, Jun Zhang2 and Fan Lin1
(1)
Department of Laboratory Medicine, Geisinger Health System, Danville, PA, USA
(2)
Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, AZ, USA
Keywords
LungMediastinumThymusAdenocarcinoma (Lepidic adenocarcinoma)Acinar adenocarcinomaPapillary adenocarcinomaMicropapillary adenocarcinomaSolid adenocarcinomaInvasive mucinous adenocarcinomaMixed invasive mucinous and nonmucinous adenocarcinomaColloid adenocarcinomaFetal adenocarcinomaEnteric adenocarcinomaMinimally invasive adenocarcinomaNonmucinousMucinousPreinvasive lesionsAtypical adenomatous hyperplasiaAdenocarcinoma in situ (nonmucinous mucinous)Squamous cell carcinomaKeratinizing squamous cell carcinomaNonkeratinizing squamous cell carcinomaBasaloid squamous cell carcinomaPreinvasive lesionSquamous cell carcinoma in situNeuroendocrine tumorsSmall cell carcinomaCombined small cell carcinomaLarge cell neuroendocrine carcinomaCombined large cell neuroendocrine carcinomaCarcinoid tumorsTypical carcinoid tumorAtypical carcinoid tumorPreinvasive lesionDiffuse idiopathic pulmonaryNeuroendocrine cell hyperplasiaLarge cell carcinomaAdenosquamous carcinomaSarcomatoid carcinomasPleomorphic carcinomaSpindle cell carcinomaGiant cell carcinomaCarcinosarcomaPulmonary blastomaOther and unclassified carcinomasLymphoepithelioma-like carcinomaNuclear protein in testis (NUT) carcinomaSalivary gland-like tumorsMucoepidermoid carcinomaAdenoid cystic carcinomaEpithelial-myoepithelial carcinomaPleomorphic adenomaPapillomasSquamous cell papilloma (exophitic inverted)Glandular papillomaMixed squamous and glandular papillomaAdenomasSclerosing pneumocytomaAlveolar adenomaPapillary adenomaMucinous cystadenomaMucous gland adenomaPulmonary hamartomaChondromaPEComatous tumorsLymphangioleiomyomatosisPEComa (benign)Clear cell tumorPEComa (malignant)Congenital peribronchial myofibroblastic tumorEpithelial hemangioendotheliomaPleuropulmonary blastomaSynovial sarcomaPulmonary artery intimal sarcomaPulmonary myxoid sarcoma with EWSR1-CREB1 translocationMyoepithelial tumorsMyoepitheliomaDiffuse malignant mesotheliomaEpithelioid mesotheliomaSarcomatoid mesotheliomaDesmoplastic mesotheliomaBiphasic mesotheliomaLocalized malignant mesotheliomaEpithelioid mesotheliomaSarcomatoid mesotheliomaBiphasic mesotheliomaWell-differentiated papillary mesotheliomaAdenomatoid tumorEpithelioid hemangioendotheliomaAngiosarcomaSynovial sarcomaSolitary fibrous tumorMalignant solitary fibrous tumorDesmoid-type fibromatosisCalcifying fibrous tumorDesmoplastic round cell tumorThymomaLymphomaSarcomaGerm cell tumorMetastatic carcinoma Candida species Aspergillus speciesPhycomycosis (such as mucormycosis) Cryptococcus neoformans Histoplasma capsulatum Blastomyces dermatitidis Coccidioides immitis Pneumocystis carinii TTF1Napsin aCalretininWT-1CK5/6p40p63MIB-1 (Ki67)ChromograninSynaptophysinCD56MOC31PAX8CD5CD117GLUT1p53p16TdTSummary of Pearls and Pitfalls
The concept of personalized medicine and the remarkable advances in lung cancer genetics and therapy in the past decade have changed lung pathology practice dramatically.
The 2015 World Health Organization (WHO) classification of tumors of the lung specifies that immunohistochemistry is required for lung cancer diagnosis, not only for small biopsies and fine needle aspiration (FNA) specimens but also for certain resected specimens such as solid adenocarcinoma (ADC), nonkeratinizing squamous cell carcinom a, large cell carcinoma , neuroendocrine tumors , and sarcomatoid carcinomas .
New criteria and terminology for the diagnosis of lung cancer based on small biopsies and cytology are proposed in the 2015 WHO classification and are summarized in Tables 6.1 and 6.2.
Table 6.1
Terminology and criteria for adenocarcinoma, squamous cell carcinoma, and non-small cell carcin oma, not otherwise specified, in small biopsies and cytology specimens compared with those for resection specimens
Small biopsy/cytology terminology
Morphology/immunohistochemistry
2015 WHO classification of resection specimens
ADC (describe patterns)
Morphologic ADC patterns clearly present
ADC predominant pattern: lepidic, acinar, papillary, solid, and micropapillary
ADC with lepidic pattern (if pure, add note: an invasive component cannot be excluded)
Minimally invasive ADC, ADC in situ, or an invasive ADC with a lepidic component
Invasive mucinous ADC (describe patterns; use term mucinous ADC with lepidic pattern if pure)
Invasive mucinous ADC
ADC with colloid features
Colloid ADC
ADC with fetal features
Fetal ADC
ADC with enteric features
Enteric ADC
NSCC, favor ADC
Morphologic ADC patterns not present but supported by special stains (i.e., TTF1 +)
ADC (solid pattern may be just one component of the tumor)
SqCC
Morphologic squamous cell pattern clearly present
SqCC
NSCC, favor SqCC
Morphologic squamous cell patterns not present but supported by stain (i.e., p40 +)
SqCC (solid pattern may be just one component of the tumor)
NSCC NOS
No clear ADC, squamous or neuroendocrine morphology or staining pattern
Large cell carcinoma
Table 6.2
Diagnostic terminology for small biopsy/cytology compared with that of the 2015 World Health Organization (WHO) in resection specimens with small cell carcin oma, LCNEC, adenosquamous carcino ma, and sarcomatoid carcino ma
Small biopsy/cytology terminology/criteria
2015 WHO classification of resections
Small cell carcinoma
Small cell carcinoma
NSCC with NE morphology and positive NE markers, possible LCNEC
LCNEC
NSCC with NE morphology. If negative NE markers comment: This is an NSCC where LCNEC is suspected, but stains fails to demonstrate NE differentiation
LCNEM
Morphologic squamous cell and ADC patterns present: NSCC, NOS. Comment that ADC and squamous components are present, and this could represent adenosquamous carcinoma
Adenosquamous carcinoma (if both components ≥10%)
No morphologic squamous cell or ADC patterns, but immunostains favor separate squamous and ADC components: NSCC, NOS. Specify the IHC results and the interpretation. Comment that this could represent adenosquamous carcinoma
ADC, SqCC, adenosquamous carcinoma , or large cell carcinoma with unclear IHC features
NSCC with spindle cell and/or giant cell carcinoma (mention if ADC or SqCC is present)
Pleomorphic, spindle cell, and/or giant cell carcinoma
The role of cytopathologists has expanded to not only making a specific diagnosis, including histopathological subtyping of tumors, but also to thoughtfully utilizing the limited material for necessary genetic studies to help personalize treatment strategies for advanced lung cancer patients.
Thyroid transcription factor 1 (TTF1 ) and napsin A are accepted markers for ADC differentiation; p40 is reported to be the most specific and sensitive marker for squamous cell differentiation. A reasonable recommendation is that, when immunohistochemistry is deemed necessary, at least one antibody each for squamous and glandular differentiation, but no more than two antibodies, should be used for an initial workup (e.g., TTF1 and p40 or p63 ). Thus a limited panel of TTF1 and p40 (or p63) is suggested for subtyping the tumor to preserve tissue for molecular testing.
Molecular testing for epithelial growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangement is recommended in tumors classified as ADC and in cases where an ADC component cannot be excluded.
When evaluating a computed tomography (CT)-guided FNA of a lung lesion in the periphery, mesothelial cells are frequently seen on smears; reactive mesothelial cells may mimic carcinoma, and caution should be taken.
Diagnosis of ADC with a lepidic growth pattern can be challenging in FNA specimens. Both quality (degree of atypia) and quantity (groups of atypical cells) need to be considered. In a typical case of ADC with a lepidic growth pattern, the smears tend to be very cellular, containing many groups of atypical epithelial cells. In contrast, in a reactive condition, such as pulmonary infarction, atypical reactive pneumocytes are usually less numerous.
In mucinous ADC with a lepidic growth pattern, the neoplastic epithelial cells may mimic pulmonary macrophages. Features such as a mucinous background, cytoplasmic mucin/vacuoles, eccentrically located nuclei, and more abundant cytoplasm are helpful in reaching a correct diagnosis.
Basaloid squamous cell carcinoma may mimic small cell carcinoma ; therefore, cellblock preparation in conjunction with immunostains will be helpful.
Infection such as aspergillosis may result in squamous cells with significant cytological atypia; therefore, infectious etiologies should be excluded before a diagnosis of well-differentiated squamous cell carcinoma is rendered.
A lesion from the mediastinum should be considered if cytological features do not fit the description of a typical “lung lesion.”
Thymoma is rare in young patients and children. In lymphocyte-dominant thymoma, the main component of the aspirate may contain cortical thymocytes with expression of terminal deoxynucleotidyl transferase (TdT ) and cluster of differentiation (CD)99; therefore, caution should be taken to avoid misdiagnosing it as a lymphoblastic lymphoma.
Thymic neuroendocrine neoplasm may mimic an epithelial-dominant thymoma; therefore, immunohistochemistry should be performed in cases with equivocal features.
Lung
Tables 6.1 and 6.2 summarize new criteria and terminology for the diagnosis of lung cancer based on small biopsies and cytology from the 2015 WHO classification .
Normal Cytology
Upper Respiratory Tract
Lower Respiratory Tract
Trachea and bronchi
Terminal bronchioles
Non-ciliated cuboidal/columnar cells (Clara cells)
Alveoli
Type I and II pneumocytes
Respiratory Infections
Viral Infections
Specific viral infections, such as herpes simplex (Fig. 6.6) and cytomegalovirus (Fig. 6.7), can cause significant cytological changes that may mimic a malignant process. The diagnosis can be confirmed by immunoperoxidase studies.
Fig. 6.6
Herpes simplex viral inclusions , H&E
Fig. 6.7
Cytomegaloviral inclusion , Pap stain
Severe acute respiratory syndrome (SARS ) caused by a novel coronavirus (SARS-CoV ) became a worldwide outbreak in 2003, affecting more than 8000 patients, with a fatality rate of 9.2%. SARS-CoV belongs to a family of large, positive, single-stranded ribonucleic acid (RNA) viruses. The key pathologic finding is diffuse alveolar damage (DAD ) . Depending on different phases in the disease progression, the composition of inflammatory cells may vary; however, macrophages (including multinucleated forms) and lymphocytes usually predominate. Other pathologic findings, such as fibrosis, prominent vascular injury, hemophagocytosis, squamous metaplasia, apoptosis, and atypical pneumocytes, including multinucleated giant pneumocytes with irregularly distributed nuclei or pneumocytes with large atypical nuclei, prominent eosinophilic nucleoli, and granular amphophilic cytoplasm, were reported. Ancillary tests, such as in situ hybridization, immunohistochemistry, viral isolation, or reverse transcription polymerase chain reaction (RT-PCR), are necessary to confirm the diagnosis. Representative images are shown in Fig. 6.8a, b.
Fig. 6.8
Alveolar lavage from a patient with severe acute respiratory syndrome, with confirmed coronavirus infection. (a) Atypical pneumocytes with large nuclei, prominent eosinophilic nucleoli, and granular amphophilic cytoplasm in a background of marked acute inflammation, Pap stain; (b) typical metaplastic squamous cells with enlarged nuclei, hyperchromatic, smudged chromatin, Pap stain
Fungal Infections
FNA is a useful means of diagnosing pulmonary fungal infection, which should be suspected whenever there is granulomatous inflammation. Silver or periodic acid-Schiff (PAS) stains are used on cellblock sections.
The common fungal infections include (1) Candida species ; (2) Aspergillus species , Fig. 6.9; (3) phycomycosis (such as mucormycosis ); (4) Cryptococcus neoformans , Fig. 6.10a–d; (5) Histoplasma capsulatum , Fig. 6.11a, b; (6) Blastomyces dermatitidis , Fig. 6.12a, b; (7) Coccidioides immitis , Fig. 6.13a, b; and (8) Pneumocystis carinii , Fig. 6.14a–c. The morphological features of these fungi are summarized in Table 6.3.
Table 6.3
Morphological features of fungi commonly seen in pulmonary cytological samples
Fungi | Forms | Hyphal branches | Average diameter (um) | Budding pattern |
|---|---|---|---|---|
Candida spp. | Budding yeast Pseudohyphae | Not applicable | 4 | Constricted neck |
Aspergillus spp. | Hyphae with 45-degree angle | 45 degree | 5–10 | Not applicable |
Mucormycosis | Hyphae with acute angle | 90 degree | 10–15 | Not applicable |
Histoplasma capsulatum | Budding yeast | Not applicable | 2–4 | Constricted neck |
Cryptococcus neoformans | Yeast | Not applicable | 5–8 | Constricted neck |
Blastomyces dermatitidis | Yeast | Not applicable | 8–15 | Broad-based |
Coccidioides immitis | Endospores Spherules | Not applicable | Endospores 2–5 Spherules −100 | Not applicable |
a Pneumocystis carinii | Helmet-shaped cysts | Not applicable | 6–8 | Not applicable |
Fig. 6.9
Aspergillus species , alveolar lavage, Pap stain. The fungal hyphae exhibit septation, with dichotomous 45 degree angle branching. There are pulmonary macrophages and neutrophil-predominant mixed inflammatory cells in the background
Fig. 6.10
Cryptococcus neoformans , bronchial brushing and alveolar lavage. (a) Round/oval, variable size yeast forms in background of respiratory epithelial cells, bronchial brushing, Pap stain; (b) alveolar lavage, showing slightly variable size, round/oval yeast forms with thick capsule and narrow-necked budding, H&E; (c) alveolar lavage, cellblock, H&E, showing round to oval yeast form; (d) alveolar lavage, the thick mucinous capsule showing bright red stain with mucicarmine, cellblock
Fig. 6.11
Histoplasma capsulatum , lung lesion, fine needle aspiration. (a) Small, budding, intracellular yeast forms, 2–5 microns, Diff-Quick; (b) cellblock, Grocott’s methenamine silver (GMS) stain, showing small yeast forms
Fig. 6.12
Blastomyces dermatitidis , lung lesion, sputum. (a) Budding yeast form, broad base, cellblock, H&E; (b) sputum, broad-based budding yeast form, Pap stain
Fig. 6.13
Coccidioides immitis . (a) Cellblock, spherule form containing endospores, H&E; (b) spherule form containing endospores, Pap stain
Fig. 6.14
Pneumocystis carinii , alveolar lavage. (a) Foamy proteinaceous spheres, Pap stain; (b) foamy proteinaceous spheres, cellblock, H&E; (c) GMS stain reveals small oval or cup-shaped yeast forms, cellblock
Strongyloidiasis
Pulmonary strongyloidiasis affects immunocompetent and, more commonly, immunosuppressed persons presenting with pneumonitis with hemoptysis. The etiological agent is the nematode. Strongyloides stercoralis in sputum is shown in Fig. 6.15.
Fig. 6.15
Strongyloides stercoralis, sputum, Pap stain
Bacterial Infection
Infection by Mycobacterium tuberculosis is often a granulomatous inflammation containing clusters of epithelioid histiocytes, lymphocytes, and Langhans giant cells, with or without necrosis. In immunocompromised patients there may be abundant acid-fast organisms without obvious granulomatous inflammation.
Acquired immunodeficiency syndrome (AIDS) patients are especially susceptible to Mycobacterium avium-intracellulare , an acid-fast organism producing negative images on Romanowsky stain. Special stains on cellblock section are particularly helpful.
Nocardia , a weakly acid-fast filamentous organism, often infects immunocompromised patients, producing cavitary nodules on radiographs, which may mimic a neoplastic process .
Other Types of Granulomatous Inflammation
Sarcoidosis
Key Clinical Features
Sarcoidosis is characterized by non-caseating granulomas in many organs, most commonly the lung.
Key Radiological Features
Chest x-ray: bilateral hilar adenopathy is a classic finding; variable lung parenchyma changes, from normal, diffuse reticular, or ground glass opacities, nodular consolidation or cystic scarring.
CT and positron emission tomography (PET) scan can also be used.
Cytological Features
Aggregates of epithelioid histiocytes, with or without Schaumann and asteroid bodies
Multinucleated giant cells and lymphocytes
Differential Diagnosis
An essential part of the diagnosis of sarcoidosis is the exclusion of alternative possibilities:
Granulomas caused by infectious agents, such as mycobacterial infection and fungal infection
Drug-induced, hypersensitivity pneumonitis, or foreign body granulomatosis
Pulmonary histiocytic disorders
Granulomatous disorders associated with vascular inflammation such as Wegener granulomatosis and Churg-Strauss syndrome
Wegener Granulomatosis
Key Clinical Features
Wegener granulomatosis is characterized by necrotizing vasculitis and may present as a lung mass with or without involvement of nasal passages and kidneys.
Key Radiological Features
Multiple pulmonary nodules on imaging
Cytological Features
Neutrophils, giant cells, necrotic collagen, and epithelioid histiocytes
The findings are nonspecific; therefore, serologic studies are necessary.
Differential Diagnosis
Granulomatous inflammations
Metastatic diseases
Non-Hodgkin lymphomas
Nodular Pulmonary Amyloidosis (Amyloid Tumor)
Key Clinical Features
Amyloid deposits in the lung, forming discrete nodular masses
Key Radiological Features
Discrete pulmonary nodules/masses (amyloidomas) on imaging
Cytological Features
Irregular, waxy, amorphous, hypocellular material with a scalloped, occasionally cracked appearance, which is blue-green on Papanicolaou (Pap) stain and shows apple-green dichroism under polarized light after staining with Congo red
Differential Diagnosis
Granulomatous inflammations
Metastatic diseases
Non-Hodgkin lymphomas
Pulmonary Neoplasms
The 2015 WHO Classification of Tumors of the Lung, Pleura, Thymus and Heart has been published recently. There are numerous important changes in the classification of lung tumors, as summarized in Table 6.4.
Table 6.4
2015 World Health Organization (WHO) classification of lung tumors
Epithelial tumors | |
Adenocarcinoma Lepidic adenocarcinoma Acinar adenocarcinoma Papillary adenocarcinoma Micropapillary adenocarcinoma Solid adenocarcinoma Invasive mucinous adenocarcinoma Mixed invasive mucinous and nonmucinous adenocarcinoma Colloid adenocarcinoma Fetal adenocarcinoma Enteric adenocarcinoma Minimally invasive adenocarcinoma Nonmucinous Mucinous Preinvasive lesions Atypical adenomatous hyperplasia Adenocarcinoma in situ Nonmucinous Mucinous Squamous cell carcinoma Keratinizing squamous cell carcinoma Nonkeratinizing squamous cell carcinoma Basaloid squamous cell carcinoma Preinvasive lesion Squamous cell carcinoma in situ Neuroendocrine tumors Small cell carcinoma Combined small cell carcinoma Large cell neuroendocrine carcinoma Combined large cell neuroendocrine carcinoma Carcinoid tumors Typical carcinoid tumor Atypical carcinoid tumor | Neuroendocrine tumors (continued) Preinvasive lesion Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia Large cell carcinoma Adenosquamous carcinoma Sarcomatoid carcinomas Pleomorphic carcinoma Spindle cell carcinoma Giant cell carcinoma Carcinosarcoma Pulmonary blastoma Other and Unclassified carcinomas Lymphoepithelioma-like carcinoma Nuclear protein in testis (NUT) carcinoma Salivary gland-like tumors Mucoepidermoid carcinoma Adenoid cystic carcinoma Epithelial-myoepithelial carcinoma Pleomorphic adenoma Papillomas Squamous cell papilloma Exophitic Inverted Glandular papilloma Mixed squamous and glandular papilloma Adenomas Sclerosing pneumocytoma Alveolar adenoma Papillary adenoma Mucinous cystadenoma Mucous gland adenoma |
Mesenchymal tumors | |
Pulmonary hamartoma Chondroma PEComatous tumors Lymphangioleiomyomatosis PEComa, benign Clear cell tumor PEComa, malignant Congenital peribronchial myofibroblastic tumor Diffuse pulmonary lymphangiomatosis Inflammatory myofibroblastic tumor | Epithelioid hemangioendothelioma Pleuropulmonary blastoma Synovial sarcoma Pulmonary artery intimal sarcoma Pulmonary myxoid sarcoma with EWSR1-CREB1 translocation Myoepithelial tumors Myoepithelioma Myoepithelial carcinoma |
Lymphohistiocytic tumors | |
Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) Diffuse large cell lymphoma Lymphomatoid granulomatosis Intravascular large B-cell lymphoma Pulmonary Langerhans cell histiocytosis Erdheim-Chester disease | |
Tumors of ectopic origin | |
Germ cell tumors Teratoma, mature Teratoma, immature Intrapulmonary thymoma Melanoma Meningioma, not otherwise specified (NOS) | |
Metastatic tumors | |
Representative Benign Neoplasms of the Lung
Pulmonary Hamartoma
Key Clinical Features
The most common benign pulmonary neoplasm
Usually asymptomatic, incidental finding
Common in males, especially elderly men
Key Radiological Features
Chest x-ray: solitary or multiple discrete, round, golf ball-like lesions (“coin lesions”), usually peripherally located, about 10% endobronchial
Cytological Features
A mixture of mesenchymal and epithelial elements
Immature fibromyxoid matrix
Mature cartilage with chondrocytes in lacunae
Benign glandular cells
Adipocytes
Representative images are shown in Fig. 6.16a, b.
Fig. 6.16
Pulmonary hamartoma . (a) Sparsely cellular chondromyxoid matrix material containing scattered, benign, spindled, and stellate mesenchymal cells, Pap stain; (b) clusters of epithelial cells embedded in stromal, Pap stain; (c, d) histopathology, well-circumscribed, lobulated nodules of mesenchymal tissue including chondroid or chondromyxoid tissue, fat, and connective tissue intermixed with clefts of respiratory epithelial cells, H&E
Differential Diagnosis
Epithelial malignancy
Histology
Round to multilobulated, well-circumscribed tumor nodules composed of mesenchymal tissues, including chondroid or chondromyxoid tissue, fat, connective tissue, smooth muscle, and bone in various proportions, intermixed with clefts of respiratory epithelial cells
Chondromyxoid tissue usually predominates.
Representative images are shown in Fig. 6.16c, d.
Immunohistochemistry
Immunohistochemistry is usually not necessary for diagnosis.
Pulmonary hamartomas have a high frequency of translocation t(3;12)(q27–28;q14–15) leading to a gene fusion of the high mobility group protein gene AT-hook 2 (HMGA2) and the lipoma preferred partner (LPP) gene.
Inflammatory Myofibroblastic Tumor
Key Clinical Features
Most often young patients, under the age of 40
Male = female
The most common endobronchial mesenchymal lesion in childhood
Key Radiological Features
Chest x-ray: a peripheral, discrete, solitary nodule. If endobronchial location, post-obstructive pneumonia and atelectasis may be evident.
Cytological Features
Spindle cells
Storiform pattern
Polymorphous inflammatory cells
Minimal to no necrosis
Differential Diagnosis
Sarcoma
Mesothelioma
Solitary fibrous tumor
Histology
Composed of a mixture of spindle cells and obscuring inflammatory cell infiltrates, including lymphocytes, plasma cells, and histiocytes.
Touton giant cells are often seen.
The spindle cells contain oval nuclei with a fine chromatin pattern, inconspicuous nucleoli, and abundant bipolar lightly eosinophilic cytoplasm arranged in fascicles or a storiform architecture.
Representative images are illustrated in Fig. 6.17a, b.
Fig. 6.17
Inflammatory myofibroblastic tumor . (a, b) Histopathology, a mixture of spindle cells and obscuring inflammatory cell infiltrates including lymphocytes, plasma cells, and histiocytes, H&E; (c) positive for SMA, IHC; (d) negative for S100, IHC
Immunohistochemistry
Positive for vimentin, smooth muscle actin (SMA), and rarely to desmin
Negative for myogenin, myoglobin, CD117 , and S100 protein
Focal cytokeratin (CK) positivity was reported in 1/3 of cases, likely due to alveolar entrapment.
Anaplastic lymphoma kinase 1 (ALK1) expression was noted in 40% of cases.
p53 is negative; however, positivity is associated with recurrence and malignant transformation.
Representative images are illustrated in Fig. 6.17c, d.
Representative Malignant Neoplasms of the Lung
Squamous Cell Carcinoma
Squamous cell carcinomas are malignant tumors that either morphologically show squamous cell differentiation (keratinization and/or intercellular bridges) or are morphologically undifferentiated non-small cell carcinomas but show squamous cell differentiation immunohistochemically. The 2015 WHO classifications of tumors of the lung reclassified squamous cell carcinomas into keratinizing, nonkeratinizing, and basaloid subtypes. The nonkeratinizing tumors require immunohistochemical proof of squamous differentiation.
Key Clinical Features
About 20% of all pulmonary malignancies
Clinical presentation is similar to other non-small cell carcinomas.
Key Radiological Features
Usually a central mass with cavitation and post-obstructive pneumonia
Cytological Features
Keratinizing squamous cell carcinoma :
Abundant dyshesive cells with dense cytoplasm, may be orangeophilic
Polygonal, rounded, or elongated cells
Tadpole or fiber-like cells
Pleomorphic, pyknotic nuclei with obscured nucleoli and chromatin detail
Anucleated cells and twisted keratin strands (Herxheimer spirals)
Representative images are shown in Fig. 6.18a–d.
Fig. 6.18
Keratinizing squamous cell carcinoma , cytology. (a) Polygonal to round cells with hyperchromatic nuclei and hard cytoplasm, Diff-Quik; (b, c) polygonal or tadpole cells with pyknotic nuclei and dense, orangeophilic cytoplasm, Pap stain; (d) keratin pearls and debris, cell block, H&E
Nonkeratinizing or basaloid squamous cell carcinoma :
Cohesive groups of cells with larger nuclei and coarsely granular chromatin
Cyanophilic cytoplasm on Pap stain
Rare or no keratinization
Representative images are shown in Fig. 6.19a–f.
Fig. 6.19
Nonkeratinizing, basaloid squamous cell carcinoma , cytology. (a) Cohesive groups of atypical cells with hyperchromatic nuclei and coarse, granular chromatin texture, basaloid, Diff-Quik; (b) similar, basaloid, Pap stain; (c) cohesive cluster of atypical epithelial cells, no keratinization identified, Diff-Quik; (d) similar to C, Pap stain; (e) tumor cell cluster in cellblock, H&E; F. p40 -decorated tumor nuclei, IHC
Differential Diagnosis
Squamous metaplasia
Cavitary infection
Pemphigus vulgaris
Radiation/chemotherapy effect
Other non-small cell carcinoma
Small cell carcinoma
Upper airway cancer contamination
Histology
Three subtypes of squamous cell carcinoma in the 2015 WHO classification of tumors of the lung: keratinizing, nonkeratinizing, and basaloid subtypes:
- 1.
Keratinizing squamous cell carcinomas exhibit recognizable keratinization, keratin pearls, and/or intercellular bridges, as illustrated in Fig. 6.20a, b.
Fig. 6.20
Squamous cell carcinoma , histopathology. (a, b) Keratinizing squamous cell carcinoma , H&E; (c) nonkeratinizing squamous cell carcinom a, H&E; (d) basaloid squamous cell carcinom a exhibits solid islands of larger, hyperchromatic tumor cells with peripheral palisading, H&E
- 2.
Nonkeratinizing squamous cell carcinomas are without recognizable keratinization, keratin pearls, or intercellular bridges, as illustrated in Fig. 6.20c.
- 3.
Basaloid squamous cell carcinomas are tumors with a basaloid component in greater than 50% of the tumor, regardless of the presence of any keratinization, as illustrated in Fig. 6.20d.
- 1.
Immunohistochemistry
Immunohistochemistry is required for the diagnosis of nonkeratinizing squamous cell carcinomas.
Squamous cell carcinomas express p40 , p63 , and CK5/6 .
TTF1 is usually negative in keratinizing squamous cell carcinomas , may be weakly focally positive in nonkeratinizing squamous cell carcinomas.
Representative images are illustrated in Fig. 6.21a–d.
Fig. 6.21
Immunophenotype of squamous cell carcinoma . (a) Positive nuclear staining for p40 , IHC; (b) positive CK5/6 staining, IHC; (c) negative TTF1 staining, IHC; (d) negative CK7 staining, IHC
Squamous cell carcinomas of lung are characterized by complex genomic alterations, frequently involving the following pathways:
- 1.
Cyclin-dependent kinase inhibitor 2A/retinoblastoma 1/nuclear factor, erythroid 2 like 2/Kelch-like ECH-associated protein 1/cullin 3 (CDKN2A/RB1, NFE2L2/KEAP1/CUL3)
- 2.
Phosphoinositide 3-kinase/protein kinase B (PI3K/AKT)
- 3.
Sex-determining region Y box 2/tumor protein 63/Notch (Drosophila) homolog 1(SOX2/TP63/NOTCH1)
- 1.
Gene copy number alterations involving chromosomes 3q (SOX2, TP63), 7p (EGFR), and 8p (fibroblast growth factor receptor 1 [FGFR1]) are characteristic. Almost all tumors display somatic mutation of tumor protein 53 (TP53). Deletion of chromosome 9p (CDKN2A) was observed in 72% of cases .
Adenocarcinoma (ADC)
Key Clinical Features
The most common primary pulmonary malignancy, accounting for about 40% of cases.
Mortality and incidence rates have generally been highest in high-income countries but are now declining, especially in younger males and females.
Has been more common in men than in women, but has begun to converge.
Key Radiological Features
Usually a solitary peripheral nodule/mass
Cytological Features
Cohesive, three-dimensional groups.
Eccentric, irregular nuclei with granular chromatin, and prominent nucleoli.
Transparent, foamy cytoplasm, may have secretory vacuoles.
Invasive mucinous ADC: high cellularity, sheets and three-dimensional groups of relatively uniform cells, nuclear enlargement and irregular contour, and nucleoli. May have pseudoinclusions, psammoma bodies, and nuclear grooves/clearing.
Poorly differentiated ADC: cohesive groups of overtly malignant cells with nuclear pleomorphism, nuclear membrane irregularity, and coarse chromatin pattern; cytoplasmic mucin is inconspicuous.
Representative images are shown in Fig. 6.22a–h.
Fig. 6.22
Adenocarcinoma , cytology. (a) Cohesive groups of tumor cells with nuclear pleomorphism, nucleoli, and abundant foamy cytoplasm, forming acinar or ductal structure, Diff-Quik; (b) the same, Pap stain; (c, d) invasive mucinous adenocarcinom a, basally located nuclei with no atypia, Pap stain; (e) mucinou s tumor cells mimic macrophages in background of mucin, Diff-Quik; Pap stain; (f) mucinou s tumor cells mimic macrophages in background of mucin, Pap stain; (g) poorly differentiated adenocarcinoma showing pleomorphic tumor cells with no mucinous features identified, Diff-Quik; (h) poorly differentiated adenocarcinoma, Pap stain
Differential Diagnosis
Metastatic ADC
Reactive/reparative changes
Goblet cell hyperplasia
Granulomatous inflammation
Vegetable cells
Histology
In 2011, the new International Association for the Study of Lung Cancer (IASLC) /American Thoracic Society (ATS) /European Respiratory Society (ERS) classification of lung ADC proposed significant changes to the 2004 WHO classification for resected tumors:
- 1.
Discontinuing the terms bronchioloalveolar carcinoma (BAC) and mixed subtype ADC
- 2.
Adding adenocarcinoma in situ (AIS) as a preinvasive lesion to join atypical adenomatous hyperplasia
- 3.
Adding minimally invasive adenocarcinoma (MIA)
- 4.
Classifying invasive ADCs according to the predominant subtype after comprehensive histologic subtyping in 5% increments
- 5.
Using of “lepidic” to describe a noninvasive component (previously BAC) as part of an invasive ADC
- 6.
Replacing mucinous BAC with invasive mucinous ADC excluding tumors that meet the criteria for AIS or MIA
- 7.
Discontinuing the subtypes of clear cell and signet ring ADC
- 8.
Discontinuing the term mucinous cystadenocarcinoma and including these under the category of colloid ADC
- 1.
In the 2015 WHO classification, large cell carcinomas with expression of TTF1 and/or napsin A are reclassified as solid ADCs even if mucin is absent. The solid ADC must be distinguished from squamous cell carcinomas and large cell carcinomas by the identification of at least two high-power fields with five or more cells showing intracytoplasmic mucin and/or the expression of TTF1 and/or napsin A.
The diagnostic criteria for AIS :
- 1.
Solitary, small tumor ≤3 cm.
- 2.
Purely lepidic growth pattern.
- 3.
No invasion: stromal, vascular, or pleural.
- 4.
No pattern of invasive ADC: acinar, papillary, micropapillary, solid, colloid, enteric, fetal, or invasive mucinous ADC.
- 5.
No spread through air spaces.
- 6.
Mainly nonmucinous cell type, rare mucinous .
- 7.
No or inconspicuous nuclear atypia.
- 8.
Septal widening with sclerosis/elastosis is common .
- 1.
The diagnostic criteria for MIA:
- 1.
Solitary, small tumor ≤3 cm.
- 2.
Predominantly lepidic growth pattern.
- 3.
≤0.5 cm invasive component in greatest dimension in any one focus.
- 4.
The invasive component to be measured includes any histologic subtype other than a lepidic pattern; tumor cells infiltrating myofibroblastic stroma.
- 5.
MIA diagnosis is excluded if the tumor invades lymphatics, blood vessels, air spaces, or pleura, contains tumor necrosis, and spreads through air spaces.
- 6.
The cell type is mostly nonmucinous, but rarely may be mucinous .
- 1.
The 2015 WHO classification of tumors of lung classifies ADC as lepidic, acinar, papillary, micropapillary, or solid according to the predominant pattern after a comprehensive histologic subtyping to identify all of the different histologic patterns in 5% increments.
Other variants of ADCs include invasive mucinous ADC, colloid ADC, fetal ADC, and enteric ADC.
Representative images are shown in Fig. 6.23a–d.
Fig. 6.23
Adenocarcinoma, histopathology and immunophenotype . (a) Lepidic growth pattern, H&E; (b) micropapillary pattern, H&E; (c) mucinou s, H&E; (d) fetal adenocarcinom a, H&E; (e) nuclear staining for TTF1 , IHC; (f) positive for CK7 , IHC; (g) positive for napsin-A , IHC; (h) negative for p40 , IHC
Immunohistochemistry
Positive for TTF1 and napsin A : commonly used markers for pneumocytes, with comparable sensitivity, about 75%; much lower TTF1 expression in solid ADCs and mucinous ADCs
Positive for CK7
Negative for squamous cell markers; however, p63 positivity was reported in up to 30% of lung ADCs.
Representative images are shown in Fig. 6.23e–h.
EGFR, Kirsten rat sarcoma viral oncogene (KRAS), and ALK mutations are specific for lung ADCs. The ADCs with EGFR or ALK alteration are usually located in the periphery; in contrast, the ADCs with KRAS mutation are frequently located in hilar region. The prevalence for KRAS and EGFR mutations is 10–30%; the transforming fusion gene echinoderm microtubule-associated protein-like 4 (EML4)-ALK is found in 5% of lung ADCs. The characteristics of patients with EGFR mutation are Asians, never smokers, with nonmucinous tumors; for ALK mutation, patients are younger age, male gender, and never or light smokers; for KRAS mutation patients are non-Asians, smokers, with invasive mucinous ADCs usually negative for TTF1 , and positive for mucin (MUC) 2,5,6 immunophenotypes .
Neuroendocrine Tumors
This group of tumor represents a morphologic and biologic spectrum of tumors that is classified by the 2015 WHO classification of tumors of the lung into four types: preinvasive lesion (including diffuse idiopathic pulmonary neuroendocrine cell hyperplasia ), carcinoid tumors (including typical and atypical carcinoid tumors ), large cell neuroendocrine carcinoma (LCNEC) , including combined LCNEC, and small cell carcinoma (including combined small cell carcinoma ).
Carcinoid Tumor
Carcinoid tumors are neuroendocrine epithelial malignancies, including typical carcinoids, defined as those with <2 mitoses/per 2 mm2, lacking necrosis, ≥0.5 cm in size, and atypical carcinoids, which are those with 2–10 mitoses/per 2 mm2 and/or foci of necrosis.
Key Clinical Features
Account for <1% of all lung cancers.
Majority (70–90%) are typical carcinoids.
More common in female, white, and <60 years old.
Clinical syndromes are uncommon, including carcinoid syndrome, Cushing syndrome, and acromegaly.
Key Radiographic Findings
Chest x-ray: usually a centrally located, lobulated mass with a prominent endobronchial component; one third of tumors in periphery.
CT using intravenous contrast medium shows considerable enhancement; calcification, especially in centrally located tumors; atelectasis; bronchiectasis; and hyperlucency for tumors with bronchial involvement.
Cytological Features
Loosely cohesive groups and single uniform cells with granular nuclei and ample eosinophilic cytoplasm and naked nuclei.
Round, columnar, or plasmacytoid cells, forming acinar or rosette-like structures.
Branching capillaries.
Clean background.
May show pleomorphism and prominent nucleoli in atypical carcinoids.
Mitoses uncommon, no necrosis in typical carcinoids; necrosis and mitosis seen in atypical carcinoids.
Representative images are shown in Fig. 6.24a, b.
Fig. 6.24
Carcinoid tumors , cytology . (a) Loosely cohesive groups and single uniform round to oval cells with granular nuclei and ample eosinophilic cytoplasm, Diff-Quik stain; (b) same, Pap stain; (c, d) typical carcinoid, composed of uniform polygonal and spindled cells arranged in organoid and trabecular patterns, H&E; (e, f) atypical carcinoid, the cells are more atypical with focal prominent nucleoli, rare necrosis, and 2–10 mitoses/per 2 mm2
Differential Diagnosis
Small cell carcinoma
Lymphoma
Benign bronchial epithelial cells
Mesenchymal tumor (spindle cell carcinoid)
ADC
Histology
Usually uniform polygonal or spindled cells arranged in organoid or trabecular patterns.
Other growth patterns also seen: rosette formation, papillary, pseudoglandular, or follicular patterns.
Significant pleomorphism and prominent nucleoli may be seen in typical carcinoids.
The differential features for atypical carcinoids are the presence of 2–10 mitoses per 2 mm2 and/or necrosis. These changes may be focal.
Representative images are shown in Fig. 6.24c–f.
Immunohistochemistry
Immunohistochemistry is recommended for the diagnosis of neuroendocrine tumors , not only in small biopsy or cytology cases but also in resected specimens.
The typical phenotype expresses neuroendocrine markers (CD56 , synaptophysin , chromogranin ); most are positive for panCK and negative for high molecular weight cytokeratins (HMWCKs) and TTF1 . However, TTF-1 expression was reported in 43–53% of cases.
The proliferative index (ki-67) is valuable in distinguishing carcinoids from high-grade neuroendocrine carcinomas, especially in small biopsies or cytology specimens with significant crush artifact. Small cell carcinomas have high proliferative index (>50%) in contrast to <10–20% in carcinoids.
Ki-67 is not recommended for the distinction of typical from atypical carcinoids due to the lack of cutoff value.
Representative images are shown in Fig. 6.25a–d.
Fig. 6.25
Carcinoids, immunohistophenotype . (a) Positive for synaptophysin , IHC; (b) positive for chromogranin , IHC; (c) positive for AE1/3, IHC; (d) very low MIB-1 , IHC
Large Cell Neuroendocrine Carcinoma (LCNEC )
Key Clinical Features
Heavy smokers in >90% of cases.
Paraneoplastic syndrome is uncommon.
Key Radiological Findings
Usually a periphery mass with irregular margin, with or without intratumoral calcification
The tumors are usually large, showing central inhomogeneous enhancement on CT with contrast.
Cavitation uncommon
Cytological Features
Overlapping with other neuroendocrine tumors and ADCs
Loosely cohesive or single, monotonous tumor cells with a hyperchromatic nuclear chromatin pattern but easily appreciated nucleoli, nuclear membrane irregularity, and preserved moderate to abundant, delicate cytoplasm
Necrosis or apoptotic debris may be seen.
Representative images are shown in Fig. 6.26a, b.
Fig. 6.26
Large cell neuroendocrine carcinoma . (a, b) Loosely cohesive cluster of mildly pleomorphic tumor cells with hyperchromatic nuclear chromatin pattern but easily appreciated nucleoli, nuclear membrane irregularity, and preserved moderate to abundant, delicate cytoplasm, Diff-Quik (a) and Pap (b) stains; (c) large tumor cells with prominent nucleoli and moderate to abundant cytoplasm, arranged in irregular nests, H&E; (d) mitotic figures are easily identified, H&E
Differential Diagnosis
Other neuroendocrine tumors , including small cell carcinoma
Other non-small cell carcinomas, such as ADC, basaloid squamous cell carcinoma , and large cell carcinoma
Melanoma
Metastasis
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