Lung and Pleura

Abstract

With every breath we take, we expose the lungs to a myriad of insults from the outside world. The patterns of injury that result encompass a broad spectrum of neoplastic and nonneoplastic pulmonary diseases. This chapter reviews the salient clinical and pathologic features of these diseases and summarizes special studies, including immunohistochemical, molecular, and genetic tests that may be helpful in diagnosing these diseases.

Nonneoplastic Diseases of the Lung

Congenital Anomalies and Pediatric Lesions

Pulmonary Sequestration

Intralobar

Clinical

• ♦ 90% lower lo bes; 55% on left; M:F = 1.1:1

• ♦ 50% over 20 years; usually presents with recurrent infections

Macroscopic (Fig. 28.1)

• ♦ Firm, cystic area within lobe

• ♦ Systemic arterial supply from elastic artery from thoracic aorta or below the diaphragm

• ♦ Venous return via normal pulmonary veins

• ♦ No communication with normal tracheobronchial tree

• ♦ Invested by normal visceral pleura

Fig. 28.1.

Intralobar seques tration. Lower segment of lobe shows end-stage changes with marked, fibrosis, and remodeled airways.

Microscopic

• ♦ Young patients: pathology may be normal

• ♦ Older patients: pathology shows chronic obstructive pneumonia; honeycomb changes are common

Extralobar

Clinical

• ♦ 60% are found in children <1 year; 90% on left side; M:F = 4:1

• ♦ Frequently found with repair of diaphragmatic defect

• ♦ 60% have other congenital anomalies such as diaphragmatic hernia and pectus excavatum (funnel chest)

Macroscopic

• ♦ Spongy, pyramidal mass outside of normal pleura; invested by own pleura

• ♦ Systemic anomalous arterial supply; venous drainage through systemic or portal systems

Microscopic

• ♦ May appear normal; may resemble congenital pulmonary airway malformation (CPAM)

Bronchogenic Cysts

Clinical

• ♦ Supernumerary lung buds from foregut; commonly found in subcarinal or middle mediastinum location

• ♦ Usually incidental findings on chest imaging

Macroscopic

• ♦ Usually unilocular cysts with smooth margins; no communication with tracheobronchial tree

Microscopic (Fig. 28.2)

• ♦ Respiratory epithelium with smooth muscle, cartilage, and submucosal glands

• ♦ Squamous metaplasia, purulent exudate, chronic inflammation, and fibrosis if infected

Fig. 28.2.

Bronchogenic cyst. Cyst lining contains normal ciliated respiratory epithelium submucosal glands (lower left) and hyaline cartilage, features seen in normal bronchials.

Differential Diagnosis

• ♦ Lung abscess

  • Frequent bronchial communication

• ♦ Enteric cysts

  • Lined by gastric epithelium

• ♦ Esophageal cysts

  • Squamous epithelium.

  • Wall contains double layer of smooth muscle and no cartilage.

Congenital Pulmonary Airway Malformation

Clinical

• ♦ Stillborn with anasarca and newborn with acute respiratory distress

• ♦ Most communicate with tracheobronchial tree

Macroscopic

• ♦ Five types of lesion

  • Type 0 – Malformation of proximal tracheobronchial tree; acinar dysplasia or dysgenesis

  • Type I

    • Most frequent type (>65% of CPAM s)

    • One or more large cysts; cured with surgical removal

    • May progress to lepidic type adenocarcinoma in older children/adults

  • Type II

    • Multiple, small, uniform cysts 0.5–2.0 cm; poor prognosis

    • Rhabdomyomatous dysplasia is a rare subgroup

  • Type III – Spongy tissue; no cysts; large bulky lesion with mediastinal shift; poor prognosis

  • Type IV – Large (up to 7 cm) thin-walled cystic lesions usually in periphery of lobe

Microscopic (Fig. 28.3)

• ♦ Type 0 – Bronchial-like structure with respiratory epithelium, smooth muscle, and cartilaginous plates

• ♦ Type I – Pseudostratified, primitive epithelium; cartilaginous islands; may progress to lepidic adenocarcinoma

• ♦ Type II – Ciliated cuboidal or columnar epithelium

• ♦ Type III – Randomly distributed bronchial-like structures with ciliated cuboidal epithelium

• ♦ Type IV – Thinned type I and type II alveolar lining cells

Fig. 28.3.

Type I congen ital pulmonary airway malformation. Pseudostratified respiratory-like epithelium and, in some areas, are more cuboidal epithelium line the cyst spaces. There are mixed inflammatory cells within the interstitium.

Differential Diagnosis

• ♦ Extralobar sequestration

  • Located outside of pleura

  • Have a separate arterial blood supply

Diffuse Pulmonary Lymphangiomatosis

Clinical

• ♦ Occurs in young children; presents with wheezing and dyspnea; slowly progressive

• ♦ Sporadic

Macroscopic

• ♦ Firm, lobulated lung

Microscopic

• ♦ Proliferation of dilated, endothelial-lined spaces; may have smooth muscle in walls

• ♦ Expands pleura and interlobular septa

Differential Diagnosis

• ♦ Lymphangioleiomyomatosis

  • Occurs only in women of reproductive years

  • Smooth muscle is HMB45+

• ♦ Lymphangiectasis

  • Dilated channels but not increased number

  • Can be a component of chromosomal disorders (Turner or Down syndrome)

Bronchopulmonary Dysplasia (BPD)

Clinical

• ♦ Early BPD has features of respiratory distress syndrome (RDS) with hypoxemia and the need for assisted ventilation for at least 28 days

• ♦ Established BPD causes chronic respiratory disease, with significant wheezing, and retractions and may have an associated pulmonary hypertension

Macroscopic (Fig. 28.4A)

• ♦ Early BPD in nonsurfactant-treated infants resembles RDS with firm, congested, and heavy lungs

• ♦ Late BPD has pleural cobblestoning caused by underlying parenchymal areas that alternate between overdistension and fibrosis

Microscopic (Fig. 28.4B)

• ♦ Early BPD has hyaline membranes with necrotizing bronchiolitis, atelectasis, and interstitial edema

• ♦ Late BPD has lobules which alternate between interstitial fibrosis and distension. Lobules with distension have constrictive bronchiolitis as a sequela of the necrotizing bronchiolitis from the early BPD

Fig. 28.4.

Bronchopulm onary dysplasia (A, B). Late BPD shows a cobblestoning gross appearance (A) due to underlying alternating areas of overdistension and fibrosis (B). Courtesy of Beverly Dahms M.D., Case Western Reserve University.

Differential Diagnosis

• ♦ Early BPD is similar to DAD

• ♦ Late BPD has features of emphysema, interstitial fibrosis, and constrictive bronchiolitis

Infantile (Congenital) Lobar Emphysema

Clinical

• ♦ Most frequent lung malformation

• ♦ Lobar overinflation within the first 6 months of life; presents with respiratory distress

• ♦ M:F = 1.8:1

Macroscopic

• ♦ Lung is overinflated

• ♦ Most commonly found in the left upper lobe

Microscopic

• ♦ Alveolar ducts and alveoli are distended (classic form)

• ♦ Absolute increase in the number of alveoli (hyperplastic form)

Differential Diagnosis

• ♦ Congenital pulmonary airway malformation, type IV

• ♦ Congenital lobar inflation

  • Normal number of alveoli

Interstitial Pulmonary Emphysema

Clinical

• ♦ Occurs in two forms:

  • Acute interstitial pulmonary emphysema (AIPE)

  • Persistent interstitial pulmonary emphysema (PIPE)

• ♦ Found in infants over ventilated and in infants of low birth weight

• ♦ Incidence decreased with the use of synthetic surfactant and high-frequency oscillatory ventilation

• ♦ Complications include pneumothorax, pneumomediastinum, and pneumopericardium

Macroscopic

• ♦ AIPE: Spherical cysts in interstitial air spaces

• ♦ PIPE: Irregular and channel-like cysts in interstitial air spaces

Microscopic

• ♦ Air within the connective tissue and possibly the lymphatics, of the perivascular and interlobular septa

• ♦ Cysts formed have no lining

• ♦ Adjacent parenchyma may display changes of hyaline membrane disease (HMD) of bronchopulmonary dysplasia (BPD)

• ♦ AIPE: No fibrosis or giant cell reaction in cyst wall

• ♦ PIPE: Fibrosis and giant cell reaction in cyst wall

Differential Diagnosis

• ♦ Pulmonary lymphangiectasis or lymphangiomatosis may mimic microscopically, but antibody D2-40 will label lymphatic endothelium and help to distinguish

Pediatric Interstitial Lung Disease

Clinical

• ♦ Interstitial lung disease presenting in the pediatric popular (<18 years of age) is quite rare

• ♦ In children <2 years of age, the term childhood interstitial lung disease in infancy (chILD) is used

• ♦ Causes of chILD include surfactant dysfunction mutations, including surfactant protein B and surfactant protein C, ABCA3, and TTF1 (NKX2.1) gene mutations, and storage disorders

Macroscopic

• ♦ Varies depending upon interstitial disease involvement; consolidation, fibrosis, and hemorrhage

Microscopic

• ♦ Desquamative interstitial pneumonia (DIP) and lymphocytic interstitial pneumonia (LIP) are most commonly seen

• ♦ DIP in children is not linked to smoking

• ♦ PAP, chronic interstitial pneumonia usually seen in surfactant gene mutation-related chILD

Differential Diagnosis

• ♦ Varies with the entity

Airways and Obstructive Diseases

Emphysema

Clinical

• ♦ Pink puffer

• ♦ Four major types found in four different clinical settings

  • Centrilobular (proximal acinar)

    • Smokers; upper lobes most affected

  • Panacinar (panlobular)

    • Alpha-1-protease inhibitor deficiency (ZZ); lower lobes most affected

    • Can be seen in talc IV drug abuse and in Ritalin use

  • Localized (distal acinar)

    • May contribute to spontaneous pneumothoraces and bullae formation in tall, asthenic male adolescent

  • Paracicatricial (irregular) emphysema

    • Most common type; around area of fibrosis

Macroscopic

• ♦ May manifest as bullae-alveolar spaces >1 cm or blebs-representing airspaces made by dissection through connective tissue

Microscopic

• ♦ Alveolar wall destruction distal to terminal bronchioles

• ♦ No fibrosis

• ♦ Four major types

  • Centrilobular (proximal acinar): proximal part of acini (Fig. 28.5A, B)

    Fig. 28.5.

    

    Emphysema (A, B, centrilobular; C, panacinar). Upper Fig. 28.5 (continued) lobe tissue destruction with bulla formation is characteristic of centrilobular emphysema (A). In this form, alveolar wall area destroyed in the area surrounding the bronchovascular area at the proximal and center of the respiratory lobule (B). In panacinar emphysema, tissue destruction results in a more even loss of alveolar walls throughout the lobule (C).

  • Panacinar: acini are uniformly involved (Fig. 28.5C)

  • Localized: peripheral acinar involved

  • Paracicatricial emphysema: emphysema adjacent to fibrosis

Differential Diagnosis

• ♦ Congenital lobar overinflation

  • No destruction of alveoli

• ♦ Honey comb lung

  • Fibrosis with metaplastic columnar epithelium

Large Airway Disease

Chronic Bronchitis

Clinical

• ♦ “Blue bloater”

• ♦ Most comm on etiology is cigarette smoking

Macroscopic

• ♦ Excessive mucous secretion within airways

Microscopic

• ♦ Goblet cell hyperplasia, thickened basement membrane, submucosal gland hyperplasia, smooth muscle hypertrophy

• ♦ Reid index: thickness of mucous gland layer/thickness of bronchial wall (normal <0.4)

Asthma

Clinical

• ♦ Nonproductive cough and wheezing; atopic, nonatopic, exercise, and occupational types

• ♦ Affects 5% of all children; 65% of asthmatics have symptoms before age 5

• ♦ M:F = 2:1

Macroscopic

• ♦ Mucous plugging of airways; overdistention with abundant air trapping

• ♦ May see saccular bronchiectasis, especially upper lobe

Microscopic

• ♦ Thickened basement membranes; mucous plugs; goblet cell hyperplasia

• ♦ Submucosal gland hypertrophy; may show eosinophilic infiltrate

• ♦ Smooth muscle hypertrophy

• ♦ Curschmann spirals, Charcot–Leyden crystals, Creola bodies

Differential Diagnosis

• ♦ Chronic bronchitis

  • Histology very similar to asthma, except found only in smokers

Bronchiectasis

Clinical

• ♦ Causes include postinflammatory, postobstructive; seen in setting of cystic fibrosis, ciliary disorders, immunologic deficiencies, and idiopathic

• ♦ Recurrent pneumonias with productive cough; hemoptysis; recurrent fevers

  • Cystic fibrosis

Macroscopic (Fig. 28.6A)

• ♦ Diffuse or localized enlarged, fibrotic cartilaginous airways; dilated airways extend to pleural surface; commonly filled with mucopurulent material

Microscopic (Fig. 28.6B)

• ♦ Ectatic dilated airways; chronically inflamed wall; follicular bronchitis may be present

• ♦ Acute and organizing pneumonia is common

Fig. 28.6.

Bronchiecta sis. Diffuse airway enlargement, fibrosis, and remodeling occur in this lung with cystic fibrosis (A). The airways are irreversibly distended and surrounded by a lymphoplasmacytic infiltrate. The overlying respiratory epithelium many times shows a metaplastic squamous epithelium (B).

Differential Diagnosis

• ♦ Mucinous tumors of the airways

  • Malignant epithelium

Small Airway Disease

Respiratory Bronchiolitis (Smoker’s)

Clinical

• ♦ Incidental fin dings in smokers

Microscopic (Fig. 28.7)

• ♦ Pigmented macrophages within terminal bronchioles and surrounding alveoli

• ♦ Mild chronic inflammation, fibrosis

Fig. 28.7.

Respiratory bronchiolitis. Pigmented macrophages accumulate around a small airway with chronic remodeling changes consisting of increased smooth muscle and mild fibrosis.

Follicular Bronchiolitis

Clinical

• ♦ Rare small airway disease; usually associated with collagen vascular diseases, including Sjögren disease and rheumatoid arthritis, and with immunodefic iencies

Microscopic (Fig. 28.8)

• ♦ Marked chronic inflammatory infiltrate surrounding small bronchioles; germinal centers are frequent; acute inflammatory cells within lumen can be seen

• ♦ Can be considered part of Diffuse Lymphoid Hyperplasia (see DLHP/LIP below)

Fig. 28.8.

Follicular bronchiolitis. A marked chronic inflammatory infiltrate with germinal centers surrounds small airways.

Constrictive (Obliterative) Bronchiolitis

Clinical

• ♦ Complication of lung or bone marrow transplantation; drug toxicity; connective tissue disease and idiopathic disease

Microscopic (Fig. 28.9)

• ♦ Bronchiolar and peribronchiolar fibrosis with narrowing and eventual obliteration of the lumen; may be preceded by a lymphocytic bronchiolitis

Fig. 28.9.

Constrictive (obliterative) bronchiolitis. Collagenous-type fibrosis narrows and eventually obliterates the lumen of the small airways.

Diffuse Panbronchiolitis

Clinical

• ♦ Seen almost exclusively in Japan; association with HLA BW54

• ♦ Etiology unknown; erythromycin offers some benefit

Microscopic

• ♦ Dense peribronchiolar infiltrate with characteristic foamy macrophages within the walls of the small bronchioles

Interstitial Diseases

Acute Lung Injury

Diffuse Alveolar Damage/Acute Interstitial Pneumonia

Clinical

• ♦ Pathologic correlate of adult respiratory distress syndrome; acute onset of dyspnea, diffuse pulmonary infiltrates, and rapid respiratory failure

• ♦ Causes include pulmonary edema, septic shock, oxygen toxicity, drugs (including chemotherapeutics), radiation, and trauma

• ♦ Idiopathic variant is known as acute interstitial pneumonia (AIP ) – Hamman–Rich syndrome

Macroscopic

• ♦ “Respirator lung”-dense, red/gray diffuse consolidation

Microscopic (Fig. 28.10A, B)

• ♦ Temporally uniform injury

• ♦ Two phases: acute and organizing

  • Acute: interstitial edema, type I pneumocyte sloughing and hyaline membranes.

  • Organizing: proliferating type II pneumocytes and interstitial fibroblasts with focal airspace organization.

  • Bronchiolar epithelial necrosis, reepithelialization and organization within airways.

  • Acute and organizing thrombi within vessels are common

Fig. 28.10.

Acute and org anizing diffuse alveolar damage. Hyaline membranes in the alveolar spaces (A) and are eventually organized into and widen the interstitium (B).

Differential Diagnosis

• ♦ Organizing pneumonia including cryptogenic organizing pneumonia (COP)/bronchiolitis obliterans organizing pneumonia (BOOP)

  • More subacute clinical course.

  • Process is patchy around bronchioles.

  • Hyaline membrane s are not seen.

  • Organization is intraluminal.

Organizing Pneumonia (COP)/Bronchiolitis Obliterans Organizing Pneumonia (BOOP)

Clinical

• ♦ A general term found in three clinical scenarios: postinfection repair process, systemic diseases such as collagen vascular disease (bronchiolitis obliterans organizing pneumonia (BOOP )), and idiopathic (cryptogenic organizing pneumonia (COP ) )

• ♦ Subacute onset of cough, dyspnea, and fever; multiple patchy airspace opacities, usually bilateral, on chest imaging

• ♦ Treated with steroids; excellent prognosis

Microscopic (Fig. 28.11)

• ♦ Temporally uniform injury

• ♦ Patchy, immature fibroblastic proliferations within bronchiolar lumina and peribronchiolar airspaces; usually sharply demarcated with adjacent normal parenchyma

• ♦ Foamy macrophages are commonly found in airspaces surrounding fibrosis

• ♦ Interstitial chronic inflammation and type II pneumocyte hyperplasia in area of fibrosis

Fig. 28.11.

Cryptogenic or ganizing pneumonia (COP)/bronchiolitis obliterans organizing pneumonia (BOOP). Organizing fibrosis in the form of fibroblastic proliferation is present within the bronchiolar and alveolar airspaces. The adjacent alveolar walls are relatively unremarkable.

Differential Diagnosis

• ♦ Diffuse alveolar damage/acute interstitial pneumonia

  • More acute clinical course.

  • More diffuse process, involving both bronchioles and alveoli.

  • Organizing fibrosis is interstitial

• ♦ Usual interstitial pneumonia

  • Temporally heterogeneous injury.

  • Interstitial fibrosis is predominantly subpleural and paraseptal with scattered fibroblastic foci.

  • Collagen deposition honeycomb foci can be found.

Idiopathic Interstitial Pneumonias

Respiratory Bronchiolitis-Associated Interstitial Lung Disease (RB-ILD)

Clinical

• ♦ Smokers’ disease

• ♦ Dyspnea, cough, mild restrictive defects

• ♦ Chest imaging usually normal; may present as interstitial infiltrates

Microscopic

• ♦ Finely granular-pigmented macrophages accumulate within lumens of distal bronchioles and surr ounding alveoli

• ♦ Mild chronic inflammation and fibrosis

Differential Diagnosis

• ♦ Desquam ative interstitial pneumonia

  • Mild interstitial fibrosis

• ♦ Pulmonary Langerhans cell histiocytosis (PLCH)

  • Characteristic nodules with Langerhans cells (S-100 protein+, CD1a+)

  • Peribronchiolar-based Langerhans cells

Desquamative Interstitial Pneumonitis (DIP)

Clinical

• ♦ Usually in middle-aged adults, 90% are smokers; insidious onset of dyspnea

• ♦ Chest imaging: bilateral, lower lobe, ground-glass opacities

• ♦ Favorable response to corticosteroids

• ♦ Mean survival = 12 years

Microscopic (Fig. 28.12)

• ♦ Striking pigmented macrophages within alveolar spaces; type II pneumocyte hyperplasia with subtle interstitial fibrosis

• ♦ Diffuse process; temporally uniform

Fig. 28.12.

Desquamative i nterstitial pneumonitis. Abundant pigmented macrophages fill the alveolar spaces. Reactive type II pneumocytes line the alveolar walls.

Differential Diagnosis

• ♦ DIP-like reaction of UIP

  • Temporally heterogeneous pattern of injury

• ♦ Pulmonary Langerhans cell histiocytosis (PLCH)

  • Patchy distribution; predominantly bronchiolar

  • Tightly packed macrophages (Langerhans cells)

  • Can be found in patients <40 years old

• ♦ Respiratory bronchiolitis-associated interstitial lung disease

  • No interstitial fibrosis

  • Less mac rophage accumulation and more airway centered

Usual Interstitial Pneumonitis

Clinical

• ♦ Insidious onset of dyspnea with chronic, progressive downhill course

• ♦ Most patients are 40–70 years old; collagen vascular diseases are commonly present

• ♦ 60% of patients die; mean survival 3 years

Macroscopic (Fig. 28.13A)

• ♦ Honeycomb changes most advanced at bases and periphery

Microscopic (Fig. 28.13 B, C)

• ♦ Temporally heterogeneous pattern of injury; “variegated” low-power appearance; fibrosis worse in subpleural and paraseptal regions

• ♦ Infiltrate is chronic with plasma cells; germinal centers commonly seen in rheumatoid arthritis

• ♦ Most fibrosis is dense collagen; intervening fibromyxoid foci are seen; large, ectatic airspaces with mucin pooling usually found in more advanced areas; areas of normal lung present centrally in lobule

• ♦ Smooth muscle hypertrophy and DIP-like reaction around bronchioles are common

• ♦ Vascular changes of intimal fibroplasia and medial hypertrophy are common

Fig. 28.13.

Usual interstitial pne umonia with honeycomb changes (A, B) and fibroblastic foci (C). Honeycomb airspaces filled with mucous are present in the base of the lobe (A). The chronic inflammation and fibrosis in this pattern of injury have a variegated low-power appearance (B) with characteristic fibroblastic foci intervening between the normal and the fibrotic areas of the lung (C).

Differential Diagnosis

• ♦ DIP

  • Macrophage accumulation is diffused.

  • Injury is temporally uniform

• ♦ COP/BOOP

  • Injury is temporally uniform

  • Clinical course is subacute

  • Fibroblastic foci are more pronounced

  • Areas of dense collagen deposition are absent

• ♦ Nonspecific interstitial pneumonia/fibrosis (NSIP)

  • Injury is temporally uniform

Nonspecific Interstitial Pneumonia/Fibrosis

Clinical

• ♦ Dyspnea and cough over several months; bilateral interstitial infiltrates on chest imaging

• ♦ Middle-aged adults; underlying connective tissue disease is common; idiopathic

• ♦ Cellular form is usually steroid responsive with good prognosis

• ♦ Fibrotic form may act similar to UIP

Microscopic (Fig. 28.14)

• ♦ Two types

  • Cellular

    • Interstitial chronic inflammation with lymphocytes and plasma cells

    • Preserved lung architecture

  • Fibrosing

    • Patchy or diffuse temporally uniform interstitial fibrosis

Fig. 28.14.

Nonspecific interst itial pneumonia. A chronic, lymphocytic infiltrate is present in the alveolar walls, and the overall lung architecture is preserved in this cellular type of NSIP.

Differential Diagnosis

• ♦ Usual interstitial pneumonia

  • Injury is temporally heterogeneous with fibroblastic foci

  • Collagen deposition and honeycomb changes are seen

  • Diffuse Lymphoid hyperplasia/Lymphocytic interstitial pneumonia here

Extrinsic Allergic Alveolitis (Hypersensitivity Pneumonitis)

Clinical

• ♦ Insidious onset of dyspnea with dry cough, fatigue, and malaise

• ♦ Exposure source not identified in 67% of cases diagnosed by pathology; diffuse interstitial infiltrates on chest X-ray

• ♦ Corticosteroids help after exposure has been eliminated

Microscopic (Fig. 28.15)

• ♦ Triad of features: interstitial pneumonitis; chronic bronchiolitis with areas of organizing pneumonia and ill-formed, nonnecrotizing granulomas or giant cells in parenchyma

Fig. 28.15.

Extrinsic alle rgic alveolitis/hypersensitivity pneumonitis. A prominent cellular bronchiolitis along with an interstitial pneumonitis is a major component.

Differential Diagnosis

• ♦ Usual interstitial pneumonia

  • Injury is temporally heterogeneous.

  • Granulomas usually not seen

• ♦ Sarcoidosis

  • Interstitial pneumonia, if present, is very mild.

  • Granulomas are well formed in lymphatic distribution

• ♦ Lymphoid interstitial pneumonia

  • Pathology is more diffusely distributed.

  • Does not have areas of organizing pneumonia.

Eosinophilic Pneumonia

Clinical

• ♦ Four clinical categories:

  • Simple: Loeffler syndrome; mild; self-limiting

  • Tropical: found in tropics due to filarial infestation

  • Acute: acute, febrile illness with respiratory failure; unknown etiology

  • Chronic: subacute illness; blood eosinophilia; F > M; patchy, peripheral infiltrate (photographic negative of pulmonary edema); etiologic agents (drugs, fungal, parasites, inhalants, and idiopathic)

Microscopic (Fig. 28.16)

• ♦ Filling of alveolar spaces with eosinophils and variable number of macrophages

• ♦ Eosinophilic abscesses and necrosis of cellular infiltrate; organizing pneumonia is common

• ♦ Features of DAD have been seen in acute form; mild, nonnecrotizing vasculitis of small arterioles and venules common

Fig. 28.16.

Eosinophilic pn eumonia. There are abundance eosinophils with scattered alveolar macrophages that fill the alveolar spaces.

Differential Diagnosis

• ♦ Churg– Strauss syndrome

  • Necrotizing granulomatous vasculitis is present

• ♦ Pulmonary Langerhans cell histiocytosis (PLCH)

  • Infiltrate is interstitial and usually peribronchiolar.

  • Seen only in smokers

• ♦ Desquamative interstitial pneumonitis

  • Eosinophilic abscesses and necrosis of infiltrate rarely seen

  • Vasculitis not seen

Pulmonary Langerhans Cell Histiocytosis

Clinical

• ♦ Occurs almost exclusively in smokers; M:F = 4:1; symptoms may be minimal; fourth decade

• ♦ Chest imaging: multiple, bilateral nodules 0.5–1.0 cm in upper lung lobes with cystic lesions

Microscopic (Fig. 28.17A, B)

• ♦ Discrete, nodular/stellate lesions; bronchiolocentric

• ♦ Langerhans cell: convoluted (kidney-bean) nuclei

Fig. 28.17.

Pulmonary Lang erhans cell histiocytosis (eosinophilic granuloma). The cellular phase of this disease shows prominent bronchiolocentric inflammation that has a somewhat stellate shape (A); histiocytes with a kidney-bean-type appearance are present (B).

Immunohistochemistry

• ♦ Langerhans cells: S100+, CDla+, HLR-DR+

Electron Microscopy

• ♦ Birbeck granule (“tennis racket” morphology)

Differential Diagnosis

• ♦ DIP

  • Inter stitial lesion

• ♦ Respiratory bronchiolitis-associated interstitial lung disease

  • Does not destroy bronchiole

  • Minimal fibrosis

  • No Langerhans cells

Sarcoidosis

Clinical

• ♦ Most common in young, African-American female (20–35 years old)

• ♦ Deficient T-cell response (cutaneous T-cell anergy and decreased helper T cells)

• ♦ Associations: functional hypoparathyroidism; hypercalciuria ± hypercalcemia; erythema nodosum; uveitis

• ♦ Kveim test: granulomatous reaction following injection of human spleen extract

• ♦ Serum ACE (angiotensin-converting enzyme)

• ♦ Radiologic stage

  • Stage 0:  Normal chest X-ray

  • Stage 1:  Hilar/mediastinal adenopathy

  • Stage 2:  Hilar/mediastinal adenopathy + interstitial pulmonary infiltrate

  • Stage 3:  Interstitial pulmonary infiltrate only

  • Stage 4:  End-stage fibrosis with honeycombing

Microscopic (Fig. 28.18)

• ♦ Interstitial noncaseating granulomata distributed in lymphatic and bronchovascular pathways; vascular and pleural involvement common

Fig. 28.18.

Sarcoidosis. Predom inantly nonnecrotizing granulomas with giant cells follow the subpleural and interlobular septa in a lymphatic type distribution.

Differential Diagnosis

• ♦ Chronic berylliosis

  • Elevated beryllium levels on tissue quantitation

  • Clinical history of beryllium exposure

• ♦ Extrinsic allergic alveolitis

  • Ill-formed granulomata; interstitial distribution

  • Accompanying interstitial pneumonia

Pulmonary Alveolar Proteinosis

Clinical

• ♦ Etiologies: dusts, drug, immunodeficiency, leukemia, kaolin

• ♦ Bronchoalveolar lavage: treatment of choice

• ♦ Idiopathic or associated with infection

• ♦ Anti-GM-CSF circulating antibody found in idiopathic variant

Microscopic Features (Fig. 28.19)

• ♦ Accumu lation of granular eosinophilic material in alveoli; PAS+ material

Fig. 28.19.

Pulmonary alveolar pro teinosis. An eosinophilic material fills the alveolar spaces; the alveolar walls are essentially unremarkable.

Electron Microscopy

• ♦ Lamel lar body

Differential Diagnosis

• ♦ Pulmonary edema

  • Interstitial/septal edema

• ♦ Mycobacterial, nocardial, or Pneumocystis pneumonia

  • Positive special stains or microbiologic cultures

Anti-Basement Membrane Antibody [ABMA] Disease (Goodpasture syndrome)

Clinical

• ♦ M: F = 9:1; bimodal distribution of presentation (peaks at 30 and 60 years)

• ♦ Smokers; DRw15, DQw6

• ♦ Cytotoxic, antibody-mediated, immune reaction; antibodies to type IV collagen in serum cross-react to both kidney and lung

• ♦ Hemoptysis, anemia, azotemia, and diffuse lung infiltrates

Microscopic

• ♦ Extensive intra-alveolar hemorrhage; nonspecific type II pneumocyte hyperplasia

• ♦ Small vessel vasculitis may be present

• ♦ Iron encrustation of elastic fibers within interstitium and vessels may be present

• ♦ Mild interstitial fibrosis can be seen

Immunofluorescence:

• ♦ Linear staining of glomerular and pulmonary basement membranes for IgG

Differential Diagnosis

• ♦ Other causes of small vessel vasculitis

  • Absence of ABMA in tissue by immunofluorescence

• ♦ Idiopathic pulmonary hemosiderosis

  • Child and adolescent.

  • Immunofluorescent linear pattern is absent.

  • No acute hemorrhage.

Idiopathic Pulmonary Hemosiderosis

Clinical

• ♦ Exclusively in children <16 years; M:F = 1:1

• ♦ Hemoptysis, hypoxemia, chest infiltrates; iron deficiency anemia

• ♦ Stachybotrys chartarum may be an etiologic agent

• ♦ Poor prognosis with death in majority at 2–5 years

Microscopic (Fig. 28.20)

• ♦ Intra-alveolar hemorrhage without capillaritis; alveolar wall thickening and type II pneumocyte hyperplasia

• ♦ Bronchoalveolar lavage with hemosiderin-laden macrophages in large numbers

Fig. 28.20.

Idiopathic pu lmonary hemosiderosis. Hemosiderin-laden macrophages are abundant adjacent to mildly thickened alveolar septa with type II pneumocytes.

Differential Diagnosis

• ♦ ABMA Disease

  • Linear immunofluorescence pattern (IgG)

  • Kidney involvement

Pneumoconioses

• ♦ A n onneoplastic reaction of the lungs to inhaled mineral or organic dust

Silicosis

Clinical

• ♦ Reaction in lung to inhaled crystalline silica: stonecutting, quarry work, or sandblasting

• ♦ 0.5–2 micron fibers: most fibrogenic

• ♦ Predisposed toward tuberculosis (TB)

Macroscopic

• ♦ Firm, discrete, rounded lesions with variable amounts of black pigment

• ♦ Nodules in lymphatic distribution: around bronchovascular bundles, in subpleural and interseptal areas

Microscopic (Fig. 28.21)

• ♦ Discrete foci of concentric layers of hyalinized collagen; dust-filled histiocytes are abundant; birefringent particles usually present

• ♦ When necrosis is present, consider complicating infection by mycobacterial tuberculosis

Fig. 28.21.

Silicotic n odule. Multiple hyalinized nodules are adjacent to bronchioles.

Differential Diagnosis

• ♦ Inactive mycobacterial or fungal infections

  • Giant cells and palisading histiocytes are usually seen

• ♦ Hyalinizing pulmonary granuloma

  • Collagen bundles are disorganized.

  • Birefringent material is unusual.

Asbestos-Related Reactions

Clinical

• ♦ Reactions of the lung to asbestos with accompanying cations (i.e., iron, calcium, magnesium, sodium); serpentine and amphibole are the most common types

• ♦ Fibrosis occurs 15–20 years after exposure and can progress after exposure stops

Macroscopic

• ♦ Firm, fibrotic lungs with areas of honeycomb change

Microscopic (Fig. 28.22)

• ♦ Marked interstitial fibrosis with minimal inflammatory infiltrate; UIP-like reactions common

• ♦ Presence of asbestos bodies, fibrosis, and exposure history is needed for definitive diagnosis

• ♦ Hyalinizing pleural plaques, pleural fibrosis, and rounded atelectasis can also be seen

Fig. 28.22.

Asbestos-r elated reactions – ferruginous body. Asbestos fiber within the core surrounded by a proteinaceous iron-containing coat takes on a dumbbell shape.

Differential Diagnosis

• ♦ Usual interstitial pneumonia

  • Temporally heterogeneous

  • Lack of asbestos bodies

Coal Worker’s Pneumoconiosis (CWP)

Clinical

• ♦ Simple: single nodule, <2 cm

• ♦ Complicated: >2 cm, including progressive massive fibrosis

• ♦ Caplan syndrome: rheumatoid nodule with CWP (progressive massive fibrosis)

Macroscopic (Fig. 28.23A)

• ♦ Dense fibrosis and anthracosis, predominantly upper and middle lobes

Microscopic (Fig. 28.23B)

• ♦ Hyalinized nodule with anthracotic pigment in lung and lymph nodes

• ♦ Macules adjacent to bronchioles; may have centrilobular emphysema

Fig. 28.23.

Progressive ma ssive fibrosis/coal worker’s pneumoconiosis. Black/tan mass involves majority of the upper lobe (A); hyalinized nodule adjacent to the airway with emphysema (B).

Hard Metal Pneumoconiosis

Clinical

• ♦ Exposure to tungsten carbide and cobalt, usually in grinding, drilling, cutting, or sharpening

• ♦ Dyspnea with restrictive pulmonary function tests

Microscopic (Fig. 28.24)

• ♦ Giant cell interstitial pneumonitis with interstitial fibrosis, peribronchiolar giant cells, and DIP-like reaction

• ♦ Giant cells are multinucleated and commonly engulf other inflammatory cells

Fig. 28.24.

Hard metal pneumoconio sis/giant cell pneumonitis. Peribronchiolar infiltrate with macrophages and scattered giant cells and prominent smooth muscle is seen in small airways.

Differential Diagnosis

• ♦ Viral bronchiolitis/pneumonitis

  • No history of tungsten carbide/cobalt exposure

• ♦ Hypersensitivity pneumonitis

  • Increased interstitial and peribronchiolar inflammatory infiltrate

  • Nonnecrotizing granulomas

Berylliosis

Clinical

• ♦ Acute: Massive exposures produce acute respiratory distress syndrome-like pictures

• ♦ Chronic: Progressive dyspnea and cough with imaging studies similar to sarcoidosis; may progress to interstitial fibrosis

Macroscopic

• ♦ Nodules (up to 2 cm) with associated emphysema

Microscopic

• ♦ Nonn ecrotizing granulomas in a lymphatic distribution

Differential Diagnosis

• ♦ Sarcoidosis

  • No history of beryllium exposure

• ♦ Infections (mycobacterial or fungal)

  • Necrotizing granulomas

  • More airway distribution

Vascular Conditions

Vasculitides (Also See Chapter XX)

Granulomatosis with Polyangiitis (GPA)

Clinical

• ♦ Triad: upper airway, lower airway (lung), and kidney; saddle nose; rarely lung only (so-called limited)

• ♦ 40% of patients in remission are c-ANCA+ (anti-proteinase 3); 90% of patients with active disease are c-ANCA+

• ♦ Chest imaging: multiple well-demarcated peripheral nodules, lower lobes; rarely as a solitary pulmonary lobule

Microscopic (Fig. 28.25)

• ♦ Triad: parenchymal (basophilic) necrosis, vasculitis, granulomatous inflammation

• ♦ Variants: eosinophil-rich, bronchiolocentric, solitary, capillaritis, and diffuse pulmonary hemorrhage

• ♦ Parenchymal necrosis may be in form of microabscesses or geographic necrosis

• ♦ Vasculitis may affect arteries, veins, or capillaries

Fig. 28.25.

Granulomatosis with polyangiitis. (A) Geographic necrosis. (B) Collagenous necrosis. A large area of basophilic necrosis (A) is lined by histiocytes and scattered giant cells (B).

Differential Diagnosis (Table 28.1)

• ♦ Lympho matoid granulomatosis

  • Atypical cytology

• ♦ Granulomatous infections

  • Well-formed, nonnecrotizing granulomas

  • Eosinophilic necrosis

• ♦ Rheumatoid nodules

  • Found only in the setting of clinical rheumatoid arthritis

  • Usually subpleural

• ♦ Necrotizing sarcoid granulomatosis

  • Well-formed nonnecrotizing granulomas in lymphatic distribution in lung adjacent to necrobiotic nodule

Table 28.1. Diffe rential Diagnosis of Granulomatous Lesions

Churg–Strauss Syndrome (Allergic Angiitis Granulomatosis)

Clinical

• ♦ Asthma, eosinophilia, systemic vasculitis, mono- or polyneuropathy

• ♦ Nonfixed lung infiltrate, paranasal sinus abnormalities; p-ANCA+

Microscopic

• ♦ Eosinophilic infiltrates, granulomatous inflammation, and necrotizing vasculitis

Differential Diagnosis (Table 28.1)

• ♦ Chronic eosinophilic pneumonia

  • Nongranulomatous

• ♦ Allergic bronchopulmonary aspergillosis

  • Bronchocentric

• ♦ Drug- induced vasculitis

• ♦ Polyarteritis nodosa

  • Rarely involves the lung

• ♦ Granulomatosis with polyangiitis

  • Geographic necrosis

Necrotizing Sarcoid Granulomatosis (NSG)

Clinical

• ♦ F:M = 2.2:1; variable age presentation; cough, chest pain, weight loss, fever

• ♦ No systemic vasculitis

• ♦ Chest imaging: bilateral lung nodules, usually lower lobe; hilar adenopathy is present in <10% of cases

Microscopic

• ♦ Lymphoplasmacytic or granulomatous vasculitis; parenchymal necrosis without necrotizing vasculitis; numerous caseating sarcoid-like granulomas

Differential Diagnosis (Table 28.1)

• ♦ Granulomatosis with polyangiitis (GPA)

  • No sarcoidal granulomas

• ♦ Infection:

  • Vasculitis not a prominent component

  • Positive organismal stains

• ♦ Churg–Strauss syndrome (allergic angiitis granulomatosis)

  • No hilar adenopathy

  • History of asthma

  • Peripheral eosinophilia

Necrotizing Capillaritis

Clinical

• ♦ Associated conditions: collagen vascular disease, especially systemic lupus erythematosus, Wegener granulomatosis, Henoch–Schönlein purpura, cryoglobulinemia, Behçet disease, drug reactions (sulfonamides), and Goodpasture disease

Microscopic (Fig. 28.26)

• ♦ Focal necrosis of alveolar septa with neutrophilic infiltration, capillary fibrin thrombi, and interstitial hemorrhage/hemosiderosis

• ♦ Often associated with foci of DAD

Fig. 28.26.

Necrotizing capill aritis. A neutrophilic infiltrate involves the alveolar septa capillaries.

Differential Diagnosis

• ♦ Acute hemorrhagic bronchopneumonia

  • Neutrophils predominate in alveolar space

Pulmonary Hypertension

Pulmonary hypertension (PH)

Clinical

• ♦ Idio pathic pulmonary hypertension

  • F:M 1.7:1

• ♦ Familial (FPAH)

  • Germline mutations in BMPR2 (chromosome 2q31-32)

• ♦ Associated with:

  • Collagen vascular disease

  • Congenital cardiac shunts

  • Portal hypertension

  • HIV infection

  • Drugs and toxins

  • Aminorex fumarate

Microscopic (Fig. 28.27)

• ♦ Path ologic changes from low grade to high grade

  • Muscularization of pulmonary arteries

  • Cellular intimal proliferation

  • Intimal concentric laminar fibrosis

  • Plexiform lesions

  • Plexiform and angiomatoid lesions

  • Necrotizing arteritis

Fig. 28.27.

Pulmonary hyperte nsion – plexogenic arteriopathy. A plexogenic lesion contains a remodeled artery wall with abnormal vascular spaces lined by myofibroblasts.

Pulmonary Veno-Occlusive Disease with Secondary Pulmonary Arterial Hypertension

Clinical

• ♦ Rare form of pulmonary hypertension; 33% occur in children

• ♦ Causes: drug toxicity, especially chemotherapeutics, viral infections

Microscopic (Fig. 28.28)

• ♦ Congestive changes with hemosiderin-laden macrophages

• ♦ Pulmonary hypertensive changes

• ♦ Intimal fibrosis and thrombosis of veins; recanalization is common

Fig. 28.28.

Pulmonary veno-occ lusive disease (PVOD). A vein containing prominent intimal fibrosis and recanalization (colander lesion) is characteristically found in this disease.

Pulmonary Capillary Hemangiomatosis

Clinical

• ♦ Rare cause of pulmonary hypertension; most patients between 20 and 40 years old

Microscopic

• ♦ Abnormal proliferation of capillary-like vessels in alveolar septa; patchy hemosiderin

• ♦ May have secondary venous changes with intimal fibrosis

Thrombotic Arteriopathy

Clinical

• ♦ Sudden shortness of breath with pleuritic pain

Macroscopic (Fig. 28.29)

• ♦ Hemorrhagic wedge-shaped peripheral lesions

Fig. 28.29.

Pulmonary infarc tion. A wedge-shaped hemorrhagic area represents a recent, hemorrhagic infarction of the lung.

Microscopic (Fig. 28.30)

• ♦ Eccentric intimal f ibrosis; colander lesions common; widespread small vessel thrombi

• ♦ Plexogenic lesions are rarely found (probably represents plexogenic arteriopathy with superimposed thrombi)

• ♦ Ischemic necrosis and surrounding areas of organization and hemosiderin pigment

Fig. 28.30.

Thrombotic arteriopa thy. An eccentric pattern of intimal fibroplasia is seen in this form of pulmonary hypertensive disease.

Differential Diagnosis

• ♦ Necro tizing pneumonia

Infections (Also See Chapter XX)

Viral

Cytomegalovirus

• Clinical

  • ♦ F ound almost exclusively in immunocompromised patients

• Microscopic (Fig. 28.31)

  • ♦ Diffuse interstitial pneumonitis and nodular (miliary) pneumonia

  • ♦ Cytopathic changes: cytomegaly (2–3 times normal cell); amphophilic/basophilic nuclear inclusions; basophilic cytoplasmic inclusions

  • ♦ Inclusions found in pneumocytes, histiocytes, and endothelial cells; PAS+; Grocott+

  Fig. 28.31.

  

  Cytomegalov irus (CMV) inclusion in alveolar macrophage. Both nuclear and cytoplasmic inclusions can be seen in this enlarged alveolar macrophage infected by CMV.

• Differential Diagnosis

  • ♦ Herpes viral pneumonia

    • Necroti zing pneumonia

    • Cowdry type A nuclear inclusions

  • ♦ Adenoviral pneumonia

    • No cytoplasmic inclusions

    • Smudge cells (nuclear inclusions)

Herpes Simplex Virus

• Clinical

  • ♦ Bloodborne or airborne dissemination; immunocompromised patient, inhalation injuries, and chronic obstructive pulmonary disease patient

  • ♦ Laryngotracheobronchitis, bronchopneumonia

• Microscopic (Fig. 28.32)

  • ♦ Miliary foci of necrosis

  • ♦ Cytopathic changes: may be difficult to find in lung; mild nucleomegaly (1.25–1.5 times normal cell); dispersion of nuclear chromatin; condensation of nuclear chromatin on nuclear membrane

  • ♦ Cowdry type A inclusions: intranuclear viral particles that coalesce

  • ♦ Multinucleation may be absent in the lung

  • ♦ Epithelial cells mainly affected

  Fig. 28.32.

  

  Herpes inclusion in alveolar macrophage. Cowdry type A inclusions with eosinophilic nuclei with a halo separating the inclusion from the nuclear membrane.

• Differential Diagnosis

  • ♦ Cytomegalo virus pneumonia

    • Affects both epithelial and mesenchymal cells

    • Cytoplasmic inclusions

Measles Virus

• Clinical

  • ♦ Immu nocompromised p atient

• Microscopic

  • ♦ Diffuse alveolar damage and acute necrotizing bronchopneumonia; multinucleated cells

  • ♦ (5–20 nuclei/cell); intranuclear and intracytoplasmic inclusions present (Feulgen–)

  • ♦ Warthin–Finkeldey cell with lymphoid hyperplasia: CD4+ T cells

• Differential Diagnosis

  • ♦ Giant cell interstitial pneumonitis/hard metal pne umoconiosis

    • Acute lung injury usually not present

    • Giant cells with 2–5 nuclei

Adenovirus

• Clinical

  • ♦ G enerally found in children; can cause fulminant pneumonia in immunosuppressed patients

• Microscopic (Fig. 28.33)

  • ♦ Destruction of bronchioles with sloughing

  • ♦ Cytopathic changes: smudge-Feulgen+ round eosinophilic intranuclear inclusions

  Fig. 28.33.

  

  Adenovirus infecti on. Dark, intranuclear inclusions are found in the “smudge” cells.

• Electron microscopy

  • ♦ Latti ce-like hexagonal viral particle

Respiratory Syncytial Virus

• Clinical

  • ♦ Usually seen in babies and young children; diagnosis usually made by serologies

• Microscopic

  • ♦ Cellular, lymphocytic bronchiolitis with intraluminal neutrophils

  • ♦ Metaplastic bronchial epithelium; can show multinucleation

  • ♦ Cytopathic effect: small, inconspicuous eosinophilic cytoplasmic inclusions in bronchiolar cells

Epstein–Barr Virus

• Clinical

  • ♦ Biopsy rarely performed for diagnosis; 10% of patients with mononucleosis show clinical symptoms of respiratory infection

• Microscopic

  • ♦ Perivascular (especially perivenular) chronic inflammation with plasmacytoid and/or immunoblastic features, cellular bronchiolitis, and interstitial infiltrates

Hantavirus Pulmonary Syndrome

• Clinical

  • ♦ Young, healthy adults; rapidly fatal; progressive pulmonary edema and hemorrhage

  • ♦ Host: deer mice

  • ♦ Diagnosis usually made by culture or serologies; biopsy rarely done for diagnosis

• Microscopic (Fig. 28.34)

  • ♦ Pulmonary edema and pleural effusions; early DAD

  • ♦ Influenza, parainfluenza virus, varicella

  Fig. 28.34.

  

  Hantavirus pulmonary syndrome. Fluid-filled alveolar spaces and interstitial edema are present.

Bacteria

Legionnaires Disease

• Clinical

  • ♦ First recognized in large outbreak at the American Legion Convention in Philadelphia

  • ♦ Acute pneumonic process with high fever, cough, chill, and chest pain; gastrointestinal symptoms are prominent; renal failure is common

  • ♦ Renal and bone marrow transplant patients at high risk

• Microscopic (Fig. 28.35A, B)

  • ♦ Acute bronchopneumonia with characteristic intra-alveolar exudate of neutrophils, macrophages, and karyorrhectic debris

  Fig. 28.35.

  

  Legionnaires disease. A pro minent intra-alveolar exudate with degenerating inflammatory cells (A) is present; the organisms, pleomorphic Gram-negative bacilli, are highlighted by Dieterle stain (B).

• Special Studies

  • ♦ Small, pleomorphic Gram-negative bacillus; cultured in modified Mueller–Hinton agar

  • ♦ Dieterle silver stain best for visualizing organism; fluorescent studies of smears and scrapes are most sensitive for diagnosis

Nocardiosis

• Clinical

  • ♦ Localized abscess or miliary bilateral infection (common) in immunocompromised host

• Microscopic

  • ♦ Mixture of acute and chronic inflammation with microabscess formation

  • ♦ Silver stain is best for diagnosis: fine, filamentous organisms – may be very difficult to find

  • ♦ Weakly a cid-fast (Fite stain) and Gram-positive

Actinomycosis

• Clinical

  • ♦ Aspiration of oral or tonsillar organisms; patients with poor dentition or repeated tonsillitis

• Microscopic (Fig. 28.36)

  • ♦ Abscess in the lung or mediastinum; sulfur granules found with palisading eosinophilic proteinaceous halo – Splendore–Hoeppli reaction

  Fig. 28.36.

  

  Actinomyces. Gram-positive sulfur granules are seen in this Splendore–Hoeppli reaction.

Malakoplakia

• Clinical

  • ♦ Nodular lesions in immunocompromised patients, particular HIV-infected individuals; Rhodococcus equi is a common etiologic agent

• Microscopic

  • ♦ Chronic infiltrate with plasma cells and lymphocytes with sheets of histiocytes containing abundant Michaelis–Gutmann bodies

Mycobacterial Infections

Mycobacterial Tuberculosis

• Clinical

  • ♦ High-risk factors include elderly, immigrants, lower socioeconomic groups, aboriginal races, HIV infection, silicosis, diabetes mellitus, hemodialysis, gastrectomy, nutritional deficiency, intravenous drug abuse, and organ transplantation

  • ♦ Clinical classification

    • Primary TB: exogenous first infection; usually self-limiting

    • Progressive TB: inadequate acquired immunity (infants or elderly); progression of original infection; <10% of patients

    • Postprimary TB (reactivation; secondary): endogenous reactivation

• Macroscopic (Fig. 28.37 A)

  • ♦ Prim ary TB

    • Ghon focus: single subpleural nodule, above or below interlobar fissure and enlarged caseous lymph nodes

  • ♦ Progressive TB

    • Cavitation and progression of initial or reactivation nodule; consolidation or miliary spread can occur

  • ♦ Postprimary TB

    • Apical lesion (due to higher oxygen tension); miliary spread can occur

• Microscopic (Fig. 28.37 B)

  • ♦ Primary/postprimary TB

    • Necrotizing gr nulomatous inflammation, airway based; nonnecrotizing granulomas commonly present away from main mass

  • ♦ Progressive TB

    • Necrotizing granulomatous inflammation with cavitation and spread throughout lung; pleura commonly involved

  Fig. 28.37.

  

  Mycobacterial tuberculo sis. A cavitating apical lesion (A) and necrotizing granulomas (B) are seen.

Nontuberculous Mycobacteria

• • ♦ Most common are Mycobacterium avium–intracellulare complex and M. kansasii

• Clinical

  • ♦ Opport unistic infections in HIV-infected patients

  • ♦ Other risk factors COPD, bronchiectasis, pneumoconioses

  • ♦ Also found in patients without underlying lung disease (nonsmoking women)

• Macroscopic

  • ♦ Can cause upper lobe cavitary lesion

  • ♦ Noncavitating form may be associated with local bronchie ctasis

• Microscopic

  • ♦ Necrotizing granulomatous inflammation most common with nonnecrotizing granulomas present

  • ♦ Organizing pneumonia and nonnecrotizing granulomas can be seen

• Special Studies

  • ♦ Ziehl–Neelsen sta in for acid-fast organisms (Fig. 28.38)

  • ♦ Auramine-rhodamine immunofluorescence stain: more sensitive

  Fig. 28.38.

  

  Mycobacterium a vium complex (MAI) in an AIDS patient. Abundant acid-fast bacilli are present within alveolar macrophages.

• Differential Diagnosis

  • ♦ Granulomatos is with polyangiitis (Table 28.1)

    • No sarcoidal-like granulomas

    • Basophilic necrosis

  • ♦ Necrotizing fungal infections

    • Results of special stains and microbiologic cultures

Mycoplasma pneumoniae

Clinical

• ♦ Community-a cquired pneumonia; dry cough with subacute course

Microscopic

• ♦ Cellular bronchiolitis with acute and chronic inflammation; plasma cells may be abundant

• ♦ Metaplastic bronchiolar epithelium without cilia; organism destroys cilia

Special Studies

• ♦ Complement fixation tests used for diagnosis; fourfold titer increase is diagnostic of infection

• ♦ Stains on Giemsa stain; DNA probe is the best way to find organisms in tissue

Fungal

Aspergillosis (Fig. 28.39)

• ♦ Aspergillus: thick- walled hyphae, septated and 45° branching; oxalic acid/calcium oxalate crystals seen in A. niger

• ♦ Four different pathologic patterns

  • Allergic bronchopulmonary aspergillosis (ABPA)

    • Seen exclusively in asthmatics

    • Mucoid impaction, bronchocentric granulomatosis, and eosinophilic pneumonia

  • Aspergilloma

    • Fungus ball growing in preexisting cavity, e.g., bulla

  • Chronic necrotizing aspergillosis

    • Usually single, upper lobe lesion, subacute clinical course.

    • Chronic, granulomatous inflammation; eosinophils are prominent; hyphae should be readily apparent; no vascular invasion.

  • Fulminant invasive aspergillosis

    • Immunocompromised host; vascular invasion and infarction

Fig. 28.39.

Aspergillus funga l hyphae. A silver stain highlights the septated hyphae with acute angle branching.

Differential Diagnosis

• ♦ Mucormycosis

  • Nonseptate, larger, right angle branching

  • Culture needed to be distinguished, especially if aspergillosis is treated

• ♦ Alternaria

  • Golden brown club-shaped macroconidia with longitudinal and transverse septation; bullous swelling near septation in hyphae

Mucormycosis (Phycomycosis)

• Clinical

  • ♦ Immunocompromised host: uncontrolled diabetes, burn injury, and renal failure

• Microscopic (Fig. 28.40)

  • ♦ Nonseptate hyphae 10–25 microns wide; irregular right angle branching; pleomorphic, collapsing walls; necrotizing bronchopneumonia with infarction

  Fig. 28.40.

  

  Mucormycosis. Nonsepta te hyphae with a ribbon-like morphology are present within infarcted lung tissue.

• Differential Diagnosis

  • ♦ Asp ergillosis

    • Septate, right angle branching

Candidiasis

• Clinical

  • ♦ Immunocompro mised hosts, burns, trauma, catheters, and gastrointestinal surgery

• Microscopic

  • ♦ Yeast forms 2–6 microns; mycelial pseudohyphae forms are common

  • ♦ Acute bronchopneumonia and emboli to other organs, especially the ki dney

Histoplasmosis

• Clinical

  • ♦ Can be seen in normal host; commonly found in Mississippi and Ohio River Valley; bird and bat feces

• Microscopic (Fig. 28.41A–C)

  • ♦ Necrotizing granulomas, similar to M. tuberculosis; yeast forms 2–5 microns; usually degenerating forms are seen; budding is unusual but seen

  Fig. 28.41.

  

  Histoplasmosis. Necrotizi ng granulomas are present over the majority of airways (A) and usually show abundant central necrosis (B). Present within the area of necrosis are budding yeast forms of Histoplasma capsulatum (C).

Coccidioidomycosis

• Clinical (Fig. 28.42)

  • ♦ Can be seen in normal host; southwest USA, dry arid climate (San Joaquin Valley fever); inhaled arthrospores develop into spherules

  • ♦ C. immitis usual organism; complement fixation tests positive in 90% patients

  Fig. 28.42.

  

  Coccidioides immitis. A silver st ain highlights large spherules containing endospores that spill out into infected lung tissue.

• Microscopic

  • ♦ Necrotizing granulomas, resembling M. tuberculosis

• Special Studies

  • ♦ Spherules (20–200 m icrons) with endospores – PAS+, GMS+

Sporotrichosis

• Clinical

  • ♦ Male, alcoholic; infe cts preexisting lung disease (emphysema); Sporothrix schenckii usually organism; found in straw, moss, timber, and plants

• Microscopic

  • ♦ Single, necrotizing lesion; significant hilar adenopathy

Blastomycosis

• Clinical

  • ♦ Can be seen in norma l host; Blastomyces dermatitidis, soil-growing fungus

  • ♦ North America around Mississippi and Ohio rivers and Southeast (Georgia)

• Microscopic (Fig. 28.43A, B)

  • ♦ Necrotizing granulomas w ith central microabscess multinucleated giant cells; yeast forms: broad-based budding

  • ♦ Bronchial lesions are common; bronchial stenosis common

  Fig. 28.43.

  

  Blastomycosis. Loosely forme d necrotizing granuloma (A) is characteristic of this infection; a silver stain highlights the broad-based budding of Blastomyces dermatitidis (B).

Cryptococcosis

• Clinical

  • ♦ Can be seen in n ormal host, most symptomatic cases are in immunocompromised hosts; predilection for CNS

  • ♦ C. neoformans most common organism; source: pigeons

• Microscopic (Fig. 28.44)

  • ♦ Granulomatous les ions with acute inflammation; pleomorphic yeast forms (2–10 microns); single bud

  Fig. 28.44.

  

  Cryptococcus neoform ans. A mucin stain highlights the presence of a capsule and budding commonly found in this yeast.

• Special Studies

  • ♦ Silver +; mucicarmine + capsule

Protozoan

Pneumocystis jiroveci Pneumonia

• Clinical

  • ♦ Immunocomp romised host, especially AIDS; insidious onset; bilateral infiltrates

• Microscopic (Fig. 28.45)

  • ♦ Frothy, eosinophilic intra-alveolar exudate with faint blue dots

  • ♦ Mild chronic interstitial pneumonitis

  • ♦ Unusual r eactions include granulomatous inflammation, diffuse alveolar damage, alveolar proteinosis, calcifications, and tissue invasion

  Fig. 28.45.

  

  Pneumocystis jiroveci pneumonia (PCP). A “frothy” intra-alveolar exudative is present with prominent type II pneumocytes (A). Pneumocystis jiroveci organisms are highlighted by a silver stain (B).

• Special Studies

  • ♦ Cyst (5–8 microns) is best seen on methenamine silver stain

  • ♦ Trophozoite (1–2 microns) is best seen on Giemsa stain

• Differential Diagnosis

  • ♦ Pulmonary alveolar proteinosis

    • Negative methenamine silver stain

      • Minimal i nterstitial reaction

      • PAS+

Dirofilarial (Dog Heart Worm) Granulomas

• Clinical

  • ♦ Dirofilaria immitis, dog heart worm; adult worm resides in the right ventricle/pulmonary artery of dogs; microfilariae in dog blood transmitted to human via mosquito bites

  • ♦ Asymptomatic coin lesion on chest X-ray

• Microscopic

  • ♦ Pathologic triad: spherical infarct, eosinophilic pneumonia, and endarteritis

  • ♦ Dirofilarial parasite is present within branch of pulmonary artery within the center of infarct

  • ♦ 100–200 microns; thick cuticle with longitudinal ridges

Toxoplasma gondii Pneumonia

• Clinical

  • ♦ Immunocompromised h ost, especially AIDS and neonate; cats are carriers

  • ♦ Infection of humans is via cat feces or raw meat

• Microscopic

  • ♦ Necrotizing nodules with central coagulative necrosis

  • ♦ Tachyzoites are present within necrosis

  • ♦ DAD can be seen

• Special Studies

  • ♦ Giemsa stains tachyzoites

  • ♦ Immunohistochemical studies are helpful for identification of cysts

Paragonimiasis (Lung Fluke)

• Clinical

  • ♦ Endemic in South America, Africa, India, Southeast Asia; in immigrants in North America

  • ♦ “Endemic hemoptysis”; pleural and blood eosinophilia; benign clinical course

• Microscopic

  • ♦ Adult flukes in human lung: red/brown and fleshy; 0.8–1.4 cm in length

  • ♦ Chronic abscess formation; upper lobes>lower lobes

• Special Studies

  • ♦ Ziehl– Neelsen stains eggshells

Lung Transplantation (Also See Chapter XX)

Histologic Grading of Pulmonary Allograft Rejection

• Acute Cellular Rejection (Fig. 28.46)

  • ♦ Perivascular and interstitial mononuclear cell infiltrates

    • Grade A0: Normal pulmonary parenchyma

    • Grade A1: Infrequent perivascular mononuclear infiltrates not obvious at low magnification

    • Grade A2: Frequent perivascular mononuclear infiltrates surrounding venules and arterioles readily recognizable at low magnification

    • Grade A3: Readily recognizable cuffing of venules and arterioles by dense perivascular mononuclear cell infiltrates, usually associated with endotheliitis; interstitial mononuclear cell infiltrates

    • Grade A4: Diffuse perivascular, interstitial, and air space infiltrates of mononuclear cells and prominent alveolar pneumocyte damage usually associated with inflammatory cell debris

  Fig. 28.46.

  

  Minimal acute vascu lar rejection of pulmonary allograft. A scattering of mononuclear cells surrounds a small vessel and is difficult to distinguish from low power.

Airway Inflammation-Lymphocytic Bronchitis/Bronchiolitis

• ♦ Grade B0: None

• ♦ Grade B1R: Low grade

• ♦ Grade B2R: High grade

• ♦ Grade BX: Not gradable

Chronic Airway Rejection/Bronchiolitis Obliterans

• ♦ Grade C0: None

• ♦ Grade C1: Present

Chronic Vascular Rejection-Accelerated Graft Sclerosis

• ♦ Fibrointimal thickening of arteries and veins of uncertain clinical significance

Antibody-Mediated Rejection (AMR)

Clinical

• ♦ Progressive respiratory failure, pulmonary edema, and opacification of allograft

Microscopic

• ♦ Diffuse alveolar damage

• ♦ Pulmonary hemorrhage with capillaritis

Special Studies

• ♦ Deposition of IgG and complement (C4d) in the alveolar septa

Differential Diagnosis

• ♦ Ischemia- reperfusion injury with acute lung injury

  • No vasculitis or capillaritis is seen.

  • Negative lymphocyte cross-match.

Masses, Tumorlike Lesions, and Deposition Diseases

Amyloidosis

Clinical

• ♦ Patients have monoclonal proteins in serum or urine

• ♦ Associated diseases include multiple myeloma, lymphoid interstitial pneumonitis, low-grade lymphomas, and Sjögren syndrome

Macroscopic

• ♦ Five types: nodular, diffuse, alveolar-septal, senile, and tracheobronchial

• ♦ Waxy, hard irregular nodules

Microscopic (Fig. 28.47)

• ♦ Amorphous, eosinophilic material in vessels, in airway, or as nodules

• ♦ Congo red shows apple-green birefringence

Fig. 28.47.

Amyloidosis. Amorph ous eosinophilic material is present surrounding vessels and within alveolar septa (A). A Congo red stain reveals “apple-green” birefringence under polarized light (B).

Differential Diagnosis

• ♦ Kappa light chain disease

  • Congo red stain not birefringent

• ♦ Pulmonary hyalinizing granuloma

  • Congo red stain−

Pulmonary Hyalinizing Granuloma

Clinical

• ♦ Asympto matic; adults

• ♦ 60% have serologic evidence of autoimmunity

Macroscopic

• ♦ Bilateral nodules; white/gray “cotton balls”

Microscopic (Fig. 28.48)

• ♦ Lamellar collagen in storiform or whorled array – “donuts”; mild lymphoplasmacytic infiltrate

Fig. 28.48.

Pulmonary hyalinizing g ranuloma. Thick bundles of collagen in storiform arrays are present.

Differential Diagnosis

• ♦ Nodular amyloidosis

  • Congo red stains for apple-green birefringence

• ♦ Hyalinized infectious granulomas

  • Collagen arranged in parallel around center

Tracheobronchopathia Osteoplastica

Clinical

• ♦ Middle-aged or elderly men with hoarseness, stridor, hemoptysis; possible relationship to tracheal amyloidosis

Macroscopic

• ♦ Hard, yellow-white papilla-like formations on cartilaginous portion of trachea or bronchi

Microscopic

• ♦ Nodules of bone and cartilage in submucosa

Benign Metastasizing Leiomyoma

Clinical

• ♦ Multiple nod ules; invariably in women

Macroscopic

• ♦ Gray/white lobulated mass; shells out from lung parenchyma

Microscopic

• ♦ Well-differentiated smooth muscle; may have type II epithelial inclusions

• ♦ ≤5 mitoses/50 hpf

Differential Diagnosis

• ♦ Hamartoma

  • Bronchial epit helium

• ♦ Metastatic leiomyosarcoma

  • >5 mitoses/50 hpf

  • Primary sarcoma

  • Usually multiple lesions

Light Chain Deposition Disease

Clinical

• ♦ Found predominantly in patients with underlying plasma cell dyscrasia or other B-cell neoplasms such as lymphomas, Waldenstrom macroglobulinemia, and chronic lymphocytic leukemia

• ♦ Prognosis is poor usually because of its association with hematologic malignancies

Macroscopic

• ♦ Bilateral pulmonary nodules with tan, well-circumscribed morphology

• ♦ Grossly similar to nodular amyloidosis

• ♦ May have a reticulonodular or interstitial pattern

Microscopic

• ♦ Amorphous eosinophilic material, similar to amyloid, but consists of nonamyloid immunoglobulin light chains

• ♦ PAS+ and refractile blue on Giemsa

• ♦ Negative by polarization with all amyloid stains

• ♦ Consist of immunoglobulin light chains, most commonly kappa type

Differential Diagnosis

• ♦ Nodular amyloidosis

  • Congo red stains for apple-green birefringence

• ♦ Hyalinized infectious granulomas

  • Collagen arranged in parallel around center

• ♦ Pulmonary hyalinizing granuloma

  • No kappa or lambda restriction on light chain

IgG4-Related Lung Disease

Clinical

• ♦ Multisystem disorder characterized by fibroinflammatory disease in many organs including the pancreas, bile du ct, salivary gland, lacrimal gland, liver, kidney, and aorta

• ♦ Elevated peripheral blood IgG4 levels

• ♦ Steroid responsive

Macroscopic

• ♦ Parenchymal nodules and infiltrates

• ♦ Tracheobronchial involvement

• ♦ Pleural nodules

• ♦ Mediastinal lymphadenopathy with fibrosing mediastinitis

Microscopic (Fig. 28.49)

• ♦ Lymphoplasmacyt ic inf iltrate with collagenous-type fibrosis, which can have a storiform pattern

• ♦ Characteristic phlebitis that can be obliterative

• ♦ Plasma cells present though exact number (per 10 hpf) still debated

  • Should represe nt majority of inflammatory cells present

Fig. 28.49.

IgG4-related lung d isease. Fibroinflammatory nodule with hyalinized collagen and scattered foci of chronic inflammatory cells (A). A Movat stain reveals a vein within nodule with intimal fibroplasia consistent with characteristic phlebitis (B). Foci of chronic inflammatory cells show scattered plasma cells (C).

Differential Diagnosis

• ♦ Nodular amyloidosis

  • Congo red s tains for apple-green birefringence

• ♦ Hyalinized infectious granulomas

  • Collagen arran ged in parallel around center

• ♦ Pulmonary hyalinizing granuloma

  • Few plasma cells and no phlebitis

• ♦ Nodular light chain disease

  • Kappa or lambda restriction of light chain

Neoplastic Diseases of the Lung

Benign Tumors

Benign Epithelial Tumors

Squamous Papillomas and Papillomatosis

Clinical

• ♦ Upper airw ay solitary; adult smoker

• ♦ Lo wer airway multiple; papillomatosis: children and young adults

Macroscopic (Fig. 28.50A)

• ♦ Multiple lobulated excrescences in bronchioles; distal bronchiectasis common

Microscopic (Fig. 28.50B)

• ♦ Fibrovascular cores with cytologically bland nonkeratinizing squamous epithelium; koilocytic changes are common; mucous-secreting, transitional, or intermediate cells are sometimes inte rspersed

Fig. 28.50.

Squamous papillomat osis. A tan-lobulated mass is present in the trachea (A) and microscopically shows cytologically bland squamous epithelium with some superficial keratinization (B).

Differential Diagnosis

• ♦ Papillary squam ous cell carcinoma

  • Marked cytologic atypia with increased dyskeratosis and hyperkeratosis

  • Invasion into adjacent tissue

Papillary Adenoma of Type II Cells

Clinical

• ♦ Asymptom atic, “coin lesion” radiographically

Microscopic

• ♦ Circums cribed lesion of branching, papillary fronds lined by cytologically bland columnar cells; no mitoses, necrosis, or infiltrative pattern; intranuclear inclusions common

Differential Diagnosis

• ♦ Metastatic papillary carcinoma

  • Rule out primary ovarian, thyroid, kidney, colon, and breast

• ♦ Sclerosing hemangiomas

  • More variegated histologic patterns including solid, sclerosing, papillary, and hemorrhagic, two cell types, cuboidal and polygonal

• ♦ Papillary adenocarcinoma

  • Cytologic atypia, mitoses, infiltrative growth

Alveolar Adenoma

Clinical

• ♦ Solitary nodule in women

Microscopic

• ♦ Multicystic, well-circumscribed with ectatic spaces filled with eosinophilic material; flat lining cells; interstitium contains collagenous matrix with myofibroblasts

Differential Diagnosis

• ♦ Lympha ngioma

  • Endothelial-lined spaces; cytokeratin negative

Mucous Gland Adenoma

Clinical

• ♦ Occurs in both children and adults; more common in women

• ♦ Large airway obstruction/irritation

Macroscopic

• ♦ Polypoid, endobronchial lesions in lobar or segmental bronchi

• ♦ Solid and cystic gelatinous surfaces

Microscopic

• ♦ Cystic, mucous-filled glands with cytologically bland, mucus-secreting epithelium; oncocytic metaplasia can be seen

Differential Diagnosis

• ♦ Low-grade mucoepidermoid carcinoma

  • Intermediate cells

• ♦ Adenocarcinomas

  • Cytologic atypia, necrosis, mitoses, lack of large cystic spaces

Mucinous Cystadenoma

Clinical

• Rare

  • ♦ Nodule in adult smokers

  • ♦ Usually asymptomatic

Macroscopic

• ♦ Mucus-f illed cysts

Microscopic

• ♦ Cystic spaces lined by benign, mucus-secreting epithelium; no invasion into adjacent tissue; borderline lesions show increased cytologic atypia

Differential Diagnosis

• ♦ Mucinous adenocarcinomas

  • No fibrous cyst wall

• ♦ Mucinous cystadenocarcinoma

  • Invasive growth into surrounding lung

Sclerosing Hemangioma

• Clinical

  • ♦ Female p redominance (80% found in women); asymptomatic

• Macroscopic

  • ♦ Gray/red circum scribed mass; 50% are in lower lobes

• Microscopic (Fig. 28.51)

  • ♦ Variegated arch itectural patterns including solid, papillary, sclerotic, and hemorrhagic

  • ♦ Cell types:

    • Small cuboidal surface cells with dark round nuclei.

    • Polygonal/round, larger stromal cells.

    • Inflammatory cells, i ncluding mast cells, may be numerous

  Fig. 28.51.

  

  Sclerosing hemangio ma. Cuboidal cells are seen lining solid and papillary areas.

• Immunohistochemistry

  • ♦ Surface and st romal polygonal cells: TTF1, EMA, and CK7 positive

• Differential Diagnosis

  • ♦ Adenocarcinoma, in situ, papillary, or solid predominant

    • One cell population, cytologic atypia, infiltrative growth

  • ♦ Epithelioid he mangioendothelioma

    • CD31, CD 34, and ERG positive; TTF1 negative

  • ♦ Carcin oid tumor

    • Neuroendocri ne markers positive; TTF1 variable staining

Benign Mesenchymal Tumors

Hamartoma

Clinical

• ♦ Central endobro nchial: cough, obstructive pneumonia

• ♦ Parenchymal: usually asymptomatic

Macroscopic (Fig. 28.52A)

• ♦ Well-circu mscribed white, bulging nodules of cartilaginous consistency

• ♦ Calcium or bone may be present

Microscopic (Fig. 28.52B)

• ♦ Usually composed predominantly of cartilage; fat, smooth muscle, and fibromyxoid tissue can be seen

• ♦ Surrounded by clefts of benign ciliated or nonciliated epithelium, entrapped metaplastic epithelium

Fig. 28.52.

Hama rtoma. A well-circumscribed white nodule (A) extrudes from the underlying lung parenchyma and contains cartilage, adipose tissue, and benign entrapped respiratory epithelium (B).

Cytogenetics

• ♦ 6p21 rearran gement activates high mobility group gene (HMGI-Y)

Differential Diagnosis

• ♦ Bronchial c hondromas as seen in young women with Carney triad (pulmonary chondromas, gastric epithelioid tumors, and extra-adrenal paragangliomas)

  • Usually connected to airway cartilage

• ♦ Benign metastasizing leiomyoma

  • Fat, cartilage, and other fibromyxoid elements are not seen

• ♦ Intrapulmonary solitary fibrous tumor

  • Stromal cells are CD 34 and STAT-6 positive.

Lipoma

Clinical

• ♦ Usually arise i n central bronchi; lead to obstruction, wheezing, and bronchiectasis

• ♦ Large variant completely enveloping bronchus can be sequela of chronic bronchiectasis

Macroscopic

• ♦ More frequent in left main bronchus than on the right side

• ♦ Smooth-wall ed polyps projecting into lumen

Microscopic

• ♦ Mature adipo se tissue; can have giant cells

Differential Diagnosis

• ♦ Hamartoma

  • Other mesenchy mal elements present

Mesenchymal Cystic Hamartoma

Clinical

• ♦ Lung cysts c ausing hemoptysis, pneumothoraces, and pleuritic chest pain

• ♦ Can be seen in children

Macroscopic

• ♦ Small cys ts with connections to bronchioles

Microscopic

• ♦ Normal respira tory or cuboidal epithelium; underlying primitive mesenchymal cells

• ♦ Hypertrophic arteries within mesenchyme

Differential Diagnosis

• ♦ Pulmonary sequ estration

• ♦ Congenital pulmonary airway malformation (congenital cystic adenomatoid malformation)

• ♦ Cystic bronchiectasis

  • None of the above contains primitive mesenchymal cells beneath epithelium

• ♦ Metastasis

  • Primary s arcoma (many of the reported cases have been metastases from uterine neoplasms)

Epithelial Preinvasive Lesions

Squamous Dysplasia/Carcinoma In Situ

Microscopic

• ♦ Dysplasia: cytologic atypia, nuclear enlargement in lower, middle and upper third of mucosa (grades: mild, moderate a nd severe); superficial surface maturation

• ♦ Carcinoma in situ: entire mucosal involvement by dysplasia without invasion through basement membrane

Atypical Adenomatous Hyperplasia

Microscopic (Fig. 28.53)

• ♦ Focal lesio ns, by definition < 5mm

• ♦ Mild/moderately atypical alveolar cuboidal cells lining alveolar walls; mitoses rare

Fig. 28.53.

Atypical adeno matous hyperplasia. A cuboidal epithelium contains hyperchromatic cells with cytologic atypia.

Differential Diagnosis

• ♦ Adenoca rcinoma in situ

  • Larger than 5 mm, greater nuclear atypia, mitoses

Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia

Clinical

• ♦ Dyspnea and cough with an obstructive pattern on pulmonary function tests

• ♦ Multiple centrilobular nodules

Microscopic

• ♦ Multipl e airways involved

• ♦ Hyperplasia: increased number of neuroendocrine cells contained within the basement membrane

• ♦ Carcinoid tumorlet: nests of neuroendocrine cells within the airway wall associated with fibrosis and rem odeling

Differential Diagnosis

• ♦ Neuroendocrine cell hy perplasia and carcinoid tumorlets secondary to chronic inflammatory pulmonary diseases

Malignant Tumors

Tumors of Salivary Gland Type

Mucoepidermoid Carcinoma

Clinical

• ♦ 50% are i n patients less than 30 years old; symptoms of large airway obstruction/ir ritation

Macroscopic (Fig. 28.54A)

• ♦ Tan/pink endobronchial n odule, most common in main or lobar bronchi

• ♦ Mucoid surface with underlying cystic areas; can ulcerate on surface

Microscopic (Fig. 28.54B)

• ♦ Mucin-secreting, squ amous, and intermediate cells

• ♦ Similar grading criteria to salivary glands using mitoses (>4/10 hpf), nuclear pleomorphism, intracystic component (>25%), ch aracteristic of invasive front (broad islands versus small infiltrating nests), lymphovascular invasion, perineural invasion, and necrosis (Brandwein)

Fig. 28.54.

Mucoepidermo id carcinoma. A tan polypoid endobronchial nodule is present in a proximal bronchus (A); microscopic features include both squamous and mucin-producing cells and more solid areas of intermediate cells (B).

Molecular

• ♦ Rearrang ement of MAML2 gene present [t(11;19)(q21;p13)]

Differential Diagnosis

• ♦ Bronchial mucous gland adenoma:

  • No interm ediate or squamous cells

• ♦ Adenosquamous cell carcinomas

  • Peripheral lesions with adja cent in situ carcinoma.

  • Intermediate cells are absent; usually keratinization is seen.

Adenoid Cystic Carcinoma

Clinical

• ♦ Most common saliv ary gland type tum or of the lower respiratory tract

• ♦ Lower trachea, main stem bronchi or lobar bronchi

• ♦ Large airway obstruction/irritation

• ♦ Recurre nce is common

Macroscopic

• ♦ Tan/gray tumors intrude bronchial wall with sessile or annular lesions; can spread subm ucosally along bronchial wall and diffusely involve adjacent airways

Microscopic (Fig. 28.55A–C)

• ♦ Small cells with hyperchromatic nuclei in cribriform, cylindromatous, trabecular, or glandular architec ture; commonly infiltrates through airway cartilage; spaces contain Alcian Blue+ basal lamina-type material; perineural invasion common

Fig. 28.55.

Adenoid cystic carci noma. A tan/white tumor mass thickens a bronchial wall (A); well-formed glands (B) with hyperchromatic cells and prominent basal lamina material are characteristic (C).

Differential Diagnosis

• ♦ Pleomorp hic adenoma

  • Epithelial and myoepithelial cells; mesenchymal chondromyxoid component; no cribriform or cylindro matous areas, no perineural invasion

• ♦ Adenocarcinomas

  • Cytologic atyp ia, mitoses, necrosis

Epithelial Tumors

Squamous Cell Carcinoma

Clinical

• ♦ 67% central; m ore common in men; second most common primary pulmonary carcinoma; strong association with smoking

• ♦ Paraneoplastic syndrome: hypercalcemia due to parathormone-related protein secretion by tumor

Macroscopic (Fig. 28.56A)

• ♦ Solid necrotic masses, commonly cavitate

Microscopic (Fig. 28.56B)

• ♦ Squamous differenti ation with intercellular bridges and/or keratinization (keratin pearls)

• ♦ Well, moderate, and poorly differentiated based on degree of squamous differentiation

• ♦ Spindle cells, osteoclastic-type tumor giant cells, and clear cell changes can be seen

• ♦ Histologic variants: papillary, clear cell, basaloid

Fig. 28.56.

Squamous cell car cinoma. A proximal, obstructing, cavitating tumor is present in a proximal airway (A). Malignant squamous cells and prominent keratinization are present (B).

Differential Diagnosis

• ♦ Squamous dysplasia

  • Lack stromal invasion

• ♦ Adenosquamous carcinoma and mucoepidermoid carcinoma

  • Glandular component

• ♦ Small cell carcinoma

  • Cells with little cytoplasm; increased N/C ratio, lack nucleoli, nuclear molding, and crush artifact s een in small biopsies; no squamous differentiation

Adenocarcinoma

Clinical

• ♦ Most common prim ary pulmonary carcinoma; most common lung cancer in women

• ♦ Paraneoplastic syndro me: Hypertrophic pulmonary osteoarthropathy

• ♦ Associated w ith smoking; however, smoking history is more variable than in other pulmonary carcinomas

Macroscopic (Fig. 28.57A)

• ♦ More comm only peripheral

• ♦ Adenocarcinoma in situ: ill-defined area of lung firmness

• ♦ Invasive adenocar cinoma: dense desmoplastic “scarred” center with a rim of firm, abnormal-looking lung

Microscopic (Fig. 28.57B)

• ♦ Adenocarcinoma in s itu: neoplastic cells lining alveolar septa without basement membrane disruption, invasion into underlying stroma, or lymphatic or pleural invasion (lepidic growth)

• ♦ Minimally invasive adenocarcinoma: adenocarcinoma measuring less than 3.0 cm with predominant lepidic pattern and an invasive focus of <0.5 cm

• ♦ Invasive adenocarcinoma: Adenocarcinoma with an invasive focus of >0.5 cm or any adenocarcinoma measuring more than 3.0 cm

• ♦ Multiple gro wth patterns, classified according to predominant component

  • Acinar predominant

  • Papillary predominant

  • Solid predominant

  • Micropapillary predominant

• ♦ Mucinou s (colloid) adenocarcinoma

  • Adenocarcinoma in situ

  • Minimally invasive adenocarcinoma

  • Invasive adenoc arcinoma

• ♦ Uncommon variants

  • Well-differentiated fetal adenocarcinoma: ribbons of neoplastic cells with nuclear stratification resembling embryonal lung tubules

  • Signet ring cell adenocarcinoma

  • Clear cell adenocarcinoma

  • Enteric-type adenocarcinoma: histologically and immunophenotypically similar to convent ional colorectal adenocarcinoma

Fig. 28.57.

Adenoc arcinoma. A peripheral tan/white tumor mass arises adjacent to the pleural surface (A) Histologically, in this acinar variant, the tumor contains malignant glands with marked atypical epithelium (B).

Immunohistochemistry

• ♦ TTF1 positive >80%, Napsin-A: positive (80%), p63 negative or focally positive, cytokeratin 7 posi tive, and cytokeratin 20 +/−

Electron Microscopy

• ♦ Short microvil li with glycocalyx and rootlets

Molecular

• ♦ Epidermal growth factor receptor (EGFR) mutations

  • Most commonly seen in nonsmokers, nonmucinous adenocarcinomas

  • Different mutations convey sensitivity or resistance to treatment with EGFR-tyrosinase kinase inhibitors

• ♦ KRAS mutations: most commonly seen in smokers

  • Alk-1 rearrangements

  • ROS-1RET-1

Differential Diagnosis

• ♦ Reacti ve alve olar proliferation

  • Heterogeneity of cell types, low N/C ratio, gaps between atypical cells, inflammatory changes present

• ♦ Atypical adenomatous hyperplasia

  • Mild to moderate cytologic atypia, no invasion

  • Focal lesion <0.5 cm

• ♦ Alveolar cell adenoma

  • Focal lesion, <0.7 cm, lack cytologic atypia

• ♦ Metastatic adenocarcinoma

  • Renal: TTF1, CK7, and CK20 negative; Napsin-A may be positiveBreast: CK7 and GATA3 posit ive; CK20, TTF1, and Napsin-A negative

  • Gastrointestinal tract: CK7 var iable; CK20 positive; CDX2 positive; TTF1 and Napsin-A negative

  • Mullerian tract: PAX8 and CK7 positive; estrogen receptors strongly positive; TTF1, Napsin-A, and CK20 negative

Adenosquamous Carcinoma

Clinical

• ♦ <4.0% of lung carcinomas

• ♦ Strong ass ociation with smoking

Microscopic

• ♦ Squamous cell ca rcinoma and adenocarcinoma components; each should be at least 10%

Differential Diagnosis

• ♦ Adenocarcinoma w ith metaplastic squamous changes

  • Bland squamous component

• ♦ Squamous cell carcinoma with entrapped bronchial epithelium

  • Bland glandular epithelium

• ♦ High-grade muc oepidermoid carcinoma

  • Lack carc inoma in situ, may contain areas of low-grade mucoepidermoid carcinoma, intermediate cells, lacks keratinization; goblet cells comprise the glandular component.

Large Cell Undifferentiated Carcinoma

Clinical

• ♦ Strongly associate d with smoking; may be peripheral or central

Macroscopic

• ♦ Central or peripheral solid usually necrotic mass; typically large with pleural invasion

Microscopic (Fig. 28.58)

• ♦ Sheets and nests of poorly differentiated atypical cells, usually with exten sive necrosis; large nuclei with prominent nucleoli; lack definitive evidence of squamous or glandular differentiation

• ♦ Giant cell, clear cell, or spindle cell changes can be present

• ♦ Variants: large cell neuroendocrine carcinoma (see neuroendocrine tumors), basaloid, lymphoepithelioma-like, and clear cell

Fig. 28.58.

Large cell undifferent iated carcinoma. Pleomorphic cells show undifferentiated architecture with no squamous or glandular features.

Electron Microscopy

• ♦ 80% show glandula r differentiation; 10% show squa mous differentiation

Differential Diagnosis

• ♦ Melanoma

  • S100, HMB45, Melan -A, and SOX-10 positive; cytokeratin negative

• ♦ Large cell lymphoma (including anaplastic type)

  • Cytokeratin n egative; CD45 positive; CD30 positive

Sarcomatoid Carcinomas

• Clinical Features:

  • Strong associat ion with smoking; m ay be peripheral or central

• Macroscopic Features

  • ♦ Solita ry and well circumscribed

• Microscopic features

  • ♦ Non-small cell ca rcinomas associated with sarcoma or sarcoma-like elements; carcinoma component can be squamous cell carcinoma, adenocarcinoma, or large cell carcinoma

  • ♦ Pleomorphic carcinoma: neoplastic spindle cells and/or giant cells present

Spindle Cell Carcinoma

• ♦ Tumor Entirely Composed of Neoplastic Malignant Spindle Cell ♦ Giant cell ca rcinoma: tumor entirely composed of neoplastic malignant giant cells

• ♦ Carcinosarcoma: carcinoma with malignant heterologous component including osteosarcoma, chondrosarcoma, and/or rhabdomyosarcoma

• ♦ Pulmonary blastoma: carcinoma component similar to well-differentiated fetal adenocarcinoma; sarcomatoid component usually with embryonic differentiation

Immunohistochemistry

• ♦ Cytoker atin elements can be negative

Differential Diagnosis

• ♦ Sarcomas, primary or metastatic:

  • Cytokeratin neg ative, clinical history important

Neuroendocrine Tumors

Typical and Atypical Carcinoid

Clinical

• ♦ May present with po stobstructive changes

• ♦ Most common in adults; can occur in children

Macroscopic (Fig. 28.59A)

• ♦ Cent ral or peripheral

• ♦ Central lesions have endobronchial component with postobstructive changes distally

• ♦ Peripheral lesions are usually subpleural

• ♦ Tan/yellow mass, highly vascularized

Microscopic (Fig. 28.59B)

• ♦ Bland ne uroendocrine cells with round to oval monotonous nuclei with finely granular chromatin and inconspicuous nucleoli

• ♦ Can have spindle cell morphology

• ♦ Organoid, trabecular, insular, palisading ribbon, and/or rosette-like arrangement

• ♦ Stromal cha nges include bone, cartilage, dense fibrosis, amyloid

• ♦ Typical carcinoid: <2 mitoses/10 hpf, no necrosis

• ♦ Atypical carcinoids: 2–10 mitoses/10 hpf and/or necrosis

Fig. 28.59.

Typical carci noid. A central, tan polypoid lesion is present in a proximal airway (A). Bland epithelial cells with finely granular chromatin are seen (B).

Differential Diagnosis

• ♦ Aden ocarcinoma:

  • Cytologic aty pia, gland formation, or mucin secretion

  • Metastatic carcinoma, spindle cell carcinoma (spindle cell lesions)

Small Cell Carcinoma

Clinical

• ♦ 20–25% of all lun g cancer; strong association with smoking

• ♦ Locally advanced neoplasm with early distant metastasis

• ♦ Paraneoplastic syndromes: inappropriate antidiuretic hormone (IADH), Cushing syndrome,

• ♦ Eaton–Lambert syndrome, encephal omyelitis; subacute sensory neuropathy s yndrome

Macroscopic

• ♦ 70% of cases pre sent as a perihilar mass with extensive mediastinal lymph node involvement

Microscopic (Fig. 28.60)

• ♦ Small cells (size less than 3 resting lymphocytes) with scant cytoplasm

• ♦ Round to spindled nuclei; faint or absent nucleoli; usually extensive necrosis present

• ♦ Combined small cell carcinoma variant: small cell carcinoma and non-small cell carcinoma components (eac h presen t at least 10%)

Fig. 28.60.

Small cell carci noma. Fusiform nuclei with prominent nuclear molding and abundant mitoses are present.

Immunohistochemistry

• ♦ Chromogr anin, synaptophysin, CD56, and CD57 usually positive but negative in 25% of cases; cytokeratin may be negative; TTF1 positive; Napsin-A negative; p63 negative, p40 negative

Cytogenetics

• ♦ 3p d eletions

Differential Diagnosis

• ♦ Non-small cell carcinoma, including large cell neu roendocrine carcinoma

  • Larger nuclei, prominent nucleoli, lower N/C ratio, lack of nuclear molding

Large Cell Neuroendocrine Carcinoma

Clinical

• ♦ Strong as sociation with smoking

Macroscopic

• ♦ Can exte nsively replace lung; central or peripheral; can be multinodular

Microscopic (Fig. 28.61)

• ♦ Organoid, palisading, trabecular patterns

• ♦ Large, polygonal nuclei and low nuclear/cytoplasmic ratio; frequent nucleoli

• ♦ High mitotic rate (>10 mitoses/10 hpf); necrosis can be prominent

Fig. 28.61.

Large cell neuroendo crine carcinoma. An organoid architecture with comedo-type necrosis is seen.

Immunohistochemistry

• ♦ Neuroen docrine differentiation should be confirmed by i mmunohistochemistry

• ♦ Chromogranin, synaptophysin, CD56, CD57, Bombesin variably positive; CEA positive; cytoker atin positive

Differential Diagnosis

• ♦ Small cell carcinoma

  • Smaller nu clei, no nucleoli, increased nuclear/cytoplasmic ratio

• ♦ Atypical carcinoid

  • Less cytologic atypia, 2–10 mitoses/10 hpf

• ♦ Large c ell undi fferentiated carcinoma

  • No evidence of neuroendocrine differentiation by light microscopy or immunohistochemical

Mesenchymal Tumors

Fibrous and Fibrohistiocytic Tumors

Inflammatory Myofibroblastic Tumor

Clinical

• ♦ 60% occ ur under the age of 40; mos t common benign tumor in children

• ♦ Usually asymptomatic, incidental finding

• ♦ Solitary, peripheral mass

Macroscopic

• ♦ Round, w ell-circumscribed rubbery tumor; can penetrate pleura or extend into adjacent mediastinal structures; white to yellow, xanthomatous in color

• ♦ Calcification and foci of necrosis can be seen

Microscopic (Fig. 28.62)

• ♦ Spindle cell s admixed with plasma cells, lymphocytes, and macrop hages in variable proportions; Touton giant cells and xanthoma cells can be seen

Fig. 28.62.

Inflammatory myofibrobl astic tumor. A prominent myofibroblasts and fibroblasts are present with scattered giant cells in the fibrohistiocytic variant (A). Touton giant cells and mitoses can be seen (B).

Immunohistochemistry

• ♦ Spindle cells variably positive for smooth muscle actin, muscle-specific actin, and desmin; anaplastic lymphoma k inase (ALK) positive

Molecular:

• ♦ Re arrange ments of 2p22–24 (ALK) gene

Differential Diagnosis

• ♦ Depends on the predominant cell population

• ♦ Inflammatory sarcomatoid carcinoma

  • Atypical spindle cells, positive for epithelial markers

• ♦ Malignant fibrous histiocytoma

  • Increased cytologic atypia, cellularity, and necrosis

  • Mitotic rate >3/50 hpf

• ♦ Solitary fibrous tumor

  • Spindle cells are CD34, Bcl-2, and STAT-6 positive.

  • Primary or metastatic sarcoma.

Malignant Fibrous Histiocytoma

Clinical

• ♦ 60–70 ye ars old; primary is rare; always consider metastatic lesion

Macroscopic

• ♦ Usually so litary mass (2–10 cm); peripheral location; rarely intrabronchial

Microscopic Features

• ♦ Spindle cells, pleomorphic giant cells, and histiocyte-like cells are present

• ♦ Storiform, fascicular, or pleomorphic architecture

• ♦ Inflammator y cells can be a significant component

Differential Diagnosis

• ♦ Pleomorphic carcinoma with spindle cells

  • Evidence of epithelial (squamous or glandular) differentiation

  • Ultrastructural evidence of desmosomes, junctional complexes, microvilli within glands, or cytoplasmic tonofibrils

  • Keratins and CEA positive

• ♦ Infl ammatory myofibroblastic tumor, fibrohistiocytic type

  • Lack cytologic atypia, <3 mitoses/50 hpf, no significant necrosis

Smooth Muscle Tumors

Leiomyosarcoma

Clinical

• ♦ Rare; cons ider possibility of metastatic lesion, especially from uterus

• ♦ Symptomatic presentation: cough, hemoptysis

Macroscopic

• ♦ Large, circumscrib ed mass; most are parenchymal

• ♦ Propensity for hilar region

Microscopic

• ♦ Malignant spindle cells, smooth muscle actin positive

Differential Diagnosis

• ♦ Leiomyoma

  • <5 mitoses/50 hpf, no cytologic atypia, no s ignificant necrosis

• ♦ Benign metastasizing leiomyoma

  • History of uterine leiomyoma

  • Multiple nodules

  • Well-differentiated smooth muscle without mitoses/necrosis/cytologic atypia

• ♦ Lymphangioleiomyomatosis

  • Seen e xclusively in women

  • Multifocal, benign-modified smooth muscle lining cystic spaces; smooth muscle actin and melanoc ytic mar kers positive

Skeletal Muscle Tumors

Rhabdomyosarcomas

Clinical

• ♦ Seen in both adults and children

Macroscopic

• ♦ Large, solid ma sses; may involve more than one lobe

Microscopic

• ♦ Cross stri ations are present; cells may be small, pleomorphic, or straplike

• ♦ Immunoreactive for desmin

Differential Diagnosis

• ♦ Metastatic rhabdomyosarcoma

• ♦ Carcinosarcoma

  • Malign ant epithelial component

• ♦ Pleuropulmonary blastoma

  • 90% are found in children <10 years of age.

  • May have fo cal ma lignant primitive epithelial component.

Vascular Tumors and Related Conditions

Epithelioid Hemangioendothelioma

Clinical

• ♦ Multiple nod ules in young women (M:F = 1:4)

• ♦ Over 50% patients are <40 years old; can be seen in children

• ♦ Concomitant multifocal disease can be seen in the bone, soft tissue, and liver

Macroscopic

• ♦ Discrete, firm white, circumscribed nodules (1–2 mm); may resemble cartilage

Microscopic (Fig. 28.63 A, B)

• ♦ Cytologically bland cells with round nuclei and small nucleoli; intracytoplasmic vacuoles present, some may contain re d blood cells; endothelial differentiation

• ♦ Myxoid to de nsely collagenized stroma that may resemble carti lage or amyloid; hypocellular center

Fig. 28.63.

Epithelioid hemangioe ndothelioma. An eosinophilic matrix is present (A), and cells are cytologically bland with intracytoplasmic lumina formation (B).

Immunohistochemistry

• ♦ Factor VIII, CD34, CD31, a nd ERG positive; epithelial markers negative

Molecular

• ♦ Rearrangemen ts involving WWTR1 and CAMTA1 genes [t(1;3)(p36;q25)]

Electron Microscopy

• ♦ Weibel– Palade bod ies

Differential Diagnosis

• ♦ Adenocarc inoma

  • Mucin+ cytoplasmic vacuoles

  • Cytokeratin+

• ♦ Metastatic chondrosarcoma

  • No endo thelial differentiation

  • S-100 protein+

• ♦ Amyloid nodules

  • Ace llular

  • Congo red+

• ♦ Hamartoma

  • Usually solitary

  • Entrapped epithelium is cytokeratin+

• ♦ Angiosarcoma

  • Mark ed cytologic atypia

  • Predominantl y intravascular

Kaposi Sarcoma

Clinical

• ♦ Rare initia l site of involvement; 25% of disseminated disease affects the lung

• ♦ Hemoptysis

Macroscopic

• ♦ Hemorrhagic bronchial plaques or nodules present in a lymphatic distribution

Microscopic

• ♦ Spindle cells p roliferating around vascular channels containing red blood cells

• ♦ Hemosiderin and plasma cells present

Immunohistochemistry

• ♦ Spindle c ells are CD34, CD31, and ERG positive; HHV8 positive

Differential Diagnosis

• ♦ Angiosa rcoma

  • Marked cytologic atypia

  • Not usually found in imm unocompromised patients

• ♦ Benign granulation tissue

  • Lack red blood cells within spaces

• ♦ Bacillary angiomatosis

  • Bacte ria id entified by special stains

Angiosarcoma

Clinical

• ♦ Hemo p tysis

Macroscopic

• ♦ Multiple, hem orrhagic nodules

Microscopic

• ♦ Atypica l endothelial cells forming vascular spaces; intra-arterial or periar terial involvement is common; epithelioid variant may be cytokeratin positive; vascular markers (CD31, CD34, and ERG) positive

Differential Diagnosis

• ♦ Kaposi s arcoma

  • Lack cytologic atypia

• ♦ Metastatic sarcoma

  • Primary lesion (e.g., heart or pulmonary artery)

• ♦ Primary/m etastatic carcinoma

  • Epithelia markers positive, vascular markers negative

Other Vascular Tumors

• ♦ Pulmonary artery and vein sarcomas (Fig. 28.64)

  Fig. 28.64.

  

  Pulmonary artery sarcoma. Undifferentiated spindle and epithelioid cells with areas of prominent necrosis in a polypoid mass in the pulmonary artery.

  • Polypoid mass involving pulmonary vessels.

  • 80% involve pulmonary trunk

• ♦ Hemangiopericytomas

  • 10% of all primary hemangiopericytomas occur in the lung.

  • Poor prognosis associated with >5 cm and increased mitotic rate

Pleuropulmonary Blastoma of Childhood

• Clinical

  • ♦ Found in chil dren

    • Type I: <1 year of age

    • Type II: <3 years of age

    • Type III: <4 years of age

  • ♦ Survival depends upon type

    • Type I: >80% 5 year survival

    • Types II and III: 40 % 5-year survival

• Macroscopic

  • ♦ Type I: Unilocular cyst

  • ♦ Type I I: Solid and cystic

  • ♦ Type III: Tan/white solid

• Microscopic (Fig. 28.65)

  • ♦ Type I: Cyst lined by benign ciliated columnar epithelium with underlying primitive small cells that can includ e rhabdomyoblasts

  • ♦ May contain anaplastic sarcomatous elements such as embryonal rhabdomyosarcoma, fibrosarcoma, chondrosarcoma , and anaplastic undifferentiated sarcoma

  • ♦ Types II and III: Mixture of sarcomatous and blastomatous elements

  Fig. 28.65.

  

  Pleuropu lmonary blastoma.

• Differential Diagnosis

  • ♦ Pulmonar y blastoma

    • Adult

    • Smoking history

  • ♦ Congenital cyst

    • No malignant mesenchyme

Lymphoproliferative Lesions of the Lung

Benign/Hyperplastic Lesions

Nodular Lymphoid Hyperplasia (Old Term “Pseudolymphoma”)

Clinical

• ♦ Adults; 30– 80 years; mo st are asymptomatic

• ♦ Can be asso ciated with autoimmune diseases such Sjögren syndrome, lupus erythematosus

• ♦ May have polyclonal hypergammaglobulinemia

Macroscopic

• ♦ Most are solitary masses but can present as multinodular lesions

• ♦ Rarely >5 cm

Microscopic

• ♦ Polymorp hous infiltrates of lymphocytes and plasma cells; germinal centers commonly seen; necrosis is rare; organizing pneumonia can be seen at the periphery of the lesion

Differential Diagnosis

• ♦ Extranodal margin al zone B-cell lymphom as of mucosa-associated lymphoid tissue (MALT)

  • Lymphoepithelial lesions; granulomatous inflammation and amyloid can be seen; airway and vascular invasion; monoclonality demonstrated by immunohistochemistry and/or molecular studies

Diffuse Lymphoid Hyperplasia (See Lymphocytic Interstitial Pneumonitis)

Clinical

• ♦ Symptoms o f interstitial disease: cough and dyspnea

• ♦ Can be seen in children and adults

• ♦ Associated with many conditions including: congenital or acquired immunodeficiency syndromes, autoimmune diseases (e.g., Sjögren), and drug-induced lung disease

Macroscopic

• ♦ Firm, co nsolidated lung

Microscopic

• ♦ Dense, diffuse lymphoplasmacytic infiltrates in alveolar walls (LIP)

• ♦ Germinal ce nters around airways (follicular bronchiolitis)

• ♦ Granulomas and giant cells can be seen

Differential Diagnosis

• ♦ Diffuse lo w-grade lymphoma

  • Monomorphous population

  • Lymphatic distribution

  • Airway, vascular, and pleural invasion

• ♦ Extrinsic allergic alveolitis

  • Areas of organization

  • Pro minent bro nchiolitis

Lymphomas (See also Chapter 9)

Extranodal Marginal B-cell Lymphoma of the Mucosa-Associated Lymphoid Tissue (MALT)

Clinical

• ♦ Adults: 60 y ears; over half case s are symptomatic

• ♦ B symptoms uncommon

• ♦ Over 20% have monoclonal serum gammopathy

• ♦ Radiology shows localized infiltrate or solitary lesion in 50%

Macroscopic

• ♦ Single or m ultiple nodules

• ♦ Commonly fleshy, nonnecrotizing mass; infiltrative growth pattern

• ♦ Large mas s lesions can be seen

Microscopic (Fig. 28.66A, B)

• ♦ Dense cellular infiltra tes of lymphocytes, monocytoid/centrocytic cells, plasma cells, and large transformed lymphocytes

• ♦ Lymphatic dist ribution usually appreciated at the edge of the lesion

• ♦ Germinal centers are commonly seen; lymphoepithelial lesions can be seen

• ♦ Airway, vascular, and pleural invasion is common

Fig. 28.66.

Marginal zone lym phoma of the BALT type. Prominent lymphoid aggregates are present throughout, usually with a lymphatic distribution (A). A monotonous population of lymphocytes with centrocyte cytoplasmic clearing is seen (B).

Immunohistochemistry

• ♦ CD20 positive B cells with a smaller population of CD3 positive T cells

• ♦ Light chain restriction usually, but not always, seen by immunohistochemistry

Molecular Studies

• ♦ Immunog lobulin (Ig) PCR shows clonal B-cell rearrangements

• ♦ Cytogenetic abnormalities include translocations involving the MALT1 gene and the API2 gene [t(11;18)(q21;q21)] or the IGH gene [t(14;18)(q32;q21)] and trisomies of chromosomes 3 and 18

Differential Diagnosis

• ♦ Nodular lym phoid hyperplasia

  • Heterogeneo us and polyclonal population

  • Solitary nodule

• ♦ Diffuse lymphoid hyperplasia

  • Heterogeneous and polyclonal population

  • No bronchial, vascular, or pleural invasion

• ♦ Secon dary pulmonary involvement by chronic lymphocytic leukemia

• ♦ Peripheral white blood cell count consistent with chronic lymphocytic leukemia

Lymphomatoid Granulomatosis (LYG)

• Clinical

  • ♦ Average age: 40–50 years; most present with multiple lung nodules

  • ♦ Skin and CNS involvement is frequent

  • ♦ Immunodeficiency is a risk factor

  • ♦ Poor prog nosis

• Macroscopic

  • ♦ Multiple nodu les of parenchymal consolidation; may have central necrosis

• Microscopic

  • ♦ Variable comb inations of large atypical cells with numerous small- to intermediate-sized lymphocytes and some histiocytes

  • ♦ Angiocentric pattern

    • Cell population may be heterogeneous; grading according to degree of cytologic atypia and number of EBV+ cells

    • Grade 1: <5 EBV+ cells.

    • Grade 2: 5–20 EBV+ cells; usually necrosis is present.

    • Grade 3: num erous EBV+ cells

• Immunohistochemistry

  • ♦ Atypic al cells CD20 and EBV positive

  • ♦ Small and interm ediate lymphocytes are positive for T-cell markers

• Molecular Studies

  • ♦ Immunoglobulin r earrangements (B cell)

• Differential Diagnosis

  • ♦ Necrotizing granulomatous infections

    • No atypic al cells; EBV negative; well-formed granulomas may be present

  • ♦ Wegener granulomatosis

    • Giant cells and neutrophilic microabscesses

    • No atypical cells; EBV negative

  • ♦ Extrano dal marginal B-cell lymphoma of MALT

    • Predominantly lymphatic distribution

  • ♦ Hodgkin disease

    • Classic Ree d–Sternberg cells; classic background of lymphocytes and eosinophils

  • ♦ Large ce ll lymphoma

    • Distinction from high-grade LYG may be arbitrary.

Posttransplant Lymphoproliferative Disorder

Clinical

• ♦ Found i n patients who have undergone organ transplantation

• ♦ Associated with EBV infection

Macroscopic

• ♦ Single or m ultiple nodules or infiltrates

Microscopic

• ♦ Varied appe arance: small cell to large cell; can be polymorphous

• ♦ Necrosis and vascular invasion can be seen

Differential Diagnosis

• ♦ Lymphomatoi d granulomatosis

  • Not restric ted to immunosuppressed patients

Other Lymphoproliferative Lesions

Intravascular Lymphomatosis (Angiotropic Lymphoma)

• ♦ Aggres sive, high-grade lymphoma with tumor cells proliferating within small vessels

  • Skin and CNS involvement are most common, but pulmonary involvement is seen.

Primary Pulmonary Hodgkin Disease

• ♦ Usually inv olves lung by direct extension from mediastinum

  • Primary lung involvement is rare.

  • Multiple nodules are common.

  • Histologic features of HD elsewhere.

Tumors of Perivascular Epithelioid Cell (PEC) Differentiation

Lymphangioleiomyomatosis

Clinical

• ♦ Occurs exclu sively in women of reproductive years

• ♦ Progressive dyspnea, chylous pleural effusions, recurrent pneumothoraces

• ♦ Chest X-ray: enlarged lungs; can show cystic or “honeycomb” changes

• ♦ Found in 40% of women with tuberous sclerosis complex (TSC-LAM)

• ♦ Nontransmissable sporadic form (S-LAM) in 3–5 women/1 million

• ♦ Classified as “low-grade malignant neoplasm” in National Cancer Institute

• ♦ Angiomyo lipomas (MLs) can occur in the kidney

Macroscopic (Fig. 28.67A)

• ♦ Randomly di stributed cystic airspaces with thin walls

Microscopic (Fig. 28.67B)

• ♦ Haphazard prolifer ation of smooth muscle in lymphatics, blood vessels, bronchioles, and alveolar septa

• ♦ Hemosiderin-laden macrophages accumulate in the alveoli, especially in subpleura

Fig. 28.67.

Lymphangioleio myomatosis. Brown/red cysts are characteristic of the gross appearance (A). Spindle-shaped cells infiltrate predominantly around veins and bronchioles (B).

Immunohistochemistry

• ♦ HMB45, SOX-10 and Cathepsin K are positive

Differential Diagnosis

• ♦ Benign metastasizing leiomyoma

  • Discrete nodul es; some contain entrapped pulmonary epithelium

• ♦ UIP with honeycomb changes

  • Small lungs, lower lobe predominant

  • Chronic inflammatory changes and fibrosis

  • Older age gro up; men and women

Benign Clear Cell (Sugar) Tumor

Clinical

• ♦ Incidenta l mass on chest X-ray; asymptomatic

Macroscopic

• ♦ Well-circumscri bed red/tan mass; shell out from surrounding lung

Microscopic

• ♦ Round cells with abundant granular eosinophilic to clear cytoplasm

• ♦ Abundant glycogen (PAS positive, PAS after diastase pretreatment negative)

• ♦ Dilated sinusoidal-like thin-walled blood vessels without a muscular coat

Immunohistochemistry

• ♦ HMB45, Me lan-A, tyrosinase, cathepsin K and SOX-10 positive; smooth muscle actin positive; desmin and S100 variably positive; cytokeratin negative; CEA negative

Differential Diagnosis

• ♦ Primary lung ca ncer with clear cell change

  • Infiltrative growth, cellular atypia, and melanocytic markers negative

• ♦ Renal c ell car cinoma

  • PAX-8 positive, HMB45, Cathepsin K negative

  • Multiple, thick-walled vessels

Miscellaneous Tumors

Minute Pulmonary Meningothelial-Like Lesion (Pulmonary Chemodectoma)

Clinical

• ♦ Incidental microscopic finding usually in resection specimens for other causes; female predominance

Microscopic (Fig. 28.68)

• ♦ Spindl e or oval-shaped cells; perivenular location

• ♦ Zellballen pattern

Fig. 28.68.

Pulmonary menin gothelial-like lesion (chemodectoma). Spindle cells form a “Zellballen” pattern.

Immunohistochemistry

• ♦ EMA positive; cytokeratin and neuroendocrine markers negative

Differential Diagnosis

• ♦ Carcinoi d tumorlets

  • Associated with bronchioles

  • Neuroendocrine markers positive

• ♦ Angiomatoid lesions of pulmonary hypertension

  • Associ ated with arteries/arterioles

  • CD34 and CD31 positive

Granular Cell Tumor

Clinical

• ♦ Schwann cell lineage

• ♦ Usually solitary mass of trachea or bronchus; can be multiple

• ♦ Also found in the skin, breast, esophagus, and rectum; respiratory tract may be metastatic lesion

• ♦ Primary lung lesions may metastasize

Macroscopic (Fig. 28.69A)

• ♦ Sessile or polypoid lesion with smooth surfaces; grow in walls of airways

Microscopic (Fig. 28.69B)

• ♦ Large polygonal to fusiform cells with granular foamy cytoplasm and eccentrically located nuclei

• ♦ Squamous metaplasia of overlying respiratory epithelium

Fig. 28.69.

Granular c ell tumor. A tan/pink sessile mass is present in the bronchi (A). Bland granular-type epithelioid cells with foamy cytoplasm are present (B).

Immunohistochemistry

• ♦ S-100 protein and neuron-specific enolase positive; cytokeratin negative

Electron Microscopy

• ♦ Osmo philic inclusions

Differential Diagnosis

• ♦ Oncocytic carcinoid

  • Neuroendocrine markers positive

Tumors of the Pleura

Tumors of the Pleura

Malignant Mesothelioma

Clinical

• ♦ Asbestos is the most frequent association; M > F

• ♦ Crocidolite and amosite asbestos fibers more carcinogenic than chrysotile fibers

Macroscopic (Fig. 28.70A)

• ♦ Nodular and plaque-like masses diffusely involving pleura including fissures; may encase the lung entirely

Microscopic Features (Fig. 28.70B, C)

• ♦ Epithelial

  • Polygonal cells with eosinophilic cytoplasm, well-defined cytoplasmic borders, and central round to oval nuclei.

  • Usually mild to moderate nuclear atypia but marked pleomorphism may occur.

  • Tubulopapillary, glandular, and solid patterns.

  • May contain myxoid matrix in the background.

  • Deciduoid, clear cell, small cell, and signet ring cell features can be seen

• ♦ Sarcomatoid

  • Spindle cells with mild to moderate atypia with fascicular growth and patternless pattern

• ♦ Desmoplastic variant: hypocellular lesions; neoplastic spindle cells with abundant collagen deposition

• ♦ Mixed epithelial and sarcomatoid

Fig. 28.70.

Malignant meso thelioma. The tan/white tumor infiltrates the pleura and compresses the underlying lung parenchyma (A). An epithelioid variant (B) and spindle cell variant (C) can be seen.

Histochemistry and Immunohistochemistry

• ♦ (Se e Table 28.2)

  Table 28.2. Ancillary Tests for Diagnosis of Mesothelioma Versus Adenocarcinoma ^*

Molecular Features

• ♦ Deletio ns of 9p21 (locus containing p16 ^INK and p14 ^ARF genes)

Differential Diagnosis

• ♦ Benign me sothelial proliferations

  • No invasion into underlying tissues; cellular “zonation”; associated inflammatory changes

• ♦ Pleural plaque

  • Orderly arrangement of spindle cells and collagen; no nodular or frankly sarcomatous growth; no invasion of underlying tissues

• ♦ Epithelial type: adenocarcinoma (see Table 28.2)

• ♦ Sarcomatoid type: primary or metastatic sarcoma

  • Cytokerat in negative; clinical history

Localized Fibrous Tumor of the Pleura

Clinical

• ♦ Most a re incidental masses

• ♦ Hypoglyce mia due to insulin-like growth factor

Macroscopic (Fig. 28.71A)

• ♦ Usually peduncul ated; can be intrapulmonary

• ♦ Well-circumscribed solid mass with whorled and fibrous-like appearance

Microscopic (Fig. 28.71B)

• ♦ Spindle cells arran ged in short storiform fascicles or in a patternless pattern alternating with hyalinized collagenized areas

• ♦ Hemangiopericytoma-like areas present

• ♦ Entrapped mesothelium and alveolar epithelium form linear epithelial inclusions at the periphery of the tumor

• ♦ Features of aggressive behavior:

  • Hypercellular areas

  • >4 mit oses/10 hpf

  • >10 cm

  • Nuclear pleomorphism

  • Necrosis

  • Parietal pleura location

  • Sessile growth

  • Local tumor recurrence following surgical resection

  • Associated pleural effusion

  • Invasion of adjacent structures

Fig. 28.71.

Solitary fibrous tu mor of the pleura. A large, tumor mass arises from the visceral pleura surface and extends into the pleural space (A). The tumor cells are spindled with storiform architecture and can have intervening strands of collagen (B).

Immunohistochemistry

• ♦ CD34 and STAT-6 positive; bcl-2 variably positive; cytokeratin negative

Differential Diagnosis

• ♦ Other spindle cell lesions including synovial sarcoma, schwannoma, inflammatory myofibroblastic tumor, a nd spindle cell carcinoma

TNM Classification of Cancer (2010 Revision)

Lung

• Primary Tumor (T)

  • TX Primary tumor cannot be assessed, or tumor proven by the presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy.

  • T0 No evidence of primary tumor.

  • Tis Carcinoma in situ.

  • T1 Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the labor bronchus* (i.e., not in the main bronchus).

  • T1a Tumor 2 cm or less in greatest dimension.

  • T1b Tumor more than 2 cm but 3 cm or less in greatest dimension.

  • T2 Tumor with any of the following features of size or extent:

    • >3 cm in greatest dimension

    • Involves main bronchus, ≤2 cm distal to the carina

    • Invades visceral pleura

    • Associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung

  • T2a Tumor more than 3 cm but 5 cm or less in greatest dimension.

  • T2b Tumor more than 5 cm but 7 cm or less in greatest dimension.

  • T3 Tumor mo re than 7 cm or one that directly invades any of the following – parietal pleura, chest wall (including superior sulcus tumors), diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium – or tumor in the main bronchus <2 cm distal to the carina, but without involvement of the carina or associated atelectasis or obstructive pneumonitis of the entire lung or separate tumor nodule(s) in the same lobe.

  • T4 Tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina, or tumor separate tumor nodule(s) in different ipsilateral lobe.

• Regional Lymph Nodes (X)

  • NX Regional lymph nodes cannot be assessed.

  • N0 No regional lymph node metastasis.

  • N1 Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.

  • N2 Metastasis in ipsilateral mediastinal and/or subcarinal lymph nodes(s).

  • N3 Metastasis to contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scale ne, or supraclavicular lymph node(s).

• Distant Metastasis (M)

  • MX Presence of distant metastasis cannot be assessed.

  • M0 No distant metastasis.

  • M1 Distant metastasis present.

  • M1a Separate tumor nodule(s) in a contralateral lobe or tumor with pleural nodules or malignant pleural (or pericardial) effusion.

  • M1b Distant metastasis. Pleura. IMIG Staging System for Diffuse Malignant Pleural Mesothelioma.

• Primary Tumor (T)

  • TX Primary tumor cannot be assessed.

  • T0 No evide nce of primary tumor.

  • T1 Tumor involves ipsilateral parietal pleura, with or without mediastinal pleura or diaphragmatic pleura involvement.

  • T1a Tumor involves ipsilateral parietal (mediastinal, diaphragmatic) pleura.

  • T1b Tumor involves also visceral pleura.

  • T2 Tumor involves each of the ipsilateral pleural surfaces with at least one of the following:

    • Invasion of diaphragmatic muscle

    • Direct involvement of lung parenchyma

  • T3* Tumor involves all of the ipsilateral pleural surfaces, with at least one of the following:

    • Invasion of the endothoracic fascia

    • Extension into mediastinal fat

    • Solitary, completely resectable focus of tumor extending into the soft tissues of the chest wall

    • Nontransmural involvement of the pericardium

  • T4** Tumor involves all of the ipsilateral pleural surfaces, with at least one of the following:

    • Diffuse or multifocal extension in the chest wall, with or without rib destruction

    • Transdiaphragmatic extension to the peritoneum

    • Direct extension to med iastinal organ(s)

    • Direct extension to the contralateral pleura

    • Direct extension to the spine

    • Direct extension to the internal surface of the pericardium with or without pericardial effusion or tumor involving the myocardium

  • *T3 Describes locally advanced but potentially resectable tumor.

  • **T4 Describes locally advanced, technically unresectable tumor.

• Regional Lymph Nodes (N)

  • NX Region al lymph nodes cannot be assessed.

  • N0 No regional lymph node metastases.

  • N1 Metastases in the ipsilateral bronchopulmonary and/or hilar lymph nodes(s).

  • N2 Metastases in the subcarinal lymph node(s) and/or the ipsilateral internal mammary or mediastinal lymph node(s).

  • N3 Metastases in the contralateral mediastinal, internal mammy, or hilar lymph no de(s) and/or the ipsilateral or contralateral supraclavicular or scalene lymph node(s).

• Distant Metastasis (M)

  • MX Distant metastases cannot be assessed.

  • M0 No distant metastases.

  • M1 Distant metastases.