(BQ) Part 1 book Robbins basic pathology presentation of content: Oral cavity and gastrointestinal tract, male genital system and lower urinary tract, female genital system and breast, endocrine system, peripheral nerves and muscles, central nervous system,...and other contents.
See Targeted Therapy available online at studentconsult.com Oral Cavity and Gastrointestinal Tract C H A P T E R 14 C H A P T E R CO N T E N T S ORAL CAVITY 551 Oral Inflammatory Lesions 552 Aphthous Ulcers (Canker Sores) 552 Herpes Simplex Virus Infections 552 Oral Candidiasis (Thrush) 552 Proliferative and Neoplastic Lesions of the Oral Cavity 552 Fibrous Proliferative Lesions 552 Leukoplakia and Erythroplakia 553 Squamous Cell Carcinoma 554 Diseases of Salivary Glands 555 Xerostomia 555 Sialadenitis 555 Neoplasms 555 Odontogenic Cysts and Tumors 557 ESOPHAGUS 558 Obstructive and Vascular Diseases 558 Mechanical Obstruction 558 Functional Obstruction 558 Ectopia 558 Esophageal Varices 559 Esophagitis 559 Lacerations 559 Chemical and Infectious Esophagitis 560 Reflux Esophagitis 560 Eosinophilic Esophagitis 561 Barrett Esophagus 561 Esophageal Tumors 562 Adenocarcinoma 562 Squamous Cell Carcinoma 563 STOMACH 564 Inflammatory Disease of the Stomach 564 Acute Gastritis 564 Acute Peptic Ulceration 565 Chronic Gastritis 566 Peptic Ulcer Disease 568 Neoplastic Disease of the Stomach 569 Gastric Polyps 569 Gastric Adenocarcinoma 570 Lymphoma 571 Carcinoid Tumor 571 Gastrointestinal Stromal Tumor 572 SMALL AND LARGE INTESTINES 573 Intestinal Obstruction 573 The gastrointestinal tract is a hollow tube consisting of the esophagus, stomach, small intestine, colon, rectum, and anus Each region has unique, complementary, and highly integrated functions that together serve to regulate the intake, processing, and absorption of ingested nutrients and the disposal of waste products The intestines also are the principal site at which the immune system interfaces with a diverse array of antigens present in food and gut microbes Thus, it is not surprising that the Hirschsprung Disease 573 Abdominal Hernia 574 Vascular Disorders of Bowel 574 Ischemic Bowel Disease 574 Hemorrhoids 576 Diarrheal Disease 576 Malabsorptive Diarrhea 576 Infectious Enterocolitis 580 Inflammatory Intestinal Disease 586 Sigmoid Diverticulitis 586 Inflammatory Bowel Disease 587 Colonic Polyps and Neoplastic Disease 592 Inflammatory Polyps 592 Hamartomatous Polyps 592 Hyperplastic Polyps 593 Adenomas 593 Familial Syndromes 595 Adenocarcinoma 596 APPENDIX 600 Acute Appendicitis 600 Tumors of the Appendix 601 small intestine and colon frequently are involved by infectious and inflammatory processes Finally, the colon is the most common site of gastrointestinal neoplasia in Western populations In this chapter we discuss the diseases that affect each section of the gastrointestinal tract Disorders that typically involve more than one segment, such as Crohn disease, are considered with the most frequently involved region ORAL CAVITY Pathologic conditions of the oral cavity can be broadly divided into diseases affecting the oral mucosa, salivary glands, and jaws Discussed next are the more common conditions affecting these sites Although common, disorders affecting the teeth and supporting structures are not considered here Reference should be made to specialized texts Odontogenic cysts and tumors (benign and malignant), which are derived from the epithelial and/or 552 C H A P T E R 14 Oral Cavity and Gastrointestinal Tract mesenchymal tissues associated with tooth development, also are discussed briefly ORAL INFLAMMATORY LESIONS Aphthous Ulcers (Canker Sores) These common superficial mucosal ulcerations affect up to 40% of the population They are more common in the first two decades of life, extremely painful, and recurrent Although the cause of aphthous ulcers is not known, they tend to be more prevalent within some families and may be associated with celiac disease, inflammatory bowel disease (IBD), and Behỗet disease Lesions can be solitary or multiple; typically, they are shallow, hyperemic ulcerations covered by a thin exudate and rimmed by a narrow zone of erythema (Fig 14–1) In most cases they resolve spontaneously in to 10 days but can recur Herpes Simplex Virus Infections Most orofacial herpetic infections are caused by herpes simplex virus type (HSV-1), with the remainder being caused by HSV-2 (genital herpes) With changing sexual practices, oral HSV-2 is increasingly common Primary infections typically occur in children between and years of age and are often asymptomatic However, in 10% to 20% of cases the primary infection manifests as acute herpetic gingivostomatitis, with abrupt onset of vesicles and ulcerations throughout the oral cavity Most adults harbor latent HSV-1, and the virus can be reactivated, resulting in a so-called “cold sore” or recurrent herpetic stomatitis Factors associated with HSV reactivation include trauma, allergies, exposure to ultraviolet light, upper respiratory tract infections, pregnancy, menstruation, immunosuppression, and exposure to extremes of temperature These recurrent lesions, which occur at the site of primary inoculation or in adjacent mucosa innervated by the same ganglion, typically appear as groups of small (1 to 3 mm) vesicles The lips (herpes labialis), nasal orifices, buccal mucosa, gingiva, and hard palate are the most common locations Although lesions typically resolve within to 10 days, they can persist in immunocompromised patients, who may require systemic antiviral therapy Morphologically, the lesions resemble those seen in esophageal herpes (see Fig 14–8) and genital herpes (Chapter 17) The infected cells become ballooned and have large eosinophilic intranuclear inclusions Adjacent cells commonly fuse to form large multinucleated polykaryons Oral Candidiasis (Thrush) Candidiasis is the most common fungal infection of the oral cavity Candida albicans is a normal component of the oral flora and only produces disease under unusual circumstances Modifying factors include: • Immunosuppression • The strain of C albicans • The composition of the oral microbial flora (microbiota) Broad-spectrum antibiotics that alter the normal micro biota can also promote oral candidiasis The three major clinical forms of oral candidiasis are pseudomembranous, erythematous, and hyperplastic The pseudomembranous form is most common and is known as thrush This condition is characterized by a superficial, curdlike, gray to white inflammatory membrane composed of matted organisms enmeshed in a fibrinosuppurative exudate that can be readily scraped off to reveal an underlying erythematous base In mildly immunosuppressed or debilitated individuals, such as diabetics, the infection usually remains superficial, but can spread to deep sites in association with more severe immunosuppression, including that seen in organ or hematopoietic stem cell transplant recipients, as well as patients with neutropenia, chemotherapy-induced immunosuppression, or AIDS S U M M A RY Oral Inflammatory Lesions • Aphthous ulcers are painful superficial ulcers of unknown etiology that may be associated with systemic diseases • Herpes simplex virus causes a self-limited infection that presents with vesicles (cold sores, fever blisters) that rupture and heal, without scarring, and often leave latent virus in nerve ganglia Reactivation can occur • Oral candidiasis may occur when the oral microbiota is altered (e.g., after antibiotic use) Invasive disease may occur in immunosuppressed individuals PROLIFERATIVE AND NEOPLASTIC LESIONS OF THE ORAL CAVITY Fibrous Proliferative Lesions Figure 14–1 Aphthous ulcer Single ulceration with an erythematous halo surrounding a yellowish fibrinopurulent membrane Fibromas (Fig 14–2, A) are submucosal nodular fibrous tissue masses that are formed when chronic irritation results in reactive connective tissue hyperplasia They Proliferative and Neoplastic Lesions of the Oral Cavity A B Figure 14–2 Fibrous proliferations A, Fibroma Smooth pink exophytic nodule on the buccal mucosa B, Pyogenic granuloma Erythematous hemorrhagic exophytic mass arising from the gingival mucosa occur most often on the buccal mucosa along the bite line and are thought to be reactions to chronic irritation Treatment is complete surgical excision and removal of the source of irritation Pyogenic granulomas (Fig 14–2, B) are pedunculated masses usually found on the gingiva of children, young adults, and pregnant women These lesions are richly vascular and typically are ulcerated, which gives them a red to purple color In some cases, growth can be rapid and raise fear of a malignant neoplasm However, histologic examination demonstrates a dense proliferation of immature vessels similar to that seen in granulation tissue Pyogenic granulomas can regress, mature into dense fibrous masses, or develop into a peripheral ossifying fibroma Complete surgical excision is definitive treatment Leukoplakia and Erythroplakia Leukoplakia is defined by the World Health Organization as “a white patch or plaque that cannot be scraped off and cannot be characterized clinically or pathologically as any other disease.” This clinical term is reserved for lesions that arise in the oral cavity in the absence of any known etiologic factor (Fig 14–3, A) Accordingly, white patches caused by obvious irritation or entities such as lichen planus and candidiasis are not considered leukoplakia Approximately 3% of the world’s population has leukoplakic lesions, of which 5% to 25% are premalignant and may progress to squamous cell carcinoma Thus, until proved otherwise by means of histologic evaluation, all leukoplakias must be considered precancerous A related but less common lesion, erythroplakia, is a red, velvety, possibly eroded area that is flat or slightly depressed relative to the surrounding mucosa Erythroplakia is associated with a much greater risk of malignant transformation than leukoplakia While leukoplakia and erythroplakia may be seen in adults at any age, they typically affect persons between the ages of 40 and 70 years, with a 2 : 1 male preponderance Although the etiology is multifactorial, tobacco use (cigarettes, pipes, cigars, and chewing tobacco) is the most common risk factor for leukoplakia and erythroplakia A B Figure 14–3 Leukoplakia A, Clinical appearance of leukoplakia is highly variable In this example, the lesion is smooth with well-demarcated borders and minimal elevation B, Histologic appearance of leukoplakia showing dysplasia, characterized by nuclear and cellular pleomorphism and loss of normal maturation 553 554 C H A P T E R 14 Oral Cavity and Gastrointestinal Tract MORPHOLOGY Leukoplakia includes a spectrum of histologic features ranging from hyperkeratosis overlying a thickened, acanthotic, but orderly mucosal lesions with marked dysplasia that sometimes merges with carcinoma in situ (Fig 14–3, B) The most severe dysplastic changes are associated with erythroplakia, and more than 50% of these cases undergo malignant transformation With increasing dysplasia and anaplasia, a subjacent inflammatory cell infiltrate of lymphocytes and macrophages is often present Squamous Cell Carcinoma Approximately 95% of cancers of the oral cavity are squamous cell carcinomas, with the remainder largely consisting of adenocarcinomas of salivary glands, as discussed later This aggressive epithelial malignancy is the sixth most common neoplasm in the world today Despite numerous advances in treatment, the overall long-term survival rate has been less than 50% for the past 50 years This dismal outlook is due to several factors, most notably the fact that oral cancer often is diagnosed at an advanced stage Multiple primary tumors may be present at initial diagnosis but more often are detected later, at an estimated rate of 3% to 7% per year; patients who survive years after diagnosis of the initial tumor have up to a 35% chance of developing at least one new primary tumor within that interval The development of these secondary tumors can be particularly devastating for persons whose initial lesions were small Thus, despite a 5-year survival rate greater than 50% for patients with small tumors, these patients often die of second primary tumors Therefore, surveillance and early detection of new premalignant lesions are critical for the long-term survival of patients with oral squamous cell carcinoma The elevated risk of additional primary tumors in these patients has led to the concept of “field cancerization.” This hypothesis suggests that multiple primary tumors develop independently as a result of years of chronic mucosal exposure to carcinogens such as alcohol or tobacco (described next) PATHOGENESIS Squamous cancers of the oropharynx arise through two distinct pathogenic pathways One group of tumors in the oral cavity occurs mainly in persons who are chronic alcohol and tobacco (both smoked and chewed) users Deep sequencing of these cancers has revealed frequent mutations that bear a molecular signature consistent with exposure to carcinogens in tobacco These mutations frequently involve TP53 and genes that regulate the differentiation of squamous cells, such as p63 and NOTCH1 The second group of tumors tends to occur in the tonsillar crypts or the base of the tongue and harbor oncogenic variants of human papillomavirus (HPV), particularly HPV-16 These tumors carry far fewer mutations than those associated with tobacco exposure and often overexpress p16, a cyclin-dependent kinase inhibitor It is predicted that the incidence of HPV-associated oropharyngeal squamous cell carcinoma will surpass that of cervical cancer in the next decade, in part because the anatomic sites of origin—tonsillar crypts, base of tongue, and oropharynx— are not readily accessible or amenable to cytologic screening (unlike the cervix) Notably, the prognosis for patients with HPV-positive tumors is better than for those with HPV-negative tumors The HPV vaccine, which is protective against cervical cancer, offers hope to limit the increasing frequency of HPV-associated oropharyngeal squamous cell carcinoma In India and southeast Asia, chewing of betel quid and paan are important predisposing factors Betel quid is a “witch’s brew” containing araca nut, slaked lime, and tobacco, all wrapped in betel nut leaf It is likely that these tumors arise by a pathway similar to that characterized for tobacco use– associated tumors in the West M O R P H O LO G Y Squamous cell carcinoma may arise anywhere in the oral cavity However, the most common locations are the ventral surface of the tongue, floor of the mouth, lower lip, soft palate, and gingiva (Fig 14–4, A) In early stages, these cancers can appear as raised, firm, pearly plaques or as irregular, roughened, or verrucous mucosal thickenings Either pattern may be superimposed on a background of a leukoplakia or erythroplakia As these lesions enlarge, they typically form ulcerated and protruding masses that have irregular and indurated or rolled borders Histopathologic analysis has shown that squamous cell carcinoma develops from dysplastic precursor lesions Histologic patterns range from well-differentiated keratinizing neoplasms (Fig 14–4, B) to anaplastic, sometimes sarcomatoid tumors However, the degree of histologic differentiation, as determined by the relative degree of keratinization, does not necessarily correlate with biologic behavior Typically, oral squamous cell carcinoma infiltrates locally before it metastasizes The cervical lymph nodes are the most common sites of regional metastasis; frequent sites of distant metastases include the mediastinal lymph nodes, lungs, and liver S U M M A RY Lesions of the Oral Cavity • Fibromas and pyogenic granulomas are common reactive lesions of the oral mucosa • Leukoplakias are mucosal plaques that may undergo malignant transformation • The risk of malignant transformation is greater in erythroplakia (relative to leukoplakia) • A majority of oral cavity cancers are squamous cell carcinomas • Oral squamous cell carcinomas are classically linked to tobacco and alcohol use, but the incidence of HPVassociated lesions is rising Diseases of Salivary Glands relaxant, analgesic, and antihistaminic agents The oral cavity may merely reveal dry mucosa and/or atrophy of the papillae of the tongue, with fissuring and ulcerations, or, in Sjögren syndrome, concomitant inflammatory enlargement of the salivary glands Complications of xerostomia include increased rates of dental caries and candidiasis, as well as difficulty in swallowing and speaking Sialadenitis A B Figure 14–4 Oral squamous cell carcinoma A, Clinical appearance demonstrating ulceration and induration of the oral mucosa B, Histologic appearance demonstrating numerous nests and islands of malignant keratinocytes invading the underlying connective tissue stroma DISEASES OF SALIVARY GLANDS There are three major salivary glands—parotid, submandibular, and sublingual—as well as innumerable minor salivary glands distributed throughout the oral mucosa Inflammatory or neoplastic disease may develop within any of these Xerostomia Xerostomia is defined as a dry mouth resulting from a decrease in the production of saliva Its incidence varies among populations, but has been reported in more than 20% of individuals above the age of 70 years It is a major feature of the autoimmune disorder Sjögren syndrome, in which it usually is accompanied by dry eyes (Chapter 4) A lack of salivary secretions is also a major complication of radiation therapy However, xerostomia is most frequently observed as a result of many commonly prescribed classes of medications including anticholinergic, antidepressant/ antipsychotic, diuretic, antihypertensive, sedative, muscle Sialadenitis, or inflammation of the salivary glands, may be induced by trauma, viral or bacterial infection, or autoimmune disease The most common form of viral sialadenitis is mumps, which may produce enlargement of all salivary glands but predominantly involves the parotids The mumps virus is a paramyxovirus related to the influenza and parainfluenza viruses Mumps produces interstitial inflammation marked by a mononuclear inflammatory infiltrate While mumps in children is most often a selflimited benign condition, in adults it can cause pancreatitis or orchitis; the latter sometimes causes sterility The mucocele is the most common inflammatory lesion of the salivary glands, and results from either blockage or rupture of a salivary gland duct, with consequent leakage of saliva into the surrounding connective tissue stroma Mucocele occurs most often in toddlers, young adults, and the aged, and typically manifests as a fluctuant swelling of the lower lip that may change in size, particularly in association with meals (Fig 14–5, A) Histologic examination demonstrates a cystlike space lined by inflammatory granulation tissue or fibrous connective tissue that is filled with mucin and inflammatory cells, particularly macrophages (Fig 14–5, B) Complete excision of the cyst and the minor salivary gland lobule constitutes definitive treatment Bacterial sialadenitis is a common infection that most often involves the major salivary glands, particularly the submandibular glands The most frequent pathogens are Staphylococcus aureus and Streptococcus viridans Duct obstruction by stones (sialolithiasis) is a common antecedent to infection; it may also be induced by impacted food debris or by edema consequent to injury Dehydration and decreased secretory function also may predispose to bacterial invasion and sometimes are associated with long-term phenothiazine therapy, which suppresses salivary secretion Systemic dehydration, with decreased salivary secretions, may predispose to suppurative bacterial parotitis in elderly patients following major thoracic or abdominal surgery This obstructive process and bacterial invasion lead to a nonspecific inflammation of the affected glands that may be largely interstitial or, when induced by staphylococcal or other pyogens, may be associated with overt suppurative necrosis and abscess formation Autoimmune sialadenitis, also called Sjögren syndrome, is discussed in Chapter Neoplasms Despite their relatively simple morphology, the salivary glands give rise to at least 30 histologically distinct tumors As indicated in Table 14–1, a small number of these neoplasms account for more than 90% of tumors Overall, 555 556 C H A P T E R 14 Oral Cavity and Gastrointestinal Tract salivary gland tumors are relatively uncommon and represent less than 2% of all human tumors Approximately 65% to 80% arise within the parotid, 10% in the submandibular gland, and the remainder in the minor salivary glands, including the sublingual glands Approximately 15% to 30% of tumors in the parotid glands are malignant By contrast, approximately 40% of submandibular, 50% of minor salivary gland, and 70% to 90% of sublingual tumors are cancerous Thus, the likelihood that a salivary gland tumor is malignant is inversely proportional, roughly, to the size of the gland Salivary gland tumors usually occur in adults, with a slight female predominance, but about 5% occur in children younger than 16 years of age Whatever the histologic pattern, parotid gland neoplasms produce swelling in front of and below the ear In general, when they are first diagnosed, both benign and malignant lesions are usually to 6 cm in diameter and are mobile on palpation except in the case of neglected malignant tumors Benign tumors may be present for months to several years before coming to clinical attention, while cancers more often come to attention promptly, probably because of their more rapid growth However, there are no reliable criteria to differentiate A Table 14–1 Histopathologic Classification and Prevalence of the Most Common Benign and Malignant Salivary Gland Tumors Benign Malignant Pleomorphic adenoma (50%) Warthin tumor (5%) Oncocytoma (2%) Cystadenoma (2%) Basal cell adenoma (2%) Mucoepidermoid carcinoma (15%) Acinic cell carcinoma (6%) Adenocarcinoma NOS (6%) Adenoid cystic carcinoma (4%) Malignant mixed tumor (3%) NOS, not otherwise specified Data from Ellis GL, Auclair PL, Gnepp DR: Surgical Pathology of the Salivary Glands, Vol 25: Major Problems in Pathology, Philadelphia, WB Saunders, 1991 benign from malignant lesions on clinical grounds, and histopathologic evaluation is essential Pleomorphic Adenoma Pleomorphic adenomas present as painless, slow-growing, mobile discrete masses They represent about 60% of tumors in the parotid, are less common in the submandibular glands, and are relatively rare in the minor salivary glands Pleomorphic adenomas are benign tumors that consist of a mixture of ductal (epithelial) and myoepithelial cells, so they exhibit both epithelial and mesenchymal differentiation Epithelial elements are dispersed throughout the matrix, which may contain variable mixtures of myxoid, hyaline, chondroid (cartilaginous), and even osseous tissue In some pleomorphic adenomas, the epithelial elements predominate; in others, they are present only in widely dispersed foci This histologic diversity has given rise to the alternative, albeit less preferred name mixed tumor The tumors consistently overexpress the transcription factor PLAG1, often because of chromosomal rearrangements involving the PLAG1 gene, but how PLAG1 contributes to tumor development is unknown Pleomorphic adenomas recur if incompletely excised: Recurrence rates approach 25% after simple enucleation of the tumor, but are only 4% after wider resection In both settings, recurrence stems from a failure to recognize minute extensions of tumor into surrounding soft tissues Carcinoma arising in a pleomorphic adenoma is referred to variously as a carcinoma ex pleomorphic adenoma or malignant mixed tumor The incidence of malignant transformation increases with time from 2% of tumors present for less than years to almost 10% for those present for more than 15 years The cancer usually takes the form of an adeno carcinoma or undifferentiated carcinoma Unfortunately, these are among the most aggressive malignant neoplasms of salivary glands, with mortality rates of 30% to 50% at years M O R P H O LO G Y B Figure 14–5 Mucocele A, Fluctuant fluid-filled lesion on the lower lip subsequent to trauma B, Cystlike cavity (right) filled with mucinous material and lined by organizing granulation tissue Pleomorphic adenomas typically manifest as rounded, welldemarcated masses rarely exceeding 6 cm in the greatest dimension Although they are encapsulated, in some locations (particularly the palate), the capsule is not fully developed, and expansile growth produces protrusions into the surrounding tissues The cut surface is gray-white and typically contains myxoid and blue translucent chondroid (cartilage-like) areas The most striking histologic feature is their characteristic heterogeneity Epithelial Odontogenic Cysts and Tumors Clinical course and prognosis depend on histologic grade Low-grade tumors may invade locally and recur in about 15% of cases but metastasize only rarely and afford a 5-year survival rate over 90% By contrast, high-grade neoplasms and, to a lesser extent, intermediate-grade tumors are invasive and difficult to excise As a result, they recur in 25% to 30% of cases, and about 30% metastasize to distant sites The 5-year survival rate is only 50% A B Figure 14–6 Pleomorphic adenoma A, Low-power view showing a well-demarcated tumor with adjacent normal salivary gland parenchyma B, High-power view showing epithelial cells as well as myoepithelial cells within chondroid matrix material elements resembling ductal or myoepithelial cells are arranged in ducts, acini, irregular tubules, strands, or even sheets These typically are dispersed within a mesenchymelike background of loose myxoid tissue containing islands of chondroid and, rarely, foci of bone (Fig 14–6) Sometimes the epithelial cells form well-developed ducts lined by cuboidal to columnar cells with an underlying layer of deeply chromatic, small myoepithelial cells In other instances there may be strands or sheets of myoepithelial cells Islands of well-differentiated squamous epithelium also may be present In most cases, no epithelial dysplasia or mitotic activity is evident No difference in biologic behavior has been observed between the tumors composed largely of epithelial elements and those composed largely of mesenchymal elements Mucoepidermoid Carcinoma Mucoepidermoid carcinomas are composed of variable mixtures of squamous cells, mucus-secreting cells, and intermediate cells These neoplasms represent about 15% of all salivary gland tumors, and while they occur mainly (60% to 70%) in the parotids, they account for a large fraction of salivary gland neoplasms in the other glands, particularly the minor salivary glands Overall, mucoepidermoid carcinoma is the most common form of primary malignant tumor of the salivary glands It is commonly associated with chromosome rearrangements involving MAML2, a gene that encodes a signaling protein in the Notch pathway MORPHOLOGY Mucoepidermoid carcinomas can grow as large as 8 cm in diameter and, although they are apparently circumscribed, they lack well-defined capsules and often are infiltrative The cut surface is pale gray to white and frequently demonstrates small, mucinous cysts On histologic examination, these tumors contain cords, sheets, or cysts lined by squamous, mucous, or intermediate cells The latter is a hybrid cell type with both squamous features and mucus-filled vacuoles, which are most easily detected with mucin stains Cytologically, tumor cells may be benign-appearing or highly anaplastic and unmistakably malignant On this basis, mucoepidermoid carcinomas are subclassified as low-, intermediate-, or high-grade S U M M A RY Diseases of Salivary Glands • Sialadenitis (inflammation of the salivary glands) can be caused by trauma, infection (such as mumps), or an autoimmune reaction • Pleomorphic adenoma is a slow-growing neoplasm composed of a heterogeneous mixture of epithelial and mesenchymal cells • Mucoepidermoid carcinoma is a malignant neoplasm of variable biologic aggressiveness that is composed of a mixture of squamous and mucous cells ODONTOGENIC CYSTS AND TUMORS In contrast with other skeletal sites, epithelium-lined cysts are common in the jaws A majority of these cysts are derived from remnants of odontogenic epithelium In general, these cysts are subclassified as either inflammatory or developmental Only the most common of these lesions are considered here The dentigerous cyst originates around the crown of an unerupted tooth and is thought to be the result of a degeneration of the dental follicle (primordial tissue that makes the enamel surface of teeth) On radiographic evaluation, these unilocular lesions most often are associated with impacted third molar (wisdom) teeth They are lined by a thin, stratified squamous epithelium that typically is associated with a dense chronic inflammatory infiltrate within the underlying connective tissue Complete removal is curative Odontogenic keratocysts can occur at any age but are most frequent in persons between 10 and 40 years of age, have a male predominance, and typically are located within the posterior mandible Differentiation of the odontogenic keratocyst from other odontogenic cysts is important because it is locally aggressive and has a high recurrence rate On radiographic evaluation, odontogenic keratocysts are seen as well-defined unilocular or multilocular radiolucencies On histologic examination, the cyst lining consists of a thin layer of parakeratinized or orthokeratinized stratified squamous epithelium with a prominent basal cell layer and a corrugated luminal epithelial surface Treatment requires aggressive and complete removal; recurrence rates of up to 60% are associated with inadequate resection Multiple odontogenic keratocysts may occur, particularly in patients with the nevoid basal cell carcinoma syndrome (Gorlin syndrome) In contrast with the developmental cysts just described, the periapical cyst has an inflammatory etiology These 557 558 C H A P T E R 14 Oral Cavity and Gastrointestinal Tract extremely common lesions occur at the tooth apex as a result of long-standing pulpitis, which may be caused by advanced caries or trauma Necrosis of the pulpal tissue, which can traverse the length of the root and exit the apex of the tooth into the surrounding alveolar bone, can lead to a periapical abscess Over time, granulation tissue (with or without an epithelial lining) may develop These are often designated periapical granuloma Although the lesion does not show true granulomatous inflammation, old terminology, like bad habits, is difficult to shed Periapical inflammatory lesions persist as a result of bacteria or other offensive agents in the area Successful treatment, therefore, necessitates the complete removal of the offending material followed by restoration or extraction of the tooth Odontogenic tumors are a complex group of lesions with diverse histologic appearances and clinical behaviors Some are true neoplasms, either benign or malignant, while others are thought to be hamartomatous Odontogenic tumors are derived from odontogenic epithelium, ectomesenchyme, or both The two most common and clinically significant tumors are ameloblastoma and odontoma Ameloblastomas arise from odontogenic epithelium and not demonstrate chondroid or osseous differentiation These typically cystic lesions are slow-growing and, despite being locally invasive, have an indolent course Odontoma, the most common type of odontogenic tumor, arises from epithelium but shows extensive deposition of enamel and dentin Odontomas are cured by local excision S U M M A RY Odontogenic Cysts and Tumors • The jaws are a common site of epithelium-lined cysts derived from odontogenic remnants • The odontogenic keratocyst is locally aggressive, with a high recurrence rate • The periapical cyst is a reactive, inflammatory lesion associated with caries or dental trauma • The most common odontogenic tumors are ameloblastoma and odontoma ESOPHAGUS The esophagus develops from the cranial portion of the foregut It is a hollow, highly distensible muscular tube that extends from the epiglottis to the gastroesophageal junction, located just above the diaphragm Acquired diseases of the esophagus run the gamut from lethal cancers to “heartburn,” with clinical manifestations ranging from chronic and incapacitating disease to mere annoyance OBSTRUCTIVE AND VASCULAR DISEASES Mechanical Obstruction Atresia, fistulas, and duplications may occur in any part of the gastrointestinal tract When they involve the esophagus, they are discovered shortly after birth, usually because of regurgitation during feeding, and must be corrected promptly Absence, or agenesis, of the esophagus is extremely rare Atresia, in which a thin, noncanalized cord replaces a segment of esophagus, is more common Atresia occurs most commonly at or near the tracheal bifurcation and usually is associated with a fistula connecting the upper or lower esophageal pouches to a bronchus or the trachea This abnormal connection can result in aspiration, suf focation, pneumonia, or severe fluid and electrolyte imbalances Passage of food can be impeded by esophageal stenosis The narrowing generally is caused by fibrous thickening of the submucosa, atrophy of the muscularis propria, and secondary epithelial damage Stenosis most often is due to inflammation and scarring, which may be caused by chronic gastroesophageal reflux, irradiation, or caustic injury Stenosisassociated dysphagia usually is progressive; difficulty eating solids typically occurs long before problems with liquids Functional Obstruction Efficient delivery of food and fluids to the stomach requires a coordinated wave of peristaltic contractions Esophageal dysmotility interferes with this process and can take several forms, all of which are characterized by discoordinated contraction or spasm of the muscularis Because it increases esophageal wall stress, spasm also can cause small diverticula to form Increased lower esophageal sphincter (LES) tone can result from impaired smooth muscle relaxation with consequent functional esophageal obstruction Achalasia is characterized by the triad of incomplete LES relaxation, increased LES tone, and esophageal aperistalsis Primary achalasia is caused by failure of distal esophageal inhibitory neurons and is, by definition, idiopathic Degenerative changes in neural innervation, either intrinsic to the esophagus or within the extraesophageal vagus nerve or the dorsal motor nucleus of the vagus, also may occur Secondary achalasia may arise in Chagas disease, in which Trypanosoma cruzi infection causes destruction of the myenteric plexus, failure of LES relaxation, and esophageal dilatation Duodenal, colonic, and ureteric myenteric plexuses also can be affected in Chagas disease Achalasia-like disease may be caused by diabetic autonomic neuropathy; infiltrative disorders such as malignancy, amyloidosis, or sarcoidosis; and lesions of dorsal motor nuclei, which may be produced by polio or surgical ablation Ectopia Ectopic tissues (developmental rests) are common in the gastrointestinal tract The most frequent site of ectopic gastric mucosa is the upper third of the esophagus, where it is referred to as an inlet patch Although the presence of such tissue generally is asymptomatic, acid released by gastric Esophagitis mucosa within the esophagus can result in dysphagia, esophagitis, Barrett esophagus, or, rarely, adenocarcinoma Gastric heterotopia, small patches of ectopic gastric mucosa in the small bowel or colon, may manifest with occult blood loss secondary to peptic ulceration of adjacent mucosa Esophageal Varices Instead of returning directly to the heart, venous blood from the gastrointestinal tract is delivered to the liver via the portal vein before reaching the inferior vena cava This circulatory pattern is responsible for the first-pass effect, in which drugs and other materials absorbed in the intestines are processed by the liver before entering the systemic circulation Diseases that impede this flow cause portal hypertension, which can lead to the development of esophageal varices, an important cause of esophageal bleeding A B PATHOGE NESIS One of the few sites where the splanchnic and systemic venous circulations can communicate is the esophagus Thus, portal hypertension induces development of collateral channels that allow portal blood to shunt into the caval system However, these collateral veins enlarge the subepithelial and submucosal venous plexi within the distal esophagus These vessels, termed varices, develop in 90% of cirrhotic patients, most commonly in association with alcoholic liver disease Worldwide, hepatic schistosomiasis is the second most common cause of varices A more detailed consideration of portal hypertension is given in Chapter 15 MORPHOLOGY Varices can be detected by angiography (Fig 14–7, A) and appear as tortuous dilated veins lying primarily within the submucosa of the distal esophagus and proximal stomach Varices may not be obvious on gross inspection of surgical or postmortem specimens, because they collapse in the absence of blood flow (Fig 14–7, B) The overlying mucosa can be intact (Fig 14–7, C) but is ulcerated and necrotic if rupture has occurred Clinical Features Varices often are asymptomatic, but their rupture can lead to massive hematemesis and death Variceal rupture therefore constitutes a medical emergency Despite intervention, as many as half of the patients die from the first bleeding episode, either as a direct consequence of hemorrhage or due to hepatic coma triggered by the protein load that results from intraluminal bleeding and hypovolemic shock Among those who survive, additional episodes of hemorrhage, each potentially fatal, occur in more than 50% of cases As a result, greater than half of the deaths associated with advanced cirrhosis result from variceal rupture C Figure 14–7 Esophageal varices A, Angiogram showing several tortuous esophageal varices Although the angiogram is striking, endoscopy is more commonly used to identify varices B, Collapsed varices are present in this postmortem specimen corresponding to the angiogram in A The polypoid areas are sites of variceal hemorrhage that were ligated with bands C, Dilated varices beneath intact squamous mucosa ESOPHAGITIS Lacerations The most common esophageal lacerations are MalloryWeiss tears, which are often associated with severe retching or vomiting, as may occur with acute alcohol intoxication Normally, a reflex relaxation of the gastroesophageal musculature precedes the antiperistaltic contractile wave associated with vomiting This relaxation is thought to fail during prolonged vomiting, with the result that refluxing gastric contents overwhelm the gastric inlet and cause the esophageal wall to stretch and tear Patients often present with hematemesis The roughly linear lacerations of Mallory-Weiss syndrome are longitudinally oriented, range in length from millimeters to several centimeters, and usually cross the gastroesophageal junction These tears are superficial and not generally require surgical intervention; healing tends to be rapid and complete By contrast, Boerhaave syndrome, characterized by transmural esophageal tears and mediastinitis, occurs rarely and is a catastrophic event The factors 559 560 C H A P T E R 14 Oral Cavity and Gastrointestinal Tract giving rise to this syndrome are similar to those for Mallory-Weiss tears, but more severe Chemical and Infectious Esophagitis The stratified squamous mucosa of the esophagus may be damaged by a variety of irritants including alcohol, corrosive acids or alkalis, excessively hot fluids, and heavy smoking Medicinal pills may lodge and dissolve in the esophagus, rather than passing into the stomach intact, resulting in a condition termed pill-induced esophagitis Esophagitis due to chemical injury generally causes only self-limited pain, particularly odynophagia (pain with swallowing) Hemorrhage, stricture, or perforation may occur in severe cases Iatrogenic esophageal injury may be caused by cytotoxic chemotherapy, radiation therapy, or graft-versushost disease The morphologic changes are nonspecific with ulceration and accumulation of neutrophils Irradiation causes blood vessel thickening adding some element of ischemic injury Infectious esophagitis may occur in otherwise healthy persons but is most frequent in those who are debilitated or immunosuppressed In these patients, esophageal infection by herpes simplex viruses, cytomegalovirus (CMV), or fungal organisms is common Among fungi, Candida is the most common pathogen, although mucormycosis and aspergillosis may also occur The esophagus may also be involved in desquamative skin diseases such as bullous pemphigoid and epidermolysis bullosa and, rarely, Crohn disease Infection by fungi or bacteria can be primary or com plicate a preexisting ulcer Nonpathogenic oral bacteria frequently are found in ulcer beds, while pathogenic organisms, which account for about 10% of infectious esophagitis cases, may invade the lamina propria and cause necrosis of overlying mucosa Candidiasis, in its most advanced form, is characterized by adherent, graywhite pseudomembranes composed of densely matted fungal hyphae and inflammatory cells covering the esophageal mucosa The endoscopic appearance often provides a clue to the identity of the infectious agent in viral esophagitis Herpesviruses typically cause punched-out ulcers (Fig 14–8, A), and histopathologic analysis demonstrates nuclear viral inclusions within a rim of degenerating epithelial cells at the ulcer edge (Fig 14–8, B) By contrast, CMV causes shallower ulcerations and characteristic nuclear and cytoplasmic inclusions within capillary endothelium and stromal cells (Fig 14–8, C) Immunohistochemical staining for viral antigens can be used as an ancillary diagnostic tool Reflux Esophagitis The stratified squamous epithelium of the esophagus is resistant to abrasion from foods but is sensitive to acid The submucosal glands of the proximal and distal esophagus contribute to mucosal protection by secreting mucin and bicarbonate More important, constant LES tone prevents reflux of acidic gastric contents, which are under positive pressure Reflux of gastric contents into the lower esophagus is the most frequent cause of esophagitis and the most common outpatient gastrointestinal diagnosis in the United B C A Figure 14–8 Viral esophagitis A, Postmortem specimen with multiple herpetic ulcers in the distal esophagus B, Multinucleate squamous cells containing herpesvirus nuclear inclusions C, Cytomegalovirus-infected endothelial cells with nuclear and cytoplasmic inclusions States The associated clinical condition is termed gastroesophageal reflux disease (GERD) PAT H O G E N E S I S Reflux of gastric juices is central to the development of mucosal injury in GERD In severe cases, duodenal bile reflux may exacerbate the damage Conditions that decrease LES tone or increase abdominal pressure contribute to GERD and include alcohol and tobacco use, obesity, central nervous system depressants, pregnancy, hiatal hernia (discussed later), delayed gastric emptying, and increased gastric volume In many cases, no definitive cause is identified M O R P H O LO G Y Simple hyperemia, evident to the endoscopist as redness, may be the only alteration In mild GERD the mucosal histology is often unremarkable With more significant disease, eosinophils are recruited into the squamous mucosa, followed by neutrophils, which usually are associated with more severe injury (Fig 14–9, A) Basal zone hyperplasia ex ceeding 20% of the total epithelial thickness and elongation of lamina propria papillae, such that they extend into the upper third of the epithelium, also may be present Clinical Features GERD is most common in adults older than 40 years of age but also occurs in infants and children The most frequently reported symptoms are heartburn, dysphagia, and, less often, noticeable regurgitation of sour-tasting gastric contents Rarely, chronic GERD is punctuated by attacks of 896 Index Myxomatous mitral valve clinical features of 390–391 degenerative valve disease as 390–391 morphology of 390b, 390f pathogenesis of 390b N Nasopharyngeal carcinoma 513 Natural killer (NK) cell 105, 125–131 as antitumor effector mechanisms 206 Necrosis clinicopathologic correlation examples for 16–18 morphology of 6f, 9b morphology of cell and tissue injury and patterns of 9–11 morphology of 10b–11b, 10f–11f Necrotizing arteriolitis 333b–334b Necrotizing enterocolitis (NEC) discussion of 252, 252f premature infants and 249 preterm birth complications and 251 Necrotizing glomerulonephritis, focal and segmental 353b–354b Necrotizing granulomatous vasculitis 353b–354b, 353f Necrotizing vasculitis 117b Necrotizing vasculitis, acute 128 Necrotizing vasculitis, noninfectious 135 Neoplasia See also Tumor, benign; Tumor, malignant cancer and etiology of 198–204 genetic lesions in 173–176 molecular basis of cancer and 173 process of carcinogenesis and 177 tumor immunity and 204–207 characteristics of 164–169, 169f clinical aspects of 207–213 effects of tumor on host and 207–208 grading/staging of 207–208 laboratory diagnosis of 210–213 summary for 209b–210b discussion of 161–162 epidemiology of 169–172 nomenclature for 162–163, 164t Neoplasm characteristics of differentiation/anaplasia and 164–166 local invasion and 167–168 metastasis and 168–169 rate of growth and 166–167 summary for 169b of the penis 657–658, 658f summary of 658b of the salivary glands 555–557, 556t mucoepidermoid carcinoma as 557 pleomorphic adenoma as 556 Neoplasm, benign differentiation and anaplasia of 164 local invasion and 167f–168f metastasis and 168–169 nomenclature for 162 rate of growth of 166–167 summary for 169b, 169f Neoplasm, embryonal 844–845 medulloblastoma as 844–845 neuroectodermal tumors and 844–845 Neoplasm, malignant differentiation and anaplasia of 164–165, 165f local invasion and 167–168, 167f–168f metastasis and 168–169 nomenclature for 162–163 rate of growth of 166 summary for 169b, 169f Neovascularization 251 Nephritic syndrome acute postinfectious glomerulonephritis as 529 glomerular disease and 529–531 hereditary nephritis as 531 IgA nephropathy as 530–531 renal syndromes and 517–518 summary for 531b Nephritis, hereditary clinical course of 531 morphology of 531b nephritic syndromes and 531 pathogenesis of 531b summary for 531 Nephrolithiasis 518 Nephron loss 523 Nephrosclerosis 333b–334b Nephrotic syndrome amyloidosis and 158 focal segmental glomerulosclerosis as 525–526 and glomerular disease 523–528, 524t membranoproliferative glomerulonephritis and dense deposit disease as 527–528 membranous nephropathy as 526–527 minimal-change disease as 524–525 renal diseases and 518 summary for 528b–529b Nervous system infections of 824–831 epidural and subdural infections of 824–825 meningitis as 825–826 parenchymal infections and 826–831 prion diseases and 831 summary for 832b patterns of injury in morphology of 811b–812b, 812f Neural tube defect 822–823, 823f Neuroblastic 258–259 Neuroblastoma of the adrenal medulla 761 clinical course and prognosis for 259–260, 260t discussion of 258–260 morphology of 259b, 259f summary for 260b Neuroborreliosis 826 Neurodegenerative disease Alzheimer disease as 836–837 amyotrophic lateral sclerosis as 841 of the central nervous system 836–841, 836t frontotemporal lobar degeneration as 838 Huntington disease as 840 Parkinson disease as 839–840 spinocerebellar ataxias as 840–841 summary of 841b–842b Neurofibroma morphology of 808b of peripheral nerve sheath 807–808 Neurofibroma, diffuse 807, 808b Neurofibroma, localized cutaneous 807 Neurofibromatosis type 1 808 Neurofibromatosis type 1, familial 179–180 Neurofibromatosis type (NF2) 806–807 Neurohypophysis See Posterior pituitary syndrome Index Neuromuscular junction, disorders of introduction to 800–801 Lambert-Eaton syndrome as 801 miscellaneous disorders of 801 myasthenia gravis as 800–801 summary for 801b Neuromyelitis optica (NMO) 834 Neuropeptides 49 Neurosyphilis 826 Neutropenia 425–426 Neutrophil extracellular trap (NET) 39, 40f Nevus flammeus 357 Newborn, hemolytic disease in 254 NextGen sequencing 265–266, 267f NF2 187–188 Niemann-Pick disease types A and B 230–231, 230f Niemann-Pick disease types C (NPC) 231 Night blindness 297 Nitric oxide (NO) 49–50 Nodular fasciitis 793 Nomenclature benign tumors and 162 malignant tumors and 162–163 for neoplasia 162–163 Nonalcoholic fatty liver disease (NAFLD) introduction to 625 pathogenesis of 625b summary for 625b Nonbacterial thrombotic endocarditis (NBTE) 394–395, 395f Non-coding RNA (ncRNA) 217–218, 217f Nongonococcal urethritis (NGU) 676 summary for 676b Non-infected vegetation Libman-Sacks endocarditis as 395 nonbacterial thrombotic endocarditis as 394–395 Noninfectious vasculitis anti-endothelial cell antibodies as 350 anti-neutrophil cytoplasmic antibodies as 349–350 immune complex-associated vasculitis as 348–350 Nonspecific interstitial pneumonia (NSIP) 473 Nontuberculous mycobacterial disease as chronic pneumonia 499 Norovirus 585 Noxious stimuli, cellular responses to 1–3, 2f Nuclear transcription factor 180 Numeric abnormality, cytogenetic disorders and 235 Nutmeg liver 368 Nutritional disease anorexia nervosa/bulimia as 295–296 diet and cancer as 306 diet and systemic diseases as 306 discussion of 293–306 malnutrition as 293–294 neurologic illnesses and 835 obesity as 302–305 protein-energy malnutrition as 294–295 summary for 302b Nutritional imbalance, cell injury and O Obesity adipose tissue and 304–305 clinical consequences of 305 gut hormones and 305 leptin and 304 nutritional diseases and 302–305 summary for 305b Obligate intracellular bacteria 311 Obstructive lesion, aortic coarctation and 373–374 Obstructive lung disease asthma as 468–470 bronchiectasis as 470–472 chronic bronchitis as 467 discussion of 463–472, 463t, 464f emphysema as 463–466 Obstructive overinflation 466 Occupational asthma 470 Occupational cancer 171t Oligodendroglioma 843 morphology of 843b–844b, 844f Oligohydramnios sequence 246–247, 247f Oncocytoma 547 Oncofetal antigens 206 Oncogene 173, 182 Oncogene, mutated 204–205 Oncogene addiction 180 Oncology 162 Onion-skin lesion 130 Opsonization 114–115, 115f, 117 Oral candidiasis (thrush) 552 Oral cavity disease of salivary glands and 555–557 odontogenic cysts and tumors of 557–558 oral inflammatory lesions of 552 proliferative and neoplastic lesions of 552–554 summary for 554b Oral contraceptive (OC) 283–284 Oral inflammatory lesion aphthous ulcers as 552 herpes simplex virus infections as 552 oral candidiasis as 552 summary for 552b Organic solvent 276 Organochlorine 276 Organ systems, ionizing radiation effects and 292–293, 292f, 292t Osler-Weber-Rendu disease See Hereditary hemorrhagic telangiectasia Osteitis deformans See Paget disease Osteoarthritis clinical course of 783, 783f the joints and 782–790 morphology of 782b–783b, 782f obesity and 305 pathogenesis of 783b summary for 790 Osteoblastoma 776 morphology of 776b Osteochondroma as cartilage-forming tumors 777–778, 777f clinical features of 778 morphology of 778b summary for 781 Osteogenesis imperfecta (OI) 767–768 Osteoid osteoma as bone-forming tumor 776 morphology of 776b, 776f summary for 781 Osteoma 775–776 Osteomalacia acquired bone disease and 771 morphology of 300b–301b vitamin D and 298–300 Osteomyelitis acquired diseases of bone and 773–774 pyogenic osteomyelitis as 773–774 tuberculous osteomyelitis as 774 897 Index 898 Osteopetrosis 767–768 Osteoporosis acquired bone disease and 768–770, 769t, 772 clinical course of 770 exogenous estrogens and 282–283 morphology of 768b–769b, 769f pathogenesis of 766f, 769b–770b, 769f vitamin D and 299–300 Osteosarcoma bone tumors as 776–777 clinical features of 777 morphology of 776b–777b, 776f pathogenesis of 777b summary for 782 Ostium primum ASD 371b Ostium secundum ASD 371b Outdoor air pollution 272–273 morphology of 273b Ovary follicle and luteal cysts and 695 other tumors of 698–700, 699t polycystic ovarian disease and 695–696 tumors of 696–698 Oxidative stress See Free radicals, oxygen-derived Oxygen deprivation Ozone 272–273, 272t P Paget disease (osteitis deformans) acquired bone disease as 770–771 clinical course of 771 morphology of 770b, 770f pathogenesis of 771b summary for 772 Paget disease, extramammary 683–684, 684f summary of 684 Paget disease of the nipple 710 Panacinar emphysema 464, 464f, 465b Pancarditis 391b Pancreas congenital anomalies of agenesis and 646 annular pancreas as 646 congenital cysts as 646 ectopic pancreas as 646 pancreas divisum as 646 overview of 645 pancreatic neoplasms and 651–654 pancreatitis and 646–651 Pancreas, congenital cysts of 646 Pancreas, ectopic 646 Pancreas, endocrine diabetes mellitus and 739–750 pancreatic neuroendocrine tumors and 751–752 Pancreas divisum 646 Pancreatic abnormality 223–227 Pancreatic carcinoma clinical features of 654 introduction to 652–654 morphology of 653b–654b, 654f pathogenesis of 653b, 653f Pancreatic neoplasm cystic neoplasms as 651–652 intraductal papillary mucinous neoplasms as 652 mucinous cystic neoplasms as 652 serous cystadenomas as 651 pancreatic carcinoma and 652–654 summary for 654b Pancreatic neuroendocrine tumor (PanNET) endocrine pancreas and 751–752 gastrinomas and 752 insulinomas and 751 Pancreatic pseudocyst acute pancreatitis and 649 morphology of 649b, 649f Pancreatitis acute pancreatitis and 646–649 chronic pancreatitis and 649–651 and the pancreas 646–651 summary for 651b Pancreatitis, acute clinical features of 648–649 inflammatory disorders of 646–649, 646t morphology of 647b, 647f pancreatic pseudocysts as 648–649 pathogenesis of 647b–648b, 648f Pancreatitis, chronic clinical features of 651 morphology of 650b, 650f the pancreas and 649–651 pathogenesis of 650b Pancreatitis, hemorrhagic 647b Pancreatitis, lymphoplasmacytic sclerosing 650b Pancytopenia 442–443 Papanicolaou smear See Cytologic (Papanicolaou) smear Papillary carcinoma of the thyroid clinical features of 733 morphology of 732b–733b, 732f summary for 735 the thyroid and 732–733 Papillary fibroelastoma 405 Papillary muscle dysfunction 383–384 Papilloma 162 Paraneoplastic syndromes 208–209, 209t Parasitic disease 585–586 Parathyroid carcinoma 736b–737b Parathyroid gland endocrine system and 735–738 hyperparathyroidism and 735–738 hypoparathyroidism and 738 Parathyroid hyperplasia 736b–737b Parenchymal hemorrhage, primary brain 817, 817f, 819 morphology of 817b Parenchymal infection arboviruses and 827 brain abscesses and 826 cytomegalovirus and 828 fungal encephalitis and 829 herpesviruses and 827–828 human immunodeficiency virus and 828 of nervous system 826–831 other meningoencephalitides as 829–831 poliovirus and 828 polyomavirus and progressive multifocal leukoencephalopathy as 828–829 rabies virus and 828 viral encephalitis and 826–829 Parenchymal injury, traumatic 820–821 morphology of 820b, 820f Parkinson disease (PD) clinical features of 839–840 morphology of 839b, 839f parkinsonism and 839–840 pathogenesis of 839b Index Paroxysmal nocturnal hemoglobinuria (PHN) hemolytic anemias and 417 pathogenesis of 417b Parvovirus B19 255–256, 256f Passive congestion circulatory disorders of liver and 633 morphology of 633b, 633f Passive smoke inhalation See Tobacco smoke, environmental Patent ductus arteriosus clinical features of 372 left-to-right shunts and 369t, 370f, 371–372 Patent foramen ovale 370–371 Pathology, introduction to Pediatric disease congenital anomalies and 245–248, 246f fetal hydrops and 254–257 introduction to 245–268, 245t molecular diagnosis of Mendelian/complex disorders and 263–268 necrotizing enterocolitis and 252 perinatal infections and 249 prematurity/fetal growth restrictions and 249–250 respiratory distress syndrome and 250–251 sudden infant death syndrome and 252–254 tumors/tumor-like lesions and 257–262 Pemphigus (vulgaris and foliaceus) blistering disorders and 858–859, 862 clinical features of 859 morphology of 859b, 859f–860f pathogenesis of 858b–859b, 859f Penis inflammatory lesions of 657 malformations of 657 neoplasms of 657–658 Peptic ulceration, acute clinical features of 565 inflammatory disease of the stomach and 565 morphology of 565b pathogenesis of 565b Peptic ulcer disease (PUD) clinical features of 568–569 epidemiology of 568 inflammatory diseases of the stomach and 568–569 morphology of 568b, 568f pathogenesis of 565f, 568b Peptide display system 123–125 Pericardial disease heart diseases and 403–404 pericardial effusions as 404 pericarditis as 403–404 Pericardial effusion 404 Pericarditis clinical features of 403–404 morphology of 403b, 403f pericardial disease as 384, 403–404 Pericarditis, acute bacterial 403b Pericarditis, chronic 403b Pericarditis, constrictive 403b Perinatal infection 249 Peripheral nerve disorder introduction to 797–799, 798f nerve injury disorders and 798–799 patterns of injury and 797–798 summary for 800b Peripheral nerve injury disorders associated with 799t chronic inflammatory demyelinating polyneuropathy as 799 diabetic peripheral neuropathy as 799 Guillain-Barre syndrome as 798–799 summary for 800b toxic, vasculitic, inherited forms of 799–800 patterns of 797–798, 798f Peripheral nerve sheath malignant tumors of 808 neurofibromas as 807 neurofibromatosis type as 808 Schwannomas and neurofibromatosis type as 806–807 traumatic neuroma as 808 tumors of 806–808 Peripheral nerve sheath schwannoma 806–808 morphology of 807b, 807f Peripheral nerve sheath tumor, malignant 808 morphology of 808b Peripheral neuropathy summary for 800b toxic, vasculitic, inherited forms of 799, 800f Peripheral T cell lymphoma 443 Peutz-Jeghers syndrome 592–593, 594f Phagocyte oxidase 143 Phagocytosis 37–39, 39f, 112f, 114–115 Phenylketonuria (PKU) 227–228, 227f summary for 228, 228b Pheochromocytoma adrenal medulla tumors and 760–761 clinical features of 761 morphology of 760b–761b, 760f–761f Phlebothrombosis 356 See also Venous thrombosis Phyllodes tumor 707 Physical agent cell injury and injury by electrical injury and 289 ionizing radiation and 289–293 mechanical trauma as 287 thermal injury and 288–289 toxicity of 271–272 Pickwickian syndrome 305 Pigeon breast deformity 300 Pigment 24, 25f Pilocytic astrocytoma 842–843 morphology of 843b Pituitary adenoma adrenocorticotropic hormone producing adenomas as 719–720 growth hormone producing adenomas as 719 morphology of 718b, 718f–719f other anterior pituitary neoplasms as 720 pathogenesis of 718b and pituitary gland 717–720, 717t (See also Hyperpituitarism) prolactinomas as 719 summary of 719, 720b Pituitary adenoma, nonfunctioning 720 Pituitary carcinoma 720 Pituitary gland as endocrine system 716–721, 716f–717f hyperpituitarism/pituitary adenomas and 717–720 hypopituitarism and 720–721 posterior pituitary syndromes and 721 prolactinomas and 719 PKU See Phenylketonuria (PKU) Placental-fetal transmission 318 Placental inflammation/infection 701 899 900 Index Plasma protein-derived mediator coagulation and Kinin system as 51–52 complement system as 50–51, 50f summary for 52b Plasminogen activator inhibitor (PAI) 80, 85f Platelet activation of 80, 82 adhesion and 82 aggregation of 82 discussion of 81–82 endothelial interaction with 81f, 82 normal hemostasis and 80f normal hemostasis and 79 summary for 82b Platelet-activating factor (PAF) 47–48 Platelet activation 82, 82b Platelet adherence 79 Platelet adhesion 80f–81f, 82 Platelet aggregation 81f, 82, 82b Platelet contraction 82 Pleiotropy 218–219 Pleomorphic undifferentiated sarcoma 794 Pleomorphic adenoma 163, 556–557, 557f morphology of 556b–557b Pleomorphic fibroblastic sarcoma 794, 794f Pleomorphism 165, 165f Pleural effusion 511 Pleural lesion of the lungs 511–512 malignant mesothelioma as 512 pleural effusion and pleuritis as 511 pneumothorax, hemothorax, chylothorax as 511–512 Pleuritis 511 Plexiform neurofibroma 807, 808b Plummer syndrome 728b Pneumoconiosis asbestosis as 477 coal worker’s pneumoconiosis as 475 as fibrosing disease 474–478, 474t mineral dust and 277 pathogenesis of 474b–475b silicosis as 476 summary for 478b Pneumocystis pneumonia in the immunocompromised host 501–502 morphology of 502b, 502f Pneumonia caused by other pathogens Haemophilus influenzae as 489 Klebsiella pneumoniae as 489–490 Legionella pneumophila as 490 Moraxella catarrhalis as 489 Pseudomonas aeruginosa as 490 Staphylococcus aureus as 489 community-acquired acute morphology of 488b, 489f pneumonias caused by other important pathogens and 488–490 as pulmonary infection 486–490 streptococcus pneumoniae infections as 487–488 community-acquired atypical clinical features of 490–491 influenza infections as 491 influenza virus type A/HINI infection as 491 morphology of 490b, 491f as pulmonary infections 490–491 summary for 491b in the immunocompromised host cytomegalovirus infections and 500–501 pneumocystis pneumonia and 501–502 as pulmonary infection 500–502 Pneumonia (P jiroveci) HIV infections and 151, 151t, 313 Pneumonia, chronic nontuberculous mycobacterial disease as 499 as pulmonary infection 492–499 tuberculosis and 493–498 Pneumonia, cryptogenic organizing 473–474, 474f Pneumonia, hospital-acquired 491–492 Pneumothorax 511 Podocyte injury 522f, 523, 528 Poliovirus 828 Pollution, environmental air pollution as 272–273 industrial/agricultural exposures as 276–277 metals as 273–276 Polyarteritis nodosa (PAN) autoimmune diseases and 135 clinical features of 352 morphology of 352b, 352f vasculitis and 352 Polycystic kidney disease, autosomal recessive clinical course of 544 cystic diseases and 544 morphology of 544b summary for 544 Polycystic ovarian disease 695–696 Polycythemia 425, 425t Polycythemia vera as chronic myeloproliferative disorder 447 clinical course of 447–448 morphology of 447b Polymerase chain reaction (PCR) analysis 264–266, 266f Polymerase chain reaction (PCR) analysis molecular diagnosis and 211 Polymorphism complex multigenic disorders and 234 genetic abnormalities and 216–217 linkage analysis and 245–246 P-450 enzymes and 271–272 Polymyositis 805, 806f Polyneuritis multiplex 798 Polyneuropathy 798 Polyomavirus 828–829 Polyp, endometrial 693 Polyp, hamartomatous colonic polyps and 592–593, 593t, 600 juvenile polyps as 592 Peutz-Jeghers syndrome as 592–593 Polyp, inflammatory colonic polyps as 592, 600 gastric polyps and 569, 572 morphology of 569b Polyp, juvenile 592 morphology of 592b, 594f Polyp, nomenclature for 162, 163f Polypoid cystitis (ureter) 668 Portal hypertension ascites and 609 liver disease and 608–609, 609f Portal vein obstruction/thrombosis 632–634 Portopulmonary hypertension 610 Port wine stain 357 Posterior fossa anomaly 823 Posterior pituitary syndrome 721 Index Postmortem clot 88b–89b Postnatal genetic analysis 268 Potter sequence See Oligohydramnios sequence Prader-Willi syndrome 243–245, 244f Preeclampsia/eclampsia clinical features of 704 diseases of pregnancy and 703–704 morphology of 704b summary for 704b Pregnancy, diseases of ectopic pregnancy as 701 gestational trophoblastic disease as 701–703 placental inflammations and infections as 701 preeclampsia/eclampsia as 703–704 Pregnancy, ectopic diseases of pregnancy and 701 morphology of 701b summary for 701b Prematurity, infant 249–250 Primary amyloidosis immunocyte dyscrasias as 155 lymphoplasmacytic lymphoma and 438 Primary biliary cirrhosis (PBC) cholestatic liver diseases and 627, 627t clinical course of 627 morphology of 627b–628b, 627f–628f pathogenesis of 627b Primary hypercoagulability 81f, 87 Primary immune deficiency common variable immunodeficiency as 141 genetic deficiencies of innate immunity as 142–143 hyper-IgM syndrome as 141 introduction to 139–143, 140f isolated IgA deficiency as 141 lymphocyte activation defects as 142 severe combined immunodeficiency as 142 summary for 142–143, 143b with thrombocytopenia and eczema 142 thymic hypoplasia as 141 X-linked agammaglobulinemia as 140–141 Primary sclerosing cholangitis (PSC) cholestatic liver diseases and 627t, 628–629 clinical course of 629 morphology of 628b, 629f Primary syphilis 672, 673f Primary tuberculosis 495–496, 496f Primitive neuroectodermal tumor (PNET) See Ewing sarcoma Prinzmetal angina 376 Prion 309–314 Prion disease Creutzfeldt-Jakob disease as 831 nervous system infections and 831–832, 831f variant Creutzfeldt-Jakob disease as 831 Progressive massive fibrosis (PMF) 475, 475f See also Coal worker’s pneumoconiosis (CWP) Progressive multifocal leukoencephalopathy (PML) 828–829 morphology of 829b, 829f Progressive pulmonary tuberculosis 497b Prolactinoma 719–720 Prostaglandin anti-inflammatory drugs and 46–47 arachidonic acid metabolites and 46–47 Prostate benign prostatic hyperplasia and 664–665 carcinoma of 665–668 male genital system and 663–668, 663f prostatitis and 663–664 Prostatitis clinical features of 664 prostate disease and 663–664 summary for 664b Prosthetic cardiac valve 395–396 Protein damage to 16 intracellular accumulation of 23 Protein, signal-transducing ABL and 180 introduction to 179–180 RAS protein and 179–180 Protein-coding gene alterations other than mutations epigenetic changes as 217 genetic abnormalities and 216–218 non-coding RNA alterations as 217–218 sequence and copy number variations as 216–217 mutations in 216 Protein-energy malnutrition (PEM) discussion of 294–295 kwashiorkor as 294–295 marasmus as 294 morphology of 295b secondary protein-energy malnutrition and 295 Proteoglycan 64 Protozoa 313 PSA test 211 Pseudogout 789–790 Pseudomonas aeruginosa 490 Psoriasis chronic inflammatory dermatosis and 854–855 clinical features of 854–855 morphology of 854b, 855f pathogenesis of 854b Pulmonary angiitis 485 Pulmonary anthracosis 475b Pulmonary disease as drug- and radiation-induced 478 of vascular origin diffuse alveolar hemorrhage syndromes as 485 pulmonary embolism, hemorrhage, infarction as 482–483 pulmonary hypertension as 484 Pulmonary disease, obstructive vs restrictive 462–463 Pulmonary embolism, hemorrhage, infarction clinical features of 483 diseases of vascular origin and 482–483 morphology of 482b, 483f summary for 483b Pulmonary eosinophilia 481 Pulmonary hypertension clinical features of 484 morphology of 484b, 485f pathogenesis of 484b of vascular origin 484 Pulmonary hypertension, secondary 134 Pulmonary hypertensive heart disease See Cor Pulmonale Pulmonary infection aspiration pneumonias as 492 chronic pneumonias as 492–499 community-acquired acute pneumonias as 486–490 community-acquired atypical pneumonias as 490–491 histoplasmosis, coccidioidomycosis, blastomycosis as 499–500 hospital-acquired pneumonias as 491–492 in human immunodeficiency virus infection 504 lung abscess as 492 the lungs and 486–504, 487f, 488t 901 Index 902 Pulmonary infection (Continued) opportunistic fungal infections as 502–504 pneumonia in the immunocompromised host as 500–502 Pulmonary thromboembolism 90, 90f Purulent inflammation See Inflammation, suppurative Pyelonephritis 746–747 Pyelonephritis, acute clinical course of 534f, 535 morphology of 534b–535b, 534f pathogenesis of 533b–534b, 534f summary for 537 tubulointerstitial nephritis and 533–535 Pyelonephritis, chronic clinical course of 536 morphology of 535b, 536f summary for 537 tubulointerstitial nephritis and 535–536 Pyelonephritis, chronic obstructive 535 Pyelonephritis, chronic reflux-associated 535 Pyogenic granuloma 358, 358f Pyogenic liver abscess 635 Pyogenic meningitis, acute 825 morphology of 825b, 825f Pyogenic osteomyelitis acquired bone disease and 773–774 clinical features of 774 morphology of 774b, 774f Pyrin 155–156 R Rabies virus 828 Radiation See Ionizing radiation Radiation carcinogenesis 200–201 summary for 201b Radon 273 Rapidly progressive glomerulonephritis (RPGN) 531–533 See also Crescentic glomerulonephritis anti-glomerular basement membrane antibody–mediated crescentic glomerulonephritis as 532 and glomerular diseases 531–533 immune complex–mediated crescentic glomerulonephritis as 532 pathogenesis of 532b pauci-immune crescentic glomerulonephritis as 532–533 summary for 533b RAS protein 179–180, 179f Rate of growth cancer stem cells/lineages and 166–167 neoplasms and 166–167 Raynaud phenomenon 355 RB gene 182–184 summary for 184b–185b RDS See Respiratory distress syndrome (RDS) Reactive oxygen species (ROS) accumulation of 14–16, 14f–15f cell-derived mediators and 49–50 ischemia-reperfusion injury and 17 production of 38 Reactive proliferation myositis ossificans as 793f nodular fasciitis as 793, 793f Reactive systemic amyloidosis 155 Reactive tuberculosis See Tuberculosis, secondary Recurrent sinonasal polyp 226 Red cell disorder anemia of blood loss 409 anemias of diminished erythropoiesis and 419–424 hematopoietic system and 408–425, 408t–409t hemolytic anemias and 409–419 polycythemia and 425 summary for 409b Red infarct 92b–93b, 93f, 94 Red thrombi 88b–89b Reflux esophagitis clinical features of 560–561 diseases of the esophagus and 560–561 the esophagus and 560–561 morphology of 560b, 561f pathogenesis of 560b Reflux nephropathy 535–536 Regeneration, cell and tissue control of cell proliferation and 59, 59f growth factors of 61–62 introduction to 59–65 proliferative capacities of tissue and 59–60 role of extracellular matrix in 63–65, 63f role of regeneration in tissue repair and 65 stem cells and 60 summary of 61b Rejection, acute 138 Rejection, antibody-mediated 137–138 Rejection, chronic 137f, 138 Rejection, hyperactive 137–138 Rejection, hyperacute 137–138, 137f Renal atherosclerosis 746–747 Renal cell carcinoma chromophobe renal carcinomas as 548 clear cell carcinomas as 547 clinical course of 548–549 morphology of 548b, 548f papillary renal cell carcinomas as 547–548 summary for 549b as tumors of the kidney 547–549 Renal cell carcinoma, papillary 548b Renal disease 517–518 Renal stones clinical course of 545 morphology of 545b pathogenesis of 545b, 545t urinary outflow obstruction and 545 Reperfusion 381–383, 382f Replicative potential, limitless cancer cells and 190–191, 191f summary for 191b Resorption atelectasis 460 Respiratory bronchiolitis 481 Respiratory distress syndrome (RDS) of the newborn 250–251, 250f clinical features of 251 morphology of 251b, 251f pathogenesis of 250b–251b summary 251b–252b premature infants and 249 Respiratory tract microbe transmission/dissemination through 316–319 Restrictive cardiomyopathy 401 morphology of 401b Retinoblastoma (RB) clinical features of 261 discussion of 260–261 morphology of 261b Retinoblastoma (RB) gene 182–184 pathogenesis of 183f Retinopathy, diabetic 744, 747, 747f Retroperitoneal fibrosis (ureter) 668 Rhabdomyomas 404b Index Rhabdomyosarcoma 794–795 morphology of 795b, 795f Rheumatic fever, acute 391b Rheumatic heart disease 110, 391b Rheumatic valvular disease clinical features of 391–392 morphology of 391b, 392f pathogenesis of 391b valvular heart disease as 391–392 Rheumatoid arthritis (RA) autoimmune diseases 131 clinical features of 785–786 of the joints 784–786 morphology of 785b, 785f–786f pathogenesis of 784b, 784f summary for 790 Rheumatoid vasculitis 355 Rickets acquired bone disease and 771 morphology of 300b–301b vitamin D and 298–300, 300f Rickettsia 311–313 Riedel thyroiditis 726 RNA virus, oncogenic 201, 201f summary for 202b Rolling 35–37, 36t ROS See Reactive oxygen species (ROS) Rotavirus 585–586 Roundworms (nematode) 314, 314f S Sacrococcygeal teratoma 258, 258f Saddle embolus 90, 90f Salivary gland, disease of neoplasms as 555–557 sialadenitis as 555 summary for 557b xerostomia as 555 Salmonellosis infectious enterocolitis and 583–584 pathogenesis of 584b Sanger sequencing 265, 266f Sarcoidosis clinical features of 480 epidemiology of 478–479 etiology and pathogenesis of 479b as granulomatous disease 478–480 morphology of 479b–480b, 479f summary for 480b Sarcoma 162 Sarcoma botryoides 685 Scar formation angiogenesis and 66–67 connective tissue remodeling and 68 fibroblasts and connective tissue in 68 growth factors involved in 42f, 68 introduction to 65–68 remodeling of connective tissue and 68 steps in 65–66, 66f summary for 69b Scarring chronic inflammation and 309–314 morphology of 325b, 325f Scleroderma See Systemic sclerosis (SS) Scleroderma, limited 132 Sclerosing adenosis 706 morphology of 706b, 706f Scrotum 658–663 Scurvy 301 Seborrheic keratosis as epithelial lesions of the skin 862–863 morphology of 862b, 862f Secondary immune deficiency 143 Secondary syphilis 672–673 Secondary tuberculosis clinical features of 498 morphology of 497b, 497f–498f as type of tuberculosis 496 Seminoma 163 Sensorimotor polyneuropathy, distal symmetric 799 Septic shock 94, 95f Sequence 216–217 Sequencing, whole genome 212–213, 212f–213f Serous carcinoma 692b, 693f Serous cystadenoma 651, 651f Serous tumor, ovarian epithelial 697 morphology of 697b, 697f Severe combined immunodeficiency (SCID) 142–143 Sexually transmitted disease (STD) chancroid as 677 genital herpes simplex as 678 gonorrhea and 674–675 granuloma inguinale as 677 human papillomavirus infection as 678 lymphogranuloma venereum as 676 male genital system and 671–678, 671t microbe dissemination and 318 nongonococcal urethritis and cervicitis as 676 trichomoniasis as 677–678 Sézary syndrome 443 Sheehan postpartum pituitary necrosis 452b Shigellosis clinical features of 584b infectious enterocolitis and 583 morphology of 583b pathogenesis of 583b Shock clinical course for 97 introduction to 94–97, 94t morphology of 97b pathogenesis of 94–96 stages of 96–97 summary for 97b Shock lung 97b Shunt, left-to-right atrial septal defect/patent foramen ovale and 370–371 congenital heart disease and 370–372, 370f patent ductus arteriosus and 371–372 ventricular septal defects and 371 Shunt, portosystemic hepatorenal syndrome and 610 liver disease and 609–610 portopulmonary hypertension/hepatopulmonary syndrome and 610 splenomegaly and 609 Shunt, right-to-left congenital heart disease and 372–373, 372f tetralogy of Fallot and 372–373 transposition of the great arteries and 373 Sialadenitis 555, 556f, 557 Sicca syndrome 131 Sickle cell anemia clinical course of 413 hemolytic anemias and 411–413 incidence of 411–413 morphology of 411f, 412b–413b 903 904 Index Sickle cell anemia (Continued) pathogenesis of 411b–412b, 412f summary for 419 SIDS See Sudden infant death syndrome (SIDS) Sigmoid diverticulitis clinical features of 586–587 inflammatory intestinal disease and 586–587 morphology of 586b, 586f, 591f pathogenesis of 586b summary for 587b Silicosis clinical features of 476 morphology of 476b, 476f as pneumoconiosis 476 summary for 478 Single-gene disorder with atypical patterns of inheritance 241–244 alterations of imprinted region disease as 243–244 mutations in mitochondrial genes disease as 243 triplet repeat mutations as 241 Single-gene disorder, transmission patterns of autosomal dominant inheritance as 219–220 autosomal recessive inheritance as 220 summary for 220b X-linked disorders as 220 Single-nucleotide polymorphism (SNP) 222–223 array-based genomic hybridization and 264 linkage analysis and 266 sequence and copy number variations and 216–217 Sinusoidal obstruction syndrome 634, 634f Sinus venosus ASD 371b Sjögren syndrome discussion of 131–132 morphology of 132b, 132f pathogenesis of 127t, 131b summary for 132b Skeletal muscle acquired disorders of 805–806 inflammatory myopathies as 805 toxic myopathies as 805–806 inherited disorders of 802–805 channelopathies, metabolic and mitochondrial myopathies as 805 dystrophinopathies as 802–804 X-linked and autosomal muscular dystrophies as 804–805 patterns of injury for 801–802, 803f summary for 806b Skeletal muscle tumor, rhabdomyosarcoma as 794–795 Skin benign and premalignant tumors of 862–869 blistering disorders of 857–861 chronic inflammatory dermatoses and 854–856 infectious dermatoses and 856–857 introduction and terminology for 851 microbe transmission/dissemination and 316, 318–319 SLE morphology and 130, 130f systemic sclerosis morphology and 133, 134f Skin wound healing by first intention and 70–71, 70f healing by second intention and 70f–71f, 71–72 summary for 72b wound strength and 72 Small airway disease See Chronic bronchiolitis Small cell carcinoma (SCLC) 506b–509b, 509f Small-for-gestational-age (SGA) infant 249–250 Small lymphocytic lymphoma (SLL) 433–434 summary for 443 Smog 272–273 Smokeless tobacco 277, 279 Smoking-related interstitial disease 481, 482f and chronic interstitial lung disease 481 Sodium retention 77–78 Soft tissue fibrohistiocytic tumors and 794 fibrous tumors and tumor-like lesions of 792 introduction to 791–796, 792t skeletal muscle tumors and 794–795 smooth muscle tumors and 795 synovial sarcoma and 795 tumors of adipose tissue and 792 Spermatocytic seminoma 660b–662b Spider telangiectasias 357–358 Spinal cord abnormality 823 Spinocerebellar ataxia (SCA) 840–841 Spirochetal infection neuroborreliosis as 826 neurosyphilis as 826 Spleen 456–457 amyloidosis and 157 SLE morphology and 130 splenomegaly as 456 Splenomegaly CML and 447 hairy cell leukemia and 442–443 portosystemic shunt and 609 spleen disorders and 456 Spondyloarthropathy, seronegative 786 Spontaneous maturation 258–259 Spontaneous regression 258–259 Squamous cell carcinoma clinical features of 863–864 of the esophagus 563–564 clinical features of 563–564 morphology of 563b, 563f pathogenesis of 563b lung tumors and 506b–509b malignant epidermal tumors and 863–864 morphology of 863b, 864f nomenclature for 162–163, 165f of the oral cavity 554 morphology of 554b, 555f pathogenesis of 554b pathogenesis of 863b of the vagina 684 Staging, cancer tumor and 208–210 Staphylococcus aureus 489 Stasis thrombi See Red thrombi Steatohepatitis, nonalcoholic 305 Steatosis See Fatty change Steatosis, drug/toxin-mediated injury with 625 morphology of 626b Steatosis, hepatocellular 621b–622b, 621f Stem cell 60, 61b, 61f cancer of 166–167 Stem cell, adult 60 Stem cell, cardiac 385 Stem cell, embryonic (ES cell) 60 Stenting, endovascular 362, 363f Stomach carcinoid tumor as 571–572 gastric adenocarcinoma as 570–571 gastric polyps as 569 gastrointestinal stromal tumor as 572 inflammatory diseases of 564–569 acute gastritis as 564 acute peptic ulceration as 565 Index chronic gastritis as 565 peptic ulcer disease as 568–569 lymphoma as 571 neoplastic disease of 569–572 carcinoid tumor as 571–572 gastric adenocarcinoma as 570–571 gastric polyps as 569 gastrointestinal stromal tumor as 572 lymphoma as 571 summary for 572b–573b Streptococcus pneumoniae infection 487–488 Stress cellular adaptations to 3–5 cellular response to 1–3, 2f Structural abnormality, cytogenetic disorders and 235–236, 235f–236f Sturge-Weber syndrome 257–258 See also Port wine stain Subdural hematoma 821–822 morphology of 821f, 822b Subdural infection of nervous system 824–825 Sudden cardiac death (SCD) 386, 386f Sudden infant death syndrome (SIDS) discussion of 252–254, 253t morphology of 253b pathogenesis of 253b summary for 254b Sulfur dioxide 273 Superior vena cava syndrome 356 Surface epithelial tumor (ovarian) 696–697 Syndrome of inappropriate ADH (SIADH) 721 Synovial cyst 790 Synovial sarcoma morphology of 795b–796b, 795f soft tissue disease and 795–796 Syphilis congenital syphilis and 673–674 male genital system and 671–674 morphology of 672b primary syphilis and 672, 673f secondary syphilis and 672–673 serologic tests for 674 summary for 674b tertiary syphilis and 673 Systemic disease diet and 306 Systemic immune complex disease 116–117, 116f Systemic inflammatory response syndrome (SIRS) 94–95 Systemic lupus erythematosus (SLE) autoantibodies in 127 as autoimmune disease 125–131, 125t clinical manifestations of 127t, 131 mechanisms of tissue injury in 127–131 morphology of 125t, 128b–130b, 129f pathogenesis of 125b–127b, 126f summary for 131b Systemic miliary tuberculosis 497b Systemic sclerosis (SS) as autoimmune disease 132–134 clinical course for 134 morphology of 133b–134b pathogenesis of 133b, 133f summary for 134b–135b T Tapeworm (cestode) 314 Tay-Sachs disease 229–230, 230f T cell HIV and 146 systemic sclerosis and 133 T cell leukemia, adult 443 T cell lymphoma, adult 443 T cell-mediated hypersensitivity (Type IV) CD4+ T cell inflammatory reactions and 118–119 delayed-type hypersensitivity and 119 introduction to 111, 117–120, 118t, 119f summary for 120b T cell-mediated cytotoxicity and 119–120 T cell mediated rejection 137 T cell receptor (TCR) 101, 101f Tenosynovial giant cell tumor (TGCT) clinical features of 791 joint tumors and 790 morphology of 790b, 791f Teratoma, benign cystic 163, 698–700, 700f Teratoma, immature malignant 700 Teratoma, specialized 700 Tertiary syphilis 673 Testicular atrophy 658–659 Testicular neoplasm 659–663, 660t clinical features of 662–663 morphology of 660b–662b, 660f–662f summary for 663b Testicular torsion 659 Testis cryptorchidism/testicular atrophy and 658–659 inflammatory lesions of 659 male genital system and 658–663 neoplasms of 659–663 vascular disturbances and 659 Tetany, hypocalcemic 298 Tetralogy of Fallot clinical features of 372–373 morphology of 372b right-to-left shunts and 369t, 372–373, 372f Thalassemia clinical course of 416 hemolytic anemias and 413–416 morphology of 415b–416b pathogenesis of 413b–415b, 414f–415f, 414t summary for 419 Thanatophoric dwarfism 767 Thermal burn morphology of 288b–289b thermal injury and 288 Thermal injury hyperthermia as 289 hypothermia as 289 thermal burns as 288 Thiamine deficiency 835 Thoracic aortic aneurysm 346 Thrombocytopenia, heparin-induced 453 Thrombin coagulation cascade and 81f, 83, 85f platelet aggregation and 82 Thromboangiitis obliterans (Buerger disease) 354–355 clinical features of 354–355 morphology of 354b, 354f Thrombocytopenia 78, 87, 424 disseminated intravascular coagulation and 452–454, 453t heparin-induced thrombocytopenia and 453 immune thrombocytopenic purpura and 452–453 thrombotic microangiopathies as 453–454 Thrombocytopenic syndrome, heparin-induced 87 905 906 Index Thromboembolism embolism and 75, 90 HRT and 283 oral contraceptives and 284 Thromboembolism, systemic air embolism as 91–92 amniotic fluid embolism as 91 embolism and 91–92 fat embolism as 91 Thrombophlebitis 356 Thromboplastin See Endothelial injury Thrombosis abnormal blood flow and 86 clotting and 75 endothelial injury and 86 fate of thrombus and 89 hypercoagulability and 87–88 introduction to 86–89, 86f morphology of 88b–89b, 88f summary for 90b Thrombotic microangiopathy pathogenesis of 453b–454b summary for 541 as blood vessel disease of the kidney 540–541 clinical course of 541 morphology of 541b pathogenesis of 540b–541b summary of 541 thrombocytopenia and 453–454 Thrombotic thrombocytopenic purpura (TTP) 541 summary for 456 thrombotic microangiopathies and 453–454 Thromboxane 46 Thrombus clinical correlations for 89 venous thrombosis and 89 fate of 89, 89f Thrush See Oral candidiasis Thymic carcinoma 457b Thymic hyperplasia 457 Thymic hypoplasia 141 Thymoma clinical features of 457 morphology of 457b thymus disorders and 457 Thymoma type I, malignant 457b Thymus disorder introduction to 456–457 thymic hyperplasia as 457 thymoma as 457 Thyroid diffuse/multinodular goiter and 728 and endocrine system 721–735, 722f Graves disease as 726–727 hyperthyroidism and 722–723 hypothyroidism and 723–724 neoplasms of 728–735 adenomas as 729–730 carcinomas of 730–735 introduction to 728–735 summary of 735b thyroiditis as 724–726 Thyroiditis chronic lymphocytic and clinical features of 725 hypothyroidism and 724–725 morphology of 724b–725b, 725f pathogenesis of 724b, 725f chronic lymphocytic (Hashimoto) and summary for 726 chronic lymphocytic thyroiditis and 724–725 other forms of thyroiditis and 726 subacute granulomatous thyroiditis and 725–726 subacute granulomatous thyroiditis (de Quervain) and clinical features of 726 morphology of 726b summary for 726 the thyroid and 725–726 subacute lymphocytic thyroiditis and 726 summary of 726b and the thyroid 724–726 Thyrotoxic myopathy 806 Thyrotroph adenoma 720 Tinea 313 Tissue injury morphology of 8–11 SLE mechanisms of 127–131 summary of 11b Tissue injury, leukocyte-induced 39–40, 41t Tissue necrosis See also Necrosis inflammatory response to infection by 324 morphology of 324b morphology of 9b patterns of 9–11 summary of 11 Tissue repair clinical examples of 70–72 fibrosis in parenchymal organs and 72 healing skin wounds and 70–72 influencing factors of 69–70, 69f overview of 29–30, 58–59, 58f role of extracellular matrix in 63–65 summary for 64b role of regeneration in 65, 65f T lymphocyte cell-mediated immunity and 105–108 effector functions of 107–108, 107f immune system and 101–102, 101f summary for 104 Tobacco smoke carcinogens in 279, 279t combined with alcohol 279, 279f components of 278–279, 279t discussion of 277–279, 278t effects of 277–278, 278f–279f, 278t, 280 indirect-acting chemicals and SLE and 126 summary for 280b Tobacco smoke, environmental 279 Toll-like receptor (TLR) 32, 32f, 52 Total-body irradiation 293, 293t Toxic agents, agricultural exposure to 276–277 Toxic disorder, nervous system and 835–836 Toxic metabolite 271, 271f–272f Toxic myopathy 805–806 TP53 gene evasion of cell death and 190 as guardian of genome 185–187, 186f summary for 187b tumor suppressor gene as 173 Transforming growth factor-β pathway (TGF-β pathway) discussion of 187 summary of 188b–189b Transmigration 36 Transmural infarct 379 Index Transplant effector mechanisms of graft rejection and 137–138 hematopoietic stem cell transplant and 139 immune recognition of allografts and 135–136 summary for 138b improving graft survival and 138–139 morphology of 137b–138b, 137f rejection of 135–139 Transposition of the great arteries clinical features of 373 right-to-left shunts and 372f, 373 Trauma central nervous system and 820–822 summary of 822b parenchymal injuries and 820–821 vascular injury and 820–821 Traumatic hemolysis 418 Traumatic neuroma 798f, 808 Trichomoniasis 677–678 Trisomy 21 (Down syndrome) 237, 238f, 239 Trophoblastic tumor, placental site 703 summary for 703 Trophozoite 313 Tuberculosis as chronic pneumonia 493–498 etiology of 493 morphology of 495b, 495f–496f pathogenesis of 493b–495b, 494f primary tuberculosis and 495–496 secondary tuberculosis and 496 summary for 499b Tuberculous meningitis 826 morphology of 826b Tuberculous osteomyelitis 774 Tuberous sclerosis (TSC) 847 morphology of 847b Tubules and interstitium, disease affecting acute tubular injury and 537–538 the kidney and 533–538 tubulointerstitial nephritis as 533–537 Tubulointerstitial nephritis (TIN) acute pyelonephritis as 533–535 chronic pyelonephritis and reflux nephropathy as 535–536 diseases affecting tubules/interstitium and 533–537 drug-induced interstitial nephritis as 536–537 summary for 537b Tumor of adipose tissue lipoma and 792 liposarcoma and 792 of the adrenal medulla neuroblastoma and 761 pheochromocytoma as 760–761 of the appendix 601 of the bone bone-forming tumors and 775–777 cartilage-forming tumors and 777–779 diseases of the bone and 774–781, 775t fibrous/fibroosseous tumors and 779–780 miscellaneous bone tumors and 780–781 summary for 781b–782b of the breast 707–713 carcinoma as 708–713 fibroadenoma as 707 intraductal papilloma as 708 phyllodes tumor as 707 of the central nervous system embryonal neoplasms as 844–845 familial tumor syndromes as 847 introduction to 842–847 meningiomas as 846 metastatic tumors as 846–847 neuronal tumors as 844 other parenchymal tumors as 845 summary for 847b–848b effects on host 207–208 of infancy/childhood benign tumors and 257–258, 257f clinical course and prognosis for 259–260 of the joint ganglion and synovial cysts as 790 joint disease and 790–791 tenosynovial giant cell tumor as 790–791 of the kidney 547–549 oncocytoma as 547 renal cell carcinoma as 547–549 Wilms tumor as 549 of the liver benign tumors as 635–639 hepatocellular carcinomas as 637–639 liver diseases and 635–639 precursor lesion of hepatocellular carcinoma as 636–637 summary for 639b of the lung carcinoid tumors as 510–511 carcinomas and 505–510 introduction to 505–511 neoplasia and 162 of the ovary Brenner tumor and 698 clinical correlations of 700 endometrioid tumors and 698 introduction of 696–698, 696f mucinous tumors and 697–698 serous tumors and 697 summary for 700b surface epithelial tumors and 696–697 of the skin benign and premalignant epithelial lesions as 862–863 malignant epidermal tumors as 863–864 melanocytic proliferations as 865–869 of the ureter 668 of the vulva 683–684 carcinoma and 683 condylomas and 683 extramammary Paget disease and 683–684 Tumor, benign focal nodular hyperplasia as 635–636 hepatic adenoma as 636 of infancy and childhood 259–260 of the liver 635–636 Tumor, dysembryoplastic neuroepithelial 844 Tumor, endometrioid 698 Tumor, fibrohistiocytic benign fibrous histiocytoma as 794 pleomorphic fibroblastic sarcoma/pleomorphic undifferentiated sarcoma 794 and soft tissue 794 Tumor, fibroosseous 779–780 Tumor, fibrous of the bone fibrous cortical defect and nonossifying fibroma as 779 fibrous dysplasia as 779–780 907 908 Index Tumor, fibrous (Continued) fibromatoses and 793 fibrosarcoma as 793–794 reactive proliferations and 793 of the soft tissue 792–794 Tumor, germ cell 845 Tumor, Krukenberg 698b Tumor, malignant in infancy and childhood 258–262, 258t neuroblastoma as 258–260 retinoblastoma as 260–261 Wilms tumor as 261–262 Tumor, malignant epidermal basal cell carcinoma as 864 squamous cell carcinoma as 863–864 summary for 864b Tumor, neuronal 844 Tumor, odontogenic 558 Tumor, parenchymal germ cell tumors as 845 primary central nervous system lymphoma as 845 Tumor, smooth muscle leiomyoma as 795 leiomyosarcoma as 795 Tumor, vascular benign and tumor-like conditions of 357–359 intermediate-grade of 360–361 introduction to 357–362, 357t malignant tumors as 361–362 summary for 362b Tumor antigen differentiation antigens and 206 glycolipids/glycoproteins and 206 introduction to 204–206, 205f mutated oncogenes/tumor suppressor genes and 204–205 oncofetal antigens and 206 oncogenic viruses and 206 other mutated genes and 205 overexpressed cellular proteins and 205 Tumor cell, homing of 194–195 Tumor immunity antigens and 204–206 introduction to 204–207 surveillance and evasion by 207 Tumor marker 211 Tumor necrosis factor (TNF) 48, 48f Tumor suppressor gene carcinogenesis and 173, 177, 184 inherited mutations and 171–172 Turner syndrome 240–241, 240f nonimmune hydrops and 255–256 22q11.2 deletion syndrome 237–239 Type diabetes (T1D) clinical features of 748, 750t diabetes mellitus and 739 pathogenesis of 741, 741f summary for 750 Type diabetes (T2D) clinical features of 748, 750t diabetes mellitus and 739 pathogenesis of 741, 742f summary for 750 Type hypersensitivity See Hypersensitivity, immediate Type II hypersensitivity See Antibody-mediated disease Type III hypersensitivity See Immune complex disease Type I interferon, SLE and 126 Typhoid fever 584 Tyrosine kinases, non-receptor 178–179 U Ultraviolet (UV) radiation 126 Upper respiratory tract acute infection 512–513 Upper respiratory tract lesion acute infections and 512–513 laryngeal tumors and 513–514 nasopharyngeal carcinoma and 513 Ureaplasma 313 Ureter 668–671 Ureteropelvic junction (UPJ) obstruction 668 Urinary bladder neoplasms of 669–671 non-neoplastic conditions of 668–669 Urinary outflow obstruction hydronephrosis and 545–547 renal stones and 545 Urinary tract infection 518 Urogenital tract 317, 319 Urolithiasis 545 Urticaria acute inflammatory dermatoses and 852 clinical features of 852 morphology of 852b pathogenesis of 852b Uterus, body of abnormal uterine bleeding and 690–691, 690t adenomyosis and 689 endometriosis and 689–690 endometritis and 689 proliferative lesions of endometrium/myometrium and 691–694 summary for 691b V Vagina female genital system and 684–685 malignant neoplasms of 684–685 clear cell adenocarcinoma as 685 sarcoma botryoides as 685 squamous cell carcinoma as 684 vaginitis and 684 Vaginitis 684 Variant Creutzfeldt-Jakob disease (vCJD) 831, 832f Varicose vein of the extremities 356 clinical features of 356 of other sites 356 Vascular change acute inflammation and 31, 31f, 33–34 changes in vascular caliber and flow and 31f, 33–34 increased vascular permeability and 33–34, 33f lymphatic vessel responses and 34 summary of 34b Vascular dissemination invasion-metastasis cascade and 194–195 Vascular ectasias 357–358 Vascular injury, traumatic central nervous system and 821–822, 821f epidural hematoma as 821 subdural hematoma as 821–822 Vascular intervention, pathology of endovascular stenting and 362 vascular replacement and 363 Index Vascular malformation 818 morphology of 818b–819b, 819f Vascular organization 328–329, 328f Vascular replacement 363 Vascular smooth muscle cell 330 Vascular tumor, benign bacillary angiomatosis as 359 glomus tumors as 359 hemangiomas as 358–359 lymphangiomas as 359 vascular ectasias as 357–358 Vascular tumor, intermediate-grade hemangioendotheliomas as 361 Kaposi sarcoma as 360–361 Vascular tumor, malignant angiosarcomas as 361–362 hemangiopericytomas as 362 Vascular wall, response to injury by intimal thickening and 334–335, 335f Vasculitis 819 discussion of 348–355, 349f infectious type of 355 noninfectious type of 348–355 summary for 355b Vasoactive amines 112 Vein, disease of superior and inferior vena cava syndromes as 356 thrombophlebitis and phlebothrombosis as 356 varicose veins of the extremities as 356 Velocardiofacial syndrome 237–239 Venoocclusive disease See Sinusoidal obstruction syndrome Venous thrombosis (phlebothrombosis) 87t, 89 paroxysmal nocturnal hemoglobinuria and 417b Ventricular aneurysm 383f, 384 Ventricular septal defect clinical features of 371 left-to-right shunts and 369t, 371, 371f morphology of 371b Verrucae (warts) infectious dermatoses and 857 morphology of 857b, 858f pathogenesis of 857b Verrucous endocarditis 88b–89b Verrucous endocarditis, nonbacterial 130 Viral encephalitis 826–829, 827f Viral hepatitis, acute 619 Viral injury, mechanism of 319–320, 319f Viral meningitis See Aseptic meningitis Virchow’s triad 86, 86f Virus autoimmunity and 124 infectious agents as 309–310, 310t, 311f Virus, oncogenic 206 Vitamin A deficiency states of 297–298 discussion of 296–298, 297f–298f function of 296–298 toxicity of 298 Vitamin B12 deficiency 835 Vitamin B12 deficiency anemia clinical features of 423 as megaloblastic anemia 423 pathogenesis of 423b Vitamin C (ascorbic acid) deficiency of 301 discussion of 301–302 function of 301–302 toxicity of 301–302 Vitamin D deficiency states of 299–301, 301f discussion of 298–301 functions of 299, 299f metabolism of 298–299, 299f toxicity of 301 Vitamin deficiency nutritional disease and 296–302, 302t–303t Vitamin A and 296–298 Vitamin C and 301–302 Vitamin D and 298–301 Von Gierke disease 232–233, 233t von Hippel-Lindau disease 847 morphology of 847b Von Willebrand disease 455 summary for 456 von Willebrand factor (vWF) 80, 81f Vulva non-neoplastic epithelial disorders of 682 tumors of 683–684 summary for 684b vulvitis and 681–682 Vulvitis 681–682 W WAGR syndrome 261–262 Waldenström macroglobulinemia 439–440 Warts See Verrucae Waterhouse-Friderichsen syndrome disseminated intravascular coagulation and 452b metabolic abnormalities and 96 Water retention 77–78 Wegner granulomatosis (WG) 353–354 clinical features of 354 diffuse alveolar hemorrhage syndromes and 485 morphology of 353b–354b, 353f Wernicke-Korsakoff syndrome 281, 302t, 835 morphology of 835b White cell disorder hematopoietic system and 425–449 neoplastic proliferations of histiocytic neoplasms and 449 neoplastic proliferations of 428–449 lymphoid neoplasms and 429–443 myeloid neoplasms as 444–448 as white cell disorders 428–449 non-neoplastic disorders of 425–428 leukopenia as 425–426 reactive leukocytosis as 426–427 reactive lymphadenitis as 427–428 White infarcts 92b–93b, 93f, 94 Wilms tumor discussion of 261–262 morphology of 262b, 262f–263f summary for 262b–263b tumors of the kidney and 549 Wilson disease clinical features of 631 as inherited metabolic disease 630–632 morphology of 631b pathogenesis of 631b Wood smoke 273 Wrist, carpal ligaments of 157–158 909 910 Index X Y Xenobiotics 271, 271f–272f summary for 273 Xeroderma pigmentosum 197 Xerophthalmia (dry eye) 297–298 Xerostomia 131, 132b, 555 X-linked agammaglobulinemia (XLA) 140, 143 X-linked disorder 220 Yellow fever 620 Yolk sac tumor 660b–662b, 661f Z Zollinger-Ellison syndrome 568b ... Tumors Benign Malignant Pleomorphic adenoma (50%) Warthin tumor (5%) Oncocytoma (2% ) Cystadenoma (2% ) Basal cell adenoma (2% ) Mucoepidermoid carcinoma (15%) Acinic cell carcinoma (6%) Adenocarcinoma... otherwise specified Data from Ellis GL, Auclair PL, Gnepp DR: Surgical Pathology of the Salivary Glands, Vol 25 : Major Problems in Pathology, Philadelphia, WB Saunders, 1991 benign from malignant lesions... (tTG) Deamidated gliadin APC HLA (DQ2 or DQ8) T MIC-A IL-15 IFNg T T cell receptor B NKG2D B cell receptor Anti-gliadin Anti-endomysium Anti-tTG Figure 14 21 Left panel, The morphologic alterations