Practical Pulmonary Pathology 3rd ed. Kevin O. Leslie, MD

Chapter 17. Nonneuroendocrine Carcinomas (Excluding Sarcomatoid Carcinoma) and Salivary Gland Analogue Tumors of the Lung

Philip T. Cagle, MD, Ross A. Miller, MD, and Timothy Craig Allen, MD, JD

Incidence

Lung cancer is the number one cancer killer of men, and, since surpassing breast cancer 3 decades ago, of women.^1,2 In 2015, over 158,000 deaths in the United States were caused by lung cancer.^2,3 Lung cancer diagnosis approaches 15% of all cancer diagnoses, and over 400,000 people in the United States today are expected to develop lung cancer in their lives.^3,4 Worldwide, lung cancer deaths approach 2 million per year, accounting for almost 20% of cancer deaths globally.⁵

Demographics

Lung cancer is typically a disease of older adults; over 80% of lung cancer patients are 60 or older.⁴ Age-adjusted lung cancer incidence rates in the United States parallel smoking prevalence rates, with the highest rates in Kentucky and the lowest rates in Utah.⁶ Although the number of lung cancer deaths in the United States is remaining steady in men, the number of women with lung cancer continues to increase.^{1,2 the} age-adjusted death rate is higher in men than in women.^1,2 In the past 3 decades, lung cancer incidence has fallen in men in the United States after it peaked in 1984.4 For women, the incidence has risen in the past 3 decades and only peaked in 1998; it is now beginning to decline.^4,5 the age-adjusted death rate for lung cancer is higher in blacks than in Caucasians.^1,2 It is almost one-third higher for black men than for Caucasian men, even though black men have a lower overall exposure to cigare The smoke; and the incidence for black women is the same as for white women despite a lower overall exposure to cigare The smoke.^4,5

Prognosis

Overall lung cancer 5-year survival in the United States is approximately 17%, and over one-half of patients die within a year of diagnosis.^4,5 For the approximately 15% of cases diagnosed at an early stage, 5-year survival is 54%; however, for the many lung cancer patients who present with distant metastases, 5-year survival is a mere 4%.^4,5

Etiology

Cigare The smoking is by far the most common cause of lung cancer, attributable to 90% of cases in men and 80% in women. Compared with people who have never smoked, male smokers are 23 times more likely to develop lung cancer, and female smokers are 13 times more likely.^5,7 Second-hand smoke exposure has also been implicated in the development of lung cancer.^5,8 Other causes of lung cancer include radon exposure, occupational exposure to carcinogens, and air pollution; these account for approximately 10%, 10%, and 2% of lung cancer cases, respectively.^5,9 Some patients will have combined risks. Asbestos-exposed workers who are nonsmokers have an approximately fivefold increased risk of developing lung cancer; however, asbestos-exposed workers who are also smokers have a greatly increased risk.^5,10

Lung Cancer Clinical Findings and Imaging

Clinical Findings

Most patients with lung cancer present with locally advanced or metastatic disease and are symptomatic at the time of diagnosis; only about 10% of patients are asymptomatic at diagnosis.^11,12 Symptoms are frequently present for months prior to diagnosis.^13,14 Symptoms related to the local effects of lung cancer, such as cough, are frequently attributed to comorbidities by both patients and their physicians.¹⁵ As a rough approximation, one-third of patients will present with symptoms related to local disease, such as an unrelenting cough; one-third will present with nonspecific symptoms related to metastatic tumor, such as weight loss and fever; and one-third will present with symptoms specifically related to metastatic disease, such as site-specific pain.¹⁶

Local symptoms include cough, the most common presenting symptom, as well as dyspnea, wheezing, chest pain, dysphagia, hoarseness, superior vena cava syndrome, and hemoptysis.¹² Cough is typically caused by bronchial, parenchymal, or hilar nodal involvement with tumor and by postobstructive changes. Wheezing usually indicates airway obstruction by tumor directly or by extrinsic compression of the airway.¹⁷ Dysphagia occurs in lung cancer patients in general because of esophageal compression caused by mediastinal tumor, especially subcarinal lymph node enlargement from tumor. Dysphagia may also indicate esophageal involvement with tumor. Hemoptysis is the most alarming symptom, usually resulting in quicker patient evaluation. Chest pain suggests pleural or chest wall involvement by tumor. A significant minority of lung cancer patients may develop hoarseness, typically due to laryngeal nerve palsy; it is more often seen in left lung tumors due to involvement of the recurrent laryngeal nerve as it loops under the aortic arch.¹² Superior vena cava syndrome is a serious complication in lung cancer patients; it is secondary to local invasion and compression. It involves approximately 5% of non-small cell lung cancer (NSCLC) patients and 10% of small cell lung cancer (SCLC) patients. Patients with superior vena cava syndrome show swelling of the face, neck, arms, and upper chest, and they are frequently dyspneic. Lung cancer is the cause of approximately three-fourths of superior vena cava syndrome cases.^12,17

Lung cancer in the lung apex may invade local structures, such as the brachial plexus, vertebrae, or ribs, and cause Pancoast syndrome, which manifests as shoulder pain, upper extremity paresthesias and weakness, and Horner syndrome. Horner syndrome—unilateral ptosis and lack of facial sweating on the involved side—is due to tumor compression or involvement of the sympathetic chain.¹⁸ Nonspecific symptoms of metastatic disease include weight loss, fever, weakness, and anorexia. Anemia is suggestive of metastatic disease, and elevated liver enzymes suggest hepatic metastases. Local symptoms of metastatic disease include bone pain and neurologic symptoms such as headache, nausea, mental status changes, and seizures.¹² Over two-thirds of patients who present with brain metastases are found to have lung cancer as the origin of the metastases.¹⁹

There are numerous paraneoplastic syndromes associated with lung cancer, including endocrine, neurologic, hematologic, rheumatologic, renal, cutaneous, skeletal, and metabolic syndromes. It is important to remember that paraneoplastic syndromes are not in and of themselves indicative of advanced disease. Approximately 10% of lung cancer patients will present with or develop a paraneoplastic syndrome.¹² Frequently paraneoplastic syndromes occur due to hormone or hormone analog secretion by tumor cells. An example of this the syndrome of inappropriate antidiuretic hormone, which arises in a significant minority of SCLC patients.²⁰ Ectopic production of adrenocorticotropin hormone may occur in half of lung cancer patients; however, only about 5% develop Cushing syndrome.^12,20 SCLC patients with Cushing syndrome

have a worse prognosis, frequently due to their increased susceptibility to opportunistic infection during chemotherapy.^20,21 Digital clubbing is a skeletal paraneoplastic syndrome that may arise in up to 30% of NSCLC patients; it is characterized by enlargement of the distal fingers and toes caused by a proliferation of connective tissue beneath the nail matrix.²² Many paraneoplastic syndromes regress upon the initiation of lung cancer treatment.

Imaging

For patients who may have lung cancer, radiology shares with pathology the need to work as a team to establish a pathologic diagnosis and efficiently stage the disease. Lung cancer computed tomography (CT) scan includes the chest and upper abdomen, which allows for visualization of the liver and adrenal glands. CT scan helps characterize the tumor’s clinical stage, specifically features such as tumor size, the existence of satellite nodules, invasion of adjacent tissues, infection or atelectasis, and regional lymph node involvement. However, CT scan alone is insufficient for lymph node staging.²³ Chest CT scan may also assist in distinguishing pleural and pericardial masses and effusions, contralateral lung lesions, and metastases. Intravenous contrast assists both in the delineation of hepatic and adrenal lesions and in the differentiation of mediastinal and hilar lymph nodes from blood vessels.

Positron emission tomography (PET) using 18-fluoro-2-deoxyglucose (FDG) is another common noninvasive method of examining lung cancer patients. Its use helps reduce the risk of patient understaging. Metabolic uptake of FDG, suggesting intense hypermetabolic activity, is displayed as a bright image on PET scan and is suspicious for malignancy. It is important to remember that other causes of intense hypermetabolism such as infection or an area of healing tissue, such as a healing operative site, will cause false positive findings. In contrast, small malignant foci may yield false negative findings on PET scan.^23,24 Physiologic uptake of FDG, such as in the gastrointestinal tract, genitourinary tract, brain, and heart, reduce PET scan precision in those areas. Currently, combined PET/CT scans are used for lung cancer patients to maximize sensitivity and specificity.^24,25 For examination of possible intracranial tumors, magnetic resonance imaging (MRI) scan is useful.

Current lung cancer screening programs are based on low-dose computed tomography (LDCT) performed on patients who meet specific criteria. ’Hiey must be aged 55 to 77, have at least a 30-pack year smoking history, and be either current smokers or previous smokers who have quit within the past 15 years.^26,27 the National Cancer Institute’s National Lung Screening Trial reported a 20% relative reduction of mortality from lung cancer with LDCT screening.²⁸

Lung Cancer Staging, Prognosis, and Traditional Therapy

Staging

Clinical staging is used as an initial assessment of lung cancer tumor burden and extent; however, the pathologic tumor, node, metastasis (TNM) stage is most important for determining the best treatment options for lung cancer patients. Pathologic staging of lung cancer is critical because staging indicates prognosis and determines treatment.^29,30 Incorrect or incomplete staging could prevent lung cancer patients from receiving potentially curative therapy. Stage IA, IB, IIA, and IIB NSCLC patients may be candidates for potentially curative surgery, whereas stage IIIA, IIIB, and IV patients are typically candidates for various forms and combinations of chemotherapy and radiotherapy.³¹ With small cell carcinoma, surgery is rarely an option; however, staging assists in determining whether chemotherapy along with radiotherapy or chemotherapy alone is the appropriate treatment.³² the College of American Pathologists’ Protocol for the Examination of Specimens From Patients With Primary Non-Small Cell Carcinoma, Small Cell Carcinoma, or Carcinoid Tumor of the Lung (based on American Joint Cancer Committee [AJCC]/Union for International Cancer Control [UICC] TNM, 7th edition) is a useful online resource for staging lung cancer.³³

Prognosis

The 5-year survival rate for patients with stage IA NSCLC is approximately 50%, and for stage IB patients it is approximately 45%. Stage IIA and IIB patients have a 5-year survival rate of approximately 30%. Stage IIIA lung cancer patients’ 5-year survival rate is approximately 14%, and the 5-year survival rate for stage IIIB patients is approximately 5%. Stage IV lung cancer patients have a 5-year survival rate of approximately 1%.³⁴

Traditional Therapy

Traditional lung cancer therapies include surgery, chemotherapy, and radiotherapy. For surgery to be potentially successful in lung cancer patients, the surgery must be appropriate based on evidence-based medical literature, the surgery must be technically feasible, and the patient must be fit enough to tolerate the surgery. Potential surgeries include wedge resection, segmentectomy, lobectomy, and pneumonectomy. Lymph node sampling is also frequently performed at surgery for pathologic staging purposes. In patients with direct chest wall extension, chest wall resection may be appropriate. Palliative resections are rarely indicated because of their significant morbidity; however, palliative resection may be appropriate in patients with massive hemoptysis or superinfection in necrotic tumors.

Chemotherapy has a primary therapeutic role in patients with Stage II and IIIA NSCLCs. Current trials are examining the role of adjuvant chemotherapy as an addition to molecular-based therapy and immunotherapy.

External beam radiotherapy plays a major role in therapy for patients with stage III and IV lung cancer. In patients with marginally resectable tumor, radiotherapy increases the chance for cure. For inoperable lung cancer patients, radiotherapy helps provide local control and increases median survival when combined with chemotherapy. In patients with advanced disease, radiotherapy often provides successful palliation.

Lung Cancer Histology

Overview of Lung Cancer Histology

Lung cancer is divided into two major categories based on histologic cell type: small cell lung cancers or SCLC (about 15% of lung cancers) and non-small cell lung cancers or NSCLC (about 85% of lung cancers). Traditionally, the NSCLC are further subdivided into three major histologic cell types: adenocarcinomas, squamous cell carcinomas, and large cell carcinomas. These cell types are diagnosed based on histologic and cytologic features that are observed on routine stains, such as hematoxylin and eosin (H&E) stain or Papanicolaou (Pap) stain, with additional diagnostic information from immunohistochemistry (IHC) stains or histochemical stains if needed. The histologic cell types are generally associated with related clinical, imaging, gross, molecular, prognostic, and therapeutic characteristics. SCLC is covered in another chapter, while this chapter focuses on NSCLC.

Before the 2015 World Health Organization (WHO) Classification of the Tumors of the Lung, Pleura, Thymus and Heart, and prior to trends in pathology practice that evolved over more than a decade before the 2015 classification, the frequency of the NSCLC cell types was approximately 50% for adenocarcinomas, 25% for squamous cell carcinomas, and up to 25% for large cell carcinomas. Based on the 2015 WHO Classification criteria and the previous developments leading up to the 2015 revisions, the cell type of large cell carcinoma has been reduced to no more than approximately 1% to 2% of NSCLC.^35-42

2015 World Health Organization Classification of Lung Cancer

Before the 2015 revision, the WHO classification of lung cancer was based on relatively stringent histologic features of surgically resected lung cancers observed on H&E stained slides. NSCLC with glandular (acinar), papillary, or lepidic architectural patterns on H&E stains were classified as adenocarcinomas. In addition, NSCLC with solid patterns that showed intracellular mucin in five or more tumor cells in each of two high-power fields, confirmed with mucin stains, were classified as solid pattern adenocarcinomas. NSCLC with keratinization and/or intercellular bridges on H&E stains were classified as squamous cell carcinomas. The remainder of NSCLC, up to 25%, which could not be classified by these relatively strict histologic criteria, were lumped together as large cell carcinomas. This latter cell type was sometimes referred to as a waste basket category, and electron microscopy studies showed that many of these tumors had ultrastructural features of adenocarcinomas and less often squamous cell carcinomas.^35,36

The treatment strategies for SCLC have differed from the treatment strategies for NSCLC going back for several decades so that a diagnosis of SCLC versus NSCLC was a crucial determination by the pathologist for many years. However, until approximately the mid-2000s, diagnosis of adenocarcinoma, squamous cell carcinoma, or large cell carcinoma was of less importance for therapy selection. ’tterefore, until approximately the mid-2000s, a diagnosis of carcinoma not otherwise specified (NOS) and, later NSCLC NOS, was considered a sufficient diagnosis for most small biopsy and cytology specimens if diagnostic criteria of a specific cell type were not observed. Diagnosis of NSCLC NOS on small biopsies and cytology specimens became an increasingly common practice in the 1990s and into the early 2000s. However, by the mid-2000s, differentiation of adenocarcinoma from squamous cell carcinoma was important to patient selection for several new therapies, including pemetrexed, bevacizumab, and tyrosine kinase inhibitors (TKIs).^39,43

Beginning in the latter 1990s and early 2000s, prior to these developments in lung cancer therapy, the diagnosis of adenocarcinoma and squamous cell carcinoma based on specific cell type markers using IHC (such as thyroid transcription factor 1 [TTF-1] for adenocarcinoma) became increasingly accepted. The diagnosis of adenocarcinoma or squamous cell carcinoma on the basis of IHC markers when strict histologic criteria were not met resulted in an increasing number of specific cell type diagnoses on small biopsies and cytology specimens in daily practice, although this technique was not yet officially mandated by the 2004 WHO Classification.^36,44-49 the 2015 WHO Classification recognized the new importance of a diagnosis of adenocarcinoma versus squamous cell carcinoma for selection of therapy, particularly on small biopsies or cytology specimens. There fore it emphasized the need to differentiate the specific cell types, including use of IHC when necessary, and to avoid a diagnosis of NSCLC NOS whenever possible for purposes of therapy.⁴² As noted previously, the daily practice of pathology was already moving in this direction.^38,39,50

Consequently, the 2015 WHO Classification resulted in changes in the criteria for diagnosing adenocarcinoma and squamous cell carcinoma compared with past editions to include IHC criteria. This resulted in new categories of adenocarcinoma and squamous cell carcinoma. ’Hiose NSCLCs formerly classified as large cell carcinomas that are immunoposi- tive for adenocarcinoma markers such as TTF-1 are now classified as adenocarcinomas with solid pattern, and those that are immunopositive for squamous cell carcinoma markers such as p40 are now classified as nonkeratinizing squamous cell carcinomas. In addition, all basaloid carcinomas are now incorporated under squamous cell carcinoma as basaloid squamous cell carcinoma, eliminating the large cell basaloid carcinoma subtype.⁴²

Along with reclassification of uncommon diagnoses previously included as subtypes of large cell carcinoma (large cell neuroendocrine carcinoma, basaloid carcinoma, and lymphoepithelioma-like carcinoma), the use of IHC criteria resulted in a significant decrease in the number of large cell carcinoma diagnoses from 10% to as much as 25% of NSCLC down to only about 1% to 2% of NSCLC. Only those NSCLCs that cannot be clearly diagnosed as adenocarcinoma or squamous cell carcinoma based on the new criteria are now included in the large cell carcinoma category. These residual cases consist mostly of large cell carcinoma with null immunohistochemical features. These are NSCLCs that are immunonegative for adenocarcinoma markers and immunonega- tive for squamous cell markers as well as negative for mucin. A lesser number of cases are large cell carcinoma with unclear immunohistochemical features (also negative for mucin) for which the immunostaining pattern for specific cell type markers is ambiguous as well as large cell carcinoma with no stains available (no IHC and no mucin stains). The clear cell variant and rhabdoid variant are no longer considered histologic variants of large cell carcinoma.⁴²

The incorporation of The 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) proposal for the classification of adenocarcinoma by the 2015 WHO Classification also introduces significant revisions over previous editions. These revisions include the elimination of the category of mixed subtype adenocarcinoma for invasive adenocarcinomas and replace it with classification of invasive adenocarcinomas by their predominant histologic subtype as lepidic predominant, acinar predominant, papillary predominant, micropapillary predominant, or solid predominant invasive adenocarcinomas. This new classification is more meaningful for prognosis and other purposes since over 90% of invasive adenocarcinomas have mixed subtype patterns making this former category largely unhelpful. The revisions also include the elimination of the term bronchioloaveolar carcinoma, which is replaced by adenocarcinomas in situ, minimally invasive adenocarcinomas, lepidic - predominant invasive adenocarcinomas, and, for the former mucinous variant, invasive mucinous adenocarcinomas.^38,42

In the following sections on lung cancer histology, we will describe the histologic features of NSCLC based on the 2015 WHO Classification.

Adenocarcinoma

Adenocarcinomas are the most frequent cell type of lung cancer and include preinvasive, minimally invasive, and invasive neoplasms. Several basic histologic patterns or cell subtypes are observed with adenocarcinomas: lepidic, acinar, papillary, micropapillary, and solid. Over 90% of individual lung cancer tumors have a mixed histologic pattern or combination of cell subtypes, but in the majority of cases, one cell subtype predominates. These cell subtypes are important to recognize for purposes of differential diagnosis. In addition, the cell subtypes have some prognostic implications, some imaging differences, and some associations with molecular alterations and biomarkers.^38,42,51-53

Lepidic Pattern and Bronchioloalveolar Carcinoma

Lepidic growth of neoplastic cells along the luminal surface of intact alveoli is observed as a major or minor histologic feature in a substantial number of invasive adenocarcinomas and is conceptually vital to preinvasive and minimally invasive adenocarcinomas. The lepidic growth pattern was central to the concept of bronchioloalveolar carcinoma for many decades and is the source of both diagnostic confusion and theories about the development and progression of pulmonary adenocarcinomas.^54-62

In 2013, Dr. Kirk Jones published the derivation of the term lepidic, which had become controversial itself.⁶¹ John George Adami, MD, was

The first to use the term lepidic (meaning a rind, skin, or membrane) in an address to the Toronto Pathological Society on January 4, 1902. He applied the term to tumors that appeared to be derived from surfacelining cells.^61,63 He also used the term in his Principles of Pathology published in 1908.^61,64 the modern use of the term lepidic as an alveolar growth of neoplastic cells along the surface of intact alveolar septa was introduced by Herbert Spencer in his classic textbook Pathology of the Lung, published in 1962.^61,65 By the 1990s and 2000s, authors erroneously attributed derivation of the term to the genus Lepidoptera, speculating a resemblance of the growth pattern to the scales or wings of butterflies. For further details, please see the excellent analysis by Dr. Jones.⁶¹

A lung cancer with an alveolar (lepidic) pattern was described by Malassez in 1876,^66,67 and a lung cancer with similar pattern was included in Ewing’s classic textbook Neoplastic Diseases in 1919.^66,67 the observation of cancer cells lining alveoli (in a lepidic pattern) without an associated bronchial origin of the cancer gave rise to the concept of a carcinoma arising from the pneumocytes of the alveoli, which is most often referred to as alveolar cell carcinoma.⁶⁶ Jaagsiekte, a retrovirus disease in sheep with proliferation of cancer cells in a lepidic pattern along alveoli surfaces, was considered an animal model for the human alveolar cell carcinoma.⁶⁸ Other terms were used to describe this entity including terminal bronchiolar carcinoma, bronchiolar carcinoma, pulmonary adenomatosis, and terminal bronchiolar carcinoma^69-73 before Dr. Avril Liebow popularized the term bronchioloalveolar carcinoma in 1960.⁵⁵ the 1970s and 1980s saw an increasing frequency of the diagnosis of bronchioloalveolar carcinoma which, as described in the subsequent paragraphs, included a wide range of entities with a lepidic component but otherwise differing features.^74-77

Lepidic growth was the key histologic feature of bronchioloalveolar carcinoma (although Dr. Liebow did not use the term lepidic in his publications), but the hypothesis that the cancer cells arose from peripheral epithelium such as type II pneumocytes, Clara cells, and bronchiolar epithelium gave rise to an abundance of scholarly articles.^{56-59,67,77,78} Since the cells of bronchioloalveolar carcinoma were presumably distinctive due to their unique origin, the ability to diagnose bronchioloalveolar carcinoma on the basis of cytologic features was widely accepted even though the lepidic growth pattern, otherwise important to the diagnosis, could not be observed on cytology specimens.⁶⁹

On the one hand, pure bronchioloalveolar carcinomas consisting only of tumor with lepidic pattern was very uncommon. However, lung cancers with varying degrees of bronchioloalveolar carcinoma as a component were frequent. The amount of lepidic growth around the periphery of tumors with acinar or other cell subtypes varied considerably, and a thin rim of bronchioloalveolar carcinoma around the margins of another adenocarcinoma cell subtype was often observed. Those tumors with a maj ority or substantial amounts of bronchioloalveolar carcinoma growing around the periphery were often classified with tumors of pure lepidic histology as bronchioloalveolar carcinomas.^56-60,78,79 First recognized in the late 1930s and early 1940s, so-called scar cancers consisted of a central scar typically with a bronchioloalveolar cancer around the margins.^80-85

The majority of bronchioloalveolar carcinomas were nonmucinous and peripheral, often subpleural, solitary lesions with a relatively good to excellent prognosis. A minority were mucinous bronchioloalveolar carcinomas that were more likely to be multifocal and even grow in a pneumonic fashion with poor prognosis. There fore, for over 50 years, the term bronchioloalveolar carcinoma was used to describe an assortment of different tumors that had in common some quantity of lepidic growth and features presumably attributable to origin from the alveolar or bronchiolar epithelium. It included purely lepidic cancers, mostly lepidic cancers and cancers with a majority or near majority lepidic component. It included most scar cancers that presented as solitary nodules. It included nonmucinous and mucinous tumors including mucinous tumors that spread through the parenchyma like pneumonias.35,37,38,42,56-60,78,79

Clinical and imaging correlates of these histologic features were equally confusing. Ground-glass pattern on CT scan was associated with bronchioloalveolar carcinoma, but, clearly, while most solitary tumors had a comparatively better prognosis than other cell subtypes, there were numerous exceptions.^86,87

It was obvious that lung cancers with differing histologies, differing clinical characteristics, and differing prognoses were classified under the term bronchioloalveolar carcinoma. The 1999 WHO classification attempted to rectify this situation by restricting the definition of bronchioloalveolar carcinoma to in situ adenocarcinoma and, thus, only purely lepidic tumors.³⁵ This definition was continued by the 2004 WHO classification.³⁶ With this strict definition, a diagnosis of bronchioloalveolar carcinoma on cytology or small biopsies could no longer be made, since invasion in an unsampled area could not be ruled out.^{35,36,51,88,89} However, the ambiguous use of bronchioloalveolar carcinoma to encompass many entities, which had been the practice for decades, remained in daily practice with many pathologists, radiologists, and oncologists.^50,78,89

The 2011 IASLC/ATS/ERS proposal for the classification of adenocarcinoma advocated eliminating the term bronchioloalveolar carcinoma altogether and replacing it with several precise entities.^38,51,52 This proposal was adopted by the 2015 WHO Classification and is the basis for current classification of lung cancers with a lepidic component.⁴²

Atypical Adenomatous Hyperplasia

Atypical adenomatous hyperplasia is a preinvasive lesion that is usually an incidental finding (<5 mm in most cases) discovered on microscopic examination of lung resections, particularly in lung cancer resections.⁴² the relationship of atypical adenomatous hyperplasia to adenocarcinoma is believed to be comparable to that of squamous dysplasia for squamous cell carcinoma.^90-93 It was originally conceived as a precursor of adenocarcinoma, analogous to the association between tubular adenomas and adenocarcinoma in the colon, and described as bronchioloalveolar adenoma by Dr. Roberta Miller.^94,95 Since There is no invasion, when completely excised, the 5-year survival rate for this lesion is 100%.⁴²

Lesions are usually 5 mm or less in size, but this is not an exact diagnostic criterion. The lesions are most often discovered within the parenchyma as incidental findings, and they may sometimes be observed as a faint, poorly defined yellow-tan nodule. Atypical adenomatous hyperplasia consists of dome-shaped to cuboidal to columnar epithelial cells with mild to moderate atypia growing in a lepidic pattern along intact alveolar septa. The alveolar septa are almost always thin and delicate without fibrosis or inflammation (Fig. 17.1).⁴²

The cytologic atypia is more uniform in atypical adenomatous hyperplasia than in most reactive pneumocyte hyperplasias and, in contrast, the epithelial proliferation is not overshadowed by the fibrosis and inflammation seen in a reactive process. Some lesions may be slightly more atypical or cellular than others. However, the degree of cellularity and cytologic atypia is generally less than that of adenocarcinoma in situ (AIS), which typically shows a more uniform moderate to high grade atypia.⁴²

Adenocarcinoma in situ

AIS is a preinvasive lesion and is defined as a small (<3 cm) solitary adenocarcinoma with pure lepidic (in situ) growth and no stromal, vascular, air space, or pleural invasion.^42,52,62 AIS is usually an incidental finding on CT scan where it classically appears as a small ground-glass opacity in the lung parenchyma. PET scan generally shows low activity in contrast to other types of lung cancer. Grossly, AIS is an ill-defined pale nodule or may grossly blend into the surrounding parenchyma, making it difficult to identify even when CT scan indicates its presence. Since There is no invasion, similar to atypical adenomatous hyperplasia, when completely excised, the 5-year survival rate for AIS is 100%.⁴²

Figure 17.1 High-power image of atypical adenomatous hyperplasia, showing domeshaped, cuboidal, or columnar epithelial cells lying in a lepidic pattern along thin alveolar septa.

The great majority of AIS are nonmucinous and were considered purely lepidic nonmucinous bronchioloalveolar carcinomas in past decades. Mucinous and mixed mucinous/nonmucinous AIS may occur and along with the minimally invasive and invasive mucinous adenocarcinomas described below were considered mucinous bronchioloalveolar carcinomas in past decades.^38,42,52,62

Nonmucinous AIS consists of cuboidal to columnar cells in a compact linear arrangement along intact alveolar septa. These cells have features of alveolar type II pneumocytes or Clara cells, but differentiation of these has no known clinical significance. The neoplastic cells display minimal atypia and are often described as bland and typically with a comparatively monotonous appearance from cell to cell for the individual tumor. The cells may have intranuclear inclusions or apical nuclei. The alveolar septa are often widened with fibrous tissue but are architecturally intact, and There is no distinct scar formation that would suggest invasion. Nonmucinous AIS is sharply demarcated from the surrounding alveolar parenchyma as a circumscribed lesion (Fig. 17.2).^38,42,52,62

This histology contrasts with reactive type II pneumocyte hyperplasia in which cells of varying degrees of reactive atypia are admixed together often with intermixed normal lining cells. This produces a variegated appearance as opposed to the generally homogeneous appearance of The neoplastic cells seen in AIS. With reactive hyperplasia, the fibrosis, perhaps accomp anied by inflammation or other features, overshadows the epithelial proliferation, particularly when viewing the entire section at low power, whereas with AIS the epithelial proliferation predominates over the septal widening. Reactive hyperplasia tends to blend into the surrounding alveolar parenchyma rather than having the sharp demarcation of AIS.^38,42,52,62

If There are any findings of invasion, including any acinar, papillary, micropapillary, solid or variant pattern, or individual infiltrating cells within adjacent desmoplastic tissue, vascular invasion, lymphatic invasion, pleural invasion, metastasis, or air space invasion including aerogenous spread or spread through airspaces (STAS), the tumor is not AIS. To exclude the possibility of invasion, the entire lesion should be examined. There fore a diagnosis of AIS cannot be rendered on a small biopsy or cytology specimen since the failure to sample foci of invasion cannot be excluded.⁴²

Figure 17.2 Medium-power image of nonmucinous adenocarcinoma in situ, showing consists of bland cuboidal to columnar cells lining widened, fibrous alveolar septa. There is no invasion.

Figure 17.3 Medium-power image of nonmucinous minimally invasive adenocarcinoma, showing a lepidic component on the left, exhibiting the same histologic features as nonmucinous adenocarcinoma in situ, and an invasive component on the right, exhibiting a focus of acinar subtype adenocarcinoma.

As noted, a minority of AIS are mucinous tumors. These are 3 cm or less solitary tumors that consist of a linear arrangement of cells with apical mucin and small basal nuclei lining intact alveolar septa that are typically thin and delicate as opposed to the widened septa most often seen with nonmucinous AIS. These tumors were once included with the mucinous bronchioloalveolar carcinomas, but it is now recognized that most of the mucinous bronchioloalveolar carcinomas were invasive cancers. Mucinous adenocarcinomas that are truly in situ have the same implications as the more frequent nonmucinous AIS. Occasional AIS may have mixed features of nonmucinous and mucinous cells.⁴²

Minimally Invasive Adenocarcinoma

Minimally invasive adenocarcinoma (MIA) is defined as a small (<3 cm) solitary adenocarcinoma with predominantly lepidic (in situ) growth and an invasive component that is 5 mm or smaller in greatest dimen- sion.^{38,42,52,60,62} Similar to AIS, MIA is usually an incidental finding on CT scan where it appears in the peripheral lung parenchyma. Classically, on CT scan, a ground-glass opacity with a solid component represents a lepidic tumor with invasion. Grossly, MIA resembles AIS but has a small solid focus or foci representing the invasive component. Similar to atypical adenomatous hyperplasia and AIS, when completely excised, the 5-year survival rate for MIA is 100%.⁴²

Similar to AIS, the majority of MIA are nonmucinous and a few cases are mucinous. The lepidic component of MIA, which makes up 95% of the tumor, has the same histologic features as nonmucinous (or occasional mucinous) AIS. The invasive component of MIA can consist of a single focus that is 5 mm or less in greatest dimension or the sum of several foci that are 5 mm or less in greatest dimension. By definition, the invasive component consists of a histologic subtype other than lepidic (in situ), including acinar, papillary, micropapillary, solid, or a variant or tumor cells infiltrating a myofibroblastic stroma (Fig. 17.3). MIA should have no lymphatics, blood vessel, air space or pleural invasion, no tumor necrosis, and no STAS.⁴²

Invasive Adenocarcinoma

The majority of adenocarcinomas and, hence, the majority of lung cancers are invasive adenocarcinomas. As described in the section on staging, about 70% of invasive adenocarcinomas present in advanced disease stages, and the only tissue samples are small biopsies and cytology specimens with resection reserved primarily for the less common early stage tumors.^38,42,50-53 On CT scan, adenocarcinoma is most often a nodule or mass in the peripheral lung parenchyma, but exceptions occur. Most are solid, indicating an invasive tumor, and the presence of ground-glass opacity around the periphery suggests a lepidic (in situ) component. Calcifications may be seen, but cavitation is not characteristic of invasive adenocarcinoma, although, again, exceptions may occur. Invasive adenocarcinomas show high activity on PET scan.⁴²

Over 90% of invasive adenocarcinomas are histologically heterogeneous with mixed subtype patterns on microscopic examination.^38,42 This is primarily noted on resection specimens where There is the opportunity to sample the tumor more extensively. It may not be apparent on the limited sample provided by a small biopsy or cytology specimen. One of the histologic patterns or subtypes often predominates. The 2015 WHO Classification recognizes several histologic subtypes or patterns of invasive adenocarcinomas (lepidic, acinar, papillary, micropapillary, and solid) and some additional histologic variants (invasive mucinous, colloid, fetal, and enteric). Any of these subtypes or variants can be the predominant pattern of an invasive adenocarcinoma. They may also be seen as a minor component of an invasive adenocarcinoma in which one of the other patterns is the predominant pattern.³⁸

Lepidic Adenocarcinoma

Invasive adenocarcinomas may display a component that is nonmucinous lepidic or in situ. If a nonmucinous lepidic pattern composes a majority of the tumor but There is more than 5 mm stromal invasive component (exceeds the definition of MIA) or other features of invasion, the tumor is a lepidic invasive adenocarcinoma. In addition to the amount of stromal invasive component (>5 mm), other features of invasion also separate invasive lepidic adenocarcinomas from MIA including tumor necrosis, invasion of the lymphatics, blood vessels and/or pleura, and aerogenous spread or STAS in contrast to MIA.^38,42,50-53

The invasive component may consist one of the other histologic patterns (acinar, papillary, micropapillary, solid, colloid, fetal, enteric) or of tumor cells infiltrating the stroma. The majority component consists of a noninvasive lepidic growth along intact alveolar septa, with the neoplastic cells either resembling bland cells of AIS as described previously or showing the same atypia as the invasive component (Fig. 17.4). While it is tempting to speculate that those cases with bland AIS-like cells represent a different pathogenesis from those cases with higher grade atypia similar to the invasive component, this has not been proven and any clinical implications are currently unknown. Tumors that have a predominantly mucinous lepidic component are separately classified as invasive mucinous adenocarcinoma discussed below.⁴²

Figure 17.4 Low-power image of lepidic adenocarcinoma, showing adenocarcinoma of which the majority component consists of a noninvasive lepidic growth along intact alveolar septa, with an area of acinar growth on the left.

Figure 17.5 High-power image of acinar adenocarcinoma, showing tumor composed of glands lined by cuboidal and columnar malignant cells.

Acinar Adenocarcinoma

Acinar adenocarcinomas are invasive adenocarcinomas with a majority of the tumor composed of glands lined by malignant cells that may be oval, cuboidal, or columnar. From tumor to tumor, and variably within tumors, glands may be of different sizes and shapes, including small round glands, glands with larger oval lumens, and glands with more complex patterns such as cribriform pattern. Acinar adenocarcinoma cells and/or the lumens of the glands may display mucin, which can be confirmed on histochemical stains such as mucicarmine, Alcian blue, and periodic acid-Schiff with digestion (Fig. 17.5).⁴²

Papillary Adenocarcinoma

Papillary adenocarcinomas are invasive adenocarcinomas with a majority of the tumor composed of malignant glandular cells growing along the surface of papillary fibrovascular cores. The presence of fibrovascular cores helps distinguish papillary from micropapillary adenocarcinoma. When the papillary pattern is present, it is not a requirement to document stromal invasion to make the diagnosis (Fig. 17.6).⁴²

Micropapillary Adenocarcinoma

Micropapillary adenocarcinomas are invasive adenocarcinomas with a majority of the tumor composed of small cuboidal tumor cells arranged in papillary tufts or florets without fibrovascular cores. The tufts may be attached to alveolar walls or “floating” in the alveolar spaces detached from the walls, sometimes including small ring-like glands. Psammoma bodies may be present, and vascular and stromal invasion are often present. This cell subtype is associated with a poorer prognosis than other subtypes (Fig. 17.7).⁴²

Figure 17.6 Low-power image of papillary adenocarcinoma, showing malignant glandular cells growing along the surface of papillary fibrovascular cores.

Solid Adenocarcinoma

Solid adenocarcinomas are invasive adenocarcinomas with a majority of the tumor composed of solid sheets or nests of polygonal tumor cells without features of lepidic, acinar, papillary, or micropapillary growth (Fig. 17.8). If the tumor is purely solid, then demonstration of intracellular mucin in 5 or more tumor cells in each of two high power fields, confirmed with histochemical stains, is diagnostic of solid adenocarcinoma. Mucin-negative purely solid tumors that were once classified as large cell carcinomas but are positive for adenocarcinoma markers such as TTF-1 on IHC are now classified as solid adenocarcinomas.⁴²

Invasive Mucinous Adenocarcinoma

Invasive mucinous adenocarcinomas are usually peripheral and may have a variety of appearances on CT scan. In addition to presenting as masses on CT scan, these tumors are much more likely than other lung cancers to present as multifocal, multilobar, bilateral, or as consolidation.

Figure 17.7 High-power image of micropapillary adenocarcinoma, showing small cuboidal tumor cells arranged in papillary tufts or florets without fibrovascular cores.

Figure 17.8 High-power image of solid adenocarcinoma, showing a solid nest of polygonal tumor cells without features of lepidic, acinar, papillary, or micropapillary growth.

Grossly, they are soft, poorly circumscribed, mucinous masses and, as expected from imaging studies, may consist of multiple disseminated nodules or as a consolidated lobe mimicking a pneumonia.⁴²

Invasive mucinous adenocarcinomas are distinguished by their neoplastic cells, which are goblet cells or columnar cells with abundant apical mucin and small, bland, uniform basal nuclei. These neoplastic cells are typically immunopositive for CK7 and CK20 and immunonega- tive for adenocarcinoma markers such as TTF-1 and napsin A, in contrast to the neoplastic cells in most other adenocarcinomas. Invasive mucinous adenocarcinomas most often grow in a lepidic pattern and may require multiple sections to identify the invasive component(s), but they also grow in acinar, papillary, or micropapillary patterns. In contrast, they do not grow in solid patterns. The alveolar spaces are often filled with mucin and the neoplastic cells may be seen floating in strips or clusters within the mucin in addition to lining the intact alveolar septa (Fig. 17.9).^38,42,50-53

Figure 17.9 High-power image of invasive mucinous adenocarcinoma, showing alveolar spaces filled with mucin and neoplastic cells lining intact alveolar septa.

As noted previously, there are rare cases of mucinous AIS consisting of a small (<3 cm) solitary adenocarcinoma with pure lepidic (in situ) growth and no stromal, vascular, air space, or pleural invasion and rare cases of mucinous MIA consisting of a small (<3 cm) solitary adenocarcinoma with predominantly lepidic (in situ) growth and an invasive component that is 5 mm or less in greatest dimension. These rare mucinous AIS and mucinous MIA have neoplastic cells similar to those for invasive mucinous adenocarcinoma. These three patterns, mucinous AIS, mucinous MIA, and the much more frequent invasive mucinous adenocarcinomas, were once collectively labeled mucinous bronchioloalveolar carcinomas.^38,42,50-53

Colloid Adenocarcinoma

Colloid adenocarcinomas are a very uncommon tumor. They are peripheral and, on CT scan, may have a low-attenuation density and may appear as cysts with smooth borders. Grossly, colloid adenocarcinomas are well-demarcated, loculated, sometimes cystic, mucinous masses.^42,96

Colloid adenocarcinoma is an uncommon pattern in which pools of mucin distend alveolar tissue and rupture their walls. The mucin pools are lined by neoplastic well-differentiated columnar cells with apical mucin. The lining of columnar cells is often sporadic with significant gaps between strips of lining cells. The cells may also “float” in the mucin pools as strips or glands (Fig. 17.10). These columnar cells may be immunopositive for CDX2 and CK20 and show only weak or focal immunostaining for TTF-1 and CK7.^{38,42,51-53,96}

Fetal Adenocarcinoma

Fetal adenocarcinomas are uncommon, are characterized by their histologic resemblance to the pseudoglandular phase of fetal lung development, and may be low-grade or high-grade malignancies. On CT scan, they are usually peripheral nodules or masses. Grossly, they are typically well-circumscribed tumor masses.⁴²

Histologically, low-grade fetal adenocarcinomas consist of complex glands, tubules and papillae, myxoid stroma, and formation of squamous morules. The neoplastic cells are columnar with supranuclear and subnuclear clearing due to glycogen. The pattern has been described as reminiscent of low-grade endometrioid carcinoma in addition to the pseudoglandular phase of fetal lung development (Fig. 17.11).^38,42,50-53

Figure 17.10 Medium-power image of colloid carcinoma, showing mucin distending alveoli, with the mucin pools sporadically lined by neoplastic tumor cells, and strips and clusters of neoplastic cells "floating” in the mucin pools.

Figure 17.11 High-power image of well-differentiated fetal adenocarcinoma, showing complex glands, tubules and papillae, myxoid stroma, and a squamous morule.

High-grade fetal adenocarcinoma has greater cytologic atypia and necrosis and lacks the squamous morules. High-grade fetal adenocarcinoma pattern is typically associated with more conventional patterns ofinvasive adenocarcinoma, and the diagnosis is made when the high-grade fetal adenocarcinoma pattern is the predominant pattern.^38,42,50-53

Enteric Adenocarcinoma

Enteric adenocarcinomas are rare and are diagnosed when the predominant pattern in an invasive adenocarcinoma histologically resembles colorectal adenocarcinoma. Before a diagnosis of an enteric adenocarcinoma of the lung can be made, a primary colorectal adenocarcinoma should be excluded. The histology consists of a cribriform glandular pattern of columnar cells, possibly with necrosis, that closely resembles colorectal adenocarcinoma. Some cases also have an immunostaining pattern that mimics colorectal cancer with immunopositive CDX2 and CK20 and immunonegative CK7 (Fig. 17.12).^38,42,50-53

Figure 17.12 Medium-power image of enteric adenocarcinoma, showing tumor closely resembling colorectal adenocarcinoma.

Figure 17.13 High-power image of signet ring cell adenocarcinoma, showing a nest of neoplastic signet ring adenocarcinoma cells.

Signet Ring and Clear Cell Features

Adenocarcinomas may exhibit signet ring features (intracytoplasmic vacuole which pushes the nucleus to one side) or clear cell features. Previously, these features were considered variants, but should no longer be diagnosed as variants or subtypes, but, if observed, may be included in the diagnosis as features associated with a predominant subtype. Most adenocarcinomas with signet ring or clear cell features are solid adenocarcinomas, but these features may also be seen in other subtypes as well (Figs. 17.13 and 17.14).^38,42-50-53

Squamous Cell Carcinoma

In previous WHO Classifications, squamous cell carcinoma was defined by strict criteria as NSCLC that displayed keratinization, keratin pearl formation, and/or intercellular bridges on routine histologic stains such as H&E.^35,36 In addition to these keratinizing squamous cell carcinomas, the 2015 WHO recognizes that There are nonkeratinizing squamous cell carcinomas that are NSCLC that lack the histologic features mentioned above but which are immunopositive for squamous cell carcinoma markers particularly p40.⁴² These nonkeratinizing squamous cell carcinomas, similar to the solid adenocarcinomas diagnosed by immunopositivity for TTF-1, were formerly classified as large cell carcinomas in prior WHO classifications and, similarly, pathology practice had already begun the process of diagnosing these tumors on the basis of IHC (see Section on 2015 World Health Organization Classification of Lung Cancer). Basaloid carcinomas, which were previously classified as large cell carcinoma in prior WHO Classifications and divided between large cell and squamous cell carcinoma categories in recent WHO Classifications, are now all classified as basaloid squamous cell carcinomas.^42,97

Figure 17.14 Medium-power image of clear cell adenocarcinoma, showing nests of clear cell adenocarcinoma cells.

Figure 17.15 Gross image of squamous cell carcinoma, showing tumor arising from a large airway.

Traditionally, squamous cell carcinomas have been considered to be centrally located tumors (Fig. 17.15). They often arise from main or lobar bronchi, sometimes obstructing the bronchial lumens and leading to post-obstructive lipid pneumonia, acute and organizing pneumonia, and/or atelectasis. Large bulky tumors with cavitation due to central necrosis are most likely to be squamous cell carcinomas. Although the central location is classic, there are ample exceptions, and many squamous cell carcinomas may arise from the periphery of the lung.⁴²

Figure 17.16 High-power image of squamous cell carcinoma, showing tumor exhibiting intracellular bridges.

Figure 17.17 High-power image of squamous cell carcinoma, showing a keratin pearl.

Histologically, the more differentiated the squamous cell carcinoma, the more keratinization that is conspicuously present. Classic keratinizing squamous cell carcinoma of the lung is usually only moderately differentiated, but There is a spectrum. Classic keratinizing squamous cell carcinomas of the lung consist predominantly of sheets or nests of polygonal cells with abundant to moderately abundant pink to clear cytoplasm, generally crisp cell borders, and vesicular nuclei with prominent nucleoli or hyperchromatic nuclei. There are foci or areas of conspicuous keratinization of tumor cells admixed within the nests of polygonal cells as described above. Those cells that are keratinizing cells show dense pink cytoplasm with small hyperchromatic nuclei. Cells with keratinized cytoplasm without nuclei may be whorled together in keratin pearls. Intercellular bridges may be observed under high power as thin lines in the spaces between cells (Figs. 17.16 and 17.17).^42,97

Many squamous cell carcinomas are nonkeratinizing and consist generally of sheets or nests ofpolygonal cells that require immunopositivity for squamous cell carcinoma markers, particularly p40, for confirmation of the diagnosis. The degree to which the histologic features suggest the nonkeratinizing component of a classic keratinizing squamous cell carcinoma varies from tumor to tumor with some tumors, suggesting a poorly differentiated nonkeratinizing squamous cell carcinoma and others having purely undifferentiated NSCLC by histology.^42,97

Basaloid squamous cell carcinoma consists of relatively small cells with hyperchromatic nuclei and relatively scant cytoplasm resulting in a high nucleus to cytoplasm ratio. The cells are arranged in lobules, trabeculae, or rosettes with peripheral palisading and a hyaline or mucoid stroma (Fig. 17.18). The overall histology is reminiscent of basal cell carcinoma of the skin. Mitoses are usually numerous, and necrosis may be present. This histology may be mixed with a keratinizing or nonkeratinizing squamous cell carcinoma component. In such cases, if more than half of the tumor is basaloid histology, the tumor is considered a basaloid squamous cell carcinoma. Basaloid squamous cell carcinomas are immunopositive for squamous cell carcinoma markers such as p40. Neuroendocrine tumors may also be in the histologic differential diagnosis. The great majority of basaloid squamous cell carcinomas are immunonegative for neuroendocrine markers, although occasional cases are immunopositive.^42,97

In the 2004 WHO Classification, squamous cell carcinomas were subtyped by architectural and cytologic features to include papillary, clear cell, small cell, and basaloid variants.³⁶ Except for the basaloid pattern just described, these variants are no longer separated and are considered features that may be seen with squamous cell carcinomas.⁴²

Mild, moderate, and severe squamous dysplasia and squamous cell carcinoma in situ are considered to be a spectrum of precursor and preinvasive lesions in the pathogenesis from normal bronchial mucosa to invasive squamous cell carcinoma of the lung. Лю increasing degrees of histologic atypia are analogous to similar histologic changes preceding invasive squamous cell carcinomas in other organs. These changes may be seen in bronchial mucosa not associated with an invasive malignancy or in bronchial mucosa in which There is an invasive malignancy. The changes are often multifocal in the airway mucosa due to the “field effect” of carcinogens since the entirety of the airway mucosa is exposed to tobacco smoke or other carcinogens. Dysplasia or carcinoma in situ may be contiguous, adjacent to, or separated from the invasive squamous cell carcinoma.⁴²

Adenosquamous Carcinoma

Adenosquamous carcinoma is an uncommon form of NSCLC that is composed of at least 10% adenocarcinoma mixed with at least 10% squamous cell carcinoma. The adenocarcinoma component and the squamous cell component can consist of any of the subtypes of the respective component. The components may exist side by side in the same tumor or be intermixed within the same tumor (Fig. 17.19). Each component should display the corresponding immunostain markers such as TTF-1 for adenocarcinoma, including the solid subtype and p40 for squamous cell carcinoma, including the nonkeratinizing subtype. These immunostains can further confirm the adenosquamous phenotype. Since the adenocarcinoma component is reported to retain response to targeted therapies for adenocarcinoma, it is important to diagnose the adenocarcinoma component even when it is less than 10% and There fore does not meet the full criteria for an adenosquamous carcinoma.⁴²

Large Cell Carcinoma

The diagnosis of large cell carcinoma is a diagnosis of exclusion. Large cell carcinoma is an undifferentiated NSCLC that lacks histologic features diagnostic of an adenocarcinoma, squamous cell carcinoma, or small cell carcinoma; lacks mucin staining diagnostic of adenocarcinoma; and lacks immunostaining results diagnostic of an adenocarcinoma, squamous cell carcinoma, or small cell carcinoma (Fig. 17.20). To completely exclude a diagnosis of adenocarcinoma, squamous cell carcinoma, or small cell carcinoma, a resection specimen must be thoroughly sampled. ’Лю diagnosis of large cell carcinoma cannot be made on a small biopsy or cytology specimen since the sample is not sufficient to exclude an adenocarcinoma, squamous cell carcinoma, or small cell carcinoma.^42,97

Large cell carcinomas consist of sheets or nests of polygonal cells with moderately abundant cytoplasm and vesicular nuclei with prominent nucleoli. As noted, they lack histologic, histochemical, and immunohistochemical features diagnostic of the other specific cell types. Most of these tumors are large cell carcinoma with null immunohistochemical features which are negative for adenocarcinoma immunostain markers such as TTF-1 and negative for squamous cell immunostain markers such as p40, as well as negative for mucin. Less commonly, depending on circumstances, a diagnosis of large cell carcinoma with unclear immunohistochemical features (also negative for mucin) when the results of the immunostains are ambiguous or large cell carcinoma with no stains available (no immunostains and no mucin stains available for review) may be made.^42,97

Figure 17.18 High-power image of basaloid squamous cell carcinoma, showing a solid lobule containing tumor cells exhibiting peripheral palisading.

Figure 17.19 Low-power image of adenosquamous carcinoma, showing squamous cell carcinoma at the top and adenocarcinoma at the bottom.

Figure 17.20 High-power image of large cell carcinoma, showing a nest of undifferentiated non-small cell tumor cells without adenocarcinomatous or squamous differentiation.

Figure 17.21 Low-power image of carcinosarcoma, showing a tumor containing a mixture of osteosarcoma and poorly differentiated adenocarcinoma.

As noted previously, the inclusion of immunostain pattern for the diagnosis of adenocarcinoma and squamous cell carcinoma in the 2015 WHO Classification removed many tumors from the large cell carcinoma category to the solid adenocarcinoma and nonkeratinizing squamous cell carcinoma.^42,97 ’Hiese classification criteria were consistent with changes that had already occurred in the practice of pathology and the greatly reduced the number of lung cancers diagnosed as large cell carci- noma.^50,98-101 In addition, large cell neuroendocrine carcinoma, basaloid carcinoma, and lymphoepithelioma-like carcinoma are reclassified elsewhere and are no longer classified as subtypes of large cell carcinoma. Plus, since clear cell features and rhabdoid features are not restricted to large cell carcinomas, these are no longer considered histologic variants of large cell carcinoma.^42,97 As a result, large cell carcinoma is reduced from 10% to 25% of lung cancers in the past series to only 1% to 2% of lung cancers by the 2015 WHO Classification criteria.^42,50,97-101

Minor Cell Types (Including Salivary Gland and Sarcomatoid Types)

Sarcomatoid Type. The term sarcomatoid carcinoma includes carcinosarcoma, blastoma, and pleomorphic carcinoma.

Carcinosarcoma. Carcinosarcoma is a rare, smoking-related tumor with a male:female ratio of 8 : 1.¹⁰² Carcinosarcoma patients range in age at diagnosis from the late 4th decade to the early 9th decade with a median age of 65.^103,104 the tumor is aggressive, frequently presenting with distant metastases, and patients present clinically in a manner similar to other NSCLCs.¹⁰⁵ Radiographically, carcinosarcoma is frequently a centrally located mass. Prognosis is poor.

Grossly, carcinosarcoma is a white-gray hemorrhagic and necrotic mass. Sections show tumor containing a mixture of sarcoma and non-small cell carcinoma. The sarcomatous portion is usually rhabdomyosarcoma, chondrosarcoma, osteosarcoma, or a combination of those.¹⁰³ the carcinomatous portion is typically squamous cell carcinoma; however, adenosquamous carcinoma may occur, and adenocarcinoma occurs in a smaller number of cases (Fig. 17.21).^106,107 Metastases may contain either sarcoma, carcinoma, or both. Almost 20% of carcinosarcomas contain a clear cell or high-grade fetal adenocarcinoma pattern.¹⁰³

Immunostains are frequently not necessary; however, they can be used to highlight the carcinomatous and sarcomatous portions of the tumor.^102,106,108 Differential diagnosis includes pleomorphic carcinoma, metastatic sarcoma, and blastoma. Molecular studies show many tumors to contain TP53 mutations, while epidermal growth factor receptor (EGFR) mutation is rare.

Blastoma. Pulmonary blastoma is extremely rare.¹⁰² Patients are typically smokers, diagnosed in the 5th decade, and have no gender predilection. Patient presentation is similar to that seen with other non-small cell carcinomas.^104,109 Pulmonary blastoma is an aggressive tumor, frequently presenting with distant metastases. Prognosis is poor.

Grossly, pulmonary blastomas are typically large, well-circumscribed peripheral tumors that often contain necrosis, hemorrhage, and lobula- tion.¹⁰⁹ Sections show variable degrees of epithelial and mesenchymal tumor. The epithelial portion is composed of low-grade fetal adenocarcinoma, showing branching tubules lined by pseudostratified columnar epithelium, often with morules. The mesenchymal portion is made up of primitive oval cells with occasional bizarre giant cells. Up to a quarter of cases contain a sarcomatous portion such as rhabdosarcoma, chondrosarcoma, or osteosarcoma.^109-111

Immunostains show keratin positivity in the carcinomatous portion, as well as positivity with carcinoembryonic antigen and TTF-1. Tumors also show focal positivity with synaptophysin and chromogranin A. The mesenchymal portion shows positivity with muscle specific actin and vimentin, with only focal keratin positivity.^109,112-114

Differential diagnosis includes fetal adenocarcinoma, metastatic sarcoma, metastatic malignant mixed mülleriantumor, and biphasic synovial sarcoma.^106,108

Pulmonary blastoma frequently has missense mutations in exon 3 of CTNNB1, and well-differentiated fetal adenocarcinoma also often contains this feature.

Pleomorphic Carcinoma. Pleomorphic carcinoma is uncommon, making up less than 1% of lung cancers.¹¹⁵ the tumor is usually smoking- related. Patients typically present with a large peripheral upper lobe mass with pleural invasion.^116,117 Pleomorphic carcinomas are, as other NSCLCs, aggressive neoplasms, often exhibiting distant metastases. Prognosis is poor regardless of stage of disease at diagnosis.

Grossly, pleomorphic carcinoma shows a gray-tan well-circumscribed cavitated or necrotic mass with a gelatinous cut surface. The tumor is usually larger than 5 cm, and sections show a spindle cell or giant cell component, or both, making up 10% or more of the tumor. This component is admixed with tumor showing carcinomatous differentiation, predominantly adenocarcinoma; however, squamous cell carcinoma may be present in up to a quarter of the tumors. A large minority contain otherwise undifferentiated non-small cell carcinomatous tumor (Fig. 17.22).^118-120

Figure 17.22 Medium-power image of pleomorphic carcinoma, showing sections with a giant cell component admixed with undifferentiated non-small cell carcinomatous tumor.

Figure 17.23 Low-power image of adenoid cystic carcinoma, showing tumor with cribriform and tubular patterns.

Spindle cell carcinoma is an extremely rare pleomorphic carcinoma that is entirely or almost entirely composed of spindle cells with no carcinomatous differentiation identified. Giant cell carcinoma is an extremely rare pleomorphic carcinoma containing only tumor giant cells, including multinucleated giant cells, with no carcinomatous differentiation identified.^102406418420

Differential diagnosis includes metastatic sarcoma and metastatic melanoma, as well as metastatic sarcomatoid carcinoma. Although immunostains are not generally necessary for the diagnosis of pleomorphic carcinoma, they may assist in differential diagnosis in less than straightforward cases.

Molecular studies confirm sarcomatoid change in the carcinoma. Molecular testing of the carcinomatous tumor is necessary as per lung cancer biomarker testing guidelines.

Salivary Gland Type. The salivary gland type lung carcinomas are uncommon, making up less than 1% of lung cancers. They have no correlation to smoking and have no gender predilection. ’Hiey typically arise within the large airways.

Adenoid Cystic Carcinoma. Adenoid cystic carcinoma typically presents, at an average age of 50 years, with cough, wheezing, and hemoptysis. Tumors often are large and obstruct the airway. ’Hiey exhibit infiltrative growth and may extend into lung parenchyma or mediastinum. Local recurrence is frequent, often due to the tumor’s propensity for perineural invasion.^121,122 Radiographically, a PET-positive central airway mass is typically identified.¹²³

Grossly, adenoid cystic carcinoma is a gray-white well-circumscribed mass with a generally homogeneous cut surface. It often shows infiltrative growth grossly. Sections show cribriform, tubular, and solid tumor patterns with small cells containing scant cytoplasm and uniform hyperchromatic nuclei. The tubular structures have a peripheral myoepithelial cell layer. Surrounding hyalinized or myxoid stroma is characteristic (Fig. 17.23). Usually perineural invasion is obvious.¹²⁴ In cases that are not obvious, immunostains are helpful in differentiating adenoid cystic carcinoma from other tumors such as basaloid squamous cell carcinoma, small cell carcinoma, and carcinoid tumor. Calponin, actin, and p63 are typically positive in adenoid cystic carcinoma.

Adenoid cystic carcinomas are typically indolent tumors; however, they frequently recur locally. Patients may exhibit multiple recurrences over 1 to 2 decades. Distant metastases are usually a late feature. Solid growth pattern, positive surgical margins, and distant lymph node metastases portend a poor prognosis.

Unlike its head and neck counterpart, pulmonary adenoid cystic carcinoma does not exhibit a fusion of the MYB oncogene and nuclear factor I/B (NFIB) transcription factor.^125,126

Mucoepidermoid Carcinoma. Mucoepidermoid carcinoma can present at any age; however, many cases arise in patients under 30 years of age. The average age period for this tumor to arise is in the 4th decade.^121,127 Patients often present with cough and wheezing. Some patients may have hemoptysis. Patients may have obstructive pneumonia. Some patients are identified incidentally and are without symptoms.^121,127 Radiographically, mucoepidermoid carcinoma typically is identified as a well-circumscribed, PET-positive endobronchial mass.¹²⁸

Grossly, mucoepidermoid carcinoma is a soft, well-circumscribed pink-tan to gray-white endobronchial mass with a variably cystic cut surface.^129,130 Mucoepidermoid carcinoma averages 3 cm. Tumor may involve lymph nodes via metastasis or direct extension.^121,127

Mucoepidermoid carcinoma may be either low grade or high grade; low-grade tumors are the most common. High-grade mucoepidermoid carcinomas are rare and must be distinguished from adenosquamous carcinoma. Low-grade mucoepidermoid carcinoma contains squamoid cells, intermediate cells, and mucin-secreting cells, typically with solid and cystic areas. The cystic areas are lined by uniform columnar cells containing mucin, and the solid areas contain squamoid and oval or polygonal intermediate cells. Mucin extravasation may cause a granulomatous reaction. High-grade mucoepidermoid carcinomas usually show a transition from low-grade to high-grade tumor, no single-cell keratinization or squamous pearl formation, and an exophytic endobronchial growth pattern. Immunostains show Napsin-A and TTF-1 negativity (Fig. 17.24).

Lymph node metastases and positive surgical margins portend a poor prognosis; however, most low-grade mucoepidermoid carcinomas have a good prognosis. High-grade mucoepidermoid carcinomas are prognostically similar to other NSCLCs.^121,127

Figure 17.24 High-power image of low-grade mucoepidermoid carcinoma, showing groups of intermediate cells and mucin-secreting cells.

Figure 17.25 Medium-power image of lymphoepithelioma-like carcinoma, showing nests of tumor cells surrounded by a marked lymphocytic infiltrate.

Mucoepidermoid carcinomas contain an exclusive MAML2 rearrangement; and many tumors, especially low-grade tumors, contain a fusion gene CRTC1-MAML2, which is a potential biomarker.¹³⁰

Epithelial-Myoepithelial Carcinoma. Epithelial-myoepithelial carcinoma usually arises between ages 30 and 70, with an average age of 50. Patients typically present with cough, dyspnea, and fever. Epithelial- myoepithelial carcinoma grossly exhibits a well-circumscribed gray-white endobronchial mass.^131,132

Sections show variable amounts of two cell types—epithelial cells and myoepithelial cells—arranged in a glandular pattern. The epithelial cells are cuboidal with uniform nuclei and eosinophilic cytoplasm, and the myoepithelial cells usually have clear cytoplasm. The myoepithelial cells may grow in a solid pattern and may predominate. Epithelial- myoepithelial carcinoma may extend into lung parenchyma and chest wall and may metastasize to lymph nodes.

Immunostains show epithelial cell positivity with keratin and myoepithelial cell positivity with S100 and actin.^133,134

Differential diagnosis includes adenoid cystic carcinoma and mucoepidermoid carcinoma, as well as clear cell tumors of the lung and metastatic renal cell carcinoma.

Epithelial-myoepithelial carcinoma is typically indolent, and surgery is often curative; however, tumors may recur and may metastasize.^132,135 Few molecular studies of pulmonary epithelial-myoepithelial carcinomas exist, and KRAS and EGFR gene mutations have not been identified.¹³⁶

Lymphoepithelioma-Like Carcinoma. Lymphoepithelioma-like carcinoma is extremely rare and is usually found in middle-aged nonsmoking Southeast Asian women.¹³⁷ the tumor is typically identified incidentally; however, some patients may exhibit cough. Some patients show typical lung cancer symptoms such as chest pain, hemoptysis, and weight loss.¹³⁷ Radiographically, lymphoepithelioma-like carcinoma usually appears as a discrete peripheral lesion similar to those seen with other non-small cell carcinomas.¹³⁸ the tumor spreads in a manner similar to other NSCLCs; however, prognosis is better. Complete resection may be curative.^137,139 Almost 90% of patients are alive at 2 years post diagnosis; and approximately two thirds are alive at 5 years.

Grossly, lymphoepithelioma-like carcinoma is a single round or ovoid well-circumscribed, rubbery, pink-white mass with a “fish flesh” appearance on cut section.¹⁴⁰ Sections show a syncytial pattern of tumor cells with large vesicular nuclei and prominent eosinophilic nucleoli surrounded by a marked lymphocytic infiltrate. Tumor nests tend to anastomose forming irregular nests and sheets (Fig. 17.25).^137,139 Immunostains show positivity with keratins p63, p40, and CK5/6. Differential diagnosis includes metastatic nasopharyngeal carcinoma and non-Hodgkin lymphoma. EGFR and KRAS mutations are not characteristic of lymphoepithelioma-like carcinoma.¹³⁷

Nuclear Protein in Testis Carcinoma. Nuclear protein in testis (NUT) carcinoma is extremely rare. It has no gender, racial, or age predilection and is not associated with smoking.^141,142 NUT carcinoma typically presents as late stage disease, and patients often present with cough, dyspnea, pleural eflusion, chest pain, and weight loss.¹⁴³ the tumor is aggressive, and its rapid progression may be documented radiographically. Patients typically have disease too advanced for surgical therapy. Median survival is 7 months after diagnosis.¹⁴⁴

Macroscopically, NUT carcinoma shows a large, expansive, tan-white, widely necrotic mass invading chest wall or hilum.¹⁴⁵ Sections show sheets of undifferentiated cells that may contain foci of keratinization. Associated lung may show prominent type 2 pneumocyte hyperplasia.^146,147 Immunostain with monoclonal nuclear NUT antibody shows positivity in most of the tumor cells; however, other immunostaining patterns are inconsistent. Tumor cells may show immunopositivity the TTF-1, synaptophysin, or chromogranin.^145,146

Differential diagnosis includes other poorly differentiated malignant neoplasms, both primary and metastatic to the lung. Immunostains showing NUT expression is extremely helpful in differentiating these neoplasms. Molecular studies show a chromosomal translocation between the NUT gene (NUTM1) on chromosome 15q14 and a variety of other genes.¹⁴²

Cytology

A criterion for diagnosing NSCLC on small biopsy and cytology specimens was proposed in the 2015 WHO classification.¹⁴⁸ Preceding editions (1967, 1981, 1999, and 2004 WHO classifications) focused on the diagnostic features of malignancy observed in larger resection speci- mens.^97,149-152 These editions did not address the findings seen on small biopsy or cytology specimens, nor did they make recommendations on diagnostic terminology used in these samples. It is now recognized that the vast majority of lung cancers are diagnosed on small biopsy and cytology specimens, as many patients have inoperable diseases when they present. As such, a need existed for uniform diagnostic terminology on these samples. The goal behind terminology recommendations (Table 17.1) is to accurately subtype cancers so that appropriate therapeutic decisions can be made. It is important to note that only NSCLC terminology is addressed in the WHO classification for small biopsy and cytology specimens. In addition, certain tumors can only be definitively diagnosed on resection specimens due to tumoral heterogeneity and histologic characteristics required for diagnosis.

Adenocarcinoma

The cytologic features of adenocarcinoma can be extremely variable because a variety of histotypes exist and tumor heterogeneity is typical. Background features can include necrosis and/or mucin. The cells are cuboidal to columnar in shape and often maintain some degree of nuclear to cytoplasmic polarity (referring to basally situated nuclei) (Figs. 17.26 and 17.27). The cytoplasm can be relatively homogeneous, foamy to vacuolar, or contain mucin. Some tumors have a large cytoplasmic vacuole that peripherally displaces the nucleus (signet ring morphology). The nuclei are often enlarged, open, and often contain a prominent nucleolus. Chromatin features include irregular clumping and hyperchromasia; however, the chromatin alterations are less pronounced compared with those seen in squamous cell carcinoma.

The architectural pattern and cell-to-cell organization can be particularly helpful in identifying adenocarcinoma, as the cells are often arranged in three-dimensional groups (Fig. 17.28), papillary clusters, or acinar structures. The 2015 WHO proposes that an identifiable pattern can be stated when present; it is important to realize that often significant tumoral heterogeneity exists and patterns observed on cytology may not correlate with the predominant pattern seen histologically on larger resection specimens. As such, the terminology used for cytology specimens includes adenocarcinoma with lepidic pattern (Fig. 17.29) or adenocarcinoma with colloid features. Certain cytomorphologic findings are/can be more so associated with certain subtypes of adenocarcinoma. For example, lepidic pattern tumors can have nuclear grooves and inclusions. Micropapillary variants may contain numerous small rounded clusters of malignant cells.

Figure 17.26 Romanowsky stain of adenocarcinoma showing columnar cells with foamy cytoplasm forming an acinar structure. The cells maintain some degree of nuclear to cytoplasmic polarity.

Table 17.1 2015 WHO Terminology

Cytology (and Small Biopsy Terminology)	Cytomorphologic Findings and Staining Patterns	Resection Specimen Terminology
Adenocarcinoma (architectural patterns can be discussed as applicable) Adenocarcinoma with lepidic pattern (comment that invasion cannot be excluded if pure lepidic pattern is seen) Invasive mucinous adenocarcinoma (can comment on lepidic pattern if applicable) Adenocarcinoma with colloid features Adenocarcinoma with fetal features Adenocarcinoma with enteric features (consider clinical history and use immunostains to exclude metastasis)	Cytomorphology of adenocarcinoma clearly present	Adenocarcinoma (list predominate pattern: lepidic, acinar, papillary, solid, micropapillary) Adenocarcinoma in situ, minimally invasive adenocarcinoma, invasive adenocarcinoma with lepidic component Invasive mucinous adenocarcinoma Colloid carcinoma Fetal adenocarcinoma Enteric adenocarcinoma
Non-small cell carcinoma, favor adenocarcinoma	Defining cytomorphologic features absent, stains supportive of adenocarcinoma	Adenocarcinoma (list patterns)
Squamous cell carcinoma	Cytomorphologic findings of squamous cell carcinoma	Squamous cell carcinoma
Non-small cell carcinoma, favor squamous cell carcinoma	Defining cytomorphologic features absent, stains supportive of squamous cell carcinoma	Squamous cell carcinoma (given cytomorphologic features are absent, the predominate pattern may be nonkeratinizing)
Non-small cell carcinoma, with squamous and adenocarcinoma patterns present (comment that this may represent adenosquamous carcinoma)	Cytomorphologic findings of squamous cell and adenocarcinoma and/or positive adeno and squamous markers in two distinct cell populations	Adenosquamous carcinoma (providing both components are >10% of the tumor)
Non-small cell carcinoma, not otherwise specified	No defining cytomorphologic findings or staining pattern	Large cell carcinoma (unless a defining histotype is present after extensive tumor sampling)
Non-small cell carcinoma with sarcomatoid features (Define cell morphology; i.e., spindle cells and/or giant ceils. Comment if adeno or squamous cell carcinoma component is present)	Sarcomatoid features represented by giant cells and/or spindle cells. May or may not have an adeno or squamous cell carcinoma component	Spindle cell, giant cell, and/or pleomorphic carcinoma

Modified from Travis WD, Brambilla E, Noguchi M, et al. International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society international multidisciplinary classification of lung adenocarcinoma. J. Thorac Oncol. 2011;6(2):244-285.

Figure 17.27 Adenocarcinoma, with foamy cytoplasm, open nuclei, and centrally placed nucleoli.

Figure 17.28 Adenocarcinoma, with a three-dimensional structure in an aspirate from a lung lesion. The chromatin is clumped; however, the nuclei remain relatively open. Note the adjacent cellular necrosis (lower left side of image).

Figure 17.29 Cellular aspirate of adenocarcinoma with lepidic pattern, cellular aspirate. The cellular architecture suggests that the malignant cells are growing along alveolar septa.

Figure 17.30 Atypical adenomatous hyperplasia. The cytomorphologic findings of atypical adenomatous hyperplasia are virtually indistinguishable from low-grade adenocarcinoma. Only rare atypical cells were seen on cytology preparations.

AIS cannot be diagnosed on cytology specimens, as invasion cannot be excluded. If a pure lepidic pattern is seen, it is recommended to use the terminology adenocarcinoma with lepidic pattern, followed by a disclaimer stating an invasive component cannot be excluded.¹⁵³ Of note, atypical adenomatous hyperplasia (Fig. 17.30) is indistinguishable from well-differentiated adenocarcinoma or AIS on cytology specimens. Because this diagnosis rests on lesional size (<5 mm), correlation with radiographic (generally not visualized on imaging studies due to its small size) and clinical findings should be done whenever possible. One should always correlate microscopic findings with all available patient history, as carcinoma mimics can be encountered (i.e., reactive atypia [Figs. 17.31 and 17.32] and therapy effects). A benign neoplasm that can mimic adenocarcinoma is sclerosing pneumocytoma (Figs. 17.33 and 17.34). This is an extremely rare adenoma that can have a papillary, solid, and/or sclerotic architecture.^154,155 Cytologically, an epithelial and stromal component can be seen. The cells are typically bland; however, atypia and intranuclear cytoplasmic invaginations may be present. Both cell types express TTF-1; however, the epithelial cells are typically positive for cytokeratin markers, while the stromal cells are negative. Findings favoring adenocarcinoma include marked cytologic atypia, pleomorphism, prominent nucleoli, and necrosis.

Figure 17.31 Reactive atypia.

Figure 17.32 Reactive atypia. Reactive atypia can mimic carcinoma, the nuclei are open and centrally placed nucleoli are seen. This patient was diagnosed with methicillin- resistant Staphylococcus aureus and passed away in the days following this aspiration. Note the polynuclear cells within the atypical cell cluster. The cell block preparation shows the atypical cells adjacent to acute inflammatory cells.

Squamous Cell Carcinoma

The three hallmark histologic findings of squamous differentiation are keratinization, squamous pearl formation, and the presence of intracellular bridges (desmosomes). In the majority of cytologic specimens, squamous pearl formation and intracellular bridges are not appreciable, particularly when There is an absence of small cellular aggregates. As such, the main cytologic finding of squamous differentiation is keratinization. Keratin imparts a dense-refractile optical quality to the cytoplasm (Fig. 17.35), which reflects the presence of intracytoplasmic keratin filaments. This is often referred to as hard cytoplasm. On Pap-stained preparation, the color can range from red-orange to light blue. When interpreting color, it is important to exercise caution, as air-drying or multilayer cell groups can appear orange. Orange color on Pap stain is not specific for squamous differentiation, and all morphologic characteristics seen in the sample along with potential artifactual findings should be considered. Romanowsky stains often impart a blue hue to the cytoplasm, which appears similar to that of a robin’s egg. Sometimes, orangeophilic cells with dense cytoplasm and elongated cytoplasmic tails (tadpole cells; Fig. 17.36) are seen and are particularly helpful. However, the presence of keratinization is often quite focal and dependent on the differentiation and morphology of the tumor. ’Лю basaloid variant of squamous cell carcinoma (Fig. 17.37) tends to lack keratinization. The cells often have less cytoplasm, are small to medium in size, and have hyperchromatic nuclei. Areas reminiscent of nuclear molding can be seen; There fore small cell carcinoma and/or adenoid cystic carcinoma may be a consideration depending on the predominant cytomorphologic features.¹⁵⁶

Figure 17.33 Sclerosing pneumocytoma. Sclerosing pneumocytoma is a rare adenoma that can mimic adenocarcinoma. Epithelial type cells were the predominant cell type in this aspirate. Prominent nucleoli and background necrosis are absent.

Figure 17.34 Resection specimen of sclerosing pneumocytoma showing a sclerotic lesion composed of both epithelial and stromal type cells.

Metaplasia and reactive atypias can mimic carcinoma; There fore the patient’s history and background cytologic findings (i.e., infectious states, inflammatory background without necrosis, post lung transplantation, and diffuse alveolar damage, etc.) should be considered to avoid false positive diagnoses. Other features of squamous cell carcinoma in general include background necrosis, aggregates of cells that appear like flattened cellular “sheets,” and cells with dark pyknotic nuclei. The cellular sheets can be three-dimensional; however, they remain in a sheet like architectural pattern opposed to three-dimensional rounded clusters seen in adenocarcinoma. The cells often have distinct or rigid cytoplasmic boarders. Because the nuclei are typically small and hyperchromatic, nucleoli are rarely seen. The nuclear features typically differ from those seen in adenocarcinoma, which tends to have more open-enlarged nuclei with conspicuous nucleoli. These nuclear differences may result from the relative proportions of euchromatin to heterochromatin and/or the amount of DNA and basophilic nuclear proteins in the malignant cells.

Figure 17.35 Keratinizing squamous cell carcinoma. The keratin imparts a dense-refractile optical quality to the cytoplasm that reflects the presence of intracytoplasmic keratin filaments. The color can range from red-orange to light blue on Papanicolaou-stained preparations.

Figure 17.36 Keratinizing squamous cell carcinoma. An orangeophilic cell is seen with dense cytoplasm and an elongated cytoplasmic tail (tadpole cell).

Some cytologic samples display features of carcinoma; however, defining cytomorphologic features of squamous or adeno differentiation is lacking or is equivocal by light microscopy alone. In these situations, a limited staining panel is suggested. The objective is to be as specific as possible regarding the histotype while conserving as much material as possible for potential molecular testing.¹⁴⁸ the 2015 WHO classification recommends using one adenocarcinoma marker (e.g., TTF-1 by IHC) and one squamous marker (e.g., p40 or p63 by IHC). A mucin stain can be added to the panel if desired; however, it is not a necessity.¹⁴⁸ As such, a tumor with non-small cell morphology lacking defining light microscopic features of adenocarcinoma or squamous cell carcinoma with positive TTF-1 and negative p40 staining would be classified as non-small cell carcinoma, favoring adenocarcinoma (Fig. 17.38). Conversely, a TTF-1 negative, p40 positive tumor would be classified as non-small cell carcinoma, favoring squamous cell carcinoma. If both adeno and squamous features are present by light microscopy and/or evaluation with stains (TTF-1 and p40 positivity in different cells), the possibility of adenosquamous carcinoma can be suggested. Definitive diagnosis of adenosquamous carcinoma is reserved for resection specimens, as the tumor should have at least 10% of either component by definition.¹⁴⁸

Figure 17.37 Basaloid squamous cell carcinoma. Features of keratinization are lacking; however, the cells are arranged in a flattened sheet and the nuclei are small and hyperchromatic.

Figure 17.38 Thyroid transcription factor immunostain of non-small cell carcinoma, favor adenocarcinoma, showing strong nuclear positivity, supporting the diagnosis of adenocarcinoma.

When stains are used for classification, a comment should be made that stains were required to establish the diagnosis. Of course, other staining patterns and nuances can exist, and in some cases, a conclusive diagnosis is not possible. When a specific histotype cannot be favored or suggested, the diagnosis of non-small cell carcinoma NOS (Fig. 17.39) can be used. This term should be used sparingly and can be avoided in up to 90% of cases when using the suggested staining panel. The term non-small cell carcinoma is preferred over non-small cell lung carcinoma to leave open the potential for a metastatic lesion.¹⁴⁸ When the diagnosis of non-small cell carcinoma NOS is being considered, the patient’s clinical history should be closely examined and additional stains (e.g., cytokeratin markers, S100, CD45, ER, GATA3, and prostate markers) should be considered as applicable to exclude or suggest metastatic processes. The diagnosis of large cell carcinoma is reserved for resection specimens with non-small cell histology that lack a differentiated component after extensive tumor sampling. Cytologically, large cell carcinomas are typically cohesive and harbor overt malignant features with enlarged centrally placed nuclei and prominent nucleoli. Rhabdoid-like features have been described and characterized by cells with eccentrically placed nuclei. These tumors tend to be less cohesive¹⁴⁸ than nonrhabdoid tumors. Resection specimens will often show some area of squamous or adeno differentiation after extensive sampling.

Figure 17.39 Cytomorphologic features of non-small cell carcinoma not otherwise specified. Unfortunately, a cell block preparation was acellular. Because definitive features of adeno or squamous differentiation are absent, the cytology specimen was diagnosed as non-small cell carcinoma not otherwise specified. The resection specimen showed adenocarcinoma.

Sarcomatoid features defined by pleomorphic, giant, and/or spindled cells can be encountered. With regard to cytologic specimens, the diagnostic algorithm does not change. For example, a tumor without defining features of adenocarcinoma or squamous cell carcinoma that has sarcomatoid features and is positive for a squamous marker and negative for adeno marker would be diagnosed as non-small cell carcinoma, favoring squamous cell carcinoma. A comment should be added stating the presence of sarcomatoid features (i.e., giant cells and/ or spindled cells). Because the entire tumor needs to be examined for definitive diagnosis of sarcomatoid carcinoma, the term is reserved for resection specimens. In samples where sarcomatoid features are seen and squamous and adeno differentiation is absent (via light microscopy and stains), the diagnosis would be non-small cell carcinoma NOS with a comment regarding the presence and relative amount of the sarcomatoid component. If the malignant cell population is composed exclusively of sarcomatoid cells, mesenchymal neoplasms should be considered.

Figure 17.40 Romanowsky stain of adenoid cystic carcinoma.

In conclusion, samples from tumors without clear defining features of adeno or squamous cell carcinoma should be worked up with a limited staining panel (one squamous marker and one adeno marker with or without mucin stain). The term non-small cell carcinoma NOS should be used sparingly and only after the suggested work-up fails to suggest a particular histotype. Although the diagnoses of adenosquamous cell carcinoma, large cell carcinoma, and sarcomatoid carcinoma are reserved for resection specimens, a comment should be included discussing cytomorphologic findings that may suggest these lesions when applicable. In all instances, emphasis is placed on conserving material for potential molecular testing. In addition, it is important to at least consider the possibility of metastasis and one should correlate findings with all available patient information whenever possible.

Salivary Gland-Like Tumors

The small bronchial glands are analogous to the minor salivary glands located in the upper respiratory tract. As such, tumors that arise from these glands are referred to as salivary gland analog tumors. Although these tumors are rare in the respiratory tract, the ones more commonly described include mucoepidermoid carcinoma, adenoid cystic carcinoma, epithelial-myoepithelial carcinoma, and pleomorphic adenoma. Because of their rarity, when malignant analog tumors are encountered, metastasis from a salivary gland primary should be excluded. The observed cytolomorphologic findings are essentially identical to those encountered in the salivary gland. In mucoepidermoid carcinoma, three intermingled cell types are characteristic, which include glandular cells, squamoid-type cells, and intermediate cells.^148,156 Adenoid cystic carcinoma has bland, basaloid cells that can show nuclear molding. The associated basement membrane-like material is particularly helpful and is considered the most characteristic finding (Figs. 17.40 and 17.41). Epithelial-myoepithelial carcinoma is composed of both epithelial and myoepithelial cells, as the name suggests. Pleomorphic adenoma (Fig. 17.42) characteristically consists of epithelial cells embedded in chondromyxoid stromal material, although the amount stromal material seen can be variable. All of these neoplasms can have overlapping features and have features of other lesions in the respiratory tract; There fore a broad differential is often considered. The endobronchial location of the lesion and the patient’s history can often help one confirm or at least suggest the diagnosis on cytology specimens.

Other Neoplasms

Lymphoepithelioma-like carcinoma can be encountered in the respiratory tract, albeit very rarely. Described cytologic findings include large malignant cells with vesicular type nuclei and conspicuous nucleoli in association with background inflammatory cells composed predominantly of lymphocytes and plasma cells. Epstein- Barr virus (EBV) is present in the nuclei can be identified by in situ hybridizations for EBV-encoded small RNAs (EBER).¹⁵⁷ Given the presence of large malignant cells, poorly differentiated carcinoma, including non-small cell carcinoma of the lung, is often considered. A potential clue to the diagnosis is seeing a prominent inflammatory background.

NUT carcinoma is a poorly differentiated malignancy characterized by the presence of nuclear protein in testis gene rearrangement (NUTM1). As such, immunohistochemical staining for NUT shows diffuse nuclear positivity, often is a speckled pattern.¹⁴⁸ the diagnosis of NUT carcinoma is particularly challenging as cytokeratin markers are often positive and nuclear staining with p63 and p40 is usually seen. In addition, TTF-1, neuroendocrine markers,¹⁴⁵ and CD34 can be expressed. The cytomorphologic features are nonspecific overlap with poorly differentiated carcinomas. Large dyshesive cells with rounded nuclei and coarse chromatin features are seen, and background necrosis is common.¹⁴⁸ Histologically, abrupt areas of keratinization can be seen and is a diagnostic clue when seen.

Figure 17.41 Adenoid cystic carcinoma, characterized by bland, basaloid cells that can show nuclear molding. The associated basement membrane like material is particularly helpful in establishing the diagnosis.

Figure 17.42 Pleomorphic adenoma showing epithelial cells embedded in chondromyxoid stromal material.

Targeted Therapy Biomarkers in Lung Cancer

Targeted therapy in lung cancer is based on TKIs of driver mutations, and prediction of response to TKIs is based on identifying specific actionable mutations or translocations in the targeted tumors. Initially, two predictive biomarkers for targeted therapy of adenocarcinoma were approved by the US Federal Drug Administration (FDA) based on strong evidence from clinical trials. These were EGFR mutations, detected by molecular tests, and anaplastic lymphoma kinase translocations, as detected by fluorescent in-situ hybridization and later IHC.¹⁵⁸ the first College of American Pathologists (CAP), IASLC, and Association for Molecular Pathology (AMP) guideline for biomarker testing in lung cancers focused on these two biomarkers.¹⁵⁹

Additional predictive biomarkers considered in the second CAP/ IASLC/AMP guideline include ROS, RET, BRAF, ERBB2, and MET for adenocarcinoma. Investigations for targeted therapies for squamous cell carcinoma and small cell carcinoma are also underway. Discovery of new drugs and corresponding predictive biomarkers is constantly evolving.⁵⁰

Pathologists select and manage lung cancer tissues for predictive biomarker testing. These tissues include resection specimens, but they most often consist of small biopsies and cytology specimens. The relative small amount, and sometimes paucity, of tumor tissue for testing requires the pathologist to be frugal in the handling of samples. Selection of tumors for testing of the previously mentioned biomarkers is based on a diagnosis of adenocarcinoma or inability to exclude a diagnosis of adenocarcinoma. Thus making the diagnosis of adenocarcinoma is important in identifying which tumors should be tested. However, sufficient tissue should be preserved for biomarker testing in making the diagnosis of cell type. There fore a minimal number of immunostains, preferably no more than TTF-1 and p40, should be performed in determining cell type on a specimen that is also to be tested for biomarkers. If the amount of tissue is very sparse, it may be prudent to send an NSCLC for testing without using tissue to diagnose a specific cell type. Methods, technology, and recommendations for handling and testing of lung cancer cytology and other specimens is constantly evolving.⁵⁰⁴⁵⁸,¹⁵⁹

Figure 17.43 Poorly differentiated adenocarcinoma.

Figure 17.44 Programmed death-ligand 1 immunohistochemical stain showing tumoral heterogeneity.

Immune Checkpoint Therapies in Lung Cancer

Programmed death ligand-1 (PD-L1) is a regulatory molecule expressed in T cells which has immunoregulatory function by dampening the immune response when bound to one of its complementary ligands. PD-L1 expression is induced by proinflammatory substances in many cell types throughout the body. The likely physiologic role of the PD-1/PD-L1 pathway is to prevent excessive tissue destruction during inflammatory states, serving as an “immune checkpoint.” Some malignancies seemingly take advantage of this immune checkpoint pathway by expressing PD-L1 on their cell surfaces and offering a means for malignant cells to evade the immune response, which is sometimes referred to adaptive resistance.¹⁶⁰ Monoclonal antibody therapies targeting the PD-1/PD-L1 pathway have been developed, which act to block ligand binding and subsequent downstream immune dampening effects. T cells are then able to recognize and attack malignant cells despite PD-L1 overexpression. Some of the therapeutics currently on the market or in the process of FDA approval include Pembrolizumab (trade name Keytruda, Merck), Nivolumab (Opdivo, Bristol-Myers Squibb), Atezoli- zumab (Roche), and Durvalumab (Astra-Zeneca). Clinical trials have been promising, as some PD-1 monoclonal antibody therapies have been associated with a 20% response rate in unselected patients with non-small cell carcinoma. Sustained tumor responses have been seen in subsets of patients,¹⁶¹ which is often when other treatment options have been exhausted. Studies suggest that patient response correlates with PD-L1 expression by IHC in tumor cells. As such, pathologists are being asked to evaluate PD-L1 immunohistochemical expression in tumor specimens to optimize patient selection for PD-1 targeted therapy. Challenges exist as a variety of immunohistochemical testing platforms are currently available, significant staining heterogeneity exists within tumors (Figs. 17.43-17.45), and “cutoff” values for what percentage of staining constitutes PD-L1 overexpression has yet to be fully established. In addition, the POPLAR trial suggests PD-L1 expression in inflammatory cells (Fig. 17.46) may also be predictive of tumor response. New data will likely continue to emerge with regard to immunohistochemical evaluation as this field develops. It is also worth mentioning that other immune checkpoint molecules and pathways exist and pathologists may be asked to evaluate their expression profiles as new immune checkpoint therapies are developed.

Figure 17.45 Positive programmed death-ligand 1 staining seen in tumor cells.

Figure 17.46 Programmed death-ligand 1 staining seen in inflammatory cell component.

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Multiple Choice Questions

1. Regarding the demographics of lung cancer, each of the following is true except:

A. The age-adjusted death rate for lung cancer is lower in Caucasians than it is in blacks.

B. Over 80% of lung cancer patients are 60 years old or older.

C. The age-adjusted death rate for lung cancer is higher in men than in women.

D. The number of lung cancer deaths in the United States continues to increase in women.

E. The age-adjusted death rate for lung cancer is almost a third higher in Caucasians than for black men, even though Caucasians have a lower overall exposure to cigare The smoke.

ANSWER: E

2. Each of the following concerning lung cancer is incorrect except:

A. Lung cancer has an overall 5-year survival of 17%.

B. Cigare The smoking causes approximately 50% of lung cancers in women and 60% in men.

C. Asbestos-exposed workers have a fivefold risk of developing lung cancer, regardless of smoking status.

D. Air pollution, occupational exposure to carcinogens, and radon exposure account for approximately 20%, 5%, and 2% of lung cancer cases, respectively.

E. Five-year survival for lung cancer patients who present with distant metastases is 13%.

ANSWER: A

3. For lung cancer patients, presenting symptoms typically include all of the below except:

A. Hemoptysis

B. Dyspnea

C. Hoarseness

D. Night sweats

E. Chest pain

ANSWER: D

4. Each of the following regarding clinical findings in lung cancer patients is true except:

A. Anemia is suggestive of metastatic disease.

B. Horner syndrome is caused by compression or involvement of the sympathetic chain.

C. Elevated liver enzymes suggest hepatic metastases.

D. Horner syndrome is characterized by bilateral ptosis and lack of facial sweating.

E. Pancoast syndrome characteristics include shoulder pain and upper extremity paresthesias and weakness.

ANSWER: D

5. All of the following regarding CT scans in lung cancer patients are true except:

A. CT scan may assist in distinguishing pleural and pericardial masses and effusions.

B. CT scan alone is sufficient for lymph node staging.

C. Lung cancer CT scan includes chest and upper abdomen, including liver and adrenal glands.

D. Intravenous contrast during CT scan assists in delineating hepatic and adrenal gland lesions.

E. CT scan is helpful in characterizing clinical stage.

6. Each of the following regarding lung cancer staging is incorrect except:

A. Lung cancer patients with any stage disease may be candidates for potentially curative surgery.

B. Clinical staging is not used as an initial lung cancer tumor burden assessment.

C. Incorrect or incomplete lung cancer staging may prevent patients from receiving potentially curative therapy.

D. Clinical staging is more important than pathologic staging in determining the best treatment options for lung cancer patients.

E. Pathologic staging of lung cancer does not indicate prognosis or determine treatment.

ANSWER: C

7. Each of the following regarding traditional lung cancer therapy is true except:

A. Potential surgeries include pneumonectomy, lobectomy, and wedge resection.

B. In patients with direct chest wall extension of lung cancer, chest wall resection may be appropriate.

C. Lymph node resection for pathologic staging purposes is not performed during lung cancer surgery.

D. Palliative resections for lung cancer are rarely indicated due to their significant morbidity.

E. Traditional lung cancer therapies include radiotherapy, surgery, and chemotherapy.

ANSWER: C

8. Regarding lung cancer histology, all of the following are true except:

A. H&E stains, histochemical stains, immunohistochemistry, and electron microscopy are routinely used for diagnosing the histologic features of lung cancers.

B. Lung cancer is divided into two major histologic cell types-small cell cancers and non-small cell cancers.

C. Prior to the 2015 WHO Classification, non-small cell lung cancer frequencies were approximately 25% for squamous cell carcinomas, 50% for adenocarcinomas, and 25% for large cell carcinomas.

D. Lung cancer histologic type is generally associated with related clinical, imaging, and therapeutic characteristics.

E. Based on the 2015 WHO Classification, large cell carcinoma makes up approximately 1% to 2% of non-small cell lung cancer cases.

ANSWER: A

9. Regarding the 2015 WHO Classification, the following are incorrect except:

A. Most large cell carcinomas are now classified as large cell carcinoma with null immunohistochemical features.

B. The 2015 WHO Classification retains the past criteria for diagnosing squamous cell carcinoma and adenocarcinoma.

C. The subtype of large cell basaloid carcinoma is retained in the 2015 WHO Classification.

D. Non-small cell carcinomas formerly classified as large cell carcinomas that are immunopositive with TTF1 are now classified as nonkeratinizing squamous cell carcinomas.

E. The 2015 WHO Classification emphasizes the importance of diagnosing non-small cell carcinoma not otherwise specified (HSCLC-NOS) whenever possible for therapeutic purposes.

ANSWER: A

10. All of the following regarding pulmonary adenocarcinoma are false except:

A. Adenocarcinoma subtypes have some associations with molecular alterations and biomarkers.

B. Adenocarcinoma subtypes include lepidic, acinar cystic, papillary, micropapillary, and solid patterns.

C. Adenocarcinoma subtypes are only important for purposes of differential diagnosis.

D. Adenocarcinomas may be preinvasive, microinvasive, minimally invasive, and invasive neoplasms.

E. Less than 20% of individual lung adenocarcinomas have a mixed histologic pattern or combination of cell subtypes.

ANSWER: A

11. Regarding pulmonary atypical adenomatous hyperplasia, the following are true except:

A. Complete excision is essentially curative.

B. Alveolar septa are thickened and contain a combination of fibrosis and mixed chronic inflammation.

C. The degree of cellularity and cytologic atypia is less than that of adenocarcinoma in situ.

D. Atypical adenomatous hyperplasia is a preinvasive lesion, often diagnosed incidentally.

E. Its relationship to adenocarcinoma is thought to be comparable to that of squamous dysplasia and squamous cell carcinoma.

ANSWER: B

12. Regarding pulmonary adenocarcinoma in situ, all of the following are incorrect except:

A. Adenocarcinoma in situ can be both a preinvasive lesion and a minimally invasive lesion.

B. Adenocarcinoma in situ is by definition greater than or equal to 5 cm in greatest dimension.

C. It is usually an incidental finding on CT scan, appearing as a small ground-glass opacity in the lung parenchyma.

D. Most adenocarcinoma in situ neoplasms are mucinous.

E. Five-year survival is approximately 75%.

ANSWER: C

13. Regarding pulmonary minimally invasive carcinoma, the following are true except:

A. It shows no lymphatic spread of tumor.

B. It is by definition less than or equal to 3 cm in greatest dimension.

C. It is usually identified incidentally on CT scan.

D. It has an invasive component that is by definition less than or equal to 1 cm in greatest dimension.

E. It is a solid lesion with predominantly lepidic pattern tumor.

ANSWER: D

14. The following regarding pulmonary minimally invasive carcinoma are false except:

A. Tumor necrosis may not be greater than 2 mm in greatest dimension.

B. The invasive component may be acinar, papillary, micropapillary, solid, or lepidic subtypes.

C. Five-year survival is 100% after complete excision.

D. The majority of cases are mucinous.

E. Most are central lesions involving bronchial or bronchiolar walls.

ANSWER: C

15. Regarding pulmonary adenocarcinoma, all of the following are true except:

A. Approximately 70% of lung adenocarcinomas present with advanced stage disease.

B. Over 90% of invasive adenocarcinomas are histologically heterogeneous.

C. The presence radiologically of a mass with peripheral ground- glass opacity suggests a lepidic component.

D. Adenocarcinomas show high activity on PET scan.

E. Cavitation is a characteristic feature of invasive adenocarcinoma.

ANSWER: E

16. All of the following are true regarding pulmonary adenocarcinoma except:

A. Micropapillary adenocarcinomas have a majority of tumor composed of small cuboidal tumor cells arranged din papillary tufts without fibrovascular cores.

B. Solid adenocarcinoma is a purely solid tumor that shows, at a minimum, histochemically confirmed intracellular mucin in five or more tumor cells in each of two high power fields.

C. Micropapillary adenocarcinoma may contain Psammoma bodies.

D. Lepidic adenocarcinoma contains, by definition, less than 5 mm of a stromal invasive component.

E. Tumor necrosis, lymphatic and vascular invasion, and aerogenous spread are features that separate lepidic adenocarcinoma from minimally invasive adenocarcinoma.

ANSWER: D

17. Regarding mucinous adenocarcinomas, all of the following are true except:

A. Unlike most other lung adenocarcinomas, they are typically immunonegative with TTF-1 and Napsin A.

B. They grow in acinar, papillary, micropapillary, and solid pattern.

C. Their neoplastic cells consist of goblet or columnar cells with abundant apical mucin and small bland basal nuclei.

D. They are more likely than other lung adenocarcinomas to present as multifocal, multilobar, bilateral lesions.

E. Rare cases of mucinous adenocarcinoma in situ and mucinous minimally invasive adenocarcinoma occur.

ANSWER: B

18. All of the following are true regarding pulmonary squamous cell carcinoma except:

A. Keratinizing squamous cell carcinoma may histologically exhibit keratin pearls, single cell keratinization, and intercellular bridges.

B. Although most pulmonary squamous cell carcinomas are central lesions, peripheral tumors may occur.

C. Basaloid squamous cell carcinoma consists of tumor cells arranged in lobules, trabeculae, or rosettes with peripheral palisading and hyaline or mucoid stroma.

D. Papillary, clear cell, and small cell variants are no longer identified in diagnosing pulmonary squamous cell carcinoma.

E. Basaloid squamous cell carcinomas are immunonegative with squamous cell markers such as p40.

ANSWER: E

19. Regarding pulmonary large cell carcinoma, all of the following are incorrect except:

A. Large cell carcinoma is a diagnosis of exclusion.

B. The diagnosis can be rendered on a biopsy or cytology specimen where There is immunohistochemical confirmation available.

C. Large cell basaloid carcinoma and lymphoepithelioma-like carcinoma are retained as distinct diagnoses in the 2015 WHO Classification.

D. Clear cell and rhabdoid variants oflarge cell carcinoma are retained as histologic variants in the 2015 WHO Classification.

E. Where no immunostains or mucin stains are available, a solid non-small cell carcinoma may be diagnosed as large cell carcinoma with null immunohistochemical features.

ANSWER: A

20. All of the following are true regarding pulmonary carcinoma except:

A. NUT carcinoma is a poorly differentiated tumor characterized by the presence of nuclear protein in testis gene rearrangement (NUTM1).

B. A minimal number of immunostains, preferably no more than TTF-1 and p40, should be performed in determining cell type on a specimen that I to be tested for biomarkers.

C. Epstein-Barr virus is present in the nuclei of tumor cells in lymphoepithelioma-like carcinoma.

D. Adenocarcinoma in situ can be diagnosed cytologically where invasion can be excluded clinically.

E. In small biopsies showing non-small cell carcinoma, not otherwise specified, additional stains such as S100, CD45, and prostate markers should be considered to exclude or suggest metastatic processes.

ANSWER: D

Case 1: Pulmonary Adenocarcinoma Carcinoma

eSlide 17.1

Clinical History

A 48-year-old female non-smoker presents to her internist with shortness of breath, increased fatigue, and cough. A CT scan show an irregular

2.2 cm nodule at the peripheral right lung base. Course spiculation was noted in the mass and There seemed to be thickening around the adjacent bronchovascular bundle. Questionable hilar lymphadenopathy was noted; however, an EBUS FNA procedure sampling the hilar lymph nodes showed no evidence of metastatic disease. A wedge resection was performed.

Microscopic Pathology

Sections from the mass show a neoplasm with a predominantly papillary architectural pattern. Tumor cells with mild to moderate cytologic atypia line fibrovascular cores, some secondary and tertiary type papilla are seen.

Diagnosis

Adenocarcinoma, papillary pattern predominate

Discussion

While cigare The smoking is highly associated with the development of lung cancer, around 25% of patients developing lung cancer are never smokers (like this patient). Various risk factors in the non-smoking population include second hand smoke, asbestos, heavy metal, cooking fume, and human papilloma virus exposure. Of interest, non-smoking patients who develop adenocarcinoma are more likely to harbor mutations in EGFR, ALK, ROS, and/or RET. Despite these association, it is important to bear in mind that the most important risk factor for developing lung cancer in general (including adenocarcinoma) is smoking.

Presentation is variable, ranging from a lack of symptoms (incidentally discovered tumor) to symptoms more commonly associated with lung cancer (including: shortness of breath, cough, hoarseness, hemoptysis, pain, and weight loss). Symptomology is generally dependent on the location and extent of the disease. Adenocarcinoma is often a peripheral tumor; tumors with coarse spiculations and thickening around bron- chovascular bundles tend to be more associated with nodal disease than those without these particular imaging findings (likely prompting the EBUS staging procedure in this patient).

Various subtypes of adenocarcinoma have been described including lepidic, acinar, papillary, micropapillary, and solid. In non-small cell lung tumors with ambiguous histologic features immunohistochemistry is often utilized to differentiate between squamous and adenocarcinoma. In order to conserve neoplastic tissue for molecular testing (as targeted therapies can be used in tumors with certain molecular aberrations), the 2015 WHO classification recommends using one adenocarcinoma marker (for example, TTF-1 by immunohistochemistry) and one squamous marker (for example, p40 or p63 by immunohistochemistry).

Of particular interest in this case (female, never smoker), papillary pattern adenocarcinomas are highly associated with EGFR mutations. Providing EGFR mutations are identified, a EGFR tyrosine kinase inhibitor would have better efficacy over standard chemotherapy.

References

Travis WD, Brambilla E, Noguchi M, et al. Diagnosis of lung cancer in small biopsies and cytology: implications of the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification. Arch Pathol Lab Med. 2013;137(5):668-684. Travis WD, Brambilla E, Nicholson AG, et al. The 2015 World Health Organization Classification of Lung Tumors: Impact of Genetic, Clinical and Radiologic Advances Since the 2004 Classification. J Thorac Oncol. 2015;10(9):1243-1260.

Akoi T, Tomoda Y, Watanabe H, et al. Peripheral adenocarcinoma: correlations of thin-section CT findings with histologic prognostic factors and survivial. Radiology. 2001;220(3):803-809.

Sun S, Schiller JH, Gazdar AF. Lung cancer in never smokers-a different disease. Nat Rev Cancer. 2007;7(10):778-790.

Subramanian J, Govindan R. Lung cancer in never smokers: a review. J Clin Oncol. 2007;25(5):561-570.

Case 2: Pulmonary Squamous Cell Carcinoma

eSlide 17.2

Clinical History

A 65-year-old male smoker presents to his pulmonologist because of worsening cough in recent months. He has noted red-rusty tinged sputum the last few weeks. A central 2.4 cm nodule is noted in the left middle lobe. The lesion is predominately solid; however, central cavitation is noted. Bronchoscopus showed a mass in the left middle lobe bronchus and an endobronchial ultrasound guided fine needle aspiration was performed.

Microscopic Pathology

Smears prepared from the endobronchial ultrasound fine needle aspiration show cohesive cellular aggregates and single cells. The cellular aggregates and single cells have dense refractile cytoplasm which is blue to orange-red in color on Papanicolaou stained smears. Definitive cell bridges are not seen in the cellular aggregates. Abundant background necrosis is noted and the cells have dark pyknotic nuclei. Cell block preparations have similar findings, and immunohistochemical stains for p40 and TTF-1 are performed on cell block material. The cells show strong nuclear positivity for p40 and are negative for TTF-1.

Diagnosis

Non-small cell carcinoma, compatible with squamous cell carcinoma

Discussion

Around 25% to 30% of lung cancers are squamous cell carcinoma; these tumor are highly associated with cigare The smoking with over 90% of this subtype occurring in those with a smoking history. Classically, these tumors occur in the inner (central) portion of the lung; however, an increasing number are being detecting in the periphery. At one time, squamous cell carcinoma was the most common subtype. However, currently adenocarcinoma is the most common subtype; this shift has been attributed to improved imaging and changes in cigare The composition.

Patients typically present with cough/shortness of breath, hemoptysis, chest pain, weight loss, and hoarseness. The tumor is typically solid on imaging and central cavitation is often noted which may represent tumoral necrosis. The classic histologic (microscopic) findings include keratinization, squamous pearl formation, and the presence of intracellular bridges (which represent desmosomes). These three findings are the hallmarks of squamous differentiation. In small biopsy specimens, cytology specimens, or in poorly differentiated tumors; these findings are often extremely subtle or nonexistent. In this setting, immunohistochemical stains for p40 (or p63) and TTF-1 can be helpful as p40 (or p63) nuclear positivity and TTF-1 negativity suggests squamous cell carcinoma ( The converse is true in adenocarcinoma). Background necrosis is commonly seen; in instances where only necrosis is present on a pathologic specimen, a definitive diagnosis may not be able to be established. Soft clues to squamous carcinoma in cytologic preparations include cell aggregates in sheets (opposed to three-dimensional rounded clusters) and dark pyknotic nuclei.

It is important to be aware that squamous cell carcinoma can have various histological patterns including clear cell, small cell, basaloid, spindle cell, and papillary features. Being aware of these features is of particular importance when considering the differential diagnosis; which includes (but is not necessarily limited to) the following: small cell carcinoma (particularly in the basaloid/small cell variant of squamous cell carcinoma), adenocarcinoma and NSCLC NOS (in poorly differentiated tumors), sarcoma (in sarcomatoid variants), and adenosquamous carcinoma. Metaplasia and reactive atypias can mimic carcinoma, particularly in small biopsy and cytology specimens.

Therapy for squamous cell carcinoma is mainly surgical (wedge resection, lobectomy, or pneumonectomy) along with chemotherapy and radiation. Targetable molecular alterations have not been identified. Therapy targeting the PD-L1 pathway has shown promise, particularly in tumors overexpressing PD-L1 antibodies.

References

Travis WD, Brambilla E, Noguchi M, et al. Diagnosis of lung cancer in small biopsies and cytology: implications of the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification. Arch Pathol Lab Med. 2013;137(5):668-684. Travis WD, Brambilla E, Nicholson AG, et al. The 2015 World Health Organization Classification of Lung Tumors: Impact of Genetic, Clinical and Radiologic Advances Since the 2004 Classification. J Thorac Oncol. 2015;10(9):1243-1260.

Case 3: Pulmonary Large Cell Neuroendocrine Carcinoma

eSlide 17.3

Clinical History

An 81-year-old man with a 110-pack-year history of smoking was brought by his daughter to the hospital’s Emergency Department because of hemoptysis. He had begun the day before coughing streaks of bright red blood into his handkerchief. CT scan shows a 6-cm central mass within the left lower lobe that involves obliterates the bronchus lumen. Postobstructive pneumonia is also present. Transbronchial biopsy is performed.

Microscopic Pathology

Biopsy shows pieces of a malignant neoplasm made up of large epithelioid cells arranged in solid nests with areas showing an organoid growth pattern and areas of surrounding desmoplastic fibrous stroma containing chronic inflammatory cells. Wide areas of necrosis are present in the biopsy, and There are numerous mitotic figures. The neoplastic cells are markedly atypical with granular nuclear chromatin and generally large nucleoli, and the cells stain with neuroendocrine immunomarkers.

Diagnosis

Pulmonary large cell neuroendocrine carcinoma Discussion

Pulmonary large cell neuroendocrine carcinoma is a high-grade neuroendocrine carcinoma; it is uncommon, making up approximately 3% of primary lung neoplasms. It is frequently found in combination with small cell lung carcinoma. The neoplasm typically arises in older men, with the median age of presentation the 7th decade. Patients usually have large pack-year histories of smoking. Primary large cell neuroendocrine carcinoma presents as other primary lung cancers with symptoms including dyspnea, cough, chest pain, and occasionally hemoptysis. The neoplasm arises both centrally and peripherally.

In the uncommon patient who presents with an early stage tumor, surgical resection with associated regional lymph node dissection may be undertaken, followed by chemotherapy. With inoperable tumors, platinum-based chemotherapy or chemotherapy based on small cell carcinoma protocols may be employed. To date, no successful molecular- based therapy has been identified. Survival is similar to pulmonary small cell carcinoma, with typically widespread metastatic disease at diagnosis, and a 5-year survival rate of approximately 15%.

In the uncommon circumstance of surgical excision, primary large cell neuroendocrine carcinoma is grossly a grayish to off-white well- circumscribed mass. Central lesions often involve the bronchus and may protrude into the bronchial lumen or obliterate the lumen with associated postobstructive pneumonia. Although excised specimens are typically small, pulmonary large cell neuroendocrine carcinoma ranges from approximately 1 to 10 cm in greatest dimension.

Histologically, pulmonary large cell neuroendocrine carcinoma exhibits no glandular or squamous differentiation. By definition, the neoplasm must exhibit both neuroendocrine histology and immunohistochemistry. Neuroendocrine histology typically consists of organoid or trabecular growth patterns similar to those found with carcinoid tumor. Fibrous desmoplastic stroma usually contains variable amounts of chronic inflammation. Wide areas of geographic necrosis are characteristic of pulmonary large cell neuroendocrine carcinoma. The neoplasm is high grade and typically exhibits a high mitotic rate and angioinvasion. Tumor cells are large with granular chromatin, prominent nucleoli, and marked atypia. Cells may exhibit peripheral palisading. Tumor cells exhibit neuroendocrine immunomarkers. Pulmonary large cell neuroendocrine carcinoma may be found in combination with small cell carcinoma and may on occasion be found in combination with adenocarcinoma or squamous cell carcinoma. Rare cases show histologic features of pulmonary large cell neuroendocrine carcinoma, but with no staining with neuroendocrine neoplasms. These neoplasms are termed pulmonary large cell carcinoma with neuroendocrine morphology. Although research of these uncommon neoplasms continues, there currently is no targetable molecular alteration identified, and no molecular therapy is available for patients with pulmonary large cell neuroendocrine carcinoma.

Differential diagnosis may be challenging, particularly on small biopsies. Differential diagnosis includes atypical carcinoid tumor (moderately differentiated neuroendocrine carcinoma), small cell carcinoma, and adenocarcinoma. Metastasis must also be considered. Differentiation from atypical carcinoid tumor is made based on large-cell histology and a high mitotic count, neither of which are characteristics of atypical carcinoid tumor. It typically is distinguished from small cell carcinoma by larger tumor cell size and the presence of prominent nucleoli; however, as both tumors have characteristically high mitotic counts, widespread necrosis, immunostaining patterns, and nuclear chromatin patterns, the differential diagnosis may be difficult. Occasionally, the tumor may mimic adenocarcinoma if rosettes are prominent. As both pulmonary large cell neuroendocrine carcinoma and pulmonary adenocarcinoma are immunopositive with TTF-1, that immunostain does not assist in determining the diagnosis.

References

Asamura H, Kameya T, Matsuno Y, et al. Neuroendocrine neoplasms of the lung: a prognostic spectrum. J Clin Oncol. 2006;24:70-76.

Iyoda A, Hiroshima K, Toyozaki T, et al. Clinical characterization of pulmonary large cell neuroendocrine carcinoma and large cell carcinoma with neuroendocrine morphology. Cancer. 2001;91:1992-2000. Jones MH, Virtanen C, Honjoh D, et al. Two prognostically significant subtypes of high-grade lung neuroendocrine tumours independent of small-cell and large-cell neuroendocrine carcinomas identified by gene expression profiles. Lancet 2004;363:775-781.

Travis WD, Linnoila RI, Tsokos MG, et al. Neuroendocrine tumors of the lung with proposed criteria for large-cell neuroendocrine carcinoma. An ultrastructural, immunohistochemical, and flow cytometric study of 35 cases. Am J Surg Pathol. 1991;15:529-553.

Case 4: Pulmonary Carcinoid Tumor

eSlide 17.4

Clinical History

A 29-year-old woman, a nonsmoker, consults a pulmonologist because of an increasingly frequent nonproductive cough and a vague sense of sternal fullness. CT scan shows a 3.5-cm well-circumscribed central mass involving the right main bronchus. Bronchoscopic biopsy is obtained.

Microscopic Pathology

Biopsy pieces show uniform-appearing cells arranged in an organoid pattern without necrosis or mitotic figures seen. The tumor cells stain positively with neuroendocrine markers.

Diagnosis

Pulmonary carcinoid tumor

Discussion

Pulmonary carcinoid tumor, also termed well-differentiated neuroendocrine tumor, is a pulmonary neuroendocrine epithelial neoplasm. It is uncommon, making up approximately 2% of primary lung neoplasms. The neoplasm arises in both men and women throughout life, with a peak incidence in the 5th decade. Pulmonary carcinoid tumors may arise centrally or peripherally, and they are typically associated with airways. Treatment usually is surgical resection; typically lobectomy. Surgery is typically curative unless tumor has metastasized. Pneumonectomy is required when a large airway is involved with tumor. Regional lymph node dissection is also indicated. Chemotherapy and radiotherapy are typically not used, and There is currently no molecular-based therapy for pulmonary carcinoid tumor. Pulmonary carcinoid tumor is a malignant neoplasm; however, most cases are indolent. Nonetheless, some cases progress locally or metastasize, ultimately killing the patient. Ten-year survival is approximately 90%.

Pulmonary carcinoid tumors are typically solitary neoplasms. Grossly, central carcinoid tumors grown in relation to large airways and typically exhibit a protruding polypoid mass in the bronchial lumen. They are usually yellow-white and of variable size. Most are 3 to 5 cm in their greatest dimension. More peripheral carcinoid tumors may not be associated with airways, and they may be asymptomatic and found incidentally.

Histologically, pulmonary carcinoid tumors are characterized by heterogeneous patterns, including alveolar, organoid, trabecular, spindle, and solid patterns. Tumor cell nuclei exhibit clumped open chromatin and inconspicuous nucleoli. Rarely, pseudoglandular, sclerosing, papillary, and mucinous patterns have been identified. Pulmonary carcinoid tumor exhibits tumor cell positivity with neuroendocrine markers. Currently, no targetable molecular alteration has been identified, and no molecular-based therapy is available.

Differential diagnosis is usually between pulmonary carcinoid tumor and pulmonary atypical carcinoid tumor. Pulmonary carcinoid tumors are distinguished from pulmonary atypical carcinoid tumors based on the lack of necrosis and the presence of less than 2 mitoses per 10 high power fields. Atypical carcinoid tumors have between 2 and 10 mitoses per 10 high power fields and may show foci of necrosis.

References

Anbazhagan R, Tihan T, Bornman DM, et al. Classification of small cell lung cancer and pulmonary carcinoid by gene expression profiles. Cancer Res. 1999;59:5119-5122.

Righi L, Volante M, Tavaglione V, et al. Somatostatin receptor tissue distribution in lung neuroendocrine tumours: a clinicopathologic and immunohistochemical study of 218 'clinically aggressive' cases. Ann Oncol. 2010;21:548-555.

Travis WD, Rush VV, Flieder DB, et al. Survival analysis of 200 pulmonary neuroendocrine tumors with clarification of criteria for atypical carcinoid and its separation from typical carcinoid. Am J Surg Pathol. 1998;22:934-944.

Yao JC, Hassan M, Phan A, et al. One hundred years after "carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008;26:3063-3072.

Case 5: Pulmonary Small Cell Carcinoma

eSlide 17.5

Clinical History

A 72-year-old male smoker (greater than 45 pack years) presents with weight loss and muscular weakness. A clinical exam is notable for predominantly proximal muscle weakness, ptosis, and decreased tendon reflexes. A CT scan shows a hilar mass (3 cm) and mediastinal lymphadenopathy.

Microscopic Pathology

A biopsy shows a neoplasm composed of small tumor cells in a sheet like growth pattern. The nuclei have fine granular chromatin and nucleoli are absent. Cell boarders are obscured and prominent “crush artifact” is seen. Mitotic figures are readily identified (> 10 mitoses per 2 mm²), nuclear molding is seen and apoptotic figures are prominent. Islands of necrosis can be seen in areas of viable tumor.

Diagnosis

Pulmonary small cell carcinoma

Discussion

Small cell lung carcinoma makes up 10-15% of newly diagnosed lung cancers worldwide and has a strong association with cigare The smoking. Tumors are often centrally located and extra pulmonary disease is often present when patient presents to their treating physician. Prognosis is particularly poor (<5% survival at 5 years) and therapy is generally limited to chemotherapy. Sometimes, surgical resection is warranted for patients with peripheral tumors and low stage disease.

Small cell carcinoma is associated with a variety of paraneoplastic syndromes including Cushing syndrome, Eaton-lambert syndrome (signs and symptoms in this patient), SIADH, encephalopy, and others. Typically imaging characteristics include a solid central/hilar mass with mediastinal lymphadenopathy (suggesting advanced disease).

Histologic findings include small cells (classically around 3 times the size of a resting lymphocyte) in a sheet like growth pattern. At times, a nested or trabecular pattern can be observed and rose The formation has been described (patterns typically associated with neuroendocrine tumors). The nuclear to cytoplasmic ratio is quite high, and cytoplasmic boarders are indistinct. The nuclei are hyperchromatic and often, fine granular chromatin is seen. Nucleoli are generally absent and mitotic figures are very high (required to be > 10 per 2 mm²; often > 60 mitoses per 2 mm² are seen). “Crush artifact” is common due to the fragility of the cells. Smudgy, basophilic material surrounding blood vessels can be encountered; a phenomenon known as the Azzopardi effect. The Azzopardi effect is thought to result from encrusted nuclear material forming around blood vessels.

Immunohistochemical findings include positivity for one or more neuroendocrine markers (chromogranin, synaptopysin, CD56). ThF-1 is often positive and the keratin markers AE1/AE3 and CAM5.2 are positive (often in a “dot-like” pattern).

The differential diagnosis can be quite broad and includes (but is not limited to) large cell neuroendocrine carcinoma, typical and atypical carcinoids (low and intermediate grade neuroendocrine tumors), nonsmall cell lung carcinoma, metastatic carcinoma (for example Merkel cell carcinoma), lymphoma, other small round blue cell tumors (i.e., Ewing tumor), and synovial sarcoma. For peripheral tumors involving the pleura, it is important to consider small cell variant of mesothelioma. Accurate tumor differentiation starts with light microscopy. Immuno- histochemistry is often required and clinical and radiographic correlation should always be utilized.

References

Travis WD, Brambilla E, Noguchi M, et al. Diagnosis of lung cancer in small biopsies and cytology: implications of the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification. Arch Pathol Lab Med. 2013;137(5):668-684. Travis WD, Brambilla E, Nicholson AG, et al. The 2015 World Health Organization Classification of Lung Tumors: Impact of Genetic, Clinical and Radiologic Advances Since the 2004 Classification. J Thorac Oncol. 2015;10(9):1243-1260.

Koletsis EN, Prokakis C, Karanikolas M, Apostolakis E, Dougenis D. Current role of surgery in small cell lung carcinoma. J cardiothorac Surg. 2009;4:30.

Campbell AM, Capling BG, Algazy KM, el-Deiry WS. Clinical and molecular featreus of small cell lung cancer. Cancer Biol Ther 2002;1(2):105-112.

Nicholoson SA, Beasly MB, Brambilla E, et al. Small cell lung carcinoma (SCLC): a clinocopathologic study of 100 cases with surgical specimens. Am J Surg Pathol. 2002;26(9):1184-1197.