PATHOLOGY CASE 2

PATHOLOGY CASE 2

INTRODUCTION

A 30-year-old male banker complains of midepigastric gnawing and boring pain for the last week. The pain is worse at night and is somewhat better immediately after he eats. He has not had any fever, nausea, or vomiting. He takes about one 500-mg acetaminophen tablet a week for headaches but does not take any other medications. Upper endoscopy reveals a 2-cm mucosal defect in the antrum of the stomach. There is mild edema in the adjacent mucosa, but there is no thickening of the edges of the ulcer.

· What is the most likely diagnosis?

· What are complications from this condition?

· What is the most likely mechanism of this disorder?

ANSWERS TO CASE 2: Peptic Ulcer Disease

Summary: A 30-year-old man has acute onset of midepigastric pain somewhat relieved by eating. Upper endoscopy reveals a 2-cm gastric ulcer.

· Most likely diagnosis: Peptic ulcer disease.

· Long-term complications: Erosion or perforation with bleeding; gastric carcinoma in patients with chronic gastritis.

· Most likely mechanism: Most often associated with Helicobacter pylori organisms that produce bacterial urease and protease, damaging the mucus layer and exposing the underlying epithelium to acid-peptic injury.

CLINICAL CORRELATION

Introduction

Ulcers are disruptions of the mucosa of the gastrointestinal tract that extend through the muscularis mucosa into the submucosa or deeper. Peptic ulcers occur most frequently in the stomach and duodenum. Peptic ulcers are often remitting, relapsing lesions that may be seen in young adults but more often occur in middle-aged to older adults. They are usually chronic, solitary lesions caused by the action of gastric acid and pepsin, both of which are thought to be required for the development of peptic ulcers. Helicobacter pylori infection of gastric mucosa is present in 90 to 100 percent of patients with a duodenal ulcer and 70 percent of those with a gastric ulcer. Damage to the protective mucus layer by bacterial urease and protease exposes the underlying epithelial cells to the influence of acid-peptic digestion and may lead to inflammation. The chronically inflamed mucosa is more susceptible to acid-peptic injury and thus more prone to ulceration.

Approach to Gastric Pathology

Definitions

Diaphragmatic hernia: Weakness or partial to total absence of a portion of the diaphragm, usually on the left, which may permit the abdominal contents to herniate into the thorax during in utero development. Diaphragmatic hernias differ from hiatal hernias in that the defect in the diaphragm does not involve the hiatal orifice.

Pyloric stenosis: Congenital hypertrophic pyloric stenosis is seen in infants usually during the second or third week of life. Hypertrophy of the muscularis propria of the pylorus results in a palpable mass and obstruction with associated regurgitation and persistent projectile vomiting. Male infants are affected 3 to 4 times more often than are females. Treatment consists of surgical splitting of the muscle. Pyloric stenosis may be acquired in adults with chronic antral gastritis or peptic ulcers near the pylorus. Other causes of acquired pyloric stenosis include gastric carcinomas, lymphomas, and adjacent carcinomas of the pancreas.

Gastritis: Inflammation of the gastric mucosa. The inflammation may be predominantly acute, with neutrophilic infiltration, or chronic, with a predominance of lymphocytes and plasma cells. The classification and pathogenesis of acute and chronic gastritis are discussed below.

Ulcer: A disruption of the mucosa extending through the muscularis mucosa into the submucosa or deeper. Ulcers may occur anywhere in the gastrointestinal tract but are seen most often in the stomach and duodenum, associated with peptic ulcer disease.

Peptic ulcer disease: Peptic ulcers are chronic, usually solitary lesions of the gastrointestinal mucosa caused by the action of acid-peptic juices. Both acid and pepsin are necessary for peptic ulcer disease to develop.

Hypertrophic gastropathy: A group of uncommon conditions characterized by enlargement of the rugal folds of the gastric mucosa caused by hyperplasia of the mucosal epithelial cells. The three variants are (1) Menetrier disease with marked hyperplasia of the surface mucous cells with atrophy of the gastric glands that may lead to severe loss of plasma proteins, (2) Zollinger-Ellison syndrome with gastric gland hyperplasia secondary to excessive gastrin secretion by a tumor (gastrinoma), and (3) hypertrophic-hypersecretory gastropathy with hyperplasia of the parietal and chief cells within the gastric glands. These three conditions may mimic gastric cancer on radiographic studies. The excessive amount of acid secretion in the second and third conditions predisposes patients to peptic ulceration.

Discussion

Normal Stomach

The stomach is divided into four anatomic regions: the cardia, fundus, body or corpus, and antrum. The pyloric sphincter demarcates the antrum from the duodenum. Infoldings of mucosa and submucosa, or rugae, extend longitudinally and are most prominent in the proximal stomach. Several types of cells are found in the stomach: Parietal cells produce gastric hydrochloric acid and intrinsic factor involved in the absorption of vitamin B₁₂, chief cells secrete the proteolytic enzymes pepsinogen I and II, surface and mucous neck cells secrete mucus involved in the protection of the mucosa from gastric acid, and G cells found in the antral, pyloric, and duodenal mucosa produce gastrin.

The secretion of gastric acid is proportional to the total number of parietal cells in the glands of the body and fundus of the stomach. The secretory process may be divided into three phases: cephalic, gastric, and intestinal. Gastrin, which is released in response to vagal stimulation, is the most important mediator of gastric acid secretion. Histamine also stimulates acid secretion. Thus, surgical interruption of vagal stimulation and inhibition of histamine stimulation by blocking the H2 receptor on the parietal cell membrane are effective maneuvers for reducing gastric acid production. Several factors act together to protect the stomach from digestion by gastric acid. Mucus secretion, bicarbonate secretion, the epithelial barrier formed by tight intercellular junctions, a rich mucosal blood flow that removes back-diffused acid, and a reflex vasodilationdilation in response to toxins or acid breach of the epithelial layer all contribute to the mucosal barrier.

Gastritis

Inflammation of the gastric mucosa occurs in a variety of clinical situations and may be acute or chronic. Acute gastritis varies in severity; it may be asymptomatic, cause epigastric pain with nausea and vomiting, or present with massive hematemesis. Acute erosive gastritis (see Table 2-1) is an important cause of acute gastrointestinal bleeding. In chronic gastritis, there are chronic mucosal inflammatory changes, usually without erosions, that may lead to mucosal atrophy and dysplastic epithelium, predisposing the patient to the development of carcinoma (Table 2-2).

Table 2-1. SELECTED ETIOLOGIES OF ACUTE GASTRITIS

Heavy use of nonsteroidal anti-inflammatory drugs (NSAIDs), particularly aspirin

Excessive alcohol consumption

Heavy smoking

Uremia

Cancer chemotherapy

Severe stress: burns (Curling ulcer), trauma, or surgery with increased intracranial pressure leading to increased vagal tone (Cushing ulcer)

Ischemia and shock

Suicide attempts with acids and alkali

Mechanical trauma (nasogastric intubation)

After distal gastrectomy

Table 2-2. SELECTED ETIOLOGIES OF CHRONIC GASTRITIS

Chronic infection, such as Helicobacter pylori

Immunologic, associated with pernicious anemia

Toxic, such as alcohol and cigarette use

Postsurgical, especially after antrectomy

Obstruction, such as bezoars

Radiation

Granulomatous conditions, such as Crohn disease

Other conditions, such as graft-versus-host disease, amyloidosis, uremia

Most cases of chronic gastritis are thought to be associated with chronic Helicobacter pylori infection. Chronic gastritis that results from H. pylori infection most often involves the antrum and is not associated with pernicious anemia. Most patients improve with antibiotic treatment, and relapses of chronic gastritis are associated with a recurrence of infection. Patients are at risk for developing peptic ulcer disease and gastric cancer, including adenocarcinoma and lymphoma.

Patients with autoimmune gastritis (diffuse atrophic gastritis) may have nausea, vomiting, and upper abdominal pain. Patients usually have autoantibodies to gastric parietal cells or intrinsic factor. Destruction of gastric glands of the fundus leads to loss of acid production (achlorhydria) and hypergastrinemia. Loss of intrinsic factor leads to pernicious anemia. Patients may have other autoimmune disorders, such as Hashimoto thyroiditis or Addison disease.

Peptic Ulcer Disease

Peptic ulcers are usually solitary, arising from exposure of the mucosal epithelium to acid-peptic secretions. Peptic ulcer disease (PUD) occurs most often in middle-aged to older adults. The most common anatomic sites are the duodenum and the stomach, in a ratio of 4:1. H. pylori infection is present in virtually all patients with duodenal ulcers and 70 percent of patients with PUD involving the stomach. H. pylori can cause damage by (1) secreting urease, protease, and phospholipases, (2) attracting neutrophils that release myeloperoxidase, and (3) promoting thrombotic occlusion of capillaries, leading to ischemic damage of the epithelium. Complications of PUD include anemia, hemorrhage, perforation, and obstruction. Malignant transformation is rare and is related to underlying chronic gastritis.

Gastric Cancer

Most (90 to 95 percent) gastric malignancies are adenocarcinomas, with a smaller number of lymphomas, carcinoids, and spindle cell tumors. Although the incidence of gastric carcinoma has been decreasing in Western countries over the last 50 years, the prognosis is still poor, with a 20 percent 5-year survival. Risk factors for gastric carcinoma include nitrates; smoked, salted, or pickled foods; lack of fresh fruits and vegetables; chronic atrophic gastritis; H. pylori infection; partial gastrectomy; gastric adenomas; blood group A; and close relatives with gastric cancer. Two types of gastric carcinoma are recognized: the intestinal type and the diffuse type (Table 2-3).

Table 2-3. GASTRIC CARCINOMA SUBTYPES
	INTESTINAL TYPE	DIFFUSE TYPE
Incidence	Decreasing	No change
Average age	55 years	48 years
Male:female ratio	2:1	1:1
Chronic gastritis	Frequently associated	No particular association
Macroscopic growth pattern	Exophytic, polypoid, fungating	Ulcerative and/or diffusely infiltrative resulting in a rigid thickened wall, linitis plastica
Microscopic growth pattern	Gland-forming columnar epithelium; associated with intestinal metaplasia; usually mucin-producing	Infiltrative growth; noncohesive; poorly differentiated, often signet ring cells; mucin-producing

These may represent two distinct forms of gastric carcinoma. Dissemination of gastric carcinoma, as well as other primary abdominal adenocarcinomas, to the ovaries is known as Krukenberg tumors. The hallmark is the "signet ring cell" on microscopy, which is indicative of large cells with mucin, that push the nuclei to the periphery of the cell.

COMPREHENSION QUESTIONS

[2.1] A 59-year-old woman presents with occasional nausea and vague upper abdominal discomfort. Upper endoscopy reveals chronic gastritis of the fundus with flattened gastric mucosa but no acute ulceration. Which of the following is most likely to be associated with this finding?

A. Autoantibodies to parietal cells

B. Diet high in nitrites

C. Hyperchlorohydria

D. Hypoparathyroidism

E. Menetrier disease

[2.2] A 40-year-old man has burning epigastric pain starting 1 to 3 hours after eating, sometimes awakening him at night. Endoscopic biopsy demonstrates an acute ulcer in the prepyloric region of the stomach. Which of the following is most likely to be associated with this finding?

A. Blood group A

B. Congenital pyloric stenosis

C. Esophageal varices

D. Gastric carcinoma

E. Helicobacter pylori infection

[2.3] A 55-year-old woman seeks medical attention for fatigue and malaise that have been worsening over the last 2 months. She also has noticed loss of appetite and early satiety. Evaluation reveals an ulcerative mass located along the lesser curvature, and a biopsy shows an infiltrating adenocarcinoma. Further evaluation by abdominal CT imaging shows bilateral ovarian masses. Which of the following is this patient most likely to have?

A. Barrett mucosa

B. Krukenberg tumor

C. Primary ovarian neoplasm

D. Uterine cancer

ANSWERS

[2.1] A. Chronic atropic gastritis often is associated with autoantibodies to parietal cells. Loss of these cells leads to decreased gastric acid (hypochlorohydria) and decreased intrinsic factor. Lack of intrinsic factor results in deceased or absent vitamin B₁₂ absorption (pernicious anemia).

[2.2] E. Helicobacter pylori infection is closely associated with peptic ulcer disease as well as gastric carcinoma and lymphoma.

[2.3] B. The findings suggest that the patient's gastric cancer has metastasized to the ovaries; this is known as a Krukenberg tumor. Histology typically shows "signet ring" cells.

REFERENCES

Del Valle J. Peptic ulcer disease and related disorders. In: Kasper DL, Fauci AS, Longo DL, et al., eds. Harrison's principles of internal medicine, 16th ed. New York: McGraw-Hill, 2004:1746-1762.

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, 2004:804-809, 816-827.

PATHOLOGY CASE 1

PATHOLOGY CASE 1

INTRODUCTION

A 42-year-old policeman has been seen by his family physician for "heartburn" of 5 years' duration. He has been intermittently taking ranitidine, a histamine-2 blocking agent, with some relief. An upper endoscopic examination that was performed recently revealed some reddish discoloration and friability of the lower esophageal region. A biopsy of the lower esophagus was performed, and the microscopic examination revealed columnar cells containing goblet cells.

· What is the most likely diagnosis?

· What is a long-term complication of this process?

· What is the most likely mechanism of this process?

ANSWERS TO CASE 1: Barrett Esophagus

Summary: A 42-year-old man has a 5-year history of heartburn unrelieved by a histamine-2 blocking agent. Upper endoscopy reveals reddish discoloration of the distal esophagus, which on biopsy shows columnar epithelium with goblet cells.

· Most likely diagnosis: Barrett esophagus.

· Long-term complication of this process: Adenocarcinoma of the esophagus.

· Most likely mechanism: Repeated acid reflux to the distal esophagus leading to metaplasia of the normal squamous epithelium into columnar epithelium.

CLINICAL CORRELATION

Introduction

The normal esophagus is lined by nonkeratinized squamous epithelium. The lower esophageal sphincter (LES) prevents reflux of gastric acid from entering the distal esophagus. With gastroesophageal reflux disease (GERD), decreased lower esophageal sphincter tone can lead to acid exposure of the distal esophagus. Through a poorly understood mechanism, the lower esophagus changes (metaplasia) from squamous to columnar epithelium, so-called Barrett esophagus. In fact, the presence of goblet cells in the columnar epithelium is a hallmark of the disease. Barrett esophagus appears reddish and friable on endoscopy and carries an increased risk for developing into adenocarcinoma.

Approach to Esophageal Pathology

Definitions

Esophageal diverticulum: Outpouching of one or more layers of the esophageal wall. When it occurs near the upper esophageal sphincter, it is called a Zenker diverticulum.

Achalasia: Condition of esophageal dilation resulting from lack of esophageal peristalsis and constant contraction of the lower esophageal sphincter associated with a loss of myenteric plexus ganglions. Affected patients complain of dysphagia (difficulty swallowing).

Gastroesophageal reflux: Condition in which gastric acid enters the distal esophagus, usually associated with decreased lower esophageal sphincter pressure. Affected patients often complain of "heartburn" that is relieved by antacids. Long-term complications of GERD include Barrett esophagus, stricture, and ulceration.

Barrett esophagus: Columnar metaplasia of the lower esophageal epithelium, predisposing to esophageal adenocarcinoma.

Esophagitis: Inflammation of the esophagus caused by GERD, infection (Candida, herpes simplex virus, cytomegalovirus), radiation, or uremia.

Hiatal hernia: Gastroesophageal defect in which a part of the stomach protrudes above the diaphragm, usually adjacent to the distal esophagus; may be associated with GERD.

Esophageal carcinoma: Worldwide, squamous cell carcinoma is the most common cell type, but in Western countries, it is divided equally in frequency between adenocarcinoma and squamous cell carcinoma. Patients typically complain of dysphagia, weight loss, and fatigue.

Discussion

Normal Esophagus

The esophagus is a muscular tube that connects the pharynx to the stomach that is lined by squamous epithelium. It has a well-developed submucosa, and the upper third is enveloped by striated muscle, whereas the lower two-thirds is encompassed by smooth muscle. The upper esophageal sphincter is located at approximately the level of the fifth cervical vertebra (C5) level, whereas the lower esophageal sphincter is located below the diaphragm and functions to prevent regurgitation of gastric acid. During the swallowing process peristalsis is initiated in the striated muscle and continues down through the smooth muscle with a coordinated temporary relaxation of the LES. Both sympathetic and parasympathetic nerve fibers innervate the intrinsic myenteric plexus, which is distributed in the striated and smooth muscle.

Congenital Anomalies

Tracheoesophageal (TE) fistulae are congenital disorders that manifest in affected newborns as hypersalivation and difficulty feeding with choking. The most common type (90 percent) involves distal esophageal atresia with a connection to the trachea. Maternal polyhydramnios may be noted in utero, resulting from the fetal inability to swallow amniotic fluid. Less common varieties of TE fistulae may involve a fistula and patent esophagus (so-called H type) or a higher location of the fistula. Recognition and surgical repair are critical.

Achalasia

Achalasia is characterized by progressive dilation of the distal esophagus caused by disturbance of the normal peristaltic process. This nearly always involves a loss of myenteric ganglion cells, although the underlying etiology is unclear. Patients typically have increased LES pressure and complain of progressive dysphagia and vomiting of partially digested or undigested food. The diagnosis is established by endoscopy or upper gastrointestinal barium swallow imaging (so-called bird's beak finding).

GERD and Barrett Esophagus

Esophagitis, or inflammation of the esophagus, has multiple etiologies and often is associated with chest pain, dysphagia, and painful swallowing. By far, the most common cause of esophagitis is gastroesophageal reflux, which may be associated with a hiatal hernia. With chronic acid exposure, the distal esophagus may become hyperemic and ulcerated and develop scars or strictures. Persistent GERD may lead to a benign epithelial change (metaplasia) of the distal esophagus; the normal squamous cell epithelium becomes columnar with the presence of intestinal goblet cells, so-called Barrett esophagus. Barrett esophagus appears reddish and friable on endoscopy and is diagnosed by biopsy; endoscopic surveillance is important because of the increased risk for developing adenocarcinoma.

Esophageal Carcinoma

Esophageal cancers account for about 10 percent of all gastrointestinal cancers in the United States and are largely asymptomatic. Familial influences are not as important as environmental exposures. Chronic alcohol and tobacco exposures significantly increase the risk of esophageal cancer. Other factors may include ingestion of nitrosamine-containing foods, chronic hot and spicy foods, and lye with stricture formation. The most common cell type worldwide is squamous cell carcinoma, usually affecting the upper and middle thirds of the esophagus. In the United States, as a result of decreased tobacco use and an increased prevalence of GERD, adenocarcinoma of the distal esophagus is encountered commonly. Periodic endoscopic surveillance with biopsy for patients with chronic GERD may identify the cancer at an early stage. Regardless of cell type, affected patients generally have few symptoms until late in the course, with those symptoms being progressive dysphagia, weight loss, and fatigue. Because the cancers are usually very large at diagnosis, surgical resection is difficult, and up to 80 percent of affected individuals die within 1 year of diagnosis.

COMPREHENSION QUESTIONS

[1.1] A 55-year-old salesman is noted to have a cancer of the lower third of the esophagus. He is a nonsmoker and occasionally drinks alcohol. Which of the following is the most likely cell type?

A. Adenocarcinoma

B. Melanoma

C. Metastatic cancer

D. Sarcoma

E. Squamous cell carcinoma

[1.2] An 18-year-old man presents with difficulty swallowing over the last 3 days. He denies ingestion of unusual substances and complains of pain even when swallowing liquids. He is an intravenous (IV) drug user and has been taking several medications to "help his immunity." Which of the following is the most likely finding on esophageal endoscopy?

A. Brown blotches scattered throughout the esophagus

B. Normal-appearing esophagus

C. Red patches in the distal esophagus

D. Reddish streaks throughout the pharynx and upper esophagus

E. White patches adherent to the esophagus

[1.3] A newborn male is noted to have difficulty feeding and "turns blue and chokes when drinking formula." The prenatal records reveal that the amniotic fluid appeared normal on ultrasound. A pediatric feeding tube is passed orally to 20 cm without difficulty, with gastric secretions aspirated. Which of the following is the most likely diagnosis?

A. Congenital heart disease

B. Floppy epiglottis

C. Respiratory distress syndrome

D. Tracheoesophageal fistula

E. Zenker diverticulum

ANSWERS

[1.1] A. Adenocarcinoma is the most common malignancy of the lower third of the esophagus and is strongly associated with Barrett esophagus. Squamous cell carcinoma is the most common type of cancer of the esophagus worldwide and usually affects the upper or middle region of the esophagus.

[1.2] E. This patient probably has HIV, and the clinical syndrome of painful and difficult swallowing is consistent with Candida esophagitis. Endoscopy probably would reveal white plaques adherent to the esophagus. Other causes of esophagitis include herpes simplex infection, cytomegalovirus (CMV) infection, and chemical-induced conditions such as those resulting from lye (suicide attempt).

[1.3] D. The vast majority newborns with TE fistulae involve a nonpatent esophagus that is diagnosed by the inability to pass a feeding tube. However, the baby in this case most likely has an unusual type of TE fistula (H type) in which the esophagus is patent but there is a connection between the esophagus and the trachea. When the baby feeds, the formula is aspirated into the tracheobronchial tree, leading to choking and cyanosis. This condition may be diagnosed with a radiologic contrast study and requires surgical correction.

PATHOLOGY PEARLS

· The normal esophagus is lined with nonkeratinized squamous epithelium.

· Gastric acid reflux into the distal esophagus may cause esophagitis, and a patient with gastroesophageal reflux disease typically complains of heartburn.

· GERD usually is treated with histamine-2 blocking agents or proton pump inhibitors, which decrease the gastric acid production.

· Long-standing GERD may lead to columnar metaplasia of the lower esophageal epithelium, so-called Barrett esophagus, which has a propensity for developing into adenocarcinoma.

· Worldwide, the most common type of esophageal cancer is squamous cell carcinoma, whereas in Western countries, adenocarcinoma is increasing in incidence because of the prevalence of GERD and Barrett esophagus.

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, 2005:804-809.

Rubin E. Essential pathology, 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 2001.

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Applying the Basic Sciences to Clinical Medicine

Applying the Basic Sciences to Clinical Medicine

PART 1. APPROACH TO LEARNING PATHOLOGY

Pathology is best learned by a systematic approach, first by learning the language of the discipline and then by understanding the function of the various processes. Increasingly, the understanding of cell and organ function plays an important role in the understanding of disease processes and the treatment of disease. Initially, some of the "language" must be memorized in the same way that the alphabet must be learned by rote; however, the appreciation of the way the "pathology words" are constructed requires an understanding of mechanisms, in essence, an awareness of "how things are put together and work together."

PART 2. APPROACH TO DISEASE

Physicians usually approach clinical situations by taking a history (asking questions), performing a physical examination, obtaining selected laboratory and imaging tests, and then formulating a diagnosis. The conglomeration of the history, physical examination, and laboratory tests is called the clinical database. After a diagnosis has been reached, a treatment plan usually is initiated, and the patient is followed for a clinical response. Rational understanding of disease and plans for treatment are best acquired by learning about the normal human processes on a basic science level, and likewise, being aware of how disease alters the normal physiologic processes is understood on a basic science level. In short, clinical problem solving involves three basic steps: (1) making a diagnosis, (2) initiating a therapy, and (3) monitoring the patient's response.

PART 3. APPROACH TO READING

There are seven key questions that help to stimulate the application of basic science information to the clinical setting.

1. Given histologic findings in an organ, what are the most likely clinical manifestations?

2. Given clinical symptoms, if a tissue biopsy is taken, what histologic findings are most likely to be seen?

3. Given clinical findings, if the microscopic photograph is shown, what is the most likely diagnosis?

4. Given a histologic description, what would be the most likely complication to the organ in question?

5. Given a gross description of a pathologic lesion, what is the most likely diagnosis?

6. Given autopsy findings, what is the most likely diagnosis?

7. Given histologic findings, what is the most likely explanation?

1. Given histologic findings in an organ, what are the most likely clinical manifestations?

This is a fundamental principle in the understanding of the discipline of pathology. The student first must understand the normal histologic structure in an organ in the context of its function. Then the student must be able to relate the abnormal histology to clinical findings, both subjective (patient complaints) and objective (physical examination findings). The organ or system is highly organized both on the gross and on the microscopic level. There also must be awareness of the mechanism that causes disruption of the normal cellular architecture.

2. Given clinical symptoms, if a tissue biopsy is taken, what histologic findings are most likely to be seen?

This is the converse of the first question and requires going backward from clinical manifestations to the probable disease process to probable histologic findings. The student must be able to translate the clinical picture to the cellular characteristics. This also requires being aware of what symptoms various cellular alterations will produce in the patient; for instance, some changes will be silent and not cause symptoms, whereas other changes will produce dramatic manifestations.

3. Given clinical findings, if the microscopic photograph is shown, what is the most likely diagnosis?

This sequence of analysis is very similar to the practice of "real-life" medicine, the role of the pathologist. The clinical history and physical examination are critical to putting the pathologic findings into context. For instance, if endometrial curettings are sent to the pathologist and on microscopy reveal crowded, complex glands, abnormal epithelial nuclei, and loss of nuclear polarity, the pathologist may render a diagnosis of cancer. However, when the information is given that the patient is 6 weeks pregnant, the diagnosis of an Arias-Stella reaction is made, an expected finding in the endometrium in light of the human chorionic gonadotropin levels of pregnancy. The next logical step is to propose a treatment. Thus, the student should be able to shift back and forth between the basic science and the clinical areas:

Pathophysiology « Histologic Findings « Diagnoisis « Treatment

4. Given a histologic description, what would be the most likely complication to the organ in question?

This analysis requires that the student be able to relate the histologic findings of one organ to a disease process and then extrapolate the probable changes to another organ. The student should become proficient at working back and forth between histologic changes and clinical findings and disease processes. The best way to acquire this skill is to think in terms of mechanisms of disease and not just memorize key words. It is the understanding of the underlying pathophysiology of the disease that allows the physician-scientist to make rational predictions of the natural history of a disease process.

5. Given a gross description of a pathologic lesion, what is the most likely diagnosis?

The student of pathology also must be able to process the visual picture of the organ, biopsy specimen, or cytology, as well as the written description. Because the pathologist often communicates with clinicians by using written reports, the student should be able to take the written description and apply that information to the clinical setting, such as making a diagnosis. For instance, if the description is that of an ovarian cyst with sebaceous material, hair, and teeth, the most likely diagnosis is a benign cystic teratoma.

6. Given autopsy findings, what is the most likely diagnosis?

This question is similar to the analysis performed by working back from gross pathologic description to the diagnosis. In cases of a patient's death, an autopsy often will be helpful in explaining the circumstances surrounding the death, or the etiology. The student of pathology must be able to correlate the postmortem examination with the probable diagnosis and be able to speculate about the interaction between disease and host. For example, the case may involve a 30-year-old female who suddenly collapses and dies, and the autopsy reveals a dilated aortic root and aortic dissection; other findings include long extremities and long fingers. The most likely diagnosis is Marfan syndrome.

7. Given histologic findings, what is the most likely explanation?

The student once again is challenged to relate the histologic findings in the context of scientific explanation and not just memorize the histologic findings of a certain disease. For example, the histologic specimen may reveal a pulmonary lesion with an area of central necrosis surrounded by epitheliod and multinucleated giant cells. The explanation would be that the organism is probably Mycobacterium tuberculae, which evades phagocytosis from macrophages because it has complement C3b antigen on its cell wall. It is incorporated into the macrophage, and the tuberculosis bacterium blocks fusion of the lysosome with the phagosome, allowing the bacterium to multiply within the macrophage. The responding T cells produce cytokines such as interferon type II (IF-2) to activate other T cells and interferon gamma (IFN-gamma), which activates macrophages, transforming them into epitheloid cells and multinucleated giant cells. Thus, it is delayed or cell-mediated immunity that is required to address the infection. The monocyte response, dictated by the type IV hypersensitivity reaction of cell-mediated immunity, leads to the caseous necrosis (acellular debris in the center), as well as the granulomatous reaction. The cell-mediated immune response also explains the need to wait 48 to 72 hours for a skin response to the purified protein derivative (PPD) test to assess for prior exposure (sensitivity) to tuberculosis.

PATHOLOGY PEARLS

· There are seven key questions to stimulate the application of basic science information to the clinical arena.

· Medicine is both an art and a science.

· The scientific aspect of medicine seeks to gather data in an objective manner, understand physiologic and pathologic processes in light of scientific information, and propose rational explanations.

· A skilled clinician must be able to translate back and forth between the basic sciences and the clinical sciences.

REFERENCES

Kumar V, Abbas AK, Fausto N. Acute and chronic inflammation. In: Robbins and Cotran pathologic basis of disease, 7th ed. Philadelphia: Elsevier Saunders, 2005:48-83.

Mark DB. Decision making in medicine. In: Kasper DL, Fauci AS, Longo DL, et al., eds. Harrison's principles of internal medicine, 16th ed. New York: McGraw-Hill, 2004:6-13.

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