Adenocarcinoma

Adenocarcinoma, NOS Classification and external resources

ICD-9 : 151.0, 182.0

ICD-O : M8140/3

MeSH : D000230

Adenocarcinoma is a cancer that originates in glandular tissue. This tissue is also part of a larger tissue category known as epithelial tissue. Epithelial tissue includes skin, glands and a variety of other tissue that lines the cavities and organs of the body. Epithelium is derived embryologically from ectoderm, endoderm and mesoderm. To be classified as adenocarcinoma, the cells do not necessarily need to be part of a gland, as long as they have secretory properties. This form of carcinoma can occur in some higher mammals, including humans. Well differentiated adenocarcinomas tend to resemble the glandular tissue that they are derived from, while poorly differentiated may not. By staining the cells from a biopsy, a pathologist will determine whether the tumor is an adenocarcinoma or some other type of cancer. Adenocarcinomas can arise in many tissues of the body due to the ubiquitous nature of glands within the body. While each gland may not be secreting the same substance, as long as there is an exocrine function to the cell, it is considered glandular and its malignant form is therefore named adenocarcinoma. Endocrine gland tumors, such as a VIPoma, an insulinoma, a pheochromocytoma, etc, are typically not referred to as adenocarcinomas, but rather, are often called neuroendocrine tumors. If the glandular tissue is abnormal, but benign, it is said to be an adenoma. Benign adenomas typically do not invade other tissue and rarely metastasize. Malignant adenocarcinomas invade other tissues and often metastasize given enough time to do so.

Diagnostic significance

A diagnosis of adenocarcinoma which is not further described, known as adenocarcinoma not otherwise specified or adenocarcinoma NOS, is significant because it indicates a cancerous process is present. However, it is not very useful for treatment decisions and prognosis, as these are determined by the tissue from which the tumour cells arose, i.e. the tissue of origin; an adenocarcinoma of the colon has a different prognosis and treatment than an adenocarcinoma of the ovary.
Adenocarcinoma not otherwise specified is often a preliminary diagnosis and can frequently be clarified by a pathologist with the use of immunohistochemistry.
Cancer for which a primary site cannot be found is called cancer of unknown primary.

Histopathology

Examples of tissues where adenocarcinomas may arise:


• colon

Gross appearance of a colectomy specimen containing two adenomatous polyps (the brownish oval tumors above the labels, attached to the normal beige lining by a stalk) and one invasive colorectal carcinoma (the crater-like, reddish, irregularly-shaped tumor located above the label).

Histopathologic image of colonic carcinoid stained by hematoxylin and eosin.

The vast majority of colorectal cancer is an adenocarcinoma. This is because the colon has numerous glands within the tissue. Normal colonic glands tend to be simple and tubular in appearance with a mixture of mucus secreting goblet cells and water absorbing cells. These glands are called glands because they secrete a substance into the lumen of the colon, this substance being mucus. The purpose of these glands are twofold. The first is to absorb water from the feces back into the blood. The second purpose is to secrete mucus into the colon lumen to lubricate the now dehydrated feces. This is crucial as a failure to lubricate the feces can result in colonic damage by the feces as it passes towards the rectum.
When these glands undergo a number of changes at the genetic level, they proceed in a predictable manner as they move from benign to an invasive, malignant colon cancer. In their research paper "Lessons from Hereditary Colorectal Cancer", Vogelstein, et al, suggested that colon cells lose the APC tumor suppressor gene and become a small polyp. Next, they suggested that k-Ras becomes activated and the polyp becomes a small, benign, adenoma. The adenoma, lacking the "carcinoma" attached to the end of it, suggests that it is a benign version of the malignant adenocarcinoma. The gastroenterologist uses a colonoscopy to find and remove these adenomas and polyps to prevent them from continuing to acquire genetic changes that will lead to an invasive adenocarcinoma. Volgelstein et al went on to suggest that loss of the DCC gene and of p53 result in a malignant adenocarcinoma.
Grossly, one will see a mass that looks of a different color than the surrounding tissue. Bleeding from the tumor is often apparent as the tumor tends to grow blood vessels into it in a haphazard manner via secretion of a number of angiogenesis promoting factors such as VEGF. Histologically, a glandular structure, similar to the healthy normal surrounding glands may be seen. If they look very similar, this is a low grade, well differentiated tumor. Often these glands will be disorganized and they will be seen growing back to back. However, if the tumor does not look like a gland anymore, it is a high grade tumor with poor differentiation. Regardless of the grade, malignant tumors tend to have a large nucleus with prominent nucleoli. There will also be a noticeable increase in the incidence of mitoses, or cell divisions.

Lung

• lung non-small cell

Currently, the most common type of lung cancer in lifelong non-smokers is the adenocarcinoma. Adenocarcinomas account for approximately 10% of lung cancers. This cancer usually is seen peripherally in the lungs, as opposed to small cell lung cancer and squamous cell lung cancer, which both tend to be more centrally located. The adenocarcinoma has an increased incidence in smokers, but is also the most common type of lung cancer seen in non-smokers. Adenocarcinoma of the lung tends to stain mucin positive as it is derived from the mucus producing glands of the lungs. Similar to other adenocarcinoma, if this tumor is well differentiated (low grade) it will resemble the normal glandular structure. Poorly differentiated adenocarcinoma will not resemble the normal glands (high grade) and will be detected by seeing that they stain positive for mucin (which the glands produce).

Other

• breast
• cervix
• pancreas (95% of pancreatic cancers are ductal adenocarcinomas.)
• prostate
• stomach
• urachus
• vagina
• Esophagus


Etymology

The term adenocarcinoma is derived from 'adeno' meaning 'pertaining to a gland' and 'carcinoma', which describes a cancer that has developed in the epithelial cells.

PAP TEST or PAP SMEAR

Pap test

Cytological specimen (ThinPrep) from a patient who was later diagnosed with cervical adenocarcinoma in situ. There is at least one mitosis.

The Papanicolaou test (also called Pap smear, Pap test, cervical smear, or smear test) is a screening test used in gynecology to detect premalignant and malignant (cancerous) processes in the ectocervix. Significant changes can be treated, thus preventing cervical cancer. An anal Pap smear is an adaptation of the procedure to screen and detect anal cancers.

The test aims to detect potentially pre-cancerous changes (called cervical intraepithelial neoplasia (CIN) or cervical dysplasia), which are usually caused by sexually transmitted human papillomaviruses (HPVs). The test remains an effective, widely used method for early detection of pre-cancer and cervical cancer. The test may also detect infections and abnormalities in the endocervix and endometrium.

It is generally recommended that females who have had sex seek regular Pap smear testing. The patient may also be referred for HPV DNA testing, which can serve as an adjunct to Pap testing.

Results

In the United States, most Pap results are normal, however about 2-3 million abnormal Pap smear results are found each year. Most abnormal results are mildly abnormal (ASC-US (typically 2-5% of Pap results) or LSIL (about 2% of results)), indicating HPV infection.

Typically about 0.5% of Pap results are HSIL, and less than 0.5% of results indicate cancer; typically 0.2 to 0.8% of results indicate ASCUS.

• Atypical glandular cells (AGC)
• Atypical squamous cells of undetermined significance (ASCUS)
• Atypical squamous cells of undetermined significance (ASCUS)
• Atypical squamous cells - cannot exclude HSIL (ASC-H)
• Low grade squamous intraepithelial lesion (LGSIL or LSIL)
• High grade squamous intraepithelial lesion (HGSIL or HSIL)
• Squamous cell carcinoma

Effectiveness

Prior to the introduction of the Pap test, carcinoma of the cervix was a leading cause of death in women.

Failure of prevention of cancer by the Pap test can occur for many reasons, including not getting regular screening, lack of appropriate follow up of abnormal results, and sampling and interpretation errors. Adenocarcinoma of the cervix has not been shown to be prevented by Pap tests. In the UK, which has a Pap smear screening program, Adenocarcinoma accounts for about 15% of all cervical cancers

A medical practitioner performing 200 tests each year would prevent a death once in 38 years, while seeing 152 women with abnormal results, referring 79 for investigation, obtaining 53 abnormal biopsy results, and seeing 17 persisting abnormalities lasting longer than two years. At least one woman during the 38 years would die from cervical cancer despite being screened.

Technical aspects

Unstained cells cannot be visualized with light microscopy.

The sample is then screened by a specially trained and qualified cytotechnologist using a light microscope.

• sensitivity 72%

• specificity 94%

Liquid based monolayer cytology

Once placed into the vial, the sample is processed at the laboratory into a cell thin-layer, stained, and examined by light microscopy. The liquid sample has the advantage of being suitable for low and high risk HPV testing and reduced unsatisfactory specimens from 4.1% to 2.6%. Proper sample acquisition is crucial to the accuracy of the test; clearly, a cell that is not in the sample cannot be evaluated.

Studies of the accuracy of liquid based monolayer cytology report:

• sensitivity 61% to 66%
• specificity 82% to 91%

Some, but not all studies, report increased sensitivity from the liquid based smears.

Human papillomavirus testing

Studies of the accuracy of HPV testing report:

• sensitivity 88% to 91% (for detecting CIN 3 or higher) to 97% (for detecting CIN2+)
• specificity 73% to 79% (for detecting CIN 3 or higher) to 93% (for detecting CIN2+)

By adding the more sensitive HPV Test, the specificity may decline. Due to the liquid based pap smears having a false negative rate of 15-35%, the American College of Obstetricians and Gynecologists and American Society for Colposcopy and Cervical Pathology have recommended the use of HPV testing in addition to the pap smear in all women over the age of 30.

Regarding the role of HPV testing, randomized controlled trials have compared HPV to colposcopy. HPV testing appears as sensitive as immediate colposcopy while reducing the number of colposcopies needed. Randomized controlled trial have suggested that HPV testing could follow abnormal cytology or could precede cervical cytology examination.

"A statistically significant decline in the HPV positivity rate correlated with the lifetime number of Pap smears received."

Practical aspects

The physician or operator collecting a sample for the test inserts a speculum into the patient's vagina, to obtain a cell sample from the cervix. Pap smears can be performed during a woman's menstrual period, especially if the physician is using a liquid-based test; if bleeding is extremely heavy, endometrial cells can obscure cervical cells, and it is therefore inadvisable to have a pap smear if bleeding is excessive. As abnormal endocervical cells may be sampled, those examining them are taught to recognize them.

The endometrium is not directly sampled with the device used to sample the ectocervix. Cells may exfoliate onto the cervix and be collected from there, so as with endocervical cells, abnormal cells can be recognised if present but the Pap Test should not be used as a screening tool for endometrial malignancy.

Gallery

pap test normal

pap test atropy




pap test endocervical cells




pap test citolysis




pap test trichomonas

pap test abnormal

Cervical intraepithelial neoplasia

Cervical intraepithelial neoplasia (CIN), also known as cervical dysplasia, is the potentially premalignant transformation and abnormal growth (dysplasia) of squamous cells on the surface of the cervix.Most cases of CIN remain stable, or are eliminated by the host's immune system without intervention. However a small percentage of cases progress to become cervical cancer, usually cervical squamous cell carcinoma (SCC), if left untreated. The major cause of CIN is chronic infection of the cervix with the sexually transmitted human papillomavirus (HPV), especially the high-risk HPV types 16 or 18. Over 100 types of HPV have been identified. About a dozen of these types appear to cause cervical dysplasia and may lead to the development of cervical cancer. Other types cause warts.
The earliest microscopic change corresponding to CIN is dysplasia of the epithelial or surface lining of the cervix, which is essentially undetectable by the woman. Cellular changes associated with HPV infection, such as koilocytes, are also commonly seen in CIN. CIN is usually discovered by a screening test, the Papanicolaou or "Pap" smear. The purpose of this test is to detect the changes early, while it has not yet progressed to invasive carcinoma, and is easier to cure. An abnormal Pap smear may lead to a recommendation for colposcopy of the cervix, during which the cervix is examined under magnification. A biopsy is taken of any abnormal appearing areas. Cervical dysplasia can be diagnosed by biopsy.

Grades

Depending on several factors such as the type of HPV and the location of the infection, CIN can start in any of the three stage, and can either progress to the next grade, or regress.
CIN is classified in grades:

• CIN1 (Grade I), the least risky type, represents only mild dysplasia, or abnormal cell growth. This corresponds to a low grade squamous intraepithelial lesion (LGSIL or LSIL) result on a Pap test. It is confined to the basal 1/3 of the epithelium. This corresponds to infection with HPV, and typically will be cleared by immune response in a year or so, though can take several years to clear.

• CIN2/3 correspond to high grade squamous intraepithelial lesions (HSIL). Sometimes this is further divided:

o CIN2 (Grade II): Moderate dysplasia confined to the basal 2/3 of the epithelium

o CIN3 (Grade III): Severe dysplasia that spans more than 2/3 of the epithelium, and may involve the full thickness. This lesion may sometimes also be referred to as cervical carcinoma in situ.

Normal cervical epithelium (H&E stain).



Grade I CIN.



Grade II CIN.



Grade III CIN.





Prevalence

Between 250,000 and 1 million American women are diagnosed with CIN annually. Women can develop CIN at any age, however, women generally develop it between the ages of 25 to 35. If caught early, CIN is usually curable.


Risk Factors

Some risk factors that have been found to be important in developing CIN are:

• Women who begin to have sex at an early age

• Women who have multiple sexual partners

• Women who have sexual partners who have had multiple sexual partners

• Women who become infected by a higher risk types of HPV, such as 16, 18, 31 or 45.

• Women who belong to a lower socioeconomic group (thought to be related to beginning intercourse at an earlier age)

• Women who smoke

• Women who are immunodeficient


Progression

Cases of CIN are thought by some to progress through these stages toward cancer in a linear fashion.
However most CIN spontaneously regress. About 50% of CIN 2 will regress within 2 years without treatment. Progression to cancer typically takes 15 (3 to 40) years. Also, evidence suggests that cancer can occur without first detectably progressing through these stages and that a high grade intraepithelial neoplasia can occur without first existing as a lower grade.
It is thought that the higher risk HPV infections, have the ability to inactivate tumor suppressor genes such as the p53 gene and the RB gene, thus allowing the infected cells to grow unchecked and accumulate successive mutations, eventually leading to cancer.

Treatment

In many cases, CIN will regress without treatment. A diet rich in fruits and vegetables, smoking avoidance and condom use increase regression of cervical dysplasia.
CIN is curable, although the lifetime recurrence rate is 20%. Methods used to treat CIN require removal or destruction of the surface cells of the cervix. These methods include cryocautery, electrocautery, laser cautery, LEEP, and cervical conization. Therapeutic vaccines are also in development.

CERVIX CANCER

Schematic frontal view of female anatomy
1: fallopian tube, 2: bladder, 3: pubic bone, 4: g-spot, 5: clitoris, 6: urethra, 7: vagina, 8: ovary, 9: sigmoid colon, 10: uterus, 11: fornix, 12: cervix, 13: rectum, 14: anus
Latin	cervix uteri
Gray's	subject #268 1259
Artery	vaginal artery, uterine artery
Precursor	Müllerian duct
MeSH	Cervix+uteri
Dorlands/Elsevier	cervix uteri

The cervix (or neck of the uterus) is the lower, narrow portion of the uterus where it joins with the top end of the vagina. It is cylindrical or conical in shape and protrudes through the upper anterior vaginal wall. Approximately half its length is visible with appropriate medical equipment; the remainder lies above the vagina beyond view. It is occasionally called "cervix uteri". Cervix means neck in Latin.

Anatomy

Ectocervix

The portion projecting into the vagina is referred to as the portio vaginalis or ectocervix. On average, the ectocervix is 3 cm long and 2.5 cm wide. It has a convex, elliptical surface and is divided into anterior and posterior lips.

External os

The ectocervix's opening is called the external os. The size and shape of the external os and the ectocervix varies widely with age, hormonal state, and whether the woman has had a vaginal birth. In women who have not had a vaginal birth the external os appears as a small, circular opening. In women who have had a vaginal birth, the ectocervix appears bulkier and the external os appears wider, more slit-like and gaping.

Endocervical canal

The passageway between the external os and the uterine cavity is referred to as the endocervical canal. It varies widely in length and width, along with the cervix overall. Flattened anterior to posterior, the endocervical canal measures 7 to 8 mm at its widest in reproductive-aged women.

Internal os

The endocervical canal terminates at the internal os which is the opening of the cervix inside the uterine cavity.

Cervical crypts

There are pockets in the lining of the cervix known as cervical crypts. They function to produce cervical fluid.^[

Histology

The epithelium of the cervix is varied. The ectocervix (more distal, by the vagina) is composed of nonkeratinized stratified squamous epithelium The endocervix (more proximal, within the uterus) is composed of simple columnar epithelium.

The area adjacent to the border of the endocervix and ectocervix is known as the transformation zone. The Transformation zone undergoes metaplasia numerous times during normal life. When the endocervix is exposed to the harsh acidic environment of the vagina it undergoes metaplasia to squamous epithelium which is better suited to the vaginal environment. Similarly when the ectocervix enters the less harsh uterine area it undergoes metaplasia to become columnar epithelium.

Times in life when this metaplasia of the transformation zone occ

CERVICAL CANCER

Cervical cancer
Classification and external resources


Histopathologic image (H&E stain) of carcinoma in situ, stage 0.
ICD-10 : C53

ICD-9 : 180

OMIM : 603956

DiseasesDB : 2278

MedlinePlus : 000893

eMedicine : med/324 radio/140

MeSH : D002583

This large squamous carcinoma (bottom of picture) has obliterated the cervix and invaded the lower uterine segment. The uterus also has a round leiomyoma up higher.


Cervical cancer is malignant cancer of the cervix uteri or cervical area.
Treatment of high grade changes can prevent the development of cancer. In developed countries, the widespread use of cervical screening programs has reduced the incidence of invasive cervical cancer by 50% or more.
Human papillomavirus (HPV) infection is a necessary factor in the development of nearly all cases of cervical cancer. HPV vaccine effective against the two strains of HPV that cause the most cervical cancer has been licensed in the U.S. and the EU. These two HPV strains together are currently responsible for approximately 70% of all cervical cancers. Since the vaccine only covers some high-risk types, women should seek regular Pap smear screening, even after vaccination.




Signs and symptoms

The early stages of cervical cancer may be completely asymptomatic. Also, moderate pain during sexual intercourse and vaginal discharge are symptoms of cervical cancer.


Causes

Human papillomavirus infection
The most important risk factor in the development of cervical cancer is infection with a high-risk strain of human papillomavirus. Types 16 and 18 are generally acknowledged to cause about 70% of cervical cancer cases. Together with type 31, they are the prime risk factors for cervical cancer.
Genital warts are caused by various strains of HPV which are usually not related to cervical cancer.
The medically accepted paradigm, officially endorsed by the American Cancer Society and other organizations, is that a patient must have been infected with HPV to develop cervical cancer, and is hence viewed as a sexually transmitted disease, but most women infected with high risk HPV will not develop cervical cancer.


Cofactors

The American Cancer Society provides the following list of risk factors for cervical cancer: human papillomavirus (HPV) infection, smoking, HIV infection, chlamydia infection, dietary factors, hormonal contraception, multiple pregnancies, exposure to the hormonal drug diethylstilbestrol (DES) and a family history of cervical cancer. T


Biopsy procedures

While the pap smear is an effective screening test, confirmation of the diagnosis of cervical cancer or pre-cancer requires a biopsy of the cervix.

Cervical intraepithelial neoplasia, the precursor to cervical cancer, is often diagnosed on examination of cervical biopsies by a pathologist.

• adenocarcinoma (about 15% of cervical cancers in the UK)
• adenosquamous carcinoma
• small cell carcinoma

For premalignant dysplastic changes, the CIN (cervical intraepithelial neoplasia) grading is used

Staging

The TNM staging system for cervical cancer is analogous to the FIGO stage.

• Stage I - limited to the cervix

• Stage II - invades beyond cervix


Treatment

Due to the possible risk of cancer spread to the lymph nodes in stage 1b cancers and some stage 1a cancers, the surgeon may also need to remove some lymph nodes from around the uterus for pathologic evaluation.

According to the US National Cancer Institute's 2005 Health Information National Trends survey, only 40% of American women surveyed had heard of human papillomavirus (HPV) infection and only 20% had heard of its link to cervical cancer.

Screening

The widespread introduction of the Papanicolaou test, or Pap smear for cervical cancer screening has been credited with dramatically reducing the incidence and mortality of cervical cancer in developed countries.
Until recently the Pap smear has remained the principal technology for preventing cervical cancer.
The HPV test is a newer technique for cervical cancer triage which detects the presence of human papillomavirus infection in the cervix. Since more than 99% of invasive cervical cancers worldwide contain HPV, some researchers recommend that HPV testing be done together with routine cervical screening.
HPV testing can reduce the incidence of grade 2 or 3 cervical intraepithelial neoplasia or cervical cancer detected by subsequent screening tests among women 32-38 years old according to a randomized controlled trial.

Together, HPV types 16 and 18 currently cause about 70% of cervical cancer cases. HPV types 6 and 11 cause about 90% of genital wart cases.

Higher levels of vegetable consumption were associated with a 54% decrease risk of HPV persistence.

Subjects in the lowest serum retinol quartile were at increased risk of CIN I compared with women in the highest quartile

A statistically significantly lower level of alpha-tocopherol was observed in the blood serum of HPV-positive patients with cervical intraepithelial neoplasia.

A 56% reduction in HPV persistence risk was observed in women with the highest plasma [lycopene] concentrations compared with women with the lowest plasma lycopene concentrations.

Fish oil

In a 1999 study, Docosahexaenoic acid inhibited growth of HPV16 immortalized cells.

Prognosis depends on the stage of the cancer.
With treatment, 80 to 90% of women with stage I cancer and 50 to 65% of those with stage II cancer are alive 5 years after diagnosis. Only 25 to 35% of women with stage III cancer and 15% or fewer of those with stage IV cancer are alive after 5 years.

Recurrent cervical cancer detected at its earliest stages might be successfully treated with surgery, radiation, chemotherapy, or a combination of the three. Thirty-five percent of patients with invasive cervical cancer have persistent or recurrent disease after treatment.
Average years of potential life lost from cervical cancer are 25.3 (SEER Cancer Statistics Review 1975-2000, National Cancer Institute (NCI)).
Regular screening has meant that pre cancerous changes and early stage cervical cancers have been detected and treated early. Figures suggest that cervical screening is saving 5,000 lives each year in the UK by preventing cervical cancer.
About 1,000 women per year die of cervical cancer in the UK.

Epidemiology

Worldwide, cervical cancer is the fifth most deadly cancer in women. Among gynecological cancers it ranks behind endometrial cancer and ovarian cancer. The incidence of new cases of cervical cancer in the United States was 7 per 100,000 women in 2004.

In Canada, an estimated 1,300 women will be diagnosed with cervical cancer in 2008 and 380 will die.

History

• 400 BCE - Hippocrates: cervical cancer incurable

• 1976 - Zur Hausen and Gisam: found HPV DNA in cervical cancer and warts


Epidemiologists working in the early 20th century noted that:

1. Cervical cancer was common in female sex workers.