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Fine Needle Aspiration Biopsy Cytology of Lung and Mediastinum: A Diagnostic Approach Based on Pattern Recognition
Currently, fine needle aspiration biopsy (FNAB) is the first diagnostic procedure used in patients presenting with a mass in the lung, mediastinum, or chest wall on chest x-ray (CXR) or computed tomography (CT) or CT positron emission tomography (PET) scan, which may have been performed as a routine screening procedure or as a part of the workup in patients with chest-related symptoms, pneumonia, malignancy in another site, or chronic lung disease or in immune-compromised patients. The most common procedure is now endobronchial ultrasound (EBUS)-directed FNAB, which has revolutionized the workup of central lung, peribronchial, and mediastinal lesions. Transthoracic FNAB still has a major role for peripheral lung, pleural, and chest wall lesions, but it has an inherent significant risk of pneumothorax requiring an intercostal drain in up to 10% of procedures and a significant false-negative rate even when combined with core biopsies. EBUS FNAB has greatly reduced the number of thoracotomies for patients with lung cancers by providing not only the diagnosis of the lung lesion but also staging information on the status of ipsilateral and contralateral lymph nodes, which EBUS can readily sample. Many patients who would have been found to have “inoperable” lung cancer at surgical pathology now are saved a thoracotomy and are appropriately treated solely on the basis of EBUS FNAB. Similarly, FNAB can diagnose infections, including tuberculosis and fungal infections, and sarcoidosis precluding the necessity for surgery and reducing patient morbidity in a cost-effective way.
FNAB may be used to complement bronchoscopic bronchial brushings and washings for intrabronchial and more diffuse parenchymal lesions. Transbronchial biopsy has been useful, particularly for endobronchial and submucosal lesions. EUS FNAB through the esophagus can also sample mediastinal lymph nodes, as well as adrenal masses thought to be metastases of lung carcinomas, and the combination of EUS FNAB with EBUS FNAB is being recommended. New algorithms for diagnosis and staging of lung cancer are evolving.
The role of the FNAB is to diagnose primary and secondary malignancy in the lung and mediastinal lymph nodes, stage primary malignancy by accessing ipsilateral and contralateral endobronchial and mediastinal lymph nodes, biopsy bronchial submucosal lesions, and sample lymph nodes and lung parenchyma for acute and chronic infections and granulomatous diseases such as tuberculosis and sarcoidosis. FNAB is particularly useful in the diagnosis of infections in immune-compromised cancer or human immunodeficiency virus (HIV)-positive patients, the chronically ill, elderly or inoperable patients, and children.
Endobronchoscopic FNAB of Lung and Mediastinum
EBUS can sample solitary lung masses, endobronchial lesions, hilar and mediastinal lymph nodes for staging or diagnosis, and mediastinal tumors. EBUS can access more lymph node stations in the chest than non–ultrasound-directed “blind” transbronchial FNAB and provides direct visualization under ultrasound, yielding a higher sensitivity of up to 94% and greater specificity up to 99% and negative predictive value and therefore is more cost-effective and reduces patient morbidity. The linear or convex probe, where the transducer is in the tip of the bronchoscope, is used for real-time ultrasound guidance of the 22-gauge (ga) needle. The radial probe rotates the ultrasound around 360 degrees penetrating up to 50 mm and can locate lesions farther from the bronchus.
EBUS is more expensive in equipment and establishment training costs, requires specific training, and is usually prefaced by conventional bronchoscopy. EBUS cannot sample the para-esophageal and subaortic lymph node stations, but these can be accessed via EUS (superior mediastinal in 4L, inferior mediastinal at 7, 8, 9), and combined EUS and EBUS FNAB is recommended by some. The complications of EBUS occur in less than 1% of cases and include bleeding and rarely infection of a bronchogenic cyst, lung abscess, possibly mediastinitis, empyema, and pneumothorax, while percutaneous FNAB performed under CT or ultrasound guidance using 22- to 25-ga needles has a rate of up to 10% of significant pneumothorax, particularly in those with preexisting lung disease and infection, and rare cases of tumor implantation along needle tracts have been reported. Transthoracic FNAB is relatively contraindicated in patients with emphysema, pulmonary hypertension, bleeding diatheses, and chronic obstructive lung disease. EBUS requires sedation, while percutaneous FNAB should not be performed in unconscious patients and those with paroxysmal coughing, and should be performed with great care in patients who have a bleeding diathesis or severe pulmonary infection. FNAB of “cysts” that turn out to be hydatid cysts are routinely safe, but there are theoretical risks of anaphylaxis. EBUS has largely replaced mediastinoscopy in assessing mediastinal lymph nodes.
The rates of sensitivity and specificity of diagnosis in FNAB by EBUS or transthoracic route relate to the expertise of the radiologist or respiratory physician performing the procedure, the quality of the direct smear making, and the experience of the cytopathologist. Common problems are sampling error and the degree of blood contamination and fibrin clotting that occur with sampling and delayed deposition of the material on the smear. Clinicians should be encouraged to minimize the time they spend with the needle in the lesion (maximum 10 seconds) and use the FNAB cutting action of repeated jabs through the lymph node or lung lesion without aspiration.
Rapid On-Site Evaluation
Wherever possible at EBUS or transthoracic FNAB, rapid on-site examination (ROSE) should be performed by a cytotechnologist or cytopathologist skilled in making direct smears. Ideally, this person should prepare both air-dried Giemsa or toluidine-stained smears during the ROSE, as well as alcohol-fixed slides by “specimen splitting.” Four passes are recommended. Slides for Pap staining can be fixed in alcohol or modified Carnoy’s fixative, which lyses the obscuring red cells. Obvious needle cast clots expelled from the FNAB needle onto the slides during ROSE should be immediately scraped into the cell block jar. EBUS transbronchial FNAB can produce considerable contamination by ciliated bronchial epithelium, fragments of cartilage, and mucin, while transthoracic FNAB can also sample mesothelial cells and even hepatocytes. Each needle used, either a 22-ga needle such as a Chiba needle, which is introduced freshly at each pass, or a 22- to 25-ga coaxial needle introduced through a lower-gauge outer needle, is rinsed in normal saline or a preservative fluid such as Roswell Park Memorial Institute (RPMI). Whole separate passes can be similarly placed directly into saline or RPMI, and this sample can then be used for flow cytometry, preparation of cell blocks, or culture depending on the ROSE triage of the case.
ROSE maximizes the appropriate triage of FNAB specimens obtained at EBUS or percutaneous biopsy and greatly reduces inadequacy rates and the need for repeat procedure.
Adequacy and Reporting
Adequacy in lung FNAB can be equated to making a specific diagnosis because a negative nonspecific diagnosis in the presence of a mass or diffuse, possibly infectious lesion does not advance the diagnosis. Does the FNAB material explain the imaging findings? Repeat study is recommended if it does not. Structured reporting of adequacy has been advocated. In EBUS FNAB of lymph nodes some lymphoid cells are required to demonstrate the node was sampled, unless a specific lesion is present such as metastatic carcinoma or granulomas. Similarly, FNAB of lung should yield at least some alveolar macrophages, which usually contain carbon and other pigment.
Reporting of lung and mediastinal lesions can be categorized into six categories:
Category 1: insufficient: there is inadequate material to make any diagnosis. Some authors regard an FNAB that does not explain the imaging findings as inadequate, but the imaging findings should be reassessed in this situation and repeat FNAB recommended.
Category 2: specific benign lesions such as organizing pneumonia, specific infections, and granulomatous infections.
Category 3: specific benign tumor diagnoses such as pulmonary hamartomas or the much rarer lesions such as sclerosing pneumocytomas or meningiomas or bronchial “salivary gland”–type tumors such as pleomorphic adenomas.
Category 4: atypical lesions, believed most likely to be benign but with some features that require further workup, such as marked atypia in bronchial type cells in a patient post chemotherapy or radiotherapy.
Category 5: a suspicious category that may have low interinstitutional reproducibility but recognizes some cases have borderline sufficient but highly atypical material that is quantitatively insufficient to make a diagnosis of malignancy, while other cases have atypical material with qualitative features falling short of an unequivocal diagnosis of malignancy (e.g., scant, highly atypical glandular material in the presence of marked inflammation). This category allows for the “malignant diagnosis” to have a high positive predictive value (PPV). Multidisciplinary meetings that correlate imaging and cytology findings are extremely useful in determining management of these patients.
Category 6: unequivocal malignant material, most commonly a primary squamous, glandular, small or large neuroendocrine or “large cell” carcinoma or a metastasis. This diagnosis must have a high PPV of malignancy. It includes carcinoid tumors.
A five-tier system merging atypical and suspicious categories will decrease the PPV of the suspicious category and increase the false-negative rate in the “atypical category.” On the other hand, specific benign lesions can include specific benign tumors, which would create a five-category system.
Ancillary Techniques
In the era of personalized medicine and specific, often expensive drugs for carcinomas, lymphomas, and sarcomas with specific genetic abnormalities, ancillary studies have become mandatory when available. It is now required to specifically diagnose wherever possible neuroendocrine carcinomas, adenocarcinomas, and squamous cell carcinomas. “Poorly differentiated” and “large cell” carcinomas do occur, but their number has greatly decreased in lung cytology with the use of immunohistochemistry (IHC). It is recognized that distinguishing poorly differentiated adenocarcinoma from poorly differentiated squamous cell carcinoma in surgically resected histopathology, core biopsies, and cell blocks can be difficult, and this is reflected in FNAB. IHC is routinely required.
Cell blocks provide material for mucin stains such as DiPAS in adenocarcinomas, IHC for the full range of stains, and molecular tests. At the FNAB procedure, ROSE can not only reduce the rates of inadequate specimens, improve the diagnostic yield, and ensure adequate material has been collected but also provide the best possible triage of the FNAB material so that extra material can be requested for cell blocks. Once direct Giemsa- and Pap-stained smears have been prepared for cytology, material from the FNAB can be placed into RPMI or similar cell culture medium, and this can be used for flow cytometry or cell blocks, or the material can be placed directly into a fixative such as CytoLyt solution (Cytic Corporation). When carcinoma has been diagnosed, it is essential to maximize the amount of material in the cell block for IHC and molecular studies. Alternative methods for collection and storage, such as directly expelling FNAB material or needle rinses onto prepared filter paper, have been developed.
Cell blocks can be supplemented by material scraped from Giemsa- and Pap-stained smears as a source of material for molecular studies. ALK can be diagnosed on Pap-stained smears using immunocytochemical staining as an alternative when cell blocks have insufficient material. Core biopsies have traditionally been regarded as offering more material for IHC and molecular testing and are still often demanded by clinical trials for entry, but recent publications have suggested that FNAB can provide similar specific diagnoses to core biopsy and sufficient material for IHC and molecular studies.
In IHC, the most useful stain in distinguishing adenocarcinoma and squamous cell carcinoma is the thyroid transcription factor–1 (TTF1) stain, which is positive in most lung adenocarcinomas and neuroendocrine carcinomas and negative in squamous cell carcinoma. Napsin A is positive in most lung adenocarcinomas and negative in neuroendocrine carcinomas but is negative in around 50% of mucinous adenocarcinoma lung primaries while being positive in some mucinous gastrointestinal tract (GIT) carcinomas. P63 or P40 and CK5/6 are positive in most squamous cell carcinomas and negative in adenocarcinomas of the lung. A first-line IHC panel of TTF1 and P40 is recommended to distinguish most adenocarcinomas from squamous cell carcinomas. CK5/6 and napsin A can be added where necessary and will highlight the rare TTF1-negative lung adenocarcinomas. If there is a history of thyroid carcinoma, thyroglobulin will be negative in TTF1-positive lung carcinomas. CK7 is positive in most lung adenocarcinomas, while CK20 and CDX2, markers of colorectal carcinomas, are negative in lung cancers except in the rare “enteric type,” which remains CK7 positive. Estrogen receptor is negative in almost all lung carcinomas. GATA3, a useful marker of breast and urothelial carcinomas, can be used to diagnose metastatic breast carcinomas. Calretinin is positive in mesotheliomas, which are also CK7, CK5/6, WT1, and D2-40 positive. Calretinin is negative in almost all lung adenocarcinomas.
Electron microscopy is uncommonly used but may help differentiate mesotheliomas with their long microvillous borders from adenocarcinomas, neuroendocrine carcinomas, and metastatic melanomas with their melanosomes, and surfactant granules may assist in diagnosing bronchogenic carcinomas.
Molecular Pathology of Lung Carcinomas
Lung carcinomas are a heterogeneous group of tumors in molecular terms, and the number of specific targeted and relatively low-toxicity treatments is rapidly growing on the basis of molecular testing. The specific molecular abnormalities can be “driver” mutations that activate oncogenes, including EGFR, KRAS, BRAF, and ERBB2; translocations such as ALK, ROS1, and RET; and gene amplifications including MET and FGRI . EGFR and ALK mutations occur mainly in peripheral adenocarcinomas in “never smokers” while KRAS and BRAF mutations most commonly occur in smokers with hilar adenocarcinomas, similar to squamous cell and neuroendocrine carcinomas.
Deoxyribonucleic acid (DNA) can be extracted from carcinoma cells found in cell blocks or present on alcohol-fixed, Pap-stained, or air-dried Giemsa-stained FNAB slides. Hematoxylin-eosin−stained slides of the cell block are assessed for adequacy of cellular material, taking into account the number of cells, presence of contaminating cells, and presence of necrosis, and the carcinoma is marked and scraped off or laser microdissected from further microtome cut slides of the cell block. Cytology direct smears can be marked, and their cover slips can be removed by soaking in xylol or freezing. Complete tumor cells can be scraped off and placed in the DNA extraction tubes. Next-generation sequencing can be performed on FNAB smear material scraped from the slide and allows for simultaneous testing for multiple deletions, insertions, translocations, base substitutions, and copy number changes, rather than single-gene analysis. FNAB material can be placed directly into ribonucleic acid (RNA) later medium in an RNAase-free Eppendorf tube and stored at 4° C until the cytology diagnosis is reached and then processed to extract and purify the RNA and DNA, which undergo polymerase chain reaction (PCR) to detect EGFR and other mutations. Similarly, FNAB material can be placed onto FTA cards with excellent RNA and DNA retrieval for molecular studies. The quality of the RNA is reported as better when obtained by FNAB versus core biopsy. In the event of a recurrence or metastasis of lung cancer, these should be resampled, most commonly by FNAB, and undergo repeat testing because of the heterogeneity of the primary and metastatic carcinoma.
The keys to maximizing the use of FNAB-derived material, either in cell blocks or scraped from direct smears, are (1) ROSE should be used to triage cases so that more passes for material can be requested once carcinoma is recognized and (2) as small a number as possible of IHC stains are used on cell blocks to confirm the carcinoma type, so as to preserve material for molecular testing. Novel ways of increasing the carcinoma cells available for molecular and ongoing chemotherapy testing include xenografting into mice.
EGFR mutations occur in 10% to 20% of adenocarcinomas in Caucasians and up to 50% of Asians, most commonly in nonsmokers. They occur in the tyrosine kinase regions in exons 18 to 21, as single-point mutations in exon 21 and short deletions in exon 19, and open up the use of specific tyrosine kinase inhibitors, such as erlotinib and gefitinib, two U.S. Food and Drug Administration–approved drugs that are effective at least in the short term. Resistance to these drugs can occur usually at 12 to 14 months, when the carcinoma acquires extra somatic EGFR mutations on exon 20 (T790), or amplification of the MET proto-oncogene or ERBB2 proto-oncogene, and rociletinib can be used as treatment. Currently EGFR IHC is of doubtful accuracy, and diagnosis is by PCR or fluorescence in situ hybridization (FISH) in most laboratories.
ALK, when fused with EMLA through a translocation, can be diagnosed on IHC and then more specifically on FISH. It is found in up to 7% of non–small cell-, KRAS-, and EGFR -negative lung adenocarcinomas, usually in nonsmokers, and can be effectively treated with crizotinib.
KRAS mutations are more common in Caucasians than East Asian patients with adenocarcinomas with rates of up to 30% and 10%, respectively. These adenocarcinomas are virtually never EGFR positive, occur in smokers, have a worse prognosis, and do not respond to tyrosine kinase inhibitors. KRAS, similarly, can be extracted for DNA analysis on PCR, with or without IHC screening or in situ hybridization (ISH).
If EGFR and KRAS FISH mutation analysis is negative and ALK is negative on IHC of an adenocarcinoma, various algorithms have been suggested to test for less common abnormalities, such as the c-ros oncogene1 (ROS1) by IHC with confirmatory break-apart FISH, which is sensitive to crizotinib but only present in 2% of cancers.
BRAF mutations, which are less common than the BRAFV600E found in melanomas, activate MEK and are seen in 2% to 10% of adenocarcinomas. HER2 or EGFR2 , when mutated in its kinase domain, is not responsive to HER2 blockers but is found in 3% to 10% of lung cancers. VEGFA , a ligand involved in tumor angiogenesis, can be targeted by a monoclonal antibody bevacizumab in conjunction with chemotherapy. RET fusions can be diagnosed on FISH and are treated with cabozantinib. NTRK1, NRG1, and RIT1 are other potential molecular targets. P13KCA mutations, FGFR1 amplifications, and PTEN mutations have been investigated in squamous cell carcinomas.
The anti-PDL1 drug nivolumab reactivates T cells bypassing “checkpoint” inhibitions diagnosed on IHC and FISH, as an immunologic agent against squamous cell carcinomas.
The number of molecular abnormalities and specific drug treatments are growing rapidly. As the number of molecular targets increases and their interactions are better understood, there will be a move to next-generation sequencing and high-throughput molecular analysis of tumors using FNAB material.
In summary, all adenocarcinoma patients should be tested for EGFR by FISH and ALK by IHC at the time of initial diagnosis, and subsequent relapse or metastases should be tested as well due to tumor and metastasis heterogeneity. If EGFR and ALK are negative, KRAS and BRAF can be tested by FISH, and ROS1 and MET can be tested initially by IHC followed by confirmatory FISH.
Diagnostic Patterns in FNAB of Lung and Mediastinum
Eight patterns are recognized, and each raises its own differential diagnosis (DD) ( Table 8-1 ). Some inflammatory processes due to specific organisms will vary over time (e.g., an acute pneumonia due to Streptococcus pyogenes may vary over time to become an organizing pneumonia, dependent on the patient’s immune status and treatment), while many fungal infections can present with suppurative or suppurative granulomatous or granulomatous tissue reactions dependent again on the host infection inter-reaction. Some carcinomas can present with varying patterns dependent on the heterogeneity of the primary carcinoma.
Table 8-1
Lung and Mediastinal FNAB Smear Patterns
Pattern 8-1 Inflammatory cells predominate
Pattern 8-2 Dispersed lymphoid cells
Pattern 8-3 Epithelial tissue fragments with or without glandular differentiation and with a variable number of dispersed cells, and with or without necrosis or mucinous background
Pattern 8-4 Epithelial tissue fragments and plentiful dispersed cells showing varying degrees of squamous differentiation with or without keratinous debris and necrosis
Pattern 8-5 Predominantly dispersed cells with discohesive epithelial tissue fragments with or without chromatin smearing and karyorrhectic debris
Pattern 8-6 Small loosely cohesive epithelial tissue fragments and dispersed cells and scattered thin capillary meshworks
Pattern 8-7 Stromal and epithelial components
Pattern 8-8 Stromal components without epithelium
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Pattern 8-1: Inflammatory Cells Predominate
The predominant inflammatory cell type can vary between neutrophils, raising a DD of acute pneumonia due to an infectious agent or inhalation or another cause such as irradiation; histiocytes, which suggest an organizing pneumonia, bronchial obstruction or atypical mycobacterial infection; and a granulomatous process, where there is a DD of mycobacterial infection, which may be associated with necrosis, fungal infection, or another noninfectious cause such as Wegener granulomatosis, sarcoidosis, anthracosis, or berylliosis. The organism should always be diagnostically worked up with special stains, culture, and PCR ( Plates 8-1A-C ).
Plate 8-1
Pattern 1 Inflammatory Cells Predominate
Plate 8-1 Table
Pattern 1: Inflammatory Cells Predominate
Entities in the Differential Diagnosis
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Pattern 8-2: Dispersed Lymphoid Cells
Reactive lymphoid processes in the lung or mediastinal lymph nodes are the commonest diagnosis with this pattern, but primary lung or mediastinal lymphomas or the more common secondary involvement of these sites by lymphoma has to be part of the DD. Thymomas can produce a predominantly lymphoid FNAB material with a difficult-to-recognize epithelial component ( Plates 8-2A-C ).
Plate 8-2
Pattern 2 Dispersed Lymphoid Cells
Plate 8-2 Table
Pattern 2: Dispersed Lymphoid Cells
Entities in the Differential Diagnosis
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Pattern 8-3: Epithelial Tissue Fragments With or Without Glandular Differentiation and With a Variable Number of Dispersed Cells, and With or Without Necrosis or Mucinous Background
This is the typical presentation of adenocarcinoma of lung, but when glandular differentiation is not present, large cell carcinoma can be diagnosed once the appropriate IHC has been carried out to exclude glandular, squamous, or neuroendocrine differentiation. Poorly differentiated metastatic carcinomas, primary or secondary germ cell tumors, mesothelioma and rare lesions such as vascular tumors of the lung, and thymic carcinomas can enter the DD. The specific DD between mucinous adenocarcinoma of lung and metastatic colorectal carcinoma requires IHC ( Plates 8-3A-C ).
Plate 8-3
Pattern 3 Epithelial Tissue Fragments With or Without Glandular Differentiation and With a Variable Number of Dispersed Cells, and With or Without Necrosis or Mucinous Background
Plate 8-3 Table
Pattern 3: Epithelial Tissue Fragments With or Without Glandular Differentiation and With a Variable Number of Dispersed Cells, and With or Without Necrosis or Mucinous Background
Entities in the Differential Diagnosis
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Pattern 8-4: Epithelial Tissue Fragments and Plentiful Dispersed Cells Showing Varying Degrees of Squamous Differentiation With or Without Keratinous Debris and Necrosis
The dispersed cells show varying degrees of keratinization and frequently pyknotic nuclei, and the diagnosis of squamous cell carcinoma ultimately relies on the recognition of nuclei with malignant nuclear criteria. The DD of primary and secondary metastatic carcinoma is difficult and requires clinical and imaging information. Basaloid carcinoma and high-grade mucoepidermoid, rare as either a metastasis or primary lesion, can be difficult to distinguish from SCC. Thymomas can present with considerable epithelium showing squamous differentiation, usually with considerable benign lymphoid material. Squamous metaplasia can be associated with infections such as aspergillomas ( Plates 8-4A-C ).
Plate 8-4
Pattern 4 Epithelial Tissue Fragments and Plentiful Dispersed Cells Showing Varying Degrees of Squamous Differentiation With or Without Keratinous Debris and Necrosis
Plate 8-4 Table
Pattern 4: Epithelial Tissue Fragments and Plentiful Dispersed Cells Showing Varying Degrees of Squamous Differentiation With or Without Keratinous Debris and Necrosis
Entities in the Differential Diagnosis
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Pattern 8-5: Predominantly Dispersed Cells With Discohesive Epithelial Tissue Fragments With or Without Chromatin Smearing and Karyorrhectic Debris
This is the typical pattern of small cell neuroendocrine carcinoma of lung. Seminoma can present with larger cells usually admixed with some lymphoid cells and stripped nuclei. Some “small-celled” adenocarcinomas, squamous cell carcinomas, and metastatic carcinomas can be poorly differentiated and enter the DD, as can small cell lymphomas, which can show pseudoaggregation ( Plates 8-5A-C ).
Plate 8-5
Pattern 5 Predominantly Dispersed Cells With Discohesive Epithelial Tissue Fragments With or Without Chromatin Smearing and Karyorrhectic Debris
Plate 8-5 Table
Pattern 5: Predominantly Dispersed Cells With discohesive Epithelial Tissue Fragments With or Without Chromatin Smearing and Karyorrhectic Debris
Entities in the Differential Diagnosis
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Pattern 8-6: Small Loosely Cohesive Epithelial Tissue Fragments and Dispersed Cells and Scattered Thin Capillary Networks
This is the typical pattern of lung carcinoid tumors and atypical carcinoid tumors. The rare pneumocyte adenoma is part of the DD, as are metastatic low-grade neuroendocrine tumors ( Plates 8-6A-C ).
Plate 8-6
Pattern 6 Small, Loosely Cohesive Epithelial Tissue Fragments and Dispersed Cells and Scattered Thin Papillary Meshworks
Pattern 8-7: Stromal and Epithelial Components
The commonest lesion is pulmonary hamartoma. An organizing pneumonia may produce large tissue fragments of alveolar septa of lung parenchyma, and fragments of cartilage may be derived from ribs and bronchi and trachea. High-grade carcinomas such as carcinosarcoma and spindle cell carcinomas and pulmonary blastoma may produce this biphasic pattern but are distinctly different to pulmonary hamartomas and usually present with Pattern 3 or 5. Tumors arising from bronchial glands can produce tumors analogous to the salivary glands with stromal and epithelial components ( Plates 8-7A-C ).
Plate 8-7
Pattern 7 Stromal and Epithelial Components
Plate 8-7 Table
Pattern 7: Stromal and Epithelial Components
Entities in the Differential Diagnosis
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Pattern 8-8 Stromal Components Without Epithelium
The commonest lesions presenting with these patterns are sarcomatoid mesothelioma and metastatic sarcomas, but rare primary sarcomas can occur in the lung, along with benign solitary fibrous tumors and inflammatory myofibroblastic tumor ( Plates 8-8A-C ).
Plate 8-8
Pattern 8 Stromal Components Without Epithelium
Acute Pneumonia
Pattern: Inflammatory Cells Predominate
Clinical
Pneumonia usually presents with an acute febrile illness with chest symptoms. CXR may show a diffuse or lobar process or occasionally a rounded mass, which will raise a DD of a tumor. Squamous cell carcinomas can cavitate and be associated with suppuration, which masks the often limited keratinous material. Mycobacterial and fungal infections can be associated purely with suppuration, particularly in immune-compromised patients, but typically granulomas with or without suppuration will be found.
The commonest bacterial causes of acute pneumonia include Streptococcus pneumonia, Staphylococcus aureus, Haemophilus influenza, Pseudomonas sp., Klebsiella pneumoniae , anaerobic bacteria, and less common bacteria in particular patient groups, such as Legionella sp., Pneumocystis jiroveci, Nocardia, and Actinomyces spp. Fungi can also cause suppuration, as can typical mycobacteria and Mycobacterium tuberculosis .
Cytopathology
Typically at FNAB, soft, sticky, viscous material will be aspirated. Even in the absence of ROSE, this should trigger a request for further passes for material to be routinely sent for culture and PCR for bacteria, mycobacteria, and fungi. In addition, a cell block should be prepared and routine Ziehl-Neelsen stain for mycobacteria should be conducted. Methenamine silver for fungi should be requested on both extra direct smears and the cell block. Many bacteria can be seen on routine Pap- and Giemsa-stained smears, and Gram stains can be performed.
Cytologic diagnostic criteria ( Plate 8-1 ; Figs. 8-1 to 8-3 )
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Pattern: inflammatory cells predominate: suppuration with or without organisms.
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Large numbers of neutrophils with variable number of histiocytes, eosinophils, lymphocytes, and plasma cells.
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Fibrinous or granular proteinaceous background.
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Specific bacteria, fungal, or other infectious agents.
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Fragments of inflamed bronchial cells and meshes of thickened alveolar septa containing neutrophils.
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Birefringent vegetable and mixed bacteria suggest aspiration pneumonia.
Normal components of lung can show inflammatory changes in a background of pus on FNAB. The ciliated bronchial cells become larger, with a high N:C ratio, prominent nucleoli, and coarse but usually evenly spread chromatin, and the nuclear outlines usually remain oval and even (see Figs. 8-3 and 8-4 ). The nuclear changes tend to be uniform across a tissue fragment or sheet with minimal dispersed single cells. Neutrophils may infiltrate the epithelium, which, along with the ciliation and recognition of the background, prevent a false-positive diagnosis.
Type II pneumocytes can become hyperplastic after diffuse alveolar damage, infectious pneumonias, chemotherapy, radiotherapy, and pulmonary infarction and may present in FNAB material as single cells, small sheets, and small tissue fragments with high N:C ratio, nuclear enlargement and atypia, coarse chromatin with large single nucleoli, and variably vacuolated cytoplasm ( Figs. 8-5 and 8-6 ). They lack cilia and can cause a false diagnosis of adenocarcinoma. If atypical cells are seen in small numbers in a suppurative background in FNAB smears, caution is warranted and a conservative approach to diagnosis of malignancy is required, especially if the history suggests an inflammatory reaction.
Metaplastic squamous cells can occur in association with abscesses and fungal infections, as well as a history of irradiation, chemotherapy, and pulmonary infarction, and may show considerable nuclear atypia. The history is usually the clue, but the DD from recurrent squamous cell carcinoma after radiotherapy can be problematic.
The filamentous organisms of Nocardia sp., 1 micron in diameter and showing acute branching ( Figs. 8-7 and 8-8 ), and Actinomycetes sp., thicker and with more acute branching, can be found in aggregates of neutrophils, known as “sulphur” granules for their yellow color on a background of pus in the case of actinomycetes. Nocardia sp. are positive in Gram, Ziehl-Neelsen, and methenamine silver stains, while actinomycetes are Ziehl-Neelsen positive.
P. jiroveci form aggregates in which the 3- to 4-micron cysts with dotlike nuclei are difficult to see in both Pap and Giemsa stains, but the recommended routine silver stain is diagnostic ( Figs. 8-9 and 8-10 ).
FLOAT NOT FOUND FLOAT NOT FOUND FLOAT NOT FOUND FLOAT NOT FOUND FLOAT NOT FOUND FLOAT NOT FOUND FLOAT NOT FOUND FLOAT NOT FOUND
Increasingly, unusual infections are being reported in FNAB of lung, including Dirofilaria immitis, the dog heartworm, presenting as peripheral nodules in the lung yielding granulomatous material, necrotic lung fragments, and only occasionally the microfilaria on FNAB. Filariasis due to Wucheria bancrofti has also been reported, and microfilaria, gravid worm, and eggs can be seen in a mainly suppurative material on FNAB.
Hydatid disease usually presents unexpectedly in FNAB of a partially cystic mass, producing a watery, granular background in which birefringent 1-micron hooklets and scoleces can be seen with fragments of multilayered chitinous material. There may be a suppurative reaction if the cyst has ruptured. There is a theoretical risk of anaphylaxis.
Ancillary Diagnostic Studies
Cultures and PCR for common causes of suppuration and fungi are mandatory. In immune-compromised patients including HIV-positive, heart, lung, renal, and bone marrow transplant, and patients with hematologic or solid malignancies, mycobacteria should also be excluded by cultures and PCR.
Organizing Pneumonia
Pattern: Inflammatory Cells Predominate
Clinical
Patients with slow-to-resolve pneumonic processes, which may produce a lesion on CXR or CT scan that has tumor in the DD, and patients with suspected obstructing bronchial tumors with resultant localized pneumonia may be investigated by FNAB.
Cytopathology
Cytologic diagnostic criteria ( Plate 8-1B ; Figs. 8-11 to 8-16 )
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Pattern: inflammatory cells predominate: predominantly histiocytes.
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Mesh tissue fragments of thickened septa often containing fibrinous or myxoid fibroblastic material and histiocytes in the collapsed alveolar spaces.
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Plentiful histiocytes often containing hemosiderin and other pigment.
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Variable number of neutrophils and lymphocytes.
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Type II alveolar pneumocytes in small sheets.
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Ciliated bronchial tissue fragments.
The parenchymal tissue fragments are often partially crushed and dense, particularly on the Giemsa-stained smears, but the pale contents of the alveolar spaces compared with the septa, which contain fine capillary vessels and elastic fibrils, can be seen more clearly on alcohol-fixed, Pap-stained slides. Some alveoli may be only partially replaced with residual recognizable pneumocytes and plentiful histiocytes and neutrophils (see Figs. 8-12, 8-13, and 8-14 ). The type II pneumocytes may be seen in sheets and do not show three-dimensional tissue fragments but can lead to an “atypical” diagnosis (see Figs. 8-5, 8-6, and 8-15 ). Similarly, ciliated bronchial cells can show atypical features (see Fig. 8-16 ).
It is not possible to make a specific diagnosis of the specific pneumonic disease process unless organisms can be seen or cultured, but carcinoma can be reasonably excluded if considerable material is present on the smears. Repeat FNAB should be recommended if clinical suspicion of a tumor is high, particularly well-differentiated adenocarcinoma or mucinous adenocarcinoma, which can present with a pneumonic consolidation-like CXR appearance.
Pulmonary alveolar proteinosis due to failed production of granulocyte-macrophage colony-stimulating factor by macrophages seen de novo or in acquired immunodeficiency syndrome (AIDS) or transplant patients produces macrophages enlarged by DiPAS-positive material, in a background of similar acellular material. Infection should be excluded by special stains and cultures on FNAB material (see Fig. 8-11 ). Atypical mycobacterial infections can be positive in the DiPAS stain.
Ancillary Diagnostic Studies
Cultures and PCR for mycobacterial and fungal infections are mandatory.
Granulomatous Lesions
Pattern: Inflammatory Cells Predominate
Clinical
Tuberculosis is endemic in the developing world. Migration, tourism, refugee movement, the increasing number of immune-compromised patients in HIV-endemic areas, transplant programs, chemotherapy, and steroid treatment of patients with chronic and autoimmune diseases have led to an increased number of patients presenting with mycobacterial infections. The commonest site of mycobacterial infection presentation is the lung.
Cytopathology
Cytologic diagnostic criteria ( Plates 8-1A-C ; Figs. 8-17 to 8-28 )
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Pattern: inflammatory cells predominate: granulomas with or without necrosis.
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Epithelioid granulomas.
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Epithelioid histiocytes with elongated, footprint, or oval nuclei with fine chromatin and small nucleoli. Low N:C ratio with considerable pale or syncytial cytoplasm.
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Variable number of lymphocytes or neutrophils and single epithelioid cells depending on etiology.
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Variable presence of necrosis in the background; caseous necrosis in M. tuberculosis infections.
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Variable number of multinucleated histiocytes.
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Other infectious organisms, including fungi.
The presence of granulomas (see Figs. 8-17 and 8-18 ) or caseous necrosis (see Fig. 8-19 ) or suppurative granulomas (see Fig. 8-20 ) at ROSE or on review of direct smears should prompt extra passes to obtain as much material as possible for culture, PCR, drug sensitivity, and special stains, which should routinely be performed on direct smears and cell blocks of all cases suspected of an infectious cause. Ziehl-Neelsen (ZN, see Fig. 8-21 ) or a variant and the auramine rhodamine stain, which allows rapid screening for mycobacteria but does require an immunofluorescent microscope, can be used. Pap stains can be examined under an appropriate light source for autofluorescence of mycobacteria (see Fig. 8-22 ), and Giemsa direct smears can be restained for ZN for acid-fast bacilli.
Granulomas in M. tuberculosis tend to have few multinucleated giant cells and are commonly associated with granular or thin caseous necrosis in the background, in which ZN-positive, curved, beaded 3- to 4-micron bacilli can be found in up to 50% of cases (see Figs. 8-17 to 8-21 ). Atypical mycobacterial infections tend to have greater numbers of mycobacteria, which may line up longitudinally, and are found cross hatched in the cytoplasm of histiocytes or as negative images in the Giemsa-stained background (see Fig. 8-23 ) and stain with both the ZN or the DiPAS stain in cell blocks. Sarcoidosis does not have necrosis, and the granulomas tend to be more rounded with lymphocytes dotted through the epithelioid histiocytes (see Figs. 8-24 and 8-25 ).
Carbon-laden macrophages and multinucleated giant cells are found in most FNAB smears and cell blocks from lung, particularly in smokers, and may be associated with birefringent crystals in silicosis, berylliosis, or anthracosis (see Fig. 8-26 ). Granulomas due to infections rarely contain carbon. It is common in EBUS FNAB of mediastinal lymph nodes to have dense tissue fragments consisting of collagenous scar tissue, carbon-laden macrophages and lymphocytes, and similar dispersed macrophages and epithelioid histiocytes and lymphocytes in the background.
A granulomatous reaction can be seen to the keratin of squamous cell carcinomas and may feature large numbers of multinucleated giant cells in a foreign body reaction with or without neutrophils. Granulomas can also be seen with other tumors such as seminomas and Hodgkin disease, but these are poorly formed in a background of tumor. Necrosis mimicking caseous necrosis can be seen associated with various carcinomas, and necrosis associated with squamous metaplasia, necrotic tissue fragments of lung, and variable histiocytes and other inflammatory cells has been reported in pulmonary infarcts, although the history and imaging findings usually have made the diagnosis.
Sarcoidosis produces noncaseating granulomas in the lung and mediastinal lymph nodes and lacks necrosis (see Figs. 8-24 and 8-25 ). The diagnosis is based on the presence of noncaseating granulomas but requires supporting CXR, CT scan, and appropriate biochemistry. It can be made confidently in most cases on EBUS FNAB of lung and lymph nodes and does not require core biopsies. The sensitivity of EBUS transbronchial FNA with ROSE on hilar and mediastinal lymph nodes is at least 94%, with a specificity and PPV up to 100%. The granulomas on FNAB tend to be numerous, with sharply demarcated edges and a lymphocytic background rather than acute inflammatory background. Necrosis is more commonly seen in fungal infections such as histoplasmosis, where yeasts are commonly seen, and in mycobacterial infections.
Wegener granulomatosis involves the upper respiratory tract, especially the nose, with or without the kidneys and the lungs, and histologically shows a vasculitis and resultant necrosis with a granulomatous reaction. FNAB of lung yields eosinophilic necrotic lung parenchyma tissue fragments along with granulomas and a variable number of neutrophils, which may or may not be seen in the tissue fragments (see Figs. 8-27 and 8-28 ). Correlation with the antineutrophil cytoplasmic antibody (ANCA) test, CXR, and clinical presentation is required for the diagnosis.
Fungal infections are often easily and specifically diagnosed on FNAB smears using standard Pap and Giemsa or methenamine silver stains, which should be prepared whenever infection of any type is suspected or seen at ROSE. Fungal infections can be associated with granulomatous or suppurative or mixed suppurative granulomatous responses depending on the organism and immune status of the patient and the timing of treatment and FNAB. The fungi can frequently be seen partially stained in standard Pap and Giemsa smears or as negative images in the cytoplasm of epithelioid histiocytes or in the suppurative or necrotic background.
Aspergillus sp. can present in a suppurative or necrotic background with eosinophils and Charcot-Leyden crystals, where the acutely branching, 5- to 7-micron diameter hyphae are seen in aggregates or singly ( Figs. 8-29 and 8-30 ). The Grocott methenamine stain (GMS) is an excellent routine stain for aspergillosis and other fungi, although overstaining can stain red cells that mimic yeasts ( Figs. 8-31 and 8-32 ). Aspergillomas are tumor-like masses with central cavitation related to invasion and necrosis of pulmonary vessels by the fungus and can have a suppurative and granulomatous component with variable atypical squamous metaplasia and conidiophores or fruiting bodies and calcium oxalate crystals. Culture is required to distinguish aspergillosis from Fusarium sp., Pseudallescheria boydii, and the pseudohyphae of Candida sp., which can be similar with Pap and methenamine silver stains ( Figs. 8-33 and 8-34 ).
Zygomycoses, due to Mucor with its nonseptate, broad, ribbon-like hyphae ( Fig. 8-35 ), and Rhizopus, Cunninghamella, and Absidia also invade vessels producing hemorrhagic necrosis, most commonly in immune-suppressed patients.
Cryptococcus neoformans yeasts are seen in routine Giemsa-stained smears as a negative capsule outlined by background serum, necrosis, or the cytoplasm of multinucleated giant cells and epithelioid histiocytes, with a variably stained body and narrow-necked budding. These yeasts can also be seen in Pap stains ( Figs. 8-36 and 8-37 ). Mucicarmine can be used to stain the capsule but is not routinely required. The yeasts are round and 5 to 15 microns but may lack a capsule in immune-suppressed patients when the DD is histoplasmosis.
Histoplasmosis capsulatum can present with nodular lung lesions and mediastinal lymphadenopathy mimicking tuberculosis or tumor. Typically it is associated with granulomas in a background of granular acellular necrosis, although suppuration may be seen. The 4- to 5-micron yeasts are difficult to see in Pap stains as negative images in giant cells or histiocytes and require a silver stain, in which they can readily be seen in the necrotic background. However, in immune-compromised patients multiple yeasts can be seen in histiocytes in the Giemsa stain ( Fig. 8-38 ). Penicillium marneffei has distinctive cigar-shaped and centrally septate 2- to 4-micron yeasts and is a common infection in AIDS patients in Thailand and Southeast Asia ( Fig. 8-39 ).
Blastomycosis dermatitidis involves the lung and, in immune-compromised patients, the skin and other sites. It is seen in the United States. The yeast is larger at 8 to 30 microns and shows broad-based budding with a suppurative granulomatous inflammation ( Fig. 8-40 ).
Coccidioides immitis is also endemic in the United States and can produce a lung mass. In smears, 20- to 120-micron diameter, faintly birefringent and Pap stain–positive spherules are seen containing 2- to 4-micron endospores, which may also be seen in methenamine silver stains in the eosinophilic necrotic or granulomatous background.
Paracoccidioides brasiliensis is another dimorphic fungus that mimics tuberculosis in southern American patients, producing granulomas associated with squamous metaplasia and a distinctive “mariner’s” wheel yeast with broad-based budding.
Sporothrix schenckii has an ovoid 2- to 4-micron yeast resembling histoplasmosis and requires culture.
Pneumocystis jiroveci is most commonly seen in AIDS patients presenting as a life-threatening pneumonia with bilateral infiltrates on CXR and rarely diagnosed on FNAB. The usual diagnosis is by bronchial lavage. The 4- to 8-micron cysts contain nuclei seen on the methenamine silver stain, but the cysts can be seen enmeshed in fibrin casts of the small bronchi in the Pap and Giemsa preparations (see Figs. 8-9 and 8-10 ). PCR reveals Pneumocystis in healthy individuals, and the diagnosis of clinically significant infection currently requires cytology and imaging as well as PCR.
Tularemia producing a granulomatous smear with necrosis produces lung lesions, which on PET-CT and CXR are indistinguishable from carcinoma. Serology and PCR on the FNAB material are diagnostic.
Ancillary Diagnostic Studies
Whenever a granulomatous pattern is seen with or without suppuration, cultures and PCR for mycobacterial and fungal infections are mandatory.
Lymphomas and Leukemias
Pattern: Dispersed Lymphoid Cells
Clinical
Primary non-Hodgkin lymphoma and Hodgkin disease in the lung are rare events and are more commonly seen in patients with HIV and autoimmune diseases such as Hashimoto thyroiditis or in transplant patients. The commonest primary non-Hodgkin lymphomas are extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT), an indolent lymphoma constituting around 70% to 90% of lung primary lymphomas, mainly occurring in middle-aged to older adults, and diffuse large B-cell lymphoma. CXR shows solid, single, or usually multiple peripheral lung masses and extension from extrapulmonary sites must be excluded on imaging.
Peripheral T-cell lymphoma and the T cell–rich B-cell lymphoproliferative disorder related to Epstein-Barr infection (also known as lymphomatoid granulomatosis ) have a far more aggressive course. Secondary or recurrent tumor involvement of lung by lymphomas is far more common, occurring in up to 50% of non-Hodgkin and Hodgkin lymphoma patients, and in this setting FNAB can distinguish opportunistic infections and recurrent tumor and fresh new malignancies.
Leukemic patients frequently have pulmonary infiltrates terminally, but chloromas can occur in the lung. FNAB is able to differentiate opportunistic infections from the overwhelming leukemic involvement.
Benign processes such as sarcoid; tuberculosis, fungal, and other infections; and Castleman disease can all produce mediastinal lymphadenopathy and are part of the imaging DD of lymphomas.
Cytopathology
High-grade lymphomas such as diffuse B-cell lymphoma and Burkitt lymphoma can readily be diagnosed by FNAB, but “small-celled” lymphomas such as mantle cell and follicular lymphoma are more difficult and flow cytometry is mandatory (see Chapter 3 ). Recurrent Hodgkin lymphoma is usually diagnosable on the basis of the presence of Reed-Sternberg cells.
Cytologic diagnostic criteria ( Plates 8-2A and B ; Figs. 8-41 to 8-45 )
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Pattern: dispersed lymphoid cells.
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Cellularity usually high.
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Dispersed lymphoid cells as either a homogeneous population of large cells in diffuse large B-cell lymphoma or a mixed lymphoid population with small lymphoid cells, plasmacytoid cells, monocytoid cells, and scattered larger centroblastic or immunoblastic cells in marginal zone lymphoma.
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Large Reed-Sternberg cells with bilobed nuclei or two nuclei with large sky blue (Giemsa) nucleoli and poorly defined pale cytoplasm, or similar Hodgkin cell variants, in background of eosinophils, plasma cells, lymphocytes, or histiocytes, in Hodgkin lymphoma.
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Fragments of lymphoid cell cytoplasm, usually in background.
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No necrosis, although there may be necrosis post treatment.
MALT lymphoma requires flow cytometry because its mix of small, mildly atypical lymphoid cells, prominent plasmacytoid lymphoid cells, and lesser numbers of larger lymphoid cells, along with apparent lymphoid nodules with dendritic cells but few tingible-body macrophages, resembles a reactive process (see Figs. 8-41 and 8-42 ). Multinucleated giant cells and occasional granulomas have been reported. Flow cytometry will show B-cell monoclonality, positive in the CD20 and Bcl2 and negative in the CD10, CD23, and usually CD5. FISH will identify MALT1 translocation and trisomy 3 abnormalities (see Fig. 8-43 ).
Diffuse large B-cell lymphoma can be diagnosed on the basis of its relatively monotonous population of large atypical lymphoid cells, which can be a mix of atypical cells resembling immunoblasts and centroblasts (see Figs. 8-44 and 8-45 ). These “large” cells are still smaller than the typical non–small cell carcinoma of lung. B-cell monoclonality and mature B-cell markers including CD20 and CD21 will be positive, while CD5 and CD10 are usually negative.
Differential Diagnosis
The DD from reactive lymphoid processes such as lymphoid interstitial pneumonia and reactive follicular and paracortical hyperplasia in lymph nodes can be difficult. The reactive processes will show a mixed lymphoid population in which small lymphocytes predominate and, if sourced from lymph nodes showing follicular hyperplasia, will have germinal centers containing dendritic cells with pale oval nuclei and no defined cytoplasm, tingible-body macrophages, and a mix of centrocytes, centroblasts, and lymphocytes. The DD requires flow cytometry in many cases.
The DD from small cell carcinoma can be difficult because lymphomas can show pseudoaggregation and even chromatin smearing and crush artifact with molding, related to the proceduralist keeping the FNAB needle too long in the lesion and to poor smearing. The distinctive stippled chromatin and the presence of nuclear molding and karyorrhectic debris and chromatin smearing across the entire smear assist in making the diagnosis of small cell carcinoma. Whenever trying to make a diagnosis of lymphoma, if the nuclear and cellular features cannot be subclassified as a particular type of lymphoma, then the smears should be reassessed and small cell carcinoma reconsidered.
Hodgkin lymphoma can be associated with a granulomatous reaction, and Reed-Sternberg cells should be actively sought when a granulomatous process is present. Large “alien” cells may also be poorly differentiated carcinomas, metastatic melanomas, and megakaryocytes, which may be part of extramedullary hematopoiesis. IHC helps in this DD.
Carcinoma of the Lung
Carcinoma of the lung is the commonest carcinoma in men and women in terms of mortality and is linked closely with cigarette consumption, as well as to a lesser extent, exposure to asbestos, irradiation, silica, and nickel. It is a heterogeneous tumor, and multiple genetic abnormalities are being described in ever increasing numbers, each a potential target for specific therapy. Subsequently, the necessity in cytology and histology is to not only diagnose tumors as small cell neuroendocrine carcinomas, which are largely treated with chemotherapy because of their propensity to metastasize early, and non–small cell carcinomas but also, wherever possible, to specifically diagnose the non–small cell carcinomas as squamous or adenocarcinomas. Now in the developed world the FNAB material is being used in almost all cases for molecular testing based on DNA extraction for PCR studies and on ISH to diagnose specific genetic abnormalities for specific treatments. EBUS and transthoracic FNAB are eminently suitable to provide the cytologic diagnosis, which can be refined using molecular studies based on small amounts of material in cell blocks and direct smears.
Most lung carcinomas are squamous, adenocarcinoma, small neuroendocrine cell, or large cell “undifferentiated” carcinoma, but in up to 50% of tumors there may be mixed differentiation on histology, electron microscopy, and IHC.
The most recent World Health Organization (WHO) Classification of the Lung, Pleura, Thymus, and Heart provides a list of lung carcinomas and other tumors in a classification that now requires not only the separation of small cell and non–small cell carcinoma but also the specific diagnosis of adenocarcinoma and squamous cell carcinomas, which can be done in about two thirds of cases on cytomorphology ( Table 8-2 ). The WHO text outlines the needs for IHC and molecular analysis to enhance the specific diagnosis of subgroups of carcinomas to provide the necessary information for the increasingly specific treatments. FNAB can provide the small amounts of material for IHC and molecular studies in a minimally invasive fashion.
Table 8-2
World Health Organization Classification of Tumors of the Lung
From Travis WD, Brambilla E, Burke AP, et al. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. 4th ed. Lyon, France: IARC; 2015.
Epithelial tumors
|
Mesenchymal tumors
Lymphohistiocytic tumors
Tumors of ectopic origin
Metastatic tumors |
Adenocarcinoma of Lung
Pattern: Epithelial Tissue Fragments With or Without Glandular Differentiation and With a Variable Number of Dispersed Cells, and With or Without Necrosis or Mucinous Background
Clinical
Adenocarcinomas of the lung classically occur peripherally in the lung; present late, sometimes with metastases; and are the commonest histologic variant. The new classification replaces bronchioloalveolar carcinoma with “preinvasive carcinoma,” which is defined by lepidic growth along intact alveolar septa and is almost always nonmucinous, although a rare mucinous variety does occur. Colorectal and pancreatic carcinoma can mimic this growth pattern.
Invasive adenocarcinomas are divided on their predominant pattern into five subtypes, but frequently there is mixed histology:
- 1.
Lepidic: pneumocytes grow along alveolar septa, similar to adenocarcinoma in situ or minimally invasive adenocarcinoma, but foci greater than 5 mm of the other histologic variants of invasive carcinoma are present or there is a desmoplastic reaction to invasive cells or vascular or pleural invasion or spread through airways;
- 2.
Acinar: glands with or without a central lumen and with or without mucin;
- 3.
Papillary: glandular cells covering fibrovascular cores;
- 4.
Micropapillary: florets or papillary tufts lacking fibrovascular cores with or without psammoma bodies;
- 5.
Solid: sheets of polygonal cells often with mucin in the cells; includes “large cell carcinomas” lacking mucin production but positive to TTF1 or napsin A.
Subclassification is difficult on FNAB and even cell blocks and core biopsies, but adenocarcinoma should wherever possible be distinguished from squamous cell carcinoma by cytology and a cell block IHC panel of TTF1 and napsin A, which are positive in more than 80% of adenocarcinomas, and CK5/6 and P40, which are positive in the squamous carcinomas. Recognized variants are as follows:
- 1.
Fetal adenocarcinoma: same features as the epithelial component of pulmonary blastoma; endometrioid epithelium in tubules and papillary architecture with subnuclear glycogen-rich vacuoles, and occasional squamous morules.
- 2.
Mucinous adenocarcinoma: previously known as mucinous bronchioloalveolar carcinoma; has characteristic goblet or columnar cell types in a background of mucin; usually TTF1 and napsin A negative, KRAS positive, and EGFR mutation negative and is difficult to DD from metastatic colonic carcinoma, which shares CK20 positivity but is CDX2 positive and CK7 negative.
- 3.
Enteric adenocarcinoma: rare peripheral tumors resembling metastatic colorectal carcinoma, which must be excluded clinically; variable IHC but may have CDX2, CK20, and CK7 positivity.
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