profile/2360PW.jpg

Lana

Cervical Intraepithelial Neoplasia (CIN)

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. One of the most significant advances in the therapy of neoplasia has been the realization that cervical carcinoma arises from precursor lesions. Most cervical cancer is the end stage of continuum of progressively more atypical changes in which one stage merges imperceptibly with the next. The first and apparently earliest change is the appearance of atypical cells in the basal layers of the squamous epithelium, but nonetheless with preexistence of normal differentiation towards the prickle and keratinizing cell layers (Robbins and Cotran, PATHOLOGIC BASIS OF DISEASE, 7th edition, pg 718-721, ISBN 9781416029731).

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.  Dysplasia, mean  “bad molding’’ or, in more scientifically terms, disordered development.  CIN is dysplastic changes beginning at the squamo-columnar junction in the uterine cervix that may be precursor of squamous cell carcinoma.


NORMAL GROSS ANATOMY OF CERVIX

The cervix of the uterus is cylindrical, relatively narrow inferior third of the uterus, approximately 2.5 cm long in an adult non pregnant woman. For descriptive purposes, two parts are described: a supravaginal part between the isthmus and the vagina, and a vaginal part, which protrudes into the vagina. The rounded vaginal part surrounds the external os of the uterus and is surrounded in turn by a narrow recess, the vaginal fornix. The spravaginal part is separated from the bladder anteriorly by loose connective tissues and from the rectum posteriorly by the rectouterine pouch.

The slit-like uterine cavity, is approximately 6 cm in length from the external os to the wall of the fundus. The uterine horns are the superolateral regions of the uterine cavity, where the uterine tube enter. The uterine cavity continues inferiorly as the cervical canal. The fusiform canal extends from a narrowing inside the isthmus of the uterine body, the anatomical internal os, through the supravaginal and vaginal part of the cervix, communicating with the lumen of the vagina through the external os. The uterine cavity (in particular, the cervical canal) and the lumen of the vagina together constitute the birth canal through with fetus passes at the end of the gestation. (Clinically oriented anatomy by Moore, Dalley & Agur, 6th edition, pg-385, ISBN- 9788184731835).

The blood supply to the cervix is by the descending branch of the uterine artery and drains into uterine vein. The pelvic splanchnic nerves emerges as S2-S3, transmit the sensation of pain from the cervix to the brain. The nerves travel along the uterosacral ligaments which pass from the uterus to the anterior sacrum. The lymphatic drainage is through internal iliac nodes. the embryonic origin of the cervix is from paramesonephric or mullerian ducts which develop around 6 weeks of emryogenesis.


DIAGNOSING AND GRADING OF CIN BY HISTOPATHOLOGY

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.

Cellular changes associated with HPV infection, such as koilocytes, are also commonly seen in CIN. CIN is usually discovered by a screening test, the Papanicolau or "Pap" smear. The purpose of this test is to detect potentially precancerous changes. Pap smear results may be reported using the Bethesda System. An abnormal Pap smear result 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. (Cervical intraepithelial neoplasia, Wikipedia the free encyclopedia.webarchive)

Dysplasia is subdivided into mild, moderate and severe forms to carcinoma in situ, depending on the extend of involvement of epithelium. Grade 1, mild dysplasia involving the lower one third or less of epithelial thickness. Grade2, moderate dysplasia with one-third to two-third involvements. Grade 3, severe dysplasia or carcinoma in situ with two-third to full thickness involvement.

Grade 1 may progress to next higher grade during a ten-year follow-up period. Grade 2 to grade 3 and so on. 3In one study, 50% of women with CIN 1 progressed to grade 3 and 28% either progressed to grade 2 or remained at grade1 for 9 years. The more severe the grade od dysplasia, the shorter is the time span for the development of carcinoma in situ. The rate of progression, however, are by no means uniform, and in general it is difficult, if not impossible for a clinician using any technique to predict the outcome in an individual patient. Careful follow-up is the only recourse. Regression does occur, but only in mild lesions and flat condylomas.

In CIN 1 there is good maturation with minimal nuclear abnormalities and few mitotic figures . Undifferentiated cells are confined to the deeper layers (lower third) of the epithelium. Mitotic figures are present, but not very numerous. Cytopathic changes due to HPV infection may be observed in the full thickness of the epithelium.

CIN 2 is characterized by dysplastic cellular changes mostly restricted to the lower half or the lower two-thirds of the epithelium, with more marked nuclear abnormalities than in CIN 1. Mitotic figures may be seen throughout the lower half of the epithelium.

In CIN 3, differentiation and stratification may be totally absent or present only in the superficial quarter of the epithelium with numerous mitotic figures. Nuclear abnormalities extend throughout the thickness of the epithelium. Many mitotic figures have abnormal forms.

A close interaction between cytologists, histopathologists and colposcopists improves reporting in all three disciplines. This particularly helps in differentiating milder degrees of CIN from other conditions with which there can be confusion.







Figure 22-20 A, Histology of CIN I (flat condyloma), illustrating the prominent koilocytotic atypia in the upper epithelial cells, as evidenced by the prominent perinuclear halos. B, Nucleic

acid in situ hybridization of the same lesion for HPV nucleic acids. The blue staining denotes HPV DNA, which is typically most abundant in the koilocytes. C, Diffuse immunostaining of

CIN II for Ki-67, illustrating widespread deregulation of cell cycle controls. D, Up-regulation of p161NK4 (seen as intense immunostaining) characterizes high-risk HPV infections

(http://screening.iarc.fr).

RISK FACTORS

Epidemiological studies have identified a number of risk factors that contribute to the development of cervical cancer precursors and cervical cancer. These include infection with certain oncogenic types of human papillomaviruses (HPV), sexual intercourse at an early age, multiple sexual partners, multiparity, long-term oral contraceptive use, tobacco smoking, low socioeconomic status, infection with Chlamydia trachomatis, micronutrient deficiency and a diet deficient in vegetables and fruits.

HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 68 are strongly associated with CIN and invasive cancer. Persistent infection with one or more of the above oncogenic types is considered to be a necessary cause for cervical neoplasia . The pooled analysis of results from a multicentre case-control study conducted by the International Agency for Research on Cancer revealed relative risks (RR) ranging from 17 in Colombia to 156 in the Philippines, with a pooled RR of 60 (95% confidence interval: 49-73) for cervical cancer. The association was equally strong for squamous cell carcinoma (RR: 62) and adenocarcinoma of the cervix (RR: 51). HPV DNA was detected in 99.7% of 1000 evaluable cervical cancer biopsy specimens obtained from 22 countries. HPV 16 and 18 are the main viral genotypes found in cervical cancers worldwide. (International Agency for research on cancer, WHO, Chapter 2: An introduction to CIN, 2013).

HPV infection is transmitted through sexual contact and the risk factors therefore are closely related to sexual behaviour (e.g., lifetime number of sexual partners, sexual intercourse at an early age). In most women, HPV infections are transient.


 
TREATMENT

Treatment for CIN 1, which is mild dysplasia, is not recommended if it lasts fewer than 2 years. Usually when a biopsy detects CIN 1 the woman has an HPV infection which may clear on its own within 12 months, and thus it is instead followed for later testing rather than treated.

Treatment for higher grade CIN involves removal or destruction of the neoplastic cervical cells by cryocautery, electrocautery, laser cautery, loop electrical excision procedure (LEEP), or cervical conization. Therapeutic vaccines are currently undergoing clinical trials. The lifetime recurrence rate of CIN is about 20%, but it isn't clear what proportion of these cases are new infections rather than recurrences of the original infection.

Surgical treatment of CIN lesions is associated with an increased risk of infertility or subfertility, with an odds ratio of approximately 2 according to a case-control study. As long as patients can be followed by means of periodic Papanicolaou smears of colposcopy, much can be gained from a conservative and individualized approach. (Robbins and Cotran PATHOLOGIC BASIS OF DISEASE, 7th edition, pg 731-733, ISBN 9781416029731).


SUMMARY

Most cervical cancer is the end stage of continuum of progressively more atypical changes in which one stage merges imperceptibly with the next. The first and apparently earliest change is the appearance of atypical cells in the basal layers of the squamous epithelium, but nonetheless with preexistence of normal differentiation towards the prickle and keratinizing cell layers

CIN is dysplastic changes beginning at the squamo-columnar junction in the uterine cervix that may be precursor of cervical cancer. Dysplasia is subdivided into mild, moderate and severe forms to carcinoma in situ, depending on the extend of involvement of epithelium. Grade 1, mild dysplasia involving the lower one third or less of epithelial thickness. Grade2, moderate dysplasia with one-third to two-third involvements. Grade 3, severe dysplasia or carcinoma in situ with two-third to full thickness involvement.

A number of risk factors that contribute to the development of cervical cancer precursors (CIN) and cervical cancer, include infection with certain oncogenic types of human papillomaviruses (HPV), sexual intercourse at an early age, multiple sexual partners, multiparity, long-term oral contraceptive use, tobacco smoking, low socioeconomic status, infection with Chlamydia trachomatis, micronutrient deficiency and a diet deficient in vegetables and fruits.

Treatment of CIN involves removal or destruction of the neoplastic cervical cells by cryocautery, electrocautery, laser cautery, loop electrical excision procedure (LEEP), or cervical conization. Therapeutic vaccines are currently undergoing clinical trials. A close interaction between cytologists, histopathologists and colposcopists improves reporting in all three disciplines. This particularly helps in differentiating milder degrees of CIN from other conditions with which there can be confusion.


REFERENCE

1.    Cervical intraepithelial neoplasia, Wikipedia the free encyclopedia.webarchive

2.    Clinically oriented anatomy by Moore, Dalley & Agur, 6th edition, pg-385, ISBN- 9788184731835.

3.    "Fertility and early pregnancy outcomes after treatment for cervical intraepithelial neoplasia: systematic review and meta-analysis". BMJ (Clinical research ed.) pg-349, (28 October 2014).

4.    International Agency for research on cancer, WHO, Chapter 2: An introduction to CIN, 2013

5.    http://screening.iarc.fr

6.    Robbins and Cotran PATHOLOGIC BASIS OF DISEASE, 7th edition, pg 718-721, ISBN 9781416029731.

7.    Robbins and Cotran PATHOLOGIC BASIS OF DISEASE, 7th edition, pg 731-733, ISBN 9781416029731).

 

 

 

 

profile/2360PW.jpg

Lana

PLEURAL EFFUSION

Background

Approximately 1 million pleural effusions are diagnosed in the United States each year. The clinical importance of pleural effusions ranges from incidental manifestations of cardiopulmonary diseases to symptomatic inflammatory or malignant diseases, as shown in the image below, requiring urgent evaluation and treatment.



Large, malignant, right-sided pleural effusion.



Other eMedicine articles on pleural effusion include Pleural Effusion (from Emergency Medicine), Effusion, Pleural (from Radiology), Pleural Effusion (from Pediatrics), and Parapneumonic Pleural Effusions and Empyema Thoracis.

Pathophysiology

The normal pleural space contains approximately 1 mL of fluid, representing the balance between (1) hydrostatic and oncotic forces in the visceral and parietal pleural vessels and (2) extensive lymphatic drainage. Pleural effusions result from disruption of this balance.

Clinical

History

Dyspnea is the most common symptom associated with pleural effusion and is related more to distortion of the diaphragm and chest wall during respiration than to hypoxemia. In many patients, drainage of pleural fluid alleviates symptoms despite limited improvement in gas exchange.

Underlying intrinsic lung or heart disease, obstructing endobronchial lesions, or diaphragmatic paralysis can also cause dyspnea, especially after coronary artery bypass surgery. Drainage of pleural fluid may partially relieve symptoms but, as importantly, may allow the underlying disease to be recognized on repeat chest radiographs.

Less common symptoms from pleural effusions include mild nonproductive cough or chest pain. Other symptoms may suggest the etiology of the pleural effusion. For example, more severe cough or production of purulent or bloody sputum suggests an underlying pneumonia or endobronchial lesion. Constant chest wall pain may reflect chest wall invasion by bronchogenic carcinoma or malignant mesothelioma. Pleuritic chest pain suggests either pulmonary embolism or an inflammatory pleural process. Persistent systemic toxicity evidenced by fever, weight loss, and inanition suggests empyema.

Physical

Physical findings, which do not usually manifest until pleural effusions exceed 300 mL, include the following:

Decreased breath sounds
Dullness to percussion
Decreased tactile fremitus
Egophony (E-to-A change)
Pleural friction rub
Mediastinal shift away from the effusion: This is observed with effusions of greater than 1000 mL. Displacement of the trachea and mediastinum toward the side of the effusion is an important clue to obstruction of a lobar bronchus by an endobronchial lesion, which can be due to malignancy or, less commonly, a nonmalignant cause such as a foreign body.
Causes

Transudates are usually ultrafiltrates of plasma in the pleura due to imbalance in hydrostatic and oncotic forces in the chest. However, they can also be caused by the movement of fluid from peritoneal spaces or by iatrogenic infusion into the pleural space from misplaced or migrated central venous catheters or nasogastric feeding tubes. Transudates are caused by a small, defined group of etiologies, including the following:

Congestive heart failure
Cirrhosis (hepatic hydrothorax)
Atelectasis (which may be due to malignancy or pulmonary embolism)
Hypoalbuminemia
Nephrotic syndrome
Peritoneal dialysis
Myxedema
Constrictive pericarditis
In contrast, exudates are produced by a variety of inflammatory conditions and often require more extensive evaluation and treatment. Exudates arise from pleural or lung inflammation, from impaired lymphatic drainage of the pleural space, and from transdiaphragmatic movement of inflammatory fluid from the peritoneal space. The more common causes of exudates include the following:

Parapneumonic causes
Malignancy (carcinoma, lymphoma, mesothelioma)
Pulmonary embolism
Collagen-vascular conditions (rheumatoid arthritis, lupus)
Tuberculous
Asbestos exposure  
Pancreatitis
Trauma
Postcardiac injury syndrome
Esophageal perforation
Radiation pleuritis
Drug use
Chylothorax
Meigs syndrome
Sarcoidosis
Yellow nail syndrome
Differential Diagnoses

Other Problems to Be Considered

Chronic pleural thickening
Malignant mesothelioma

Workup

Laboratory Studies

Thoracentesis should be performed for new and unexplained pleural effusions when sufficient fluid is present to allow a safe procedure. Observation of pleural effusion(s) is reasonable when benign etiologies are likely, such as in the setting of overt congestive heart failure, viral pleurisy, or recent thoracic or abdominal surgery.

Laboratory testing helps distinguish pleural fluid transudates from exudates; however, certain types of exudative pleural effusions might be suspected simply by observing the gross characteristics of the fluid obtained during thoracentesis. Note the following:

Frankly purulent fluid indicates an empyema.
A putrid odor suggests an anaerobic empyema.
A milky, opalescent fluid suggests a chylothorax, resulting most often from lymphatic obstruction by malignancy or thoracic duct injury by trauma or surgical procedures.
Grossly bloody fluid may result from trauma, malignancy, postpericardiotomy syndrome, and asbestos-related effusion, and this indicates the need for a spun hematocrit test of the sample. A pleural fluid hematocrit level of more than 50% of the peripheral hematocrit level defines a hemothorax, which often requires tube thoracostomy.
Classification of transudates and exudates

The initial diagnostic consideration is distinguishing transudates from exudates. Although a number of chemical tests have been proposed to differentiate pleural fluid transudates from exudates, the tests first proposed by Light et al have become the criterion standards.[1 ]

The fluid is considered an exudate if any of the following apply: 

Ratio of pleural fluid to serum protein greater than 0.5
Ratio of pleural fluid to serum lactate dehydrogenase (LDH) greater than 0.6
Pleural fluid LDH greater than two thirds of the upper limits of normal serum value
These criteria require simultaneous measurement of pleural fluid and serum protein and LDH. However, a meta-analysis of 1448 patients suggested that the following combined pleural fluid measurements might have sensitivity and specificity comparable to the criteria from Light et al for distinguishing transudates from exudates[2 ]:

Pleural fluid LDH value greater than 0.45 of the upper limit of normal serum values
Pleural fluid cholesterol level greater than 45 mg/dL
Pleural fluid protein level greater than 2.9 g/dL
Clinical judgment is required when pleural fluid test results fall near the cutoff points.

The criteria from Light et al and these alternative criteria identify nearly all exudates correctly, but they misclassify approximately 20-25% of transudates as exudates, usually in patients on long-term diuretic therapy for congestive heart failure because of the concentration of protein and LDH within the pleural space due to diuresis.[3 ]

Using the criterion of serum minus pleural protein concentration level of less than 3.1 g/dL, rather than a serum/pleural fluid ratio of greater than 0.5, more correctly identifies exudates in these patients.[4 ]

Although pleural fluid albumin is not typically measured, a gradient of serum albumin to pleural fluid albumin less than 1.2 g/dL also identifies an exudate in such patients.[5 ]

In addition, studies suggest that pleural fluid levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) are elevated in effusions due to congestive heart failure.[6 ]More recently, elevated pleural NT-proBNP was shown to out-perform pleural fluid BNP as a marker of heart failure–related effusion.[7 ]Thus, at institutions where this test is available, high pleural levels of NT-proBNP (defined in different studies as >1300-4000 ng/L) may help to confirm heart failure as the cause of an otherwise idiopathic chronic effusion.

Pleural fluid LDH

Pleural fluid LDH levels greater than 1000 IU/L suggest empyema, malignant effusion, rheumatoid effusion, or pleural paragonimiasis. Pleural fluid LDH levels are also increased in effusions from Pneumocystis jirovecii pneumonia; the diagnosis is suggested by a pleural fluid/serum LDH ratio greater than 1, with a pleural fluid/serum protein ratio less than 0.5.

Pleural fluid glucose and pH

In addition to these tests, glucose and pleural fluid pH should be measured during the initial thoracentesis in most situations.

A low pleural glucose concentration (30-50 mg/dL) suggests malignant effusion, tuberculous pleuritis, esophageal rupture, or lupus pleuritis, and a very low pleural glucose concentration (ie,