapy. For left-side, primary testicular tumors, the left renal hilum must be encompassed. Treatment of pelvic lymph nodes is sometimes required for T4 primary tumors or for scrotal violations with tumor spillage. An involved spermatic cord margin at the internal ring may also require field extension.

Observation

Although the dose of radiation therapy is low and the cure rate exceptionally high, long-term sequelae include the potential for an increased incidence of gastrointestinal neoplasms (see later). As a consequence, studies have been performed investigating observation as the only management after orchiectomy, to be followed by chemotherapy at relapse. The relapse rate is approximately 15%, but the median time to relapse is about 12 months, longer than that observed for nonseminomatous GCT. Moreover, relapses have occurred at intervals more than 5 years from diagnosis, implying that abdominal CT scanning to detect late relapses must occur indefinitely in patients with seminoma. Therefore, in the United States, observation for clinical stage I seminoma is not considered routine.

NONSEMINOMATOUS GERM CELL TUMORS

Nonseminomatous GCT is relatively radioresistant. Therefore, radiation therapy plays no role in its initial management. If a patient has clinical stage I disease at the conclusion of initial staging, three management options remain, the choice of which depends on specific histologic features and status of serum tumor marker concentrations.
Retroperitoneal Lymph Node Dissection

Because of predictable lymphatic metastatic spread, the conventional approach to patients with clinical stage I nonseminomatous GCT has been the modified, bilateral RPLND. Adequate exposure for RPLND can be achieved through either a transthoracic or a transabdominal approach. The standard bilateral infrahilar RPLND template, which remains the standard against which therapeutic alternatives are judged, includes the paracaval, interaortocaval, preaortic, paraaortic, and common iliac lymph nodes bilaterally.

Despite refinement of radiologic imaging, 15% to 40% of patients are clinically understaged. Retroperitoneal metastases will be found in about 30% of patients judged preoperatively to be clinical stage I. Retroperitoneal relapse will occur in about 20% to 25% of patients on clinical stage I surveillance protocols, and teratoma or viable cancer will be found pathologically in 20% of patients with a normal postchemotherapy CT scan.

Infield recurrence is rare after a properly performed RPLND, which is a curative procedure in the majority of patients with N1 disease, with relapse rates less than 35% without adjuvant chemotherapy and essentially no relapses for higher stage nodal disease followed by two cycles of cisplatin-based chemotherapy. Surgical mortality is less than 1%. Major complications are unusual but can include pancreatitis, renal vascular or ureteral injuries, chylous ascites, aortic wall necrosis, bowel obstruction, pulmonary emboli, hemorrhage, and wound dehiscence. Minor complications include lymphocele, atelectasis, wound infection, and prolonged ileus.

Most patients undergoing bilateral RPLND experience retrograde ejaculation and subsequent infertility. An improved understanding of the neuroanatomy of seminal emission and ejaculation, the pattern of retroperitoneal metastasis for right- and left-sided tumors, and surgical mapping studies led to modification of infrahilar surgical boundaries and techniques. Two approaches have been used: (1) formal dissection and preservation of sympathetic fibers, and (2) modified template that avoids (but does not specifically identify) sympathetic fibers.

Testicular Cancer

Testicular cancer is the most common solid tumor in men between the ages of 20 and 35 years. There are three modal peaks: infancy, ages 25 to 40, and about age 60.

A solid testicular mass in a man aged 50 or greater is usually a lymphoma. An estimated 6000 new cases and 350 deaths due to testicle cancer occured in the United States in 1995. The lifetime probability of developing a GCT is approximately 0.2% for an American Caucasian male. The incidence of testis cancer varies significantly according to geographic area. The reported incidence is highest in Scandinavia, Switzerland, Germany, and New Zealand; intermediate in the United States and Great Britain; and lowest in Africa and Asia. The worldwide incidence of testis GCT has more than doubled in the past 40 years.

EPIDEMIOLOGY

GCTs are seen principally in young Caucasians, rarely in African-Americans. The published ratio between Caucasian and African-American patients is approximately 4 to 5:1, although it was closer to 40:1 ratio in the US Military. In African-Americans, GCT behaves similarly to that of the general population, and the incidence of GCT in African-Americans has not increased over the past 40 years. Familial clustering has been observed, particularly among siblings.
The cause of GCT is unknown. Hypotheses implicating an endocrine-driven, pituitary stimulation of damaged germinal epithelium have not been proved. Instead, random genetic events occurring during the early stages of meiosis seem to be responsible for the malignant transformation of germ cells (see section on biology). A few congenital developmental defects predispose to the disease.

CRYPTORCHIDISM

The risk of GCT occurring in the cryptorchid testis is several times the risk in normally descended testes. Between 5% and 20% of patients with a history of cryptorchidism develop a tumor in the normally descended testis.An abdominal cryptorchid testis is more likely to develop GCT than an inguinal cryptorchid testis. The protective effect of orchiopexy is difficult to quantify, but most data suggest a reduced likelihood of GCT if orchiopexy is performed prior to puberty. If the testis is inguinal, hormonally functioning, and easily examined, surveillance is recommended. If the testis is not amenable to orchiopexy or cannot be adequately examined, orchiectomy is recommended.

Fusion defects. Endometrial Polyps

Fusion defects include unicornuate uterus (AFS class II), uterus didelphys (AFS class III), bicornuate uterus (AFS class IV), and septate uterus (class V).

A unicornuate uterus has a single hemi-uterus that is attached to its fallopian tube. It may also be associated with a rudimentary cavity from the contralateral side. A didelphys uterus has two uterine cavities, and each has a separate cervix. The fundus of the uterus also has a deep cleft between the cavities. A bicornuate uterus has a single cervix, a heart-shaped fundus, and two uterine cavities separated by myometrium. Conversely, a septate uterus has a single cervix, a flat fundus, and two uterine cavities separated by relatively avascular scar tissue.

Two clinically relevant points for fusion defects are:
In a woman with a unicornuate uterus, a rudimentary horn can result in pain because of obstruction orretrograde flow, either of which may cause endometriosis or be a site of infection.
Fusion defects may be associated with reproductive problems, from recurrent miscarriage to premature labor. The incidence of these problems is uncertain, however, because in women who have had only uncomplicated pregnancies, anomalies may never have been noted.
Among patients with AFS class I to IV uterine anomalies, there is an increased incidence of renal anomalies, usually renal agenesis ipsilateral to the associated hypoplastic mullerian defect. Therefore, a search for uterine anomalies should be conducted in patients with renal agenesis, and pelvic pain, or reproductive dysfunction.

Advances in the Treatment of Endometrial Polyps

Endometrial polyps are benign tumors consisting of surface endometrium, fibrous stroma, and thick-walled, centrally positioned blood vessels. A clonal rearrangement of chromosome 6p21 is common in the mesenchymal (stroma) cells in the polyp. The endometrial cells do not have the chromosome 6 rearrangement. One possible explanation of these findings is that an endometrial polyp begins when a stromal cell undergoes a rearrangement in chromosome 6p21 resulting in an abnormal signal to grow. The stromal elements proliferate and bring the endometrial glands along as “innocent bystanders.”

Most endometrial polyps are solitary. In approximately 20% of cases multiple polyps are present. Polyps peak between ages 40 and 50 years, but many cases occur in menopausal women. In fewer than 1% of cases, polyps are associated with cancer. The usual presenting symptom is intermenstrual bleeding or menometrorrhagia.

Polyps are typically diagnosed by sonography (especially sensitive in the follicular phase), saline infusion hysterosonography, hysterosalpingography, hysteroscopy, or curettage. Curettage often fails to remove endometrial polyps because of the mobility of their body and tip. In menopausal women taking hormone replacement therapy who have abnormal uterine bleeding, polyps are commonly found by hysteroscopy. Multiple case reports indicate that tamoxifen treatment may stimulate the development and growth of endometrial polyps.

Other Benign Uterine Disorders

Adenofibromas are benign tumors of epithelium and stroma that contain fewer that 4 mitoses per 10 high-power fields. Women with adenofibromas usually are elderly. Abnormal vaginal bleeding is the most frequent presentation.

Uterine Conservation at the Time of Adnexal Removal

In women who desire future childbearing, every effort should be made to preserve ovarian tissue unless a cancer diagnosis necessitates the removal of both ovaries. Occasionally, the clinician is confronted with a large benign ovarian cyst and must decide whether to remove the entire ovary or perform a cystectomy. If the woman has a desire for more children, an effort should be made to perform a cystectomy and to leave as much ovarian tissue as possible.

For some conditions, both ovaries require surgical removal. The clinician then is confronted with the issue of uterine conservation. If the woman has clearly and consistently communicated that she has no interest in further pregnancies and does not desire to retain her uterus, the uterus can be removed. If the woman has clearly expressed an interest in future childbearing, the uterus may be left in place so she may be able to become pregnant through oocyte or embryo donation.