Pathology CASE 10

CASE 10

INTRODUCTION

A 21-year-old nulliparous woman complains of lower abdominal "heaviness." She takes an oral contraceptive and is in a monogamous relationship. On examination, she has a normal-sized, nontender uterus, and a 9-cm right adnexal mass is palpated. Her pregnancy test is negative. On sonography, the mass appears cystic and solid.

· What is the most likely diagnosis?

· What are some of the histologic findings expected in this mass?

ANSWERS TO CASE 10: Ovarian Teratoma

Summary: A 21-year-old nulliparous woman has a 9-cm right adnexal mass that on sonography appears cystic and solid.

· Most likely diagnosis: Benign cystic teratoma of the ovary.

· Expected histologic findings in this mass: Any tissue may be found, but the most common are sebum, skin, hair, teeth, thyroid, and neurologic tissues.

CLINICAL CORRELATION

Introduction

This young woman has an ovarian mass that on ultrasound has cystic and solid components, a classic presentation of a benign cystic teratoma (dermoid cyst) of the ovary. Although benign cystic teratomas are often asymptomatic, larger dermoids (as in this case) can present with pelvic pain, pressure, fullness, or dyspareunia. The patient's pregnancy test was reported as negative; however, in rare cases, degenerating ectopic pregnancies can be missed with urine human chorionic gonadotropin (hCG) assays because of the low sensitivity of urine pregnancy tests in the presence of very low (<25 mIU/mL) serum hCG levels. The fact that the patient is engaged in a monogamous relationship should decrease the risks of her contracting gonorrhea or Chlamydia, hence decreasing the possibility of pelvic inflammatory disease and tuboovarian abscess (TOA). The patient also gives a history of oral contraceptive (OC) use, which also serves to decrease the risk of pelvic inflammatory disease and/or TOA. Oral contraceptives also greatly decrease the likelihood of the mass being a physiologic ovarian mass (follicular cyst, hemorrhagic corpus luteum cyst, etc.). The ultrasound shows a complex (both cystic and solid) ovarian mass, which also is not consistent with an abscess or a physiologic ovarian or paraovarian cyst.

Although some disagreement exists over the timing and indications for surgery in complex masses under 6 cm or simple cysts of any size, a 9-cm complex ovarian mass almost always needs to be explored surgically. This is due primarily to the small but not insignificant risk of malignancy. Upon confirmation of benign intraoperative findings, efforts should be directed at salvaging all normal tissue from the affected ovary and removing only that tissue which has undergone neoplastic degeneration.

Approach to Ovarian Neoplasm

Definitions

Tuboovarian abscess: An abscess formed within the adnexal space consisting of ovary, fallopian tube, and matted bowel caused by untreated or inadequately treated pelvic inflammatory disease.

Endometrioma: A large (6- to 8-cm) loculated collection of endometrial tissue that can develop in the pelvis in females with endometriosis. As this tissue degenerates, it turns brownish in color and is known as a chocolate cyst.

Struma ovarii: A benign teratoma in which functional thyroid tissue is the predominant histologic finding. Approximately 2 to 3 percent of teratomas are classified as struma ovarii. Thyrotoxicosis is clinically apparent in 5 percent of these cases.

Ovarian torsion: A condition in which the ovary twists on its attachment to the infundibulopelvic ligament, thus interrupting ovarian blood supply. This usually is seen in conjunction with pathologic enlargement of the ovary and can be dynamic (intermittent) in nature or complete; the latter results in infarction and necrosis of the affected ovary.

Table 10-1. DIFFERENTIAL DIAGNOSES OF A PELVIC MASS

Full bladder

Intrauterine or extrauterine pregnancy

Functional ovarian cysts (follicular or corpus luteum)

Tuboovarian abscess

Diverticular abscess

Appendiceal abscess

Matted bowel and/or omentum

Paratubal or paraovarian cyst

Stool in sigmoid colon

Leiomyomas (submucosal, subserosal, pedunculated, or intraligamentous)

Pelvic kidney

Mullerian abnormality (e.g., bicornuate uterus)

Benign or malignant ovarian tumors

Discussion

Although they may present in any decade of life, benign cystic teratomas are the most common ovarian neoplasm found in females under age 35 (excluding physiologic follicular and corpus luteum cysts) and are also the most common ovarian neoplasm found in pregnancy. Approximately 10 to 15 percent of all cases involve both ovaries. Table 10-1 lists the differential diagnoses of a pelvic mass, and Table 10-2 lists the categories of ovarian neoplasms.

Table 10-2. OVARIAN NEOPLASMS
Benign epithelial ovarian tumors
	Serous cystadenoma
	Mucinous cystadenoma
	Brenner tumor
Malignant epithelial ovarian tumors
	Serous cystadenocartcinoma
	Mucinous cystadenocarcinoma
	Endometroid adenocarcinoma
	Transitional cell carcinoma
Malignant germ cell tumors
	Dysgerminoma
	Endodermal sinus tumor
	Embryonal carcinoma
	Polyembryonal carcinoma
	Choriocarcinoma
	Teratoma (immature)
Benign germ cell tumors
	Benign cystic teratoma (dermoid)
Sex cord-stromal tumors
	Thecoma
	Sertoli-Leydig cell tumor
	Granulosa-theca cell tumor

Benign cystic teratomas arise from a single germ cell in the ovary and have a normal female karyotype (46,XX). Because of the pleuripotent nature of germ cells, teratomas can differentiate into tissues derived from all three embryologic cell lines (endoderm, ectoderm, and mesoderm). Thus, a "mature" teratoma often contains skin, fat, sebaceous glands, sweat glands, hair, smooth and striated muscle, cartilage, bone, teeth, neural tissue, and gastrointestinal tissue (see Figure 10-1). Functional thyroid tissue is found in approximately 12 percent of benign cystic teratomas, and rarely this tissue will proliferate into the predominant cellular element in the teratoma. This unique teratoma hence is referred to as struma ovarii and will secrete enough functional thyroid hormone to cause acute thyrotoxicosis in approximately 5 percent of cases.

Benign cystic teratomas are usually asymptomatic and are found most commonly during routine gynecologic screening or incidentally during unassociated surgical or radiographic procedures. Larger teratomas give rise to acute adnexal torsion in approximately 11 percent of cases. The increased risk of torsion with teratomas compared with other causes of ovarian enlargement is thought to be due to fat content, allowing the teratoma to "float" in the abdominal cavity instead of lodging against other structures. Other significant complications include secondary infection and acute hemorrhage with the potential for septic and/or hypovolemic shock. Rupture or perforation is seen in less than 5 percent of cases and occurs more frequently in association with pregnancy. When acute rupture occurs, spillage of the contents of the teratoma into the abdominal cavity often precipitates a surgical emergency, whereas more chronic leakage of contents can produce a severe chemical peritonitis that also requires surgical intervention. Malignant degeneration occurs in less than 2 percent of all recognized teratomas.

Other germ cell tumors include dysgerminomas, endodermal sinus tumors, and choriocarcinomas. These neoplasms usually occur in females under age 30 years. Dysgerminomas are rapidly growing and very radiosensitive and chemosensitive. Endodermal sinus tumors often secrete alpha-fetoprotein, whereas choriocarcinomas secrete human chorionic gonadotropin.

Epithelial tumors of the ovary most commonly affect females over age 30 years, particularly postmenopausal women. Malignant serous cystadenocarcinomas are the most common, usually presenting with ascites. Treatment includes surgical excision followed by combination chemotherapy. Mucinous tumors may become very large, sometimes exceeding 30 pounds in weight; their rupture can lead to chronic bouts of bowel obstruction (pseudomyxoma peritonei).

Stromal tumors of the ovary are often functional, secreting estrogen (granulosa-theca cell tumors) or androgens (Sertoli-Leydig cell tumors). These neoplasms can present as precocious puberty, postmenopausal bleeding, or hirsutism. They are usually solid tumors that are slow growing and rarely metastasize early. Surgery is the best treatment for these tumors.

Figure 10-1. Gross photograph of an ovarian teratoma. Note the hair. (Courtesy of Dr. Aaron Han, Reading, PA.)0

COMPREHENSION QUESTIONS

[10.1] A 58-year-old woman is noted to have bilateral adnexal masses on physical examination. Which of the following is most suggestive of these adnexal masses being malignant?

A. CT imaging revealing that they are primarily cystic

B. Elevation of the serum alkyline phosphatase level

C. Family history of lung cancer

D. The presence of ascites

E. The presence of low-grade fever

[10.2] A 25-year-old woman is noted to have a solid and cystic right ovarian mass measuring 10 cm on ultrasound. Which of the following is the most likely histologic subtype?

A. Serous

B. Mucinous

C. Brenner

D. Teratoma

E. Fibroma

[10.3] A 4-year-old girl is noted to have breast enlargement and vaginal bleeding. On physical examination, she is noted to have a 9-cm pelvic mass. Which of the following is the most likely etiology?

A. Cystic teratoma

B. Dysgerminoma

C. Endodermal sinus tumor

D. Granulosa cell tumor

E. Mucinous tumor

[10.4] A 44-year-old woman undergoes an exploratory lapartomy for suspected ovarian cancer. Upon removal of the right ovary, a frozen section reveals "signet ring" cells. Which of the following is the most likely etiology?

A. Dysgerminoma

B. Metastatic

C. Mucinous

D. Serous

E. Teratoma

ANSWERS

[10.1] D. The presence of ascites and ovarian masses is strongly associated with ovarian cancer. Other features of malignancy include solid ovarian masses, bilaterality, and lymphadenopathy.

[10.2] D. The benign cystic teratoma or dermoid cyst is the most common type of ovarian tumor in females younger than age 30 years. Dermoid cysts usually have solid and cystic components.

[10.3] D. This young girl has signs of precocious puberty. Thus, the adnexal mass is likely to be an estrogen-secreting granulosa-theca cell tumor. These low-grade malignancies are slow-growing so-called stromal cell tumors. The androgen-secreting tumors are usually Sertoli-Leydig cell tumors and may cause virilism.

[10.4] B. Signet ring cells suggest a Krukenberg tumor, usually metastatic from the gastrointestinal tract (stomach, colon) or breast. The mucin that fills the cell pushes the nucleus to the periphery of the cell, leading to the appearance of a signet ring.

PATHOLOGY PEARLS

· Benign cystic teratomas are the most common nonphysiologic ovarian tumor in females under age 35.

· Ten to 15 percent of all teratomas are bilateral.

· Ovarian torsion occurs frequently with teratomas.

· The most common ovarian cancers are epithelial in origin and usually occur in postmenopausal women. Surgical excision followed by combination chemotherapy is the best treatment.

· Ovarian cancer is associated with ascites.

· Granulosa-theca cell tumors often secrete estrogen, and Sertoli-Leydig cell tumors often secrete androgens.

· Metastatic tumors to the ovary may have a "signet ring" appearance on microscopy and are called Krukenberg tumors.

REFERENCES

Crum CP. The female genital tract: The gastrointestinal tract. In: Kumar V, Assas AK, Fausto N, eds. Robbins and Cotran pathologic basis of disease, 7th ed. Philadelphia: Elsevier Saunders, 2004:1092-1104.

Novak E, Hillard PA, Berek J. Novak's gynecology, 13th ed. Philadelphia: Lippincott Williams & Wilkins, 2002.

Stenchever MA, Droegmueller W, Herbst HR, Mishell D. Comprehensive gynecology, 4th ed. Philadelphia: Mosby, 2002.

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Copyright © 2006 by the McGraw-Hill Companies, Inc. All rights reserved.

Pathology CASE 9

CASE 9

INTRODUCTION

A 54-year-old woman notes a 6-month history of progressive vaginal discharge with an odor. She also has noted vaginal spotting after intercourse. She had gone through menopause 2 years earlier and took an oral contraceptive for 10 years. She has smoked one pack of cigarettes per day for 20 years. She denies a cough or dyspnea. She complains of right back pain and right leg swelling. The speculum examination shows a 4-cm irregular fungating mass arising from the cervix.

· What is the most likely diagnosis?

· What is the next step?

· What is the likely pathophysiology for this condition?

ANSWERS TO CASE 9: Cervical Cancer

Summary: A 54-year-old postmenopausal woman has a 6-month history of an odiferous vaginal discharge and postcoital spotting. She has smoked one pack of cigarettes per day for 20 years. She complains also of right back pain and right leg swelling. The speculum examination shows a 4-cm irregular fungating mass arising from the cervix.

· Most likely diagnosis: Cervical cancer.

· Next step: Biopsy of the lesion to confirm the diagnosis, followed by staging to assess the extent of the disease.

· Likely pathophysiology: Human papillomavirus.

CLINICAL CORRELATION

Introduction

This patient most likely has cervical cancer. Indications leading the clinician to the diagnosis in this case include the patient's risk factors and presenting symptoms. Her risk factors for cervical cancer include age, a history of oral contraceptive use, and a history of smoking. The presenting symptoms of malodorous vaginal discharge and postcoital bleeding are characteristic of cervical cancer. The history should guide the clinician to examine the cervix. In this case, a grossly visible lesion was seen on the cervix during speculum examination. The next step in management is to biopsy the lesion for a definitive diagnosis.

Approach to Cervical Dysplasia and Cancer

Definitions

Cervical intraepithelial neoplasia (CIN): Dysplastic growth and development of the epithelial cells of the cervix. Lesions may be defined by mild, moderate, or severe, or CIN I, CIN II, or CIN III (see Figure 9-1).

Human papillomavirus (HPV): A double-stranded DNA virus associated with condyloma, cervical intraepithelial lesions, and cervical cancer. Cellular changes seen in HPV infection include an expanded parabasal cell layer and koilocytes but normal maturation and mitoses. There are over 70 types of HPV, which have varying oncogenic capacities. High-risk HPV types are those most often associated with high-grade lesions and invasive cancer. These types include 16,18, 31, 39, 45, 56, 58, and 68.

Koilocyte: A viral expression of E4 protein that disrupts cytoplasmic keratin matrix in squamous cells and causes pleomorphism, hyperchromasia, perinuclear halos, and nuclear changes, including enlarged nuclei with abnormal edges, multinucleation, and variations in nuclear size.

Figure 9-1. Cervical epithelium showing normal, CIN I, CIN II, and CIN III.0

Discussion

Cervical cancer is the third most common cancer of the female lower reproductive system. More than 80 percent of cervical dysplasias and more than 90 percent of cervical cancers are associated with HPV infection. Because HPV is transmitted through sexual contact, many of the risk factors for cervical cancer involve behaviors that increase the risk of all sexually transmitted diseases. These risk factors include early intercourse, many sexual partners, high-risk sexual partners, infection with other sexually transmitted diseases, and immunosuppression by HIV infection. Relative risk factors may include oral contraceptive use, tobacco use, and immunodeficiency. Other possible risk factors are under investigation.

Cervical dysplasia is found most often in females in their twenties, whereas cervical cancers usually become evident in the fifth decade of life. The classic presentation of cervical malignancies includes abnormal bleeding and leukorrhea. The bleeding can range from blood streaking in a discharge or spotting to heavy bright red blood. Foul-smelling purulent leukorrhea is often present. Other symptoms, such as pelvic or leg pain, urinary or fecal material in the vagina, weight loss, and generalized weakness, are suggestive of advanced disease.

The squamocolumnar junction is where the squamous ectocervix abuts the columnar endocervix. Just distal to this junction there is an area of squamous metaplasia that is influenced by factors such menarche, pregnancy, local hormonal influences, infection, and trauma. As columnar epithelium is replaced by squamous cells, a new squamocolumnar junction is formed. The area between the old junction and the new junction is called the transformation zone. It is in this transformation zone that most cervical cancers arise.

Cervical cancer begins with infection of cervical epithelium by human papillomavirus. Most infections resolve spontaneously without progression to cancer. This suggests that viral infection alone is not responsible for cervical cancer and that other, undefined factors are involved in the pathogenesis. Additionally, there are many types of HPV that vary in oncogenic potential, with subtypes 16 and 18 being found most commonly in cervical caner.

Progression to dysplasia will occur if the viral genome is integrated into the nucleus of the cell under the influence of other factors that contribute to a favorable environment. Distinct cellular changes will occur, representing malignant transformation to low-grade cervical intraepithelial neoplasia (CIN I). A typical lesion will appear slightly raised or thickened with koilocytes in the upper and middle epithelial layers. Koilocytes are cells that have undergone cellular changes because of the presence of a virus. These cells are pleomorphic, hyperchromic, and multinucleated and have perinuclear halos. There are few if any mitotic figures and no atypical mitotic figures in CIN I, usually involving the lower third of the epithelium.

These low-grade CIN I lesions may regress spontaneously without treatment but may progress to higher-grade lesions. When atypical cells spread to between the lower 1/3 and 2/3 of the epithelium or the majority of the cells of the keratinizing layers, the lesion is defined as CIN II. These lesions demonstrate some areas of maturation but have areas of immature atypical koilocytic cells with a decreased nuclear to cytoplasmic ratio and increased numbers of mitotic figures (see Figure 9-2). Progression to CIN III involves the upper 1/3 of the epithelium by atypical cells with loss of maturation, an increase in hyperchromasia, and more mitotic figures with atypical mitoses. As the lesion progresses to squamous carcinoma in situ, the dysplastic cells may lose their cell walls and form syncytial-like groups. Many small round nuclei with scant cytoplasm can be seen. The majority of cells are atypical and are more hyperchromatic with coarse chromatin, a higher degree of pleomorphism, and increased atypical mitoses. Carcinoma in situ becomes invasive squamous cell carcinoma when atypical cells invade the basement membrane. Invasive carcinoma has wide variations of irregularly shaped cells and may have keratin pearls. There may also be evidence of necrosis, hemorrhage, and inflammatory cells.

The progression from CIN to cervical cancer is a slow process that usually occurs over several years. This allows many opportunities for screening before advanced-stage disease is evident. Most cases of cervical dysplasia are asymptomatic, and the diagnosis is made when a Pap smear reveals abnormal cytology. Good screening of asymptomatic patients, including a thorough history and physical, and routine Pap smears have led to a decreased incidence of cervical cancer. The role of the Pap smear is paramount in early detection of cervical dysplasia to afford timely treatment and avoid progression to invasive cervical cancer. Even after the development of cervical cancer, a Pap smear has an important role in detection because diagnosis early in the disease process may offer a better prognosis. Treatment of early cervical cancer offers a 95 percent cure rate, whereas more advanced stages often lead to death in more than a third of cases. This underscores the importance of diligent efforts by the physician in counseling patients to receive an annual Pap smear.

Figure 9-2. Microscopy of cervical dysplasia. (Courtesy of Dr. Margaret Uthman, Houston, TX.)0

COMPREHENSION QUESTIONS

[9.1] A 24-year-old woman is noted to have atypical cells on a Pap smear. Which of the following features most likely would indicate the need for further investigation of cervical biopsy?

A. HPV viral subtype revealing that type 16 is present

B. Presence of diabetes mellitus

C. Presence of endocervical cells

D. Presence of vulvar condylomata

E. Three lifetime sexual partners

[9.2] A 32-year-old woman is noted to have a 2-cm fungating lesion of the cervix. Which of the following is the best next step?

A. Application of tricyclic acetic acid (TCA)

B. Biopsy of the lesion

C. Pap smear of the cervix

D. Repeat examination after 6 months

[9.3] A hysterectomy specimen is performed, and the cervix is examined by the pathologist. The pathologist determines that the patient has CIN I. Which of the following is the most likely histologic finding?

A. Cells with enlarged nuclei and loss of polarity involving the upper third of the epithelium

B. Cells with enlarged nuclei involving the middle third of the epithelium

C. Cells with enlarged nuclei and loss of polarity involving the lower third of the epithelium

D. Cells with large nuclei and mitotic figures below the basement membrane but not more than 3 mm

ANSWERS

[9.1] A. In the Besthesda system of Papanicolau cytology reporting, findings can include atypical squamous cells of uncertain significance (ASCUS), low-grade intraepithelial neoplasia, high-grade intraepithelial neoplasia, and invasive cancer. ASCUS does not necessarily translate into a serious condition, and some practitioners will repeat the Pap smear in 3 to 6 months. However, if a high-risk viral subtype such as 16 or 18 is detected, colposcopic examination with directed cervical biopsies is recommended to assess the extent of disease.

[9.2] B. The Pap smear is for cytologic analysis of a normal-appearing cervix and is used as a screening test. An abnormal cervix (i.e., lesion) should be biopsied.

[9.3] C. CIN I entails mild dysplasia that involves the lower third of the epithelium. Because the basal cells (those closest to the basement membrane) are the actively dividing cells, they are the ones affected by HPV.

PATHOLOGY PEARLS

· Cervical intraepithelial neopalsia is a precursor to cervical cancer.

· The vast majority of cases of cervical dyspasia and cancer are associated with human papillomavirus, particularly subtypes 16 and 18.

· The best method for analyzing a visible cervical lesion is biopsy, not a Pap smear.

· The Pap smear has decreased the incidence of cervical cancer in the United States dramatically.

· The Bethesda classification for pap smears reports atypical squamous cells of uncertain significance (ASCUS), low grade squamous intraepithelial lesion (LSIL), high grade squamous intraepithelial lesion (HSIL), and invasive cancer.

· LSIL includes human papilloma viral changes and CIN I.

· HSIL includes CIN II and CIN III and carcinoma in situ.

REFERENCES

Crum CP The female genital tract. In: Kumar V, Assas AK, Fausto N, eds. Robbins and Cotran pathologic basis of disease, 7 ed. Philadelphia: Elsevier Saunders, 2004:1072-1079.

DeCherney A, Lauren N. Current obstetric & gynecologic diagnosis and treatment, 9th ed. Chicago: Mcgraw-Hill, 2003.

Stenchever M, et al. Comprehensive gynecology, 4th ed. St. Louis: Mosby, 2001.

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Copyright © 2006 by the McGraw-Hill Companies, Inc. All rights reserved.

Pathology CASE 8

CASE 8

INTRODUCTION

A 55-year-old woman presents to the emergency department with profuse bright red bleeding with emesis diagnosed as bleeding esophageal varices. She also is icteric and is suspected of having cirrhosis. She has been followed for several years for Sjogren syndrome and Raynaud syndrome. Investigation into the cause of her cirrhosis reveals negative hepatitis antibodies but elevated antimitochondrial antibodies.

· What is the most likely underlying etiology for her liver disease?

· What is the most likely mechanism?

ANSWERS TO CASE 8: Primary Biliary Cirrhosis

Summary: A 55-year-old woman has cirrhosis and elevated antimitochondrial antibodies.

· Most likely diagnosis: Primary biliary cirrhosis.

· Most likely mechanism: The etiology of primary biliary cirrhosis is not known; however, evidence points toward an autoimmune basis to the disease.

CLINICAL CORRELATION

Introduction

This 55-year-old woman presents with bleeding esophageal varices and cirrhosis. The first priorities in her management include ABC: airway, breathing, and circulation. She should receive oxygen by a nasal cannula, and two large-bore intravenous lines should be established. Her blood pressure and heart rate should be monitored to assess for volume loss and replacement with blood as needed. Because of her liver disease, she may have a coagulopathy caused by depletion of vitamin K-dependent factors (factors II, VII, IX, and X). Transfusion with coagulation factors and initiation of vitamin K may be indicated. Endoscopic examination to determine the etiology of the upper gastrointestinal bleeding is paramount. Bleeding esophageal varices may be treated with sclerotherapy injected into the bleeding vessels. Also, a tamponade may be attempted with special esophageal devices.

After the acute situation has been addressed, attention should be directed to the etiology of her liver disease. A careful history and physical examination and selected laboratories usually yield the diagnosis. Toxic effects such as with alcohol use and infections such as with hepatitis viruses are the most common causes of cirrhosis. This patient's hepatitis serology studies are negative, but she does have a history of Sjogren syndrome, Raynaud syndrome, and antimicrosomal antibodies. These findings are consistent with primary biliary cirrhosis. Careful history may reveal pruritis years before frank cirrhosis.

Approach to Chronic Liver Disease

Definitions

Primary biliary cirrhosis (PBC): A chronic progressive cholestatic liver disease associated with intrahepatic biliary tree destruction and finally cirrhosis.

Chronic liver disease: Liver disease that lasts for 6 months or more and includes chronic hepatitis and cirrhosis.

Cirrhosis: Progressive and irreversible condition of the liver in which hepatocyte damage and destruction occur. Regenerating hepatocytes form nodules.

Discussion

Primary Biliary Cirrhosis

The etiology of primary biliary cirrhosis is not known; however, evidence points toward an autoimmune basis of the disease. Other autoimmune diseases are associated with this condition and include Sjogren syndrome, scleroderma, rheumatoid arthritis, and thyroiditis. Abberant human lymphocyte antigen (HLA) class II molecules are expressed in the biliary epithelium of patients with PBC; this might be responsible for the triggering of an inflammatory response. Defective immunoregulation allows cytotoxic T cells to damage bile ducts. A liver biopsy usually shows a portal tract infiltrate composed of mainly lymphocytes and plasma cells (see Figure 8-1). In approximately half the patients, granulomas may be seen. Destruction of medium-sized bile ducts with bile ductular proliferation will be evident. With time, hepatocyte necrosis and fibrosis are apparent. After years to decades, the clinical features of cirrhosis will be present. There is an increased synthesis of IgM because of failure to switch from immunoglobulin M (IgM) to IgG antibody synthesis. Most patients have antimitochondrial antibodies in their serum, with the antigen M2 being specific to PBC. The role of this antibody in the pathogenesis of PBC is not clear.

Features of cholestatic liver disease dominate the initial clinical picture. This includes pruritus, which may precede jaundice by years. High serum alkaline phosphatase with normal or nearly normal alanine aminotransferase (ALT) and aspartate aminotransferase (AST) is characteristic in the early part of the disease. Secondary hypercholesteremia with features such as xanthelasma may be seen. After a variable amount of time (usually years), the features of cirrhosis, such as icterus, bleeding, and ascites, may become apparent. Table 8-1 shows the laboratory findings that are consistent with a diagnosis of PBC.

Table 8-1. LABORATORY FINDINGS CONSISTENT WITH PRIMARY BILIARY CIRRHOSIS

1. High serum alkaline phosophatase

2. High serum cholesterol

3. High serum IgM

4. High antimitochondrial antibodies; M2 antibody is specific

5. Liver biopsy; portal infiltrate with lymphocytes and plasma cells; granulomas; bile duct damage with ductular proliferation; eventual cirrhosis

Management

Treatment addresses the symptoms and disease course of the patient. Because the disease is thought to be autoimmune, corticosteroids have been tried. These agents improve the biochemical and histologic picture of the disease but lead to significant osteoporosis. Patients with primary biliary cirrhosis are prone to osteoporosis caused by cholestasis and subsequent impaired malabsorption of vitamin D. Complications associated with cirrhosis require management. Liver transplantation remains the specific treatment and has a 5-year survival of at least 80 percent.

Figure 8-1. Microscopic pictograph of primary biliary cirrhosis. (Courtesy of Dr. Aaron Han, Reading, PA.)0

Cirrhosis and Chronic Hepatitis

Chronic liver disease includes chronic hepatitis and cirrhosis (see Table 8-2). In chronic hepatitis, inflammatory cells consisting of lymphocytes, macrophages, and plasma cells are present in the portal tract. Interface hepatitis and bridging necrosis are signs of active liver damage. Lymphoid aggregates are seen in cases caused by hepatitis C virus. The hallmark of irreversible liver damage is deposition of fibrous tissue. This brings about the onset of cirrhosis. Initially, the fibrosis is periportal. With time, bridging fibrosis between lobules is seen. Regenerating nodules from surviving hepatocytes complete the picture of cirrhosis. Based on the size of the nodules, there are two types of cirrhosis: micronodular (nodules less than 3 mm) and macronodular. Micronodular cirrhosis is seen in alcoholics, whereas macronodular cirrhosis is seen after hepatitis.

Table 8-2. CAUSES OF CHRONIC HEPATITIS
Viruses
	Hepatitis B and C
Autoimmune
Hereditary
	Alpha1-antitrypsin deficiency, Wilson disease
Drugs
	Methyldopa, isonicotine hydrazine, ketoconazole
Causes of cirrhosis
	Alcohol (common)
	Viral hepatitis caused by B or C (common)
	Autoimmune hepatitis
	Primary biliary cirrhosis
	Wilson disease
	Hemochromatosis
	Alpha1-antitrypsin deficiency
	Drugs: methotrexate
Complications of cirrhosis
	Portal hypertension and gastrointestinal hemorrhage
	Ascites

Autoimmune Liver Disease

Autoimmune liver disease is seen most frequently in females and is associated with other autoimmune diseases. Autoantibodies such as antinuclear, anti-smooth muscle and anti-liver and kidney microsomal antibodies (anti-LKM) are frequently present. Serum IgG levels may be elevated.

Alpha₁-Antitrypsin Deficiency

Alpha₁-antitrypsin deficiency is inherited as an autosomal recessive condition. Alpha₁-antitrypsin is a glycoprotein whose main role is to inhibit the proteolytic enzyme neutrophil elastase. Deficiency results in liver damage and emphysema, especially in smokers. Serum levels are low, and liver biopsy shows periodic acid-Schiff (PAS) positive diastase-resistant globules within the hepatocytes.

Wilson Disease

Wilson disease is inherited as an autosomal recessive condition. The copper-transporting protein ceruloplasmin is reduced in amount because of poor synthesis. There is also failure of biliary excretion of copper. As a result, free copper is deposited in various sites, including liver basal ganglia and cornea (with resultant Kayser-Fleischer rings), resulting in damage to those organs. Urinary excretion of free copper also is increased. Acute hepatitis, chronic hepatitis, cirrhosis, and extrapyramidal features (caused by basal ganglia damage) are the usual clinical features.

Hereditary Hemochromatosis

Hereditary hemochromatosis also is inherited as an autosomal recessive condition. There is an association with HLA-A3. Excessive iron absorption results in iron deposition and damage to various organs, including liver, pancreas, heart, joints, and pituitary gland. At the same time excess iron deposition is observed in the skin. This results in bronze discoloration of skin. This, along with diabetes resulting from pancreatic damage, explains the synonym of hemochromatosis, bronze diabetes. Other features include cirrhosis, cardiomyopathy, hypogonadism, and arthropathy. As females lose iron through blood loss from menstruation, the features are milder or are seen later in them.

Alcoholic Liver Disease

The spectrum of alcoholic liver disease includes fatty liver, acute hepatitis, and cirrhosis. Fatty liver (hepatic steatosis) consists of microvesicular lipid droplets in the liver cells, displacing the nucleus to the periphery. On gross inspection, the liver appears yellow and greasy. Refraining from alcohol generally leads to reversal of these changes. In acute hepatitis, there is infiltration with polymorphonucleocytes and hepatocyte necrosis. Cytoplasmic inclusions resulting from intermediate filaments known as Mallory bodies are seen. Eventually, fibrosis ensues. Finally, cirrhosis develops as an end-stage result of chronic alcohol use. The liver is small and shrunken. Microscopy reveals fibrous septae that create a micronodular and macronodular pattern with regeneration. Clincally, the patient may develop portal hypertension, ascites, jaundice, and peripheral edema.

COMPREHENSION QUESTIONS

[8.1] A 37-year-old woman presents with fatigue and pruritus. Laboratory evaluation finds the presence of antimitochondrial antibodies in her serum, but the tests for viral hepatitis antibodies were negative. A biopsy of her liver reveals numerous lymphocytes in the portal tracts, along with occasional granulomas. Which one of the substances listed below is most likely to have markedly elevated serum levels in this individual?

A. Acid phosphatase

B. Alanine aminotransferase

C. Alkaline phosphatase

D. Aspartate aminotransferase

E. Conjugated bilirubin

[8.2] A 42-year-old woman presents with signs of jaundice and hepatic failure. Physical examination finds that she has uncontrolled choreiform movements of the arms, and a rust-colored ring is seen at the periphery of both corneas. Laboratory examination finds increased serum and urine levels of copper with decreased levels of ceruloplasmin. What is the best diagnosis?

A. Alpha₁-antitrypsin deficiency

B. Budd-Chiari syndrome

C. Primary biliary cirrhosis

D. Whipple disease

E. Wilson disease

[8.3] Which one of the abnormalities listed below is most likely to be found in an individual with hereditary hemochromatosis?

A. Black cartilage

B. Blue sclera

C. Bronze skin

D. Red pupils

E. White hair

ANSWERS

[8.1] C. The presence of antimitochondrial serum antibodies, particularly to the M2 antigen, in an individual with liver disease is highly suggestive of primary biliary cirrhosis. Individuals with this autoimmune disorder, which is more common in women, develop clinical signs of cholestatic liver disease with pruritus. Before the development of jaundice, however, patients will have high serum levels of alkaline phosphatase with normal or nearly normal levels of ALT and AST.

[8.2] E. Increased serum levels of copper with decreased levels of ceruloplasmin in a patient with liver disease are diagnostic of Wilson disease. This autosomal recessive disorder is characterized by the deposition of copper in multiple sites, which include the liver, the basal ganglia, and the cornea of the eye. Destruction of the basal ganglia leads to extrapyramidal signs such as choreiform movements, whereas deposition of copper at the periphery of the cornea produces characteristic Kayser-Fleischer rings.

[8.3] C. Patients with hereditary hemochromatosis develop clinical signs because of the deposition of excess iron in many organs. The classic triad of clinical signs includes a bronze skin color, diabetes mellitus, and cirrhosis. The combination of the bronze skin color and diabetes mellitus sometimes is referred to as bronze diabetes. Deposition of iron in the islets of Langerhans in the pancreas leads to the destruction of the beta cells, and subsequent decreased levels of insulin lead to diabetes mellitus. The abnormal skin color results from the deposition of iron in the skin. In addition, deposition of iron in the adrenal cortex leads to decreased cortisol levels. This in turn will increase levels of proopiomelanocortin (POMC) and lead to increased melanin-stimulating hormone (MSH) activity.

PATHOLOGY PEARLS

· Primary biliary cirrhosis is thought to be an autoimmune disease seen predominantly in middle-aged women.

· In PBC patients, serum IgM is elevated and antimitochondrial antibody (M2 is specific) is found.

· Cirrhosis is a progressive and irreversible condition of the liver in which there occurs hepatocyte damage and destruction. Regenerating hepatocytes form nodules.

· Complications of cirrhosis include portal hypertension, gastrointestinal hemorrhage, ascites, portosystemic encephalopathy, hepatorenal syndrome, and hepatocellular carcinoma.

· Alpha₁-antitrypsin deficiency is an autosomal recessive condition in which liver damage and emphysema are the main features.

· Wilson disease is an autosomal recessive condition characterized by liver and basal ganglia damage.

· Hereditary hemochromatosis, or bronze diabetes, also is inherited in an autosomal recessive fashion. Deposition of iron and organ damage occur in liver, pancreas, heart, joints, and pituitary gland.

· In alcoholic hepatitis there occurs infiltration with polymorphonucleocytes and heaptocyte necrosis. Cytoplasmic inclusions caused by intermediate filaments known as Mallory bodies are seen.

REFERENCES

Chung RT, Podolsky DK. Cirrhosis and its complications. In: Kasper DL, Fauci AS, Longo DL, et al. Harrison's principles of internal medicine, 16th ed. New York: McGraw-Hill, 2004:1860-1862.

Crawford JM. The gastrointestinal tract. In: Kumar V, Assas AK, Fausto N, eds. Robbins and Cotran pathologic basis of disease, 7th ed. Philadelphia: Elsevier Saunders, 2004:914-915.

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Pathology CASE 7

CASE 7

INTRODUCTION

A 62-year-old man returns home from playing bingo, complaining of midline abdominal pain. He denies being hit or suffering any other trauma. Over the next few hours the pain does not remit but becomes more severe and is localized to the lower right quadrant. He also develops nausea and vomiting. He denies diarrhea and has not had similar episodes. The patient lies down in bed, and over the next 24 hours, the pain worsens and he develops fever and chills and is brought to the emergency center. On examination, he has a temperature of 102°F and appears ill. His abdomen is mildly distended and has hypoactive bowel sounds. The abdomen is diffusely tender to palpation, particularly in the right lower quadrant.

· What is the most likely diagnosis?

· What additional tests would help in making an accurate diagnosis?

ANSWERS TO CASE 7: Appendicitis

Summary: A 62-year-old man complains of midline abdominal pain. He denies being hit or suffering any other trauma. Over the next few hours, the pain worsens and is localized to the lower right quadrant. He also develops nausea and vomiting and, after 24 hours, develops fever and chills and an acute abdomen.

· Most likely diagnosis: Acute appendicitis.

· Additional diagnostic tests: CT scan of the abdomen and pelvis.

CLINICAL CORRELATION

Introduction

This older man has a typical picture of a ruptured appendicitis with sepsis. He originally had mild right lower quadrant abdominal pain, but it worsened, and after 24 hours he developed fever and chills. Perhaps the most worrisome finding on physical examination is that he "appears ill." He probably has sepsis, which is a systemic condition of infection-mediated illness. The chills probably reflect bacteremia. The emergency physician should expeditiously manage this situation, because delay could lead to morbidity or mortality, particularly in a geriatric patient. The blood pressure is not mentioned, but the patient could be in septic shock. Treatment should be addressed in a systematic manner: airway, breathing, and circulation (ABC) with oxygen administered, two large-bore intravenous lines (IVs), volume repletion for the probable volume depletion and sepsis, blood cultures, urine culture, and antibiotic therapy aimed at gram-negative bacilli and anaerobic bacteria. Blood work to be obtained includes a complete blood count and a chemistry panel to assess electrolytes and serum creatinine for kidney function. After stabilization, the patient should be taken to the operating room. If the diagnosis is unclear, a CT scan of the abdomen sometimes can help distinguish other abdominal pathologies, such as diverticulitis.

Approach to Appendicitis

Definitions

Appendicitis: Inflammation of the vermiform appendix.

Diverticulitis: Inflammation of an outpouching of the diverticulum.

Diverticulosis: A condition of outpouching of the large bowel near the taeniae coli where the blood vessels penetrate. Complications include hemorrhage (lower gastrointestinal bleeding) and inflammation.

Approach to Appendicitis and Diverticulitis

Discussion

Appendicitis

Acute appendicitis is a common disease in Western countries and is uncommon in Africa and Asia. The incidence of the disease in the United States has fallen considerably over the last 30 years; however, it remains the most common abdominal emergency in childhood, adolescence, and early adult life. Fewer than 5 percent of cases of acute appendicitis occur in patients over age 60 years.

The pathologic process begins on the mucosal surface of the appendix, and there is often an element of obstruction of the appendicular lumen by a fecalith. This may lead to pressure necrosis of the mucosa and invasion of the appendicular wall by bacteria. Common causes of obstruction include elongation or kinking of the appendix, adhesions, and neoplasias such as carcinoma and carcinoid tumors, both of which are rare. Some cases spontaneously resolve, but more commonly, infection of the wall of the appendix progresses, leading to impairment of its blood supply. When the pathologic process has extended throughout the wall of the appendix to involve the parietal peritoneum, the pain and tenderness are classically over the McBurney point at the site of the appendix. The pathologic process may continue and produce gangrene, perforation, and more generalized peritonitis. Once perforation has occurred, the advancing bacteria may be controlled by the ability of the omentum to wall off the inflammation; alternatively, the peritonitis may become more widespread. In advanced appendicitis, a mass may develop; alternatively, generalized peritonitis may lead to the septic inflammatory response syndrome (SIRS), ultimately with the development of multiple organ failure and death.

The site of the pain in appendicitis may vary. When the appendix is retrocecal in position, somatic pain may be perceived in the flank and loin rather than in the right lower quadrant. Anorexia is an almost invariable symptom in association with appendicitis. The presence of hunger usually eliminates this diagnosis. In association with anorexia, nausea is common and tends to proceed to vomiting. Diarrhea sometimes occurs and may be a result of the appendix lying in a pelvic position.

Laboratory investigations commonly performed include the peripheral white blood cell count, which may be elevated with a predominance of polymorphonuclear leukocytes. The urinalysis is usually normal. A CT scan of the abdomen may show thickening of the appendix with periappendicular inflammation and the presence of intraperitoneal fluid.

The differential diagnosis includes acute gastroenteritis, which typically has vomiting and diarrhea as prominent symptoms and abdominal pain that is less well defined. Intestinal obstruction must be considered and typically presents with vomiting and abdominal distention. Mesenteric adenitis may mimic appendicitis closely but is associated with a generalized viral illness and causes less severe pain. Inflammation of Meckel diverticulum may produce symptoms remarkably similar to those of appendicitis, and laparoscopy or laparotomy may be needed for the diagnosis. Crohn disease may closely simulate appendicitis; affected patients generally have intestinal obstruction, and usually conservative management is the best therapy. Gynecologic disorders such as pelvic inflammatory disease with cervical motion tenderness and adnexal tenderness may present similarly to appendicitis. Ureteral colic is associated with pain and tenderness of the flank area, radiating to the groin region. Other conditions include acute diverticulitis, colonic carcinoma, acute cholecystitis, and pancreatitis.

Appendicitis in the elderly may have a more rapid course. Gangrene and perforation are more common in those over age 60 years, and this may be due to a delay in diagnosis. A classic picture of the appendicitis may be lacking, and the pain may be a less prominent feature. Overall, although there has been a decline in the incidence of peritonitis, paradoxically, it has increased among the elderly. Thus, appendicitis should be at the forefront of the differential diagnosis in males with right lower quadrant pain and tenderness.

The treatment of uncomplicated appendicitis is surgical, consisting of an appendectomy. The abdomen is opened, and if the appendix is found to be normal in the absence of any other pathology, it should be removed prophylactically. At the present time, most appendixes are removed laparoscopically rather than in an open operation.

Diverticulitis

Diverticuli are blind pouches involving the bowel. They result from herniation of the mucosa through the circular muscle at the site of small penetrating blood vessels. Their walls consist of an outer layer of serosa and an inner mucosa. There is no muscle in the wall of the diverticulum. Diverticular disease is associated with increased intraluminal pressure in the large intestine with hypertrophy of both circular and longitudinal muscle layers. Diverticula can occur anywhere in the large bowel and small bowel but are found most commonly in the sigmoid colon. Muscle hypertrophy predates the development of diverticula and results in a narrowing of the bowel and, consequently, an increase in the intraluminal pressure.

Diverticular disease may produce central or left lower quadrant abdominal pain together with an alteration in bowel habit with occasional rectal bleeding. The diagnosis is confirmed by barium enema or colonoscopy, which will show muscle thickening and multiple diverticula with small orifices emerging through the colonic wall. Diverticular disease of the colon is common in Western countries and rare in central Africa, the Middle East, the Far East, and the Pacific islands. The incidence of the disease in Japan is increasing, possibly because of the adoption of a more westernized diet. African Americans residing in the United States now have an incidence of the disease equal to that of the white population. Epidemiologic studies support the concept that the disease is not racially determined but is related to changes in the environment and to dietary factors. Postmortem studies in the Western countries report an incidence of about 40 percent overall and one as high as 60 percent in those over age 60 years.

Acute or chronic inflammation within a diverticulum is designated diverticulitis. It is estimated that the approximately 20 percent of patients with diverticulosis will manifest diverticulitis. Localized inflammation, or even perforation and peritonitis, may occur. Pneumaturia, resulting from a colovesical fistula, may occur, and on occasion, fecal material may be passed in the urine. CT imaging of the abdomen remains the primary method of diagnosing the acute process, whereas barium enema and endoscopic examinations are relatively contraindicated during acute infection.

Known complications of diverticulitis include bleeding, abscess formation, peritonitis, and fistula formation. Colonic obstruction also can occur. The treatment of diverticulitis includes broad-spectrum antibiotics, intravenous fluids, and nothing by mouth until the condition settles. Frank peritonitis or abscess formation usually requires surgical intervention, commonly involving excision of the affected area, such as a sigmoid colectomy. Postoperatively, patients should be instructed to eat a high-residue diet and drink plenty of liquids.

COMPREHENSION QUESTIONS

[7.1] A 20-year-old woman presents with the sudden development of nausea, vomiting, and right lower abdominal pain. Physical examination finds a mild fever, and laboratory evaluation finds an increased peripheral leukocyte count. She is taken to surgery, where an appendectomy is performed. Which one of the following histologic changes is most likely to be present in her appendix?

A. Amorphic mucinous material within the lumen

B. Caseating granulomas within the periappendiceal fat

C. Hyperplastic lymphoid follicles within the lamina propria

D. Multinucleated giant cells within the epithelium

E. Numerous neutrophils within the muscular wall

[7.2] A 61-year-old woman presents with nausea, vomiting, and the sudden onset of left-sided abdominal pain. Physical examination finds a low-grade fever, and laboratory evaluation finds increased numbers of neutrophils in her peripheral blood. What is the most likely diagnosis?

A. Appendicitis

B. Cholecystitis

C. Colitis

D. Diverticulitis

E. Pancreatitis

[7.3] Which one of the clinical findings listed below is most likely to be present in an older individual with diverticulosis?

A. Abdominal colic caused by intestinal obstruction

B. Iron deficiency anemia caused by chronic blood loss

C. Megaloblastic anemia caused by vitamin B₁₂ deficiency

D. Steatorrhea caused by malabsorption of fat

E. Chronic diarrhea caused by decreased absorption of protein

ANSWERS

[7.1] E. The histologic hallmark of acute inflammation, such as that seen with acute appendicitis, is the presence of numerous acute inflammatory cells, namely, neutrophils. Therefore, histologic sections of an appendix surgically removed from an individual with acute appendicitis will reveal numerous neutrophils within the muscular wall. The inflammation can be so marked that it causes complete destruction of the muscular wall, which can lead to perforation and peritonitis.

[7.2] D. Acute inflammation of diverticula (diverticulitis) will produce the sudden onset of left-sided abdominal pain accompanied by fever and peripheral leukocytosis (mainly neutrophils). These clinical signs are essentially the same as those seen with acute appendicitis except that the abdominal pain is on the left side rather than the right side. As such, diverticulitis sometimes is referred to as left-sided appendicitis.

[7.3] B. Diverticulosis refers to the presence of numerous diverticula in the colon. The diverticula usually are located in the sigmoid colon in older individuals. Although they may become inflamed and produce signs of acute diverticulitis, more often they produce chronic blood loss as a result of chronic bleeding, which will lead to heme-positive stools and iron deficiency anemia.

PATHOLOGY PEARLS

· Appendicitis usually is a 24-hour disease with periumbilical pain localizing to the right lower quadrant.

· The primary treatment of appendicitis is surgical.

· Appendicitis continues to have high morbidity and mortality in older patients.

· Diverticula usually involve the left colon, particularly the sigmoid colon.

· Diverticulitis presents as left lower abdominal pain, fever, and nausea and vomiting.

· CT imaging is helpful in diagnosing both acute appendicitis and diverticulitis.

REFERENCES

Liu C, Crawford JM. The gastrointestinal tract. In: Kumar V, Assas AK, Fausto N, eds. Robbins and Cotran pathologic basis of disease, 7th ed. Philadelphia: Elsevier Saunders, 2004:854-856, 870-872.

Silen AW. Acute appendicitis and peritonitis. In: Kasper DL, Fauci AS, Longo DL, et al. Harrison's principles of internal medicine, 16th ed. New York: McGraw-Hill, 2004:1805-1806.

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Copyright © 2006 by the McGraw-Hill Companies, Inc. All rights reserved.

PATHOLOGY CASE 6

CASE 6

INTRODUCTION

A 22-year-old woman has had recurrent episodes of diarrhea, crampy abdominal pain, and slight fever over the last 2 years. At first the episodes, which usually last 1 or 2 weeks, were several months apart, but recently they have occurred more frequently. Other symptoms have included mild joint pain and sometimes red skin lesions. On at least one occasion, her stool has been guaiac-positive, indicating the presence of occult blood. Colonoscopy reveals several sharply delineated areas with thickening of the bowel wall and mucosal ulceration. Areas adjacent to these lesions appear normal. Biopsies of the affected areas show full-thickness inflammation of the bowel wall and several noncaseating granulomas.

· What is the most likely diagnosis?

· What are the common complications of this disease?

ANSWERS TO CASE 6: Crohn Disease

Summary: A 22-year-old woman has a 2-year history of recurrent diarrhea, abdominal pain, slight fever, joint pain, and red skin lesions. Colonoscopy reveals several sharply delineated areas with thickening of the bowel wall and mucosal ulceration, which on biopsy show full-thickness inflammation of the bowel wall and several noncaseating granulomas.

· Most likely diagnosis: Crohn disease.

· Common complications of this disease: Malabsorption and malnutrition, fibrous strictures of the intestine, and fistulae to other organs, such as from bowel to skin or bowel to bladder.

CLINICAL CORRELATION

Introduction

The patient's presentation is very characteristic for inflammatory bowel disease, that is, a several-year history of diarrhea and abdominal pain. Additionally, the colonoscopy revealing full-thickness inflammation with noncaseating granulomas is consistent with Crohn disease. Crohn disease is a chronic inflammatory condition that is ubiquitous in its distribution in the gastrointestinal tract. It most commonly manifests in the small intestine, in particular the terminal ileum. The disease exhibits aggressive activity of the gastrointestinal immune system, but the exact cause is unknown. Published studies in the United States report incidence rates that vary between 1.2 and 8.8 per 100,000 population; the prevalence is 44 to 106 per 100,000. The condition is more common in the cold climates of the northeastern United States than in the south. Those of Jewish ethnicity have a high incidence. The disorder, which is slightly more common in females, has a bimodal age distribution, peaking in the early twenties and again emerging in the mid-sixties. Theories regarding pathogenesis have referred to genetics, infection, autoimmune or allergic processes, thromboembolic disorders, and dietary disorders.

Approach to Inflammatory Bowel Disease

Discussion

The predominant symptoms of Crohn disease are diarrhea, abdominal pain, and weight loss. These symptoms may be widely variable, depending on the distribution of the inflammatory lesions in the patient's intestines. The principal stimulus for diarrhea is the mucosal immune response in association with cytokine release. If the colon is involved, diarrhea may be more marked and tenesmus may occur. Abdominal pain may be due to local inflammation or obstruction if it is experienced in the central abdomen or right lower quadrant. Abscesses or fistulae also may produce pain. Secondary causes of abdominal pain in relation to Crohn disease are gallstones and renal colic. Malabsorption leading to weight loss and failure to thrive may occur in children. Fat, protein, mineral, and vitamin deficiencies may be associated with extensive or recurrent disease. About one-third of patients develop perineal symptoms or signs such as anal fistulae or fissures.

Nongastrointestinal symptoms of Crohn disease involve the skin, joints, or eyes. Skin lesions include erythema nodosum, pyoderma gangrenosa, aphthous stomatitis, and finger clubbing. The rheumatologic manifestations often present as a large joint polyarthropathy resembling ankylosing spondylitis or a small joint fleeting polyarthropathy that is like rheumatoid arthritis. The human lymphocyte antigen B-27 (HLA-B27) may be present. Inflammatory eye lesions are confined to the anterior chamber, such as uveitis, iritis, episcleritis, and conjunctivitis. A chronic active hepatitis may develop; more seriously, sclerosing cholangitis can progress to cirrhosis. There is a predisposition to gallstones when terminal ileal disease is present.

Physical Examination

Physical examination may reveal a nutritional deficiency. The extraintestinal manifestations may be apparent. Abdominal examination may suggest partial bowel obstruction, an inflammatory mass, focal areas of tenderness, or enterocutaneous fistulae. Perineal examination may reveal fistulae or abscesses. Perianal skin tags with bluish discoloration may be present. On rectal examination there may be a stricture, a palpable ulcer, or perirectal abscesses. Bloody diarrhea may be detectable. Clinical features compatible with anemia or hypoalbuminemia may be present. Hypoalbuminemia may manifest with peripheral edema.

Approach to Inflammatory Bowel Disease

Plain abdominal radiographs provide important information in the acute presentation of symptoms, as they may demonstrate intestinal obstruction or evidence of perforation. Biliary or renal calculi, arthropathy, or osteoporosis also may be detected. Endoscopy of the lower and upper gastrointestinal tract is used to identify disease and provide biopsy evidence. Barium follow-through examination or small bowel enteroclysis may demonstrate discrete lesions in the small intestine. Fistulograms are helpful to surgeons by providing information about the site of the fistula and the presence of obstruction or abscess cavity in association with it.

Computerized tomography is the mainstay in terms of providing information about thickened loops of bowel, abscesses, and fistulous tracts. Magnetic resonance imaging, including cholangiography, may be helpful. Ultrasound may reveal thickened terminal ileum, abscesses, and evidence of bilary tract disease. Ultrasound examination of the renal tract may reveal obstruction or stone formation. Endoscopic ultrasound may be useful in assessing bowel wall involvement and the extent of the disease process. Studies of bone density may be required.

Endoscopy allows detailed examination of the mucosa of the upper and lower intestines, with the added advantage of allowing biopsies of abnormal areas to be taken. Capsule endoscopy is an innovation that permits detailed photography of the small intestinal lumen. There may be eletrolyte abnormalities in Crohn disease. The erythrocyte sedimentation rate (ESR) frequently is elevated above 30 mm/h, and the serum vitamin B₁₂ level may be reduced.

Crohn Disease Versus Ulcerative Colitis

These inflammatory bowel diseases share certain features, but there are fundamental and often distinguishing features. On occasion it may be very difficult to determine whether a patient has Crohn disease or ulcerative colitis, and in these circumstances the condition often is designated indeterminate colitis. The fundamental differences between Crohn disease and ulcerative colitis are that Crohn disease begins in the submucosa and ulcerative colitis begins in the mucosa of the gut. Ulcerative colitis, as its name suggests, is a disease confined to the colon and rectum, whereas, as was stated above, Crohn disease is ubiquitous throughout the bowel. Full-thickness involvement of the bowel, although more common in Crohn disease, may occur in both disorders. Fibrosis cicatrization and fistula formation are confined almost exclusively to patients with Crohn disease. The histopathologic feature that differentiates the two conditions is the presence of granulomas in Crohn disease. Aphthoid ulcers are more likely to occur in patients with Crohn disease. Both conditions are associated with an increased incidence of colon cancer, which, however, is more likely to develop in long-standing ulcerative colitis than in Crohn disease. The incidence of malignant change in the colon or rectum of ulcerative colitis is about 20 percent after 25 years of disease activity. Many patients develop ulcerative colitis at a young age and therefore may develop cancerous changes in the colon in their forties or fifties. A further important consideration is that patients with inflammatory bowel disease live with episodes of diarrhea and occasional rectal bleeding so that the heralding features of malignancy may be observed by referring to the underlying inflammatory disease.

Treatment

Pain Control and Anti-Inflammatory Agents

The treatment of Crohn disease can be divided into four areas of management: dealing with symptoms, treating mucosal inflammation, nutritional management, and surgery. Abdominal pain and diarrhea are dealt with mostly by addressing intestinal inflammation. Pain may be due to the stretching of nerve endings as a result of distention from obstruction or inflammation. Nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided, and narcotics lead to addiction in this chronic condition. Acetominophen, Tramadol and Darvocet are used most frequently for pain control. 5-Aminosalicylic acid derivatives such as Azulfidine, Asacol, Pentasa, and Rowasa are used widely and have some effect. They are more effective in ulcerative colitis than in Crohn disease.

Steroids

Corticosteroids have been the mainstay in the acute treatment of Crohn disease for many years. Steroids should be used only when more conservative measures fail. The strategy employed is to induce remission by using high doses (prednisolone 60 mg per day) in the short term, followed by a temporary regime as soon as remission is induced. Maintenance therapy should employ the lowest dose possible. About 20 percent of patients require long-term steroids.

Second-Line Agents

Steroid sparing in long-term management can be achieved with 6-mercaptopurine. This drug is slow to act and unpredictable in terms of achieving a therapeutic response. In doses of 50 to 125 mg daily, bone marrow suppression and other side effects are rare. The antibiotic metronidazole is also used as second-line therapy with a degree of success, particularly in treating fistulae. In addition to its properties as an antibiotic, the drug has an effect on the immune system. Other antibiotics that have been used to some effect are ciprofloxacin and clarithromycin.

Immune Suppressants

The immune suppressants methorexate and cyclosporine have been shown to confer some benefit in the short term. The latest, still experimental, strategy in the treatment of Crohn disease involves the role of cytokines. Anti-tumor necrosis factor has been shown to be effective. Other cytokine therapies, such as the use of interleukin-11 (IL-11) and IL-10, have been reported to be efficacious in about 30 percent of cases.

Surgery

The cumulative risk of undergoing surgery sometime in their lives for patients with Crohn disease is nearly 90 percent, and the cumulative risk of recurrent disease at 20 years is 70 percent. Many recurrences may be asymptomatic, however. The major indication for surgery is failed medical therapy, usually in the presence of obstruction, fistula formation, and electrolyte or nutritional problems.

Controversy still exists over how radical the surgeon should be in treating Crohn disease. Some studies show that the more disease-free the margins are after the resection, the less likely there is to be recurrent disease. Conversely, there is a danger that overly radical resections will leave the patient with the short bowel syndrome and its nutritional consequences. Conservative surgery in the form of stricturoplasty for short stenotic lesions that are producing obstructions can be helpful without the loss of any bowel. For longer diseased segments, resection is preferred to bypass. For colonic Crohn disease with severe rectal and anal involvement, a proctocolectomy with ileostomy may be required. Meticulous care is required in performing anastomoses in patients with Crohn disease, as healing is often impaired and the risk of anastomotic leakage therefore is increased.

COMPREHENSION QUESTIONS

[6.1] A 44-year-old man presents with multiple episodes of bloody diarrhea accompanied by cramping abdominal pain. A colonoscopy reveals the rectum and distal colon to be unremarkable, but x-ray studies find areas of focal thickening of the wall of the proximal colon, producing a characteristic "string sign." Biopsies from the abnormal portions of the colon revealed histologic features that were diagnostic of Crohn disease. Which of the following histologic features is most characteristic of Crohn disease?

A. Dilated submucosal blood vessels with focal thrombosis

B. Increased thickness of the subepithelial collagen layer

C. Noncaseating granulomas with scattered giant cells

D. Numerous eosinophils within the lamina propria

E. Small curved bacteria identified with special silver stains

[6.2] Which one of the therapies listed below is used most often to treat an individual with a history of Crohn disease who acutely develops abdominal pain and bloody diarrhea but has no clinical evidence of obstruction or fistula formation?

A. Aspirin

B. Interleukin-10

C. Metronidazole

D. Prednisolone

E. Surgery

[6.3] What is the fundamental distinguishing feature between Crohn disease and ulcerative colitis?

A. Crohn disease begins in the rectum; ulcerative colitis may have "skip lesions."

B. Crohn disease begins in the submucosa; ulcerative colitis begins in the mucosa.

C. Crohn disease has an increased risk of malignancy; ulcerative colitis has a very low association with malignancy.

D. Crohn disease is associated with crypt abscesses; ulcerative colitis, with pericolonic abscesses.

E. Crohn disease is associated with the formation of inflammatory polyps; ulcerative colitis, with hamartomatous polyps.

ANSWERS

[6.1] C. Microscopic examination of the abnormal bowel from an individual with Crohn disease will reveal transmural inflammation with fibrosis, but the histologic feature that is most diagnostic of Crohn disease is the presence of noncaseating granulomas. This characteristic histologic feature, however, may be present in only about 50 percent of patients; however, the diagnosis of Crohn disease can still be made without finding granulomas by the characteristic clinical presentation, which includes the production of fissures, fistulae, and bowel obstruction by the transmural inflammation.

[6.2] D. In the absence of bowel obstruction or fistula formation, several types of medical therapies have been used to treat the acute inflammation associated with Crohn disease. Corticosteroids, such as high-dose prednisolone, have been used commonly to treat the acute symptoms and induce remissions. In contrast, the antibiotic metronidazole may be used to treat patients with fistula formation, whereas the use of cytokines such as interleukin-10 is experimental. Surgical resection of bowel usually is done to treat problems such as obstruction.

[6.3] B. Crohn disease and ulcerative colitis are both inflammatory bowel diseases characterized by marked acute inflammation, but the fundamental difference is that with Crohn disease the inflammation begins in the submucosa and may involve the entire bowel wall, whereas ulcerative colitis begins in the mucosa and the inflammatory response remains superficial in location. Another important difference is that the inflammation in ulcerative colitis begins in the rectum and distal portions of the colon and precedes proximally without "skip lesions," whereas the inflammation in Crohn disease can be found throughout the gastrointestinal tract.

PATHOLOGY PEARLS

· Crohn disease is transmural (full thickness) and can occur anywhere along the gastrointestinal tract.

· Intestinal strictures and fistulae are complications of Crohn disease.

· Individuals with Crohn disease have an increased risk of colon cancer, but the risk is lower than that with ulcerative colitis.

· Nongastrointestinal symptoms of Crohn disease involve the skin, joints, and eyes. Skin lesions include erythema nodosum, pyoderma gangrenosa, aphthous stomatitis, and finger clubbing.

REFERENCES

Friedman S, Blumberg RS. Inflammatory bowel disease. In: Kasper DL, Fauci AS, Longo DL, et al. Harrison's principles of internal medicine, 16th ed. New York: McGraw-Hill, 2004:1776-1788.

Liu C, Crawford JM. The gastrointestinal tract. In: Kumar V, Assas AK, Fausto N, eds. Robbins and Cotran pathologic basis of disease, 7th ed. Philadelphia: Elsevier Saunders, 2004:846-849.

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Copyright © 2006 by the McGraw-Hill Companies, Inc. All rights reserved.