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

Chapter 18. Metastatic Tumors in the Lung: A Practical Approach to Diagnosis

Kim R. Geisinger, MD, and Stephen Spencer Raab, MD

The most common form of pulmonary neoplasm is a metastasis from outside the lungs. Based on autopsy data, the lungs are involved by metastatic lesions in 25% to 55% of malignant diseases,^1-5 and, in up to one-fourth of those cases, the pulmonary parenchyma and pleura are the only sites of distant spread.⁴ On the other hand, the most common lung tumor encountered by a practicing surgical pathologist or cyto- pathologist is primary bronchogenic carcinoma; distinguishing primary from secondary pulmonary neoplasms is a major challenge. This chapter provides a concise background discussion of the pathobiologic principles and clinicoradiologic findings of metastases in the lungs and offers a framework for the practitioner to identify such lesions with an optimal level of certainty.

Routes of Spread for Intrapulmonary Metastases

Extrapulmonary malignancies may spread to the lungs through the vascular system or the lymphatics or by direct extension; technically, direct extension does not represent metastasis as it is usually defined.

Primary lung cancers likewise may involve other pleuropulmonary zones by similar means or by aerogenous dissemination through the alveolar pores of Kohn. Clinical and radiologic features of a particular metastatic lesion depend on which of these avenues of spread applies.

Vascular Metastases

Most metastatic tumors in the lungs have arrived at that destination hematogenously. There are two principal reasons for this: the lungs receive the entire cardiac output, and they contain a rich vascular network comprising a huge capillary bed. The detailed principles underlying vascular metastasis have been outlined elsewhere.^6-8 Malignant tumors may contain subclones⁹ of cells with differing metastatic potential, and some of them acquire the ability to enter the bloodstream as microemboli. At selected distant sites, they adhere to endothelial basement membranes, and through a process known as extravasation, the tumor cells move through the extracellular matrix to form metastatic deposits in various parenchymal structures. In this paradigm, the original micrometastasis then proliferates to yield a larger mass, which later (often as long as several years) may become visible clinically or radiographically. Most pulmonary metastases show nests of neoplastic cells that are surrounded by, and intercalated with, a variable quantity of fibrous stroma. At this stage, no cells typically remain inside the pulmonary arterial, venous, or capillary system unless they arrived later in a newer microembolus.

The rate at which potentially metastasizing cellular subclones develop (if they do at all) in primary tumors varies considerably; the probability that such lesions will spread hematogenously depends on both tumor- related factors and conditions in the milieu of the host tissues. For reasons that are largely unknown, some tumors, such as osteosarcoma, often shed micrometastases before the primary tumor is detected clinically; other tumors may show metastasis only very late in their biologic evolution.¹⁰

The clinical presentation of patients with hematogenous pulmonary metastases is variable. Most patients have no symptoms,¹¹ and their lesions are detected only through imaging studies that are undertaken for staging purposes or for surveillance during treatment. The radiographic appearance of metastatic pulmonary lesions may be that of a single central or peripheral mass, multiple central or peripheral masses, diffuse infiltrates, or a combination of the latter two possibilities. Metastases tend to manifest rather smooth or rounded contours

radiographically in contrast to much more irregular shapes of primary carcinomas. If a patient is symptomatic, the clinical findings reflect the location and extent of the metastatic deposits and commonly include chest pain, dyspnea, cough, hemoptysis, and wheezing, to name a few.

In addition to the concept of microembolization, tumors may also spread as macroscopic emboli that involve large or medium pulmonary arteries.¹² Large-vessel tumor emboli may cause acute heart failure, sudden death, rapidly evolving pulmonary hypertension, and pulmonary infarcts.^13-15 the tumors that most commonly give rise to macroscopic emboli are those associated with major systemic veins (e.g., renal or hepatic carcinomas invading the renal and hepatic veins) and primary tumors of the heart (myxomas and sarcomas).¹⁶

In rare cases, hematogenous metastasis principally occurs in the lung with occlusive luminal tumor plugs in small vessels (arterioles and capillaries) without interstitial involvement or formation of masses.¹⁷ In a sense, those tumors have not gone through all of the biologic steps normally associated with the metastatic sequence, but they are nonetheless potentially lethal as they may cause severe pulmonary hypertension. Neoplasms that may show that pattern of spread (sometimes called tumor-related thrombotic pulmonary microangiopathy™) include carcinomas of the breast, gastrointestinal tract, liver, pancreas, uterus, gallbladder, prostate, and ovary.¹⁷ Soares et al. reported that most malignant tumors that occlude small pulmonary vascular channels also can be seen simultaneously within larger vessels.¹⁹ Patients with metastatic microvascular occlusion typically present with progressive dyspnea and cor pulmonale.^17,18

As a general rule of physiology, all caval venous blood flows through the lungs and portal venous return passes through the liver. Consequently, depending on the primary site of the tumor, metastases preferentially are seen in one of these two organs. Malignant neoplasms that arise in sites with other pathways of vascular drainage (e.g., prostatic tumors preferentially shed into the paravertebral venous plexus) infrequently involve the lungs secondarily. Arterially borne metastases to the lungs are relatively rare and are usually mediated by the bronchial arteries; the most common source of such lesions is a primary lung cancer that has gained access to the pulmonary venous system.

Hematogenous metastasis in the lung is associated with a spectrum of radiologic findings. The most common roentgenographic appearance is that of multiple, bilateral, variably sized masses (Figs. 18.1-18.3): occasionally, a solitary intraparenchymal nodule is seen. The metastatic implants usually appear in the mid- to lower lung field because that is where the greatest parenchymal perfusion occurs. In up to 90% of patients with bilateral secondary disease, the lesions are peripheral and subpleural (Fig. 18.4).^1,20 Variability in the size of the metastatic nodules is related to the different “ages” of the lesions, dissimilar growth rates, and other factors. Such lesions are usually smaller than primary pulmonary carcinomas, measuring less than 3 to 4 cm in maximum diameter. Metastases also tend to enlarge more rapidly than lung carcinomas do, except perhaps for small cell carcinoma.

Tumors involving small vessels may produce linear parenchymal infiltrates, and patients who have both masses and metastases in small vessels or lymphatic spaces present with opacities and linear streaks. Embolic tumors in the large pulmonary arteries may show the radiographic appearance of an infarct, with a wedge-shaped peripheral zone of consolidation and possible pleural effusion.

Figure 18.2 Gross photograph of metastatic carcinoma in the lungs showing several subpleural nodules of varying size.

Solitary metastases in the lungs are seen in up to 10% of all malignant tumors involving those organs.^21-23 Filderman and coworkers suggested that solitary lesions larger than 5 cm in diameter most likely originate in the breast, kidney, or soft tissue.⁶ Metastasis in the form of a solitary mass on plain films may appear as multiple contiguous or coalescent masses on computed tomograms. Quint and colleagues reported that, statistically, patients with carcinomas of the head and neck, bladder, breast, cervix, bile ducts, esophagus, ovary, prostate, or stomach were more likely to have a solitary metastasis to the lung than a new primary bronchogenic tumor, even when a significant period had elapsed after diagnosis of the extrapulmonary neoplasms.²⁴ On the other hand, patients with a history of malignant melanoma, sarcoma, or malignant germ cell tumor were more likely to have a second primary malignancy of the lung under the same circumstances.²⁴

Large metastatic foci may undergo cavitation or result in pneumothorax or bronchopleural fistulization (Fig. 18.5). The most common secondary tumor that cavitates is squamous cell carcinoma (SCC), often originating in the head and neck and frequently are extensively keratinized.²⁵ Metastatic sarcoma and adenocarcinoma also may exhibit that feature.²⁵ Pneumothoraces and transpleural fistulae result from erosion by the metastatic tumor through the pleura, as seen most frequently in pediatric mesenchymal malignancies (e.g., osteosarcoma).²⁶

Figure 18.3 (A) Gross photograph from another case of metastatic carcinoma involving the lungs (from a primary tumor in the breast). The multifocal nature and heterogeneous size of metastatic lesions are well shown. (B) the variably sized metastatic tumor nodules are found diffusely within lung parenchyma.

Figure 18.4 (A) Gross image of pleura showing multiple variably sized subpleural metastases. (B) Photomicrograph from a case of metastatic adenocarcinoma in the lung showing a subpleural peripheral distribution of tumor within the pulmonary parenchyma.

Lymphogenous Metastases

One study²⁷ reported that up to 56% of pulmonary metastases were lymphogenously mediated, although a more generally accepted figure is 5% to 8%.^28,29 Most patients with lymphatic-borne lung metastases have a poor prognosis, with 90% dying within 6 months.²⁹

The radiographic appearance of lymphangitic metastasis is variable; in 50% of cases, plain chest films show no apparent abnormality.³⁰ Yang and Lin described four radiologic patterns for this condition²⁹:

1. Bilateral linear infiltrates without hilar enlargement or intrapulmonary masses

2. Hilar masses with centripetal parenchymal extension (seen most commonly with cervical, gastric, and breast cancers; Fig. 18.6)

3. Focal linear infiltration of the parenchyma associated with a central primary tumor

4. Parenchymal radiations from a peripheral primary tumor

With the first two patterns representing secondary tumors, pleural or, less frequently, hilar lymph nodal involvement may be seen. More than 90% of these cases are metastatic adenocarcinomas.²⁹ It is estimated that fewer than 1% of patients with pulmonary metastases from tumors arising outside the thorax also have hilar adenopathy.³¹ Although this figure may appear low, hilar adenopathy in patients with secondary pulmonary malignancies is not uncommon in absolute terms because of the high prevalence of patients with metastatic disease.

Carcinomas may gain access to the pulmonary lymphatic system by retrograde spread, direct invasion of the pulmonary lymphatics, and passage through adjacent blood vessels. The most common route of spread is the last of these three possibilities³²; tumor first spreads hematogenously to the lung and results in small areas of interstitial growth. The neoplastic cells are then absorbed into the lymphatics and permeate further throughout the lungs (Fig. 18.7). Tumor in alveolar spaces may likewise be absorbed through the lymphatics adjacent to terminal bronchioles. There fore patients who have lymphangitic intrapulmonary metastases generally also have had previous hematogenous spread.³² Direct lymphatic invasion is most often associated with tumors arising in the breast or stomach^29,33,34; in this mode, metastases may be seen exclusively in the pulmonary lymphatic spaces, without the formation of mass lesions. Other metastatic carcinomas capable of showing the same pattern of spread are those arising in the ovary, thyroid, bladder, esophagus, liver, and appendix after the development of pseudomyxoma peritonei.^29,32,35

Direct Seeding

Metastatic disease arising through direct “seeding” occurs when a malignant tumor gains access to a serosally lined cavity, such as the pleural space. Neoplasms that directly seed the pleura include primary lung cancers and malignancies of various lineages that originate in the chest wall or mediastinum. In some cases, primary lung tumors, such as peripheral pulmonary carcinoma, grow through the visceral pleura; this phenomenon is less common in cases of chest wall sarcoma. The malignant cells attach themselves to multiple pleural sites and invade the subjacent tissues There after. Hence, multiple subpleural nodules may eventuate near a larger serosally based secondary lesion.

Pleural Metastases

Metastases are the most common form of pleural malignancy. Most derive from primary neoplasms of the chest wall, mediastinum, or lungs,⁶ although extrathoracic primary malignancies are also well represented. The largest tumor nodules tend to be basally situated in the chest (Fig. 18.8).³⁶

At least two-thirds of malignant pleural effusions can be diagnosed by cytologic sampling of the pleural fluid. More than 90% of cases are recognized on the first specimen,^37,38 but sensitivity predictably increases with successive sampling; three specimens are routinely recommended if the clinical suspicion of pleural metastasis is high.³⁹

Malignancy is second only to congestive heart failure as a cause of pleural effusions.⁴⁰ Neoplastic effusions are typically described as massive or copious, ranging up to 2500 mL in volume,⁴¹ and they are often bloody. Nevertheless, malignant involvement of the pleura may also be associated with scant fluid production and a serous character.³⁶ Obviously, not all pleural effusions in patients with a history of malignancy contain tumor cells,⁴² and benign effusions in such cases may be secondary to lymphatic obstruction, altered lymphatic drainage as a result of chemotherapy or radiation therapy,⁴³ heart failure, or other causes. Because most sarcomas do not spread via lymphatic channels, metastases in the lung and pleura are not usually accompanied by a tumorous effusion.⁴⁴ Up to 90% of malignant pleural effusions caused by metastatic lung or breast cancers are ipsilateral with regard to the site of the original tumor.³⁶ Patients with malignant pleural effusions typically have a dismal prognosis, and most die within a few months of diagnosis.^45-47 Selected subgroups of patients, such as those with lymphoma, breast cancer, or some pediatric malignancies, may fare somewhat better.

Chretien and Jaubert reported that 42% of cytologically sampled pleural effusions contained malignant cells.⁴⁸ the likely site of tumor origin in such cases appears to depend on patient demographics, although most series have reported that primary pulmonary carcinomas are the most common.^46,49 SCCs of the lung do not usually involve the pleural fluid; however, adenocarcinomas often do (Fig. 18.9), followed by small cell carcinoma.^50,51 Almost any other extrathoracic malignancy may metastasize to the pleural space, but the most common tumors that do so are carcinomas arising in the breast, gastrointestinal tract, and ovary; non-Hodgkin lymphoma is also well represented.^46,49,52 Up to 7% of metastatic carcinomas in the pleura must be classified as originating in an unknown primary location.⁴⁹ In one analysis of malignant pleural effusions, women predominated by a ratio of 2 : 1,⁴¹ but no sex preferences were seen in other series.⁴⁶ It should be recalled that most epithelioid mesotheliomas are associated with a positive effusion, which, however, may be very difficult to diagnose cytologically.

Figure 18.5 (A) Chest radiograph from a case of metastatic oropharyngeal squamous cell carcinoma involving the lungs showing cavitating nodular lesions throughout both lung fields. (B) the cavitary nature of the lesions is well shown.

Figure 18.6 Chest radiograph (A) and computed tomography scan (B) in a case of metastatic breast carcinoma in the lungs, assuming a centripetal lymphangitic pattern. Tumor is seen in the lymph nodes in both hilar regions, and it also involves the lung fields in an arborizing pattern that follows the lymphatic channels.

Endobronchial Metastases

Endobronchial metastases are considered as a separate category due to their distinctive clinical findings, principally the syndrome of adult-onset asthma. The reported incidence of endobronchial and endotracheal metastatic disease is 1% to 18% of patients who also have intrapulmonary metastases.^11,53,54 the most common sites of tumor origin in patients from North America and Western Europe are the breast, bone, soft tissue, large intestine, kidney, and skin (melanoma).^11,55-59 More than one-third of endobronchial metastases are sarcomatous.^54,58 In populations with a high prevalence of acquired immune deficiency syndrome, the most common secondary malignancies of the bronchi are Kaposi sarcoma and malignant lymphoma.⁶⁰ Nasopharyngeal and laryngeal carcinomas are frequent sources of endobronchial metastasis in Asia.⁶¹

Figure 18.7 A linear pattern of lymphangitic metastatic disease in the lung parenchyma is seen in gross photographs (A and B) and a low-magnification photomicrograph (C). (D) At higher magnification, metastatic carcinoma fills and expands the lymphatic channels in the lungs.

Figure 18.8 Chest radiograph from a case of metastatic leiomyosarcoma massively involving the left pleura. The left hemithorax and anterior mediastinum are largely obliterated by the tumor mass and an accompanying pleural effusion.

Figure 18.9 Metastatic adenocarcinoma of pulmonary origin is seen in this preparation of a cytologic specimen of pleural fluid. The tumor cells are arranged in a vaguely three-dimensional configuration, and small nucleoli are seen.

Endobronchial metastases may be either hematogenous or lymphogenous.^11,54,58 Aerogenous spread of an upper-airway malignancy has also been suggested as a possibility. Tumors that originate in the lung, hilar lymph nodes, or mediastinum may spread by direct extension into the bronchial system. Endobronchial lesions cause symptoms early in their course of growth, namely, cough with sputum production, dyspnea, wheezing, and hemoptysis.^61,62 However, up to 25% of patients are asymptomatic.⁵⁹ Radiographically, an endobronchial mass is typically visible only on computed tomography or magnetic resonance scan, while plain film studies commonly show only postobstructive consolidation or atelectasis (Fig. 18.10). The mean interval between diagnosis of the original tumor and the appearance of endobronchial metastasis is 4 to 5 years.⁶² These patients have a poor survival, with a median of 11 months⁶²; patients with breast cancer may have a better prognosis.^55,58,59

In histologic and cytologic specimens, endobronchial metastases may be confused with primary tumors. However, primary endobronchial epithelial neoplasms are typically SCCs, neuroendocrine carcinomas, or salivary gland-type tumors. Endobronchial adenocarcinomas other than salivary morphotypes should, there fore, raise the suspicion of metastatic disease. An exuberant reactive stromal proliferation around such lesions may also be confused with metastatic spindle cell sarcoma.

Modalities for the Diagnosis of Pleuropulmonary Metastases

The diagnostic tests that are typically used for any suspected pleuropulmonary tumor are also applicable to the study of metastatic disease.

Figure 18.10 (A) Chest radiograph showing left upper lobar atelectasis in a case of intrabronchial metastasis of renal cell carcinoma. (B) Computed tomography scan showing another case of metastatic intrabronchial carcinoma (from the breast), affecting the right mainstem bronchus. (C) Bland polygonal tumor cells with characteristic clear cytoplasm are seen in the biopsy specimen. (D) the associated bronchial brushing shows renal cell carcinoma cells with relatively uniform nuclei and clear cytoplasm. Continued

Figure 18.10 cont'd (E) Intrabronchial metastasis of melanoma, represented by a pigmented polyploid mass. (F) the tumor contains abundant melanin.

These include sputum cytology,^63,64 bronchoscopy with brushing, washing, alveolar lavage, transbronchial or transtracheal aspiration and biopsy,^65-67 transthoracic fine-needle aspiration (FNA),^68,69 thoracoscopic biopsy (video-assisted thoracic surgery),^70-72 open thoracotomy and biopsy, and effusion cytology.⁴⁷ In some cases, expectant management is undertaken, with sequential radiologic studies.^73,74 Computed tomography scans may be obtained to delineate further abnormalities and possibly to aid in the distinction between primary and secondary malignancies; for example, mediastinal adenopathy favors a primary lung tumor.⁷⁵ When multiple radiographic lesions of the lung or pleura are detected radiographically in some patients with well-documented histories of malignancy, further diagnostic evaluations may be eschewed.

For the most part, the diagnostic accuracy of tests that yield tissue for pathologic examination has generally not been determined in this specific context. The accuracy is believed to depend principally on the size and location of the lesion rather than its specific histologic nature. For example, the sensitivity of FNA is 93% if the lesion is larger than 2 cm in diameter and 60% for those smaller than 1 cm. Higher sensitivity is realized in the sampling of peripheral nodules compared with central lesions regardless of whether they are primary or secondary.⁷⁶ Pilotti et al. reported that the sensitivity of FNA in the detection of metastatic pleuropulmonary disease was 89%, whereas it was 92% for primary malignancies.⁷⁷ Another interinstitutional study reported 96% specificity for transthoracic FNA.⁷⁸ the sensitivity of bronchoscopy also depends on the location of the lesion; as expected, that technique is particularly well suited for the visualization and sampling of endobronchial metastases.^65-67 In the proper hands, sensitivity of transbronchial sampling is enhanced with navigational bronchoscopy (but not at umc).⁷⁹ Thoracoscopy is a sensitive means of accessing peripheral lesions and has a high level of accuracy overall. It may be viewed as a treatment option as well as a diagnostic test in patients who have limited metastatic disease, especially if lung function is compromised.^70-72

Kern and Schweizer concluded that the sensitivity of sputum cytology for the detection of intrapulmonary metastasis was similar to that associated with primary lung cancers.⁸⁰ Similarly, that technique is much more likely to be productive if the metastatic lesions are large and centrally located.⁸⁰

Practical Approach to Differential Diagnosis

A definite challenge in pulmonary pathology is determining whether a newly detected lung mass is primary or secondary in patients with or without a history of extrapulmonary malignancy. If no previous tumor has been seen and the lesion has the morphologic attributes of a nonpulmonary proliferation, it is necessary to search for a primary site. Malignancies that are clinically occult and present with pulmonary metastases are not unusual; they account for approximately 2% to 5% of all metastatic carcinomas of unknown origin (MCUOs).^81,82 Due to the treatment-related and prognostic issues concerning secondary malignancies of the lung, it may be decided that additional resources are not justified to determine the primary location of the tumor.⁸³

With regard to the general distinction of primary and metastatic pulmonary tumors, one generally depends on clinical data (e.g., history of tumor elsewhere, smoking history) radiographic findings, histologic features, microscopic comparison of the current lesion with any previous malignancies, and the use of ancillary pathologic studies, such as immunohistochemistry, cytochemistry, molecular biologic techniques, cytogenetic methods,⁸⁴ and electron microscopy (EM). If paraffin- embedded tissue from previous tumor material is available, immuno- pathologic studies of the previous tumor and the current specimen can be obtained comparatively.

Useful information for the distinction between primary and secondary neoplasms in the lung may be derived from details of the clinical evaluation and physical findings.^85,86 For example, the characteristically spiculated appearance of primary lung cancers (Fig. 18.11) on imaging studies of the chest distinguishes them from the more rounded and well-delimited appearance of metastases. Unfortunately, such information is often not made available to pathologists, even though it is well known to enhance diagnostic accuracy.⁸⁷ A high index of suspicion must be maintained, and communication with the radiologist should occur whenever the pathologist has increased concern, morphologic or otherwise, that a tumor may be a metastasis. Open communication is essential if the patient has a history of oncologic disease.

Figure 18.11 (A) Chest radiograph from a case of primary adenocarcinoma of the lung showing a peripheral nodule in the lower right lung field (arrow). (B) Computed tomography scan showing irregular spiculated margins, typical of a primary pulmonary neoplasm.

The light microscopic features of any given lesion are the cornerstone of pathologic diagnosis. The appearance of the lesion after hematoxylin and eosin staining is often sufficient to determine whether the tumor is primary or metastatic. Carcinomas arising in the lung typically have evolved over several years before coming to clinical attention. Consequently, the host responds to such lesions by surrounding them with an irregular cuff of fibroinflammatory tissue (Fig. 18.12). The mixture of proliferation and degeneration that characterizes primary carcinomas commonly causes central zones of fibrosis, with entrapment of some residual native pulmonary structures. In contrast, metastases to the lung parenchyma have a “clean” interface with the surrounding tissue and are usually not associated with peripheral zones of fibroinflammatory response. As they are rapidly growing vis-à-vis bronchogenic neoplasms, metastatic carcinomas also lack centrally sclerotic regions. These “rules” do not apply universally to all tumor types. Specifically, primary and metastatic sarcomas, adenocarcinomas with a lepidic growth pattern, and small cell carcinomas are essentially superimposable morphologically.

The rest of this section considers five categories of tumors in patients with a known history of extrapulmonary malignant neoplasms:

1. Adenocarcinoma variants

2. Spindle cell and pleomorphic malignancies

3. Small round cell neoplasms

4. Squamous cell carcinomas and their simulants

5. Undifferentiated large polygonal cell malignancies

In each group, the differential diagnosis includes at least one primary pulmonary lesion. Although specific neoplastic entities are discussed, the presentation is not all-inclusive. The approach taken in this chapter is intended to provide an example of a differential diagnostic framework. There is inevitably some overlap in categories. For example, in selected cases, hepatocellular carcinomas (HCC) potentially may present any of the following morphologic appearances: adenocarcinoma, not further specified; oncocytoid carcinoma; clear cell carcinoma; undifferentiated large polygonal cell malignancy; or even sarcomatoid (spindle cell and pleomorphic) carcinoma. Accordingly, this presentation is organized to reflect the most common morphologic groups in which specific neoplasms are usually placed.

Figure 18.12 Fibroinflammatory host reaction is seen in and around this primary squamous cell carcinoma of the lung, serving as a marker of its pulmonary origin.

The discussion also incorporates information on immunohistologic panels that can be used to distinguish nosologically different but morphologically similar tumors. These panels are presented in that manner because immunohistochemistry today is such an integral part of cytopathology and histopathology. However, the differential diagnosis does not rest on adjuvant studies alone, but rather involves the melding of light microscopic observations, clinical information, and data derived from ancillary procedures. The availability of these techniques varies among medical institutions; There fore the antibody profiles presented here show the authors’ approach but should not be regarded as definitive or mandatory, especially considering the rapid evolution of adjunctive technology in pathology and low resource areas, on the other hand.

Table 18.1 Immunophenotypes of Adenocarcinomas Potentially Seen in the Lung

Origin

PK

CK7

CK20

EMA

THY

CEA

ER

HEP

GCDFP

S-100

TTF1

PSA

INHB

CA125

CA19-9

CD10

Lung

P

P

N

P

N

P

N

N

N

N

P

N

N

N

PN

N

Breast

P

P

N

P

N

P

P

N

P

PN

N

N

N

PN

N

N

Thyroid

P

P

N

PN

P

PN

N

N

N

PN

P

N

N

N

N

N

Salivary duct

P

P

P

P

N

PN

N

N

PN

PN

N

PN

N

N

N

N

Ovary (serous)

P

P

N

P

N

N

P

N

N

PN

N

N

N

P

N

N

Kidney

P

PN

N

P

N

N

N

N

N

PN

N

N

N

N

N

P

Stomach

P

PN

PN

PN

N

PN

N

N

N

PN

N

PN

N

PN

PN

N

Pancreas

P

P

PN

P

N

P

N

N

N

N

N

N

N

PN

P

N

Colorectal

P

PN

P

P

N

P

N

N

N

PN

N

N

N

PN

PN

N

Prostate

P

PN

PN

PN

N

PN

N

N

PN

N

N

P

N

N

N

N

Adrenocortical

N

N

N

N

N

PN

N

N

N

N

N

N

P

N

N

N

Hepatocellular

P

PN

PN

PN

N

P

N

P

N

PN

N

N

N

N

N

PN

CEA, Carcinoembryonic antigen; EMA, epithelial membrane antigen; ER, estrogen receptor; GCDFP, gross cystic disease fluid protein; HEP, hepatocyte-related antigen in paraffin sections-1; INHE, inhibin;

N, <10% of tumors; P >75% of tumors; PK, pan-keratin; PN, 10%-75% of tumors; PSA, prostate specific antigen; S-100, S-100 protein; THY, thyroglobulin; TTF1, thyroid transcription factor-1.

Adenocarcinoma Variants

Adenocarcinoma is the most common form of primary lung cancer.⁸⁸ In patients who have a history of an extrapulmonary adenocarcinoma, the distinction between a primary and secondary lesion may be challenging. In some cases, morphologic appearances alone are sufficient to accomplish that task, as discussed later. Immunopathology is also helpful in the recognition of some of these tumors. Table 18.1 shows the immunohistologic profile of specific adenocarcinomas based on their site of origin.⁸⁹

Papillary Adenocarcinomas

Silver and Askin reported that primary papillary pulmonary adenocarcinomas—defined as such if 75% or more of the neoplasm shows papillary architecture—are not uncommon.⁹⁰ According to Travis et al.,⁸⁸ a tumor is considered papillary if it accounts for the most common pattern present in a resected adenocarcinoma. Moreover, micropapillae may be seen in conventional adenocarcinomas of the lung and are associated with a poorer prognosis (Fig. 18.13).⁹¹’⁹² Metastatic adenocarcinomas in the lung also may contain micropapillary structures. In FNA specimens, papillary adenocarcinomas contain fibrovascular fragments covered by cuboidal or low-columnar neoplastic cells. Micropapillae may be represented by floret-like aggregates that distinctly lack a stromal core.

Metastatic papillary adenocarcinomas may originate in various organs, especially the thyroid, breast, ovary, or kidney (Fig. 18.14). Thyroid carcinomas of all histologic subtypes have the potential to metastasize to the lung. Of all thyroid carcinomas that spread to distant sites other than lymph nodes, up to 50% involve the pulmonary parenchyma.^93-95 Papillary thyroid carcinoma (PTC) almost always metastasizes to regional cervical lymph nodes first⁹³; in addition, this tumor may directly invade the trachea and produce an endoluminal mass. Anaplastic thyroid carcinoma shares the latter potential. Hilar and mediastinal lymph nodes are also involved by PTC in half of patients with lung metastasis.⁹⁶ Secondary PTC may grow very slowly and remain solitary for extended periods, simulating the biologic characteristics of a primary pulmonary neoplasm.⁹³ In addition to its papillary substructure, other cytologic clues to metastatic PTC include its characteristic n uclear features, including nuclear grooves, nuclear membrane irregularities, cytoplasmic invaginations (pseudoinclusions), and nuclear overlap—as well as the formation of colloid and psammoma bodies (Fig. 18.15). However, all of these attributes may be found in primary lung adenocarcinoma.

All types of ovarian carcinoma may metastasize to the lungs and up to 50% of stage IV cases feature pulmonary involvement.⁹⁷ the papillary serous form is the most common subtype. The pleura is often involved early by lymphatic spread through the diaphragm, and the peripheral lung parenchyma is then affected. Malignant pleural effusions caused by papillary serous carcinomas are present in 40% of cases with metastases,⁹⁷ while solitary pulmonary nodules are present in 7%.⁹⁸ Intrapulmonary lymphangitic growth of ovarian malignancies is associated with a rapid demise.^99,100

Immunopathologic studies to determine the site of origin of a papillary carcinoma in the lung are outlined in Table 18.2.⁸⁹ We recommend using at least one marker (e.g., vimentin or pan-keratin) that should be positive in each of the differential diagnostic possibilities to establish the antigenic integrity of the tissue (Fig. 18.16).¹⁰¹

Another malignancy that often has a papillary pseudocarcinomatous appearance, especially in pleural fluid specimens, is the epithelioid variant of malignant mesothelioma (Fig. 18.17). Renshaw and colleagues estimated that the sensitivity of pleural fluid cytology for the diagnosis of mesothelioma was only 32%,¹⁰² as epithelioid tumor cells often have a bland nuclear appearance, and the sarcomatoid variant of mesothelioma rarely sheds into the pleural space. Many reports have considered the diagnostic distinction of mesothelioma from metastatic adenocarcinoma. Immunopathologic are generally used to make this distinction.^103-106 Table 18.3 shows a typical immunopathologic antibody panel that can be used to distinguish mesothelial proliferations from epithelial tumors.¹⁰³’¹⁰⁷’¹⁰⁸ Imlay and Raab examined the utility of immunohistochemistry in this context in hospital practice.⁴⁶ They reported that immunopathologic techniques were applied to 2.6% of all pleural fluid specimens. In 71.9% of these cases, a firm interpretation was facilitated by the results of such analyses.⁴⁶ However, none of the diagnoses in that series were based solely on immunopathology.⁴⁶ the low prevalence of mesothelioma in the general population explains the rarity of this interpretation in the experience of most practicing pathologists. The judicious use of antibodies directed against certain antigens (e.g., cal- retinin, D2-40, and TTF-1) may greatly aid in this distinction.

Figure 18.13 (A to C) Micropapillary architecture and microcalcifications are apparent in this adenocarcinoma of the lung. This feature can be seen in both primary and secondary pulmonary epithelial tumors.

Although quite uncommon, primary lung adenocarcinomas may have a predominant micropapillary pattern.⁸⁸ Histologically, it is characterized by small cohesive aggregates free within airspaces. The clusters often possess bland nuclei that may demonstrate grooves or pseudoinclusions, but they lack fibrovascular cores. Micropapillary adenocarcinomas may arise in other organs (e.g., breast, ovary, urinary bladder) and spread to the lung. Here, immunohistochemistry may play an important role.

Figure 18.14 Metastatic renal cell carcinoma with a micropapillary architecture.

Table 18.2 Immunohistologic Differential Diagnosis of Papillary Adenocarcinoma

Origin	Antil	body
	PK	TTF1	GATA-3	THY	ERP	GCDFP	CEA	S-100
Lung	P	P	N	N	N	N	P	N
Thyroid	P	P	N	P	N	N	PN	PN
Breast	P	N	P	N	P	P	P	PN
Ovary (serous)	P	N	N	N	P	N	N	PN
Kidney	P	N	N	N	N	N	N	PN

CEA, Carcinoembryonic antigen; CK20, cytokeratin 20; ERP, estrogen receptor protein; GCDFP, gross cystic disease fluid protein; N, negative (<10% of cases); P positive (>80% of cases); PK, pan-keratin; PN, variably positive (10%-80% of cases); S-100, S-100 protein; THY, thyroglobulin; TTF1, thyroid transcription factor-1.

Table 18.3 Immunohistologic Differential Diagnosis Between Malignant Mesothelioma and Metastatic Adenocarcinoma

Tumor	Antib	ody
	PK	CK5/6	CEA	CD15	Ber-EP4	B72.3	CALR
Malignant mesothelioma	P	P	N	N	N	N	P
Adenocarcinoma	P	N	P	P	P	P	N

CALR, Calretinin; CEA, carcinoembryonic antigen; CK, cytokeratin; CK5/6, cytokeratin 5/6; N, negative (<10% of cases); P, positive (>80% of cases); PK, pan-keratin.

Clear Cell Adenocarcinomas

Clear cell features are best seen in histologic specimens, in which the cytoplasm of the neoplastic cells is lucent and only the cell borders are distinct. Clear cell change is often an artifact of formalin fixation, and in cytologic specimens, the cytoplasm of the neoplastic cells has a more vacuolated appearance. Primary clear cell tumors of the lung are rare and have variable cellular lineage; they are usually peripherally located.¹⁰⁹ Clear cell change also may be seen focally in common tumor types. For example, biopsy specimens of primary SCCs may show that alteration. Currently, the World Health Organization (WHO) classification of lung malignancies does not recognize a clear cell form of adenocarcinoma, as it had in the past; rather, it is considered a morphologic alteration that may present focally or diffusely in any form of adenocarcinoma. That phenomenon is seen less frequently in cytologic specimens, in which the cytoplasm of the neoplastic cells maintains a classic metaplastic appearance.

Figure 18.15 (A) Fine-needle aspirate of metastatic papillary thyroid carcinoma in the lung showing characteristic whorled cytomorphologic and nuclear features. (B) An isolated micrometastatic focus of papillary thyroid carcinoma in a surgical lung biopsy specimen shows characteristic nuclear features. (C) Metastatic nodule of thyroid carcinoma within the lung parenchyma showing colloid formation adjacent to papillary nests of tumor cells. (D) Microcalcification within a papillary focus of metastatic thyroid carcinoma.

Figure 18.16 (A) Metastatic clear cell carcinoma of the ovary showing glandular formations containing tumor cells with a "hobnail” appearance. (B) Immunostaining with CA-125 supports the müllerian origin of this tumor.

Figure 18.17 (A) Cytologic preparation of pleural fluid in a case of malignant epithelioid mesothelioma showing a micropapillary array of atypical mesothelial cells. (B) Subsequent biopsy confirmed the micropapillary nature of the neoplasm, as seen here. ([A] Courtesy Dr. Diva Salomao.)

Metastatic clear cell adenocarcinomas in the lungs may emanate from organs including the kidney, breast, adrenal cortex, salivary gland, or other locations; primary clear cell malignancies have been described in practically every organ. The most common clear cell neoplasm in the lung is metastatic renal cell adenocarcinoma (Figs. 18.18 and 18.19).¹¹⁰ Hughes and associates reported that among 12 lung FNA specimens with clear cell features, 10 originated in the kidney, 1 in the cervix, and 1 in an undetermined site.¹¹¹ Clear cell carcinomas are only a subset of renal tumors that may metastasize to the lungs; papillary, oncocytic, and sarcomatoid neoplasms may also do so. Because epithelial malignancies of the kidney have a proclivity for invading the renal veins and bypassing the hepatic circulation, the first site of secondary disease may be the lungs.^110,112 the pulmonary parenchyma is involved in up to 75% of cases of metastatic renal cell carcinoma.^112,113 Almost half of these patients have no symptoms that suggest extrathoracic disease (Fig. 18.20).^113,114118 Metastatic renal cell carcinoma is an example of a neoplasm that may grow very slowly and become clinically evident only many years after the primary diagnosis.¹¹⁹

As with ovarian carcinomas, clear cell carcinomas of the kidney are difficult to identify definitively by immunohistologic studies. Most are reactive for carbonic anhydrase-9, CD10, PAX2, adipophilin, renal cell carcinoma antigen, and cytokeratin 8 (Figs. 18.21 and 18.22). In combination, these are highly suggestive of the diagnosis.¹²⁰¹²³

Signet-Ring Cell Adenocarcinomas

A signet ring cell is relatively small and has an eccentrically placed nucleus indented by a large cytoplasmic vacuole or less often multiple vacuoles. Typically, their nuclei are crescentic in contour, darkly stained, and their ends may form sharply pointed tips. Signet ring cell differentiation is uncommon in most primary pulmonary adenocarcinomas. If it is present, a secondary malignancy is favored (Fig. 18.23). Sources of such metastases include the stomach and other gastrointestinal sites, breast, and pancreas. Metastatic signet ring cell carcinomas are usually associated with a dismal prognosis; they characteristically spread to regional lymph nodes before involving the lungs. Some esophageal signet ring cell tumors originating in foci of Barrett esophagus may directly invade the lung or pleura.¹²⁴ Multiple pulmonary nodules are virtually always seen rather than a solitary secondary lesion.¹²⁴ Primary lung adenocarcinomas with a signet ring component may well be associated with an anaplastic lymphoma kinase translocation.

Well-Differentiated Adenocarcinomas

The authors use the term well-differentiated adenocarcinoma in more than just a descriptive fashion to mean a malignant glandular proliferation that is morphologically difficult to differentiate from benign or reactive pulmonary proliferations. The current WHO definition of well- differentiated adenocarcinomas includes adenocarcinoma in situ, minimally invasive adenocarcinoma, and lepidic predominant adenocarcinomas.⁸⁸ the recognition of these tumors is often extremely difficult or even impossible in cytologic specimens because of the lack of contextual architecture and the low nuclear-to-cytoplasmic ratios and minimal nuclear atypia. Other tumors that may be considered low grade are the salivary gland neoplasms and low-grade fetal adenocarcinoma. However, well-differentiated adenocarcinomas in the lung may also be metastases, especially when sharply defined mass lesions are seen macroscopically. Sites of origin for secondary adenocarcinomas with these attributes include the breast, pancreas, kidney, thyroid, and salivary glands.

Figure 18.18 (A) Gross photograph of a lung with multiple intrapulmonary metastases of renal cell carcinoma that presented in the absence of a known primary tumor in the kidney. The masses have a yellowish appearance and are well demarcated from the surrounding lung parenchyma. (B) Typical arrangement of packeted clear cells in a highly vascularized stroma. (C) Clear cell tumor cells may be arranged in a trabecular pattern.

Figure 18.19 (A) Example of resected metastatic renal cell carcinoma that is more solid and includes tumor cells with an oncocytoid appearance. (B) A previous fine-needle aspirate in the same case shows fine cytoplasmic vacuolization, serving as a clue to the renal nature of the lesion.

Figure 18.20 (A) Chest radiograph from a patient with occult renal cell carcinoma presenting with metastasis to the pleura and lungs. The left hemithorax is partially opacified by metastatic tumor and an accompanying pleural effusion. (B) Computed tomography scan from another case shows widespread metastatic renal cell carcinoma involving the lung and pleura.

Figure 18.21 Immunoreactivity for PAX2 (A) and CD10 (B) in metastatic renal cell carcinoma. These markers are found in most malignant renal epithelial tumors.

Mammary carcinomas may metastasize to the lungs, pleura, or both. In most cases, the malignant cells are easily identified, but in some FNA or pleural fluid specimens, the malignant cells are bland; this is especially true of lobular carcinoma (Fig. 18.24).^{125 128} Fifty percent of metastatic breast cancers are associated with pleural effusions.^33,129 Casey et al. reported that 3% of primary mammary carcinomas were associated with a lung mass at the time of initial diagnosis; 43% of the pulmonary lesions were breast metastases, 52% were concurrent primary lung cancers, and the rest were nonneoplastic.¹²⁸ the lungs and pleura are the first sites of tumor recurrence in 10% of cases of mammary carcinoma.¹²⁷ In patients with a history of breast carcinoma and an adenocarcinoma in the lung, Raab and coworkers showed with immunohistochemical studies (for estrogen receptor, gross cystic disease fluid protein-15, S-100 protein, and carcinoembryonic antigen) that 50% of the pulmonary lesions were metastatic mammary tumors, 37% were primary pulmonary carcinomas, and 13% were indeterminate (Figs. 18.25 and 18.26).¹³⁰ Dabbs and associates found that some primary lung cancers may label for hormone receptor proteins but not for the other specified markers.¹³¹ Mammaglobin is another breast-related polypeptide that is valuable in the immunohistochemical recognition of metastatic mammary carcinoma.¹³² On the other hand, positivity for thyroid transcription factor-1 (TTF-1) and, to a slightly lesser extent, napscin-A (Fig. 18.27) is compelling evidence in favor of pulmonary derivation in this context, as discussed later. These two antibodies often parallel the positive and negative reactions in lung adenocarcinomas; we prefer TTF-1 due to its crisp nuclear reactivity. As antibodies directed against TTF-1, napscin-A, and GATA-3 were not available for the two previously cited studies, the indeterminant category was high compared to current testing. Recent on the horizon is GATA-3. This is positive in many breast cancers, including triple negative tumors, but not in lung adenocarcinomas.¹³³

Figure 18.22 Immunoreactivity for cytokeratin 8 in metastatic renal cell carcinoma. This keratin subtype is characteristic of nononcocytic tumors of the kidney.

Oncocytic and Granular Cell Carcinomas

Neoplasms composed of cells containing granular cytoplasm may be oncocytic or nononcocytic. Both subtypes contain cells that have an eosinophilic appearance on conventional stains. In oncocytic cells, this reflects the presence of numerous mitochondria. Nononcocytic cells instead contain a preponderance of other cytoplasmic organelles, especially lysosomes and neurosecretory granules. Primary pulmonary malignancies that may have a granular cell constituency include conventional adenocarcinomas, salivary gland-type adenocarcinomas, and carcinoids (grade 1 neuroendocrine carcinomas). However, this cytologic feature is rare in lung tumors. Secondary neoplasms with granular cytoplasm include carcinomas of the kidney, thyroid, and liver (Fig. 18.28).

The lungs are involved in up to 70% of cases of metastatic HCC.^134-136 Several patterns of intrapulmonary spread have been reported; through transdiaphragmatic lymphatics, HCC may enter the right lower lobe. In this setting, several parenchymal mass lesions and pleural involvement are typically present.^137,138 Alternatively, HCC may transit the venous system through the hepatic vein and inferior vena cava, manifesting as a large intravascular mass or “showering” the lungs with small emboli that appear as miliary tumors.¹³⁷ Cytologically, the cells of this neoplasm often show multinucleation; this feature is uncommon in most primary pulmonary malignancies. Moreover, bile may be seen in metastatic HCC (Fig. 18.29). In addition, the tumor cells cluster around intralesional blood vessels, endothelial wrapping, and “stripped” nuclei may be seen.¹³⁹ Pathologists must avoid misinterpretation of FNA specimens obtained from the right lower pulmonary lobe as well-differentiated oncocytic or granular cell carcinomas; these specimens may simply represent normal liver that has been mistakenly sampled instead of the lung. A monoclonal antibody raised against paraffin-embedded tissue from HCC, and designated Hep-PAR1, has shown reasonably good discrimination in labeling that tumor except when it is high grade.¹⁴⁰ Renal cell carcinomas may show prominent cytoplasmic granularity, especially in higher-grade clear cell carcinomas and chromophobe carcinomas.¹⁴¹ Helpful clues include a proportion of the malignant cells with optically clear cytoplasm, fine chromatin with well-developed nucleoli, prominent vasculature, perinuclear clear zones, and crenated nuclei.

Figure 18.23 (A) Metastatic adenocarcinoma in a fine-needle aspiration specimen showing focal signet ring cell differentiation with formation of cytoplasmic vacuoles. (B) the same feature is seen in this cell block preparation. The primary tumor was lobular carcinoma of the breast.

Figure 18.24 (A) Bland nuclear features are seen in this metastatic lobular carcinoma of the breast involving the lung parenchyma. (B) Metastatic ductal carcinoma with mucin-filled acinar structures and moderate nuclear atypia.

Figure 18.25 (A) Adenocarcinoma in the lung with a histologically indeterminate appearance. It is unclear morphologically whether the tumor is primary or secondary. (B) Immunoreactivity for gross cystic disease fluid protein-15, a breast marker, establishes the diagnosis of metastatic ductal mammary carcinoma.

Figure 18.26 Metastatic breast carcinoma in a pleural fluid preparation, showing intense immunoreactivity for estrogen receptor protein.

Figure 18.27 Immunoreactivity for thyroid transcription factor-1 in primary adenocarcinoma of the lung. This marker is present only in thyroid and pulmonary proliferations.

Figure 18.28 (A) Metastatic large cell carcinoma in the lung with a granular cytoplasmic appearance. (B) Cytoplasmic granules are more evident in a fine-needle aspiration specimen. The primary tumor was in the liver.

Figure 18.29 Multifocal bile formation (right) in metastatic hepatocellular carcinoma.

Largely Necrotic Adenocarcinomas

The most commonly necrotic primary tumors of the lung are SCC, small cell carcinoma, large cell carcinoma, and large cell neuroendocrine carcinoma. Except for the fleeting rare primary enteric adenocarcinoma, primary pulmonary adenocarcinomas rarely show this alteration unless they are very large or poorly differentiated. Thus statistically, necrotic adenocarcinomas are more likely to be secondary malignancies in the lungs. Metastatic colorectal carcinomas characteristically have central dirty necrosis cytologically regardless of the degree of differentiation. FNA and core biopsy specimens also show fusiform nuclei arranged in a “picket fence” pattern or in small glandular formations. Yet, other extrapulmonary tumors may yield the image of necrotic metastatic carcinoma.

In up to 50% of metastatic colorectal adenocarcinomas, the lungs are involved.¹⁴² Most show multiple pulmonary masses radiographically,¹⁴² but approximately 40% of all solitary metastases in the lung are also derived from the large intestine.^21,22 Right-sided colonic tumors especially may produce lung metastases without liver metastases.¹⁴³¹⁴⁶ These lesions are often cystic, and FNA specimens may be mistakenly interpreted as showing cavitary SCC. In histologic sections, zones of necrosis may be surrounded by limited numbers of viable tumor cells; in cytologic preparations, rare viable cells may be seen. Flint and Lloyd suggested that “dirty” (karyorrhectic) necrosis (Figs. 18.30 and 18.31) was more often seen in metastatic colorectal tumors than in primary adenocarcinomas of the lung.¹⁴⁷ Immunopathologic studies are often helpful in distinguishing secondary colonic malignancies from primary adenocarcinomas of the lung. Colorectal tumors generally are reactive for cytokeratin 20 but negative for cytokeratin 7 and TTF-1; the converse is true for primary pulmonary adenocarcinomas, even those that have an enteric morphologic image on conventional microscopy.¹⁴⁸¹⁵¹ Still, extremely rare primary colonic adenocarcinomas express TTF-1. A cytoskeletal protein known as villin is also selectively seen in gastrointestinal malignancies, as are the plasmalemmal glycoprotein recognized by monoclonal antibody CA-19-9 and the nuclear transcription factor CDX2 (Figs. 18.32 and 18.33).^{152 154}

Figure 18.30 (A) Metastatic colonic adenocarcinoma in the lung represented by a solitary lesion. (B) Microscopic appearance showing characteristically incomplete tumor glands and basally oriented tumor cell nuclei. Fine-needle aspiration biopsy of the nodule showing a tendency for parallel alignment of tumor cell nuclei (C) and the generic appearance of an adenocarcinoma (D).

Figure 18.31 (A and B) "Dirty” necrosis is apparent in the centers of tumoral glands in metastatic colonic adenocarcinoma.

Figure 18.32 Nuclear immunoreactivity for CDX2, a gut marker, in metastatic poorly differentiated colonic adenocarcinoma involving the lung.

Figure 18.33 Immunoreactivity for CA19.9, another gastrointestinal tract-related protein, in metastatic colonic adenocarcinoma.

Mucinous Adenocarcinomas

Primary mucin-producing carcinomas of the lung include some lepidic predominant adenocarcinomas, mucoepidermoid carcinomas, and other rare primary mucinous tumors, some of which have the appearance of colloid carcinomas (Fig. 18.34).¹⁵⁵ Most such tumors have relatively specific radiologic attributes, and when these images are absent and a mucinous carcinoma is seen microscopically, metastasis may be suspected. However, large amounts of postobstructive mucin production by the lung may surround nonmucinous malignancies. Thus pathologists should be cautious in interpreting FNA specimens containing carcinoma cells and abundant mucin as bona fide mucinous carcinomas. The most common sites of origin for metastatic mucinous adenocarcinomas are the intestine (including the vermiform appendix), ovary, and breast. Pathologic specimens of these secondary tumors in the lung may show rare malignant cells and copious mucin pools. The neoplastic cells are often well differentiated and are arranged in small clusters. The immunopathologie features of metastatic colorectal adenocarcinoma of the colloid type are essentially the same as those of ordinary colon cancers; this also applies to secondary mucinous breast carcinoma. However, mucinous ovarian carcinomas differ from other epithelial malignancies of the ovary immunophenotypically; they typically lack CA-125 and instead exhibit an enteric antigenic profile similar to that of intestinal neoplasms.¹⁵⁶

Other Metastatic Malignancies That Mimic

Adenocarcinomas of the Lung

The immunopathologic profiles of prostatic, endometrial, and adrenocortical carcinomas are shown in Table 18.1. Prostatic and endometrial tumors rarely metastasize selectively to the lungs^157,158; only 10% of prostatic carcinomas yield lung metastases,^159,160 and fewer than 3% of endometrial carcinomas do so.¹⁵⁸ Both of these malignancies usually first involve other sites, such as lymph nodes, bones, or liver.¹⁵⁷ When these lesions spread to the lungs, multiple masses usually are apparent.¹⁶¹ Metastatic prostatic carcinomas may produce endobronchial masses, lymphangitic carcinomatosis, or thoracic lymph nodal spread.^162-164 Antibodies to prostate-specific antigen, prostate-specific acid phosphatase, and prostate-specific membrane antigen are highly specific for tumors of prostatic origin (Figs. 18.35-18.37).¹⁶⁵ No fully specific markers are currently available to identify endometrial neoplasms. However, a recent predictive antigen, PAX-8, may be very helpful. Biopsy specimens of metastatic adrenocortical carcinoma may show lipidized cytoplasm in the tumor cells and extensive cellular dyshesion. The immunoprofile of this neoplasm is unusual in that it features scant keratin production (if any), vimentin reactivity, and labeling for inhibin, MART-1/Melan-A (Figs. 18.38 and 18.39), or both, despite S-100 protein negativity.

Figure 18.34 Metastatic colloid carcinoma (mucinous adenocarcinoma) from the rectum involving the lung. Narrowly branching profiles of tumor cells are suspended in pools of extracellular mucin in a fine-needle aspiration specimen (A) and in tissue sections (B and C). These images are highly suggestive of metastasis rather than a primary pulmonary tumor.

Inhibin and MART-1 are typically associated with ovarian stromal tumors and melanocytic proliferations, respectively. Why they should be present in an epithelial tumor is unknown, but their presence makes adrenocortical carcinoma a singularly identifiable form of metastasis in the lung.

Pleomorphic Carcinomas (current WHO term). The most common primary pulmonary malignancy with a spindle cell or pleomorphic growth pattern is pleomorphic carcinoma that is always high grade. It must be distinguished from primary and metastatic sarcomas and other types of malignant spindle cell tumors (e.g., sarcomatoid mesothelioma and spindle cell melanoma). Pathologic specimens of these tumors often show foci of spindle cell growth admixed with areas of more obvious epithelial differentiation term no longer used by WHO, but examples with no epithelioid components are also seen (Figs. 18.40 and 18.41).

Figure 18.36 Immunoreactivity for prostate-specific antigen in metastatic prostatic adenocarcinoma.

Figure 18.37 Immunoreactivity for prostate-specific membrane antigen in metastatic prostatic adenocarcinoma.

Figure 18.39 Immunoreactivity was seen for inhibin (A) and MART-1 (B) in the tumor shown in Fig. 18.38B, consistent with an adrenocortical origin.

Figure 18.40 Simplified report of genetic homology between a metastatic carcinoma of unknown origin in the lung and a reference group of carcinomas in various anatomic sites.

Figure 18.41 (A) Metastatic biphasic sarcomatoid carcinoma of thyroidal origin involving the lung. (B) Another view of the lesion shows the juxtaposition of sarcoma-like elements, including rhabdomyoblasts (top left) and obvious carcinoma (bottom right).

Pleomorphic carcinomas may include homologous or heterologous foci of divergent mesenchymal-like differentiation (Figs. 18.42 and 18.43). Primary neuroendocrine carcinoma, especially spindle cell carcinoid, may also enter the differential diagnosis, but pleomorphic carcinomas do not show the nuclear features in these neuroendocrine lesions such as bland and distinctly granular chromatin; furthermore, cellular pleomorphism is far less evident.

The immunophenotypes of specific spindle cell tumors in the lung are shown in Table 18.4.¹⁶⁶ In practice, the number of antibodies applied in immunohistologic studies varies according to the clinicopathologic setting. The ultimate diagnosis of sarcomatoid pulmonary lesions may require extensive adjunctive pathologic analysis.

Most patients with clinically apparent metastatic intrapulmonary spindle cell malignancies have metastatic sarcomas. Secondary spindle cell carcinomas in the lungs are more unusual.¹⁶⁷ In most cases of metastatic sarcoma in the lungs, a history of the tumor is well known when pulmonary involvement becomes apparent. Solitary sarcomatous lesions of the lung and pleura are more difficult to recognize diagnostically, as the sarcoma morphotypes that occur primarily in these locations are also seen in extrathoracic tissues and organs.

Extrathoracic sarcomas are associated with a high incidence of pulmonary metastasis. Autopsy series have found involvement of the lungs in up to 95% of cases.^168,169 Most metastatic sarcomas form multiple nodules in the pulmonary parenchymal and/or pleural surfaces, although solitary or multifocal endobronchial disease occasionally is seen.^170-176

Metastatic uterine smooth muscle tumors deserve special mention. Both high-grade leiomyosarcomas (LMSs) and low-grade myogenous tumors of the uterus (sometimes termed metastasizing leiomyomas) may spread secondarily to the lungs.^177-179 In either instance, multiple and occasionally cystic nodular lesions are seen in the parenchyma and pleura; in rare cases, the metastatic tumor assumes a miliary pattern.^180,181 Metastases of uterine smooth muscle neoplasms are usually seen in women of reproductive age or older,^182,183 but secondary intrapulmonary LMS has also been reported in men with primary soft tissue tumors.¹⁸² Many of these patients have no symptoms, although dyspnea, cough, and cyanosis can be present. Some lesions may lead to respiratory failure.^182,184 Large smooth muscle tumors can yield neoplastic emboli and tumor-related pulmonary infarction.¹⁸⁵

Grossly, metastatic smooth muscle tumors are white and well circumscribed with a “whorled” cut surface. Histologically, the constituent spindle cells may have a bland appearance, especially in metastasizing uterine leiomyomas. In these lesions, mitoses are rare or absent (Fig. 18.44).^182,183 Other examples of secondary LMS are easily recognized as malignant lesions due to the high degree of nuclear atypia and mitotic activity.

Figure 18.42 Metastatic monophasic sarcomatoid carcinoma comprising fusiform cells with no obvious sign of epithelial differentiation. Distinction from carcinoma is virtually impossible with conventional morphologic studies.

Figure 18.43 Divergent osseous differentiation is seen in this metastatic sarcomatoid carcinoma of uterine origin, involving the lung.

Table 18.4 Immunohistologic Differential Diagnosis of Spindle Cell Malignancies in the Lung

Tumor	Antibod]	y
	VIM	CEA	PK	ACT	CALR	CD31	CD34	S-100	MART	CD99	EMA
Sarcomatoid carcinoma	P	PN	PN	N	N	N	N	N	N	N	PN
Mesothelioma	P	N	PN	PN	PN	N	N	N	N	PN	PN
Melanoma	P	N	N	N	N	N	N	P	PN	PN	N
Synovial sarcoma	P	PN	PN	PN	PN	N	N	N	N	PN	PN
MPNST	P	N	PN	PN	PN	N	PN	PN	N	N	PN
Leiomyosarcoma	P	N	PN	P	N	N	PN	N	N	N	N
Angiosarcoma	P	PN	PN	PN	N	PN	PN	N	N	N	N
Kaposi sarcoma	P	N	N	PN	N	PN	P	N	N	N	N
PLUS	P	N	PN	PN	N	N	PN	N	N	PN	PN

ACT Actin; CALR, calretinin; CEA, carcinoembryonic antigen; EMA, epithelial membrane antigen; MART MART-1; MFH, malignant fibrous histiocytoma; MPNST malignant peripheral nerve sheath tumor; N negative (<10% of cases); P positive (>80% of cases); PK, pan-keratin; PLUS, pleomorphic undifferentiated sarcoma; PN variably positive (10%-80% of cases); S-100, S-100 protein; VIM, vimentin.

Some authors have suggested that metastasizing leiomyomas are actually multifocal pulmonary hamartomas rather than metastatic tumors. That argument has focused on the bland appearance of the smooth muscle cells, the lack of mitoses, and the occasional presence of admixed glandular elements. Even so, the authors believe that metastasizing leiomyomas are a separate pathologic entity,¹⁸² based partly on aggregated clinicopathologic information. Most patients with such lesions have a history of surgical removal of uterine smooth muscle tumors (usually diagnosed as leiomyomas) or neoplasms of that type are found at autopsy. Synchronous metastatic implants have also been seen in abdominal, retroperitoneal, and pelvic soft tissue and lymph nodes in women who have metastasizing leiomyomas in the lungs.¹⁸⁶ the argument that these intrapulmonary smooth muscle tumors are derived from uterine lesions gained strong support from a study by Patton and colleagues.¹⁸⁷ Through paired analysis of uterine and pulmonary neoplasms in the same patients, they showed that the lesions were clonal by assessing a nucleotide sequence from the human androgen receptor gene and measuring telomere lengths. Metastasizing leiomyomas must be distinguished from lymphangioleiomyomatosis.

Malignant Small Round Cell Tumors

Malignant small round cell tumors (small blue cell malignancies) prototypically are composed of cells with round to oval nuclei, scant cytoplasm, and often extensive cellular dissociation. Scanning microscopy often shows a “sheet” of nuclei. An organoid growth pattern is also potentially apparent (Figs. 18.45 and 18.46). The primary pleuropul- monary lesions in this category include neuroendocrine carcinomas, malignant lymphomas, and very rare malignancies, such as Askin tumor or small cell mesothelioma. Metastatic small round cell tumors also include neuroendocrine carcinomas of extrapulmonary sites and malignant lymphomas, but additional sarcomas and other tumor types must also be considered (e.g., malignant melanoma, rhabdomyosarcoma [RMS], mesenchymal chondrosarcoma, small cell osteosarcoma, hepatoblastoma, neuroblastoma [NB], and Wilms tumor). Selected primary and secondary nonneuroendocrine carcinomas also may have a small cell composition.¹⁸⁸’¹⁸⁹

The most common primary intrathoracic small round cell malignancy is small cell carcinoma of the lung (SCCL).¹⁸⁹ This tumor is histologically and cytologically identical to small cell carcinoma originating in other sites (Figs. 18.47 and 18.48). Clinically, most SCCLs are centrally located and accompanied by enlarged mediastinal lymph nodes; they quickly metastasize and are usually advanced in stage at diagnosis. Regardless of their anatomic origins, metastatic foci of small cell neuroendocrine carcinoma (SCC) are typically characterized radiographically by multiple intrapulmonary masses; mediastinal involvement is often lacking when the tumor has arisen outside the lungs. The morphologic features of these lesions include darkly stained, granular dispersed nuclear chromatin, nuclear fragility, nuclear molding, cellular clumping, and necrosis. Those attributes are generally associated with neuroendocrine differentiation. Immunopathologically, SCCs often show a characteristic reactivity pattern for keratin, with dot-like perinuclear labeling. They may or may not show additional positivity for synaptophysin, chromogranin-A, CD56, and CD57. Byrd-Gloster and coworkers reported that 97% of SCCLs were reactive for TTF-1, whereas most (but not all) SCCs of nonpulmonary derivation lacked that marker.¹⁹⁰ However, it is recognized that at least 60% of prostate small cell carcinomas are positive for TTF-1.¹⁹¹ On the other hand, cytokeratin 20 positivity is potentially seen in primary extrathoracic SCCs, but it is uncommon in primary pulmonary small cell carcinoma.^192,193 SCC of the lung and other sites may also contain a non-small cell component (combined SCCL).

Figure 18.44 (A to C) Metastasizing leiomyoma of the uterus involving the lung. There is no appreciable nuclear atypia or mitotic activity in this bland spindle cell proliferation.

Figure 18.45 (A) Fine-needle aspiration biopsy of a primitive neuroectodermal tumor metastatic to the lungs from a primary site in the chest wall. Relatively uniform small cells mold to one another and show small nucleoli with dispersed chromatin. (B) the original biopsy specimen shows sheets of small round cells transected by a delicate fibrovascular stroma.

Figure 18.46 Primitive rose The formation is apparent in a primitive neuroectodermal tumor.

Figure 18.47 Metastatic Merkel cell carcinoma of the skin involving the lung. Fine-needle aspirate shows tumor cells with scant cytoplasm and nuclear molding.

Metastatic well- or moderately differentiated neuroendocrine carcinomas in the lung include low-grade neuroendocrine carcinomas of gastrointestinal, uterine cervical, pancreas, parathyroid, and thyroid (medullary) derivations (Fig. 18.49).^194,195 Many of those tumors are associated with specific symptoms related to their production of neuropeptides or amines. However, in histologic or cytologic specimens, such lesions are potentially identical to primary neuroendocrine neoplasms of the lung. Data on discriminating immunostains are still evolving for this group of tumors, but TTF-1 reactivity may favor a pulmonary origin.^196-199

Primary pulmonary lymphomas are discussed in Chapter 15, but most malignant lymphoid tumors of the lung are secondary lesions that occur in the context of systemic dissemination. Primary malignant lymphomas in this organ are typically low grade, whereas secondary hematolymphoid malignancies may represent any histologic subtype and grade. For example, 30% of patients with mediastinal Hodgkin

lymphoma have lung involvement by direct extension.²⁰⁰ Malignant lymphomas that secondarily affect the pulmonary parenchyma are not believed to be truly metastatic, because they may populate lymphoid structures that are normally present in the lungs and pleura. One form of lymphomatous involvement is characterized by diffuse interstitial lymphocytic permeation with focal formation of micronodules (Fig. 18.50).^201,202 When the constituent cells are relatively mature, the image of lymphocytic interstitial pneumonia may be obtained. However, discrete nodules also may occur, especially with high- grade large cell neoplasms (Fig. 18.51), and these commonly simulate metastatic nonhematopoietic lesions clinically, radiologically, and pathologically.

Involvement of the pleura may be unilateral or bilateral in malignant lymphoma. Lymphoma and metastatic carcinoma are the two most common causes of malignant bilateral pleural effusion.⁴⁰ In cytologic practice, it is difficult to be certain that effusion specimens containing atypical lymphoid cells are definitively positive for lymphoma; such cells may represent contamination of the sample by lymphocytes from the peripheral blood, and especially when they are relatively mature, discrimination from other causes of lymphoid pleural effusion depends mainly on the findings of adjunctive studies.²⁰³ Flow cytometry is probably optimally suited for this application.²⁰⁴

In the pediatric age group, some small round cell malignancies may metastasize to the lungs, as cited earlier (Fig. 18.52). Immunohistochemical studies and cytogenetic analyses are helpful in differentiating these lesions in difficult cases.¹⁸⁸ Table 18.5 shows the immunopatho- logic profile of several primary and secondary small round cell tumors.¹⁸⁸

Squamous Cell Carcinomas and Morphologic Simulants

The differential diagnosis of primary SCCs of the lung obviously includes secondary carcinomas with squamous differentiation and other epithelioid malignancies with metaplastic or “hard” eosinophilic cytoplasm. Examples are transitional cell carcinoma and some malignant melanomas.

Based on morphologic findings alone, the site of origin for SCC is impossible to determine with certainty (Figs. 18.53 and 18.54). Most squamous carcinomas in the lung have arisen There , and although multifocal SCCs suggest metastatic disease, that picture is also seen with multiple primary synchronous lung carcinomas. The usual sources of metastastic SCC in the lung are mucosal sites of the head and neck, esophagus, uterine cervix, and skin.

SCCs of the head and neck that involve the lungs may originate in the larynx, nasopharynx, oropharynx, or hypopharynx, and lesions in the lungs may be single or multiple.^85,205,206 As all of these tumors are associated with the use of alcohol or tobacco or with infection with human papillomavirus (HPV), patients with SCC in site also commonly have separate metachronous or synchronous primary squamous malignancies in other mucosal sites or in the lungs.²⁰⁷ In patients with both pulmonary lesions and SCC in the head or neck, Malfetto and colleagues reported that 53% had separate primary bronchogenic carcinomas and 19% had metastatic SCC in the lung.²⁰⁷ Cervical lymph nodal involvement is also present in up to 80% of cases of metastatic intrapulmonary SCC.^85,86 the cumulative incidence of second malignancies in patients who have SCC of the head and neck is approximately 4% per year, and 30% of these tumors arise in the lungs.²⁰⁸

Almost all cervical carcinomas are related to prior HPV infection. A large proportion of SCCs arising in the oropharynx have a similar origin. On the other hand, HPV only rarely is implicated in primary lung SCC. Thus testing for HPV in a tumor may be helpful in distinguishing a primary versus a metastatic neoplasm. One may also use p16 immunohistochemistry as a surrogate marker of HPV infection and intergration.

Figure 18.50 Micronodular arrays of small lymphocytes are seen in the pulmonary interstitium in this example of mucosal-type lymphoma involving the lungs.

Figure 18.51 Nodules of anaplastic polygonal cells are seen in this case of large cell non-Hodgkin lymphoma involving the lungs.

Figure 18.52 Metastatic alveolar rhabdomyosarcoma in the lung in a child. The tumor is composed of sheets of small round undifferentiated cells. (A) Fine-needle aspirate. (B) Biopsy specimen.

Figure 18.53 Metastatic well-differentiated (A) and moderately differentiated (B) squamous cell carcinoma of the head and neck involving the lungs. These tumors cannot be distinguished reliably from primary squamous pulmonary carcinomas.

Table 18.5 Immunohistologic Differential Diagnosis of Small Round Cell Malignancies in the Lung

Tumor	Antibodie:	s
	VIM	PK	S-100	TTF1	CD45	CD56	DES	SYN	CD
Small cell carcinoma	N	P	N	P	N	PN	N	PN	PN
Rhabdomyosarcoma	P	N	N	N	N	N	P	N	PN
Non-Hodgkin lymphoma	P	N	N	N	P	N	N	N	N
Melanoma	P	N	P	N	N	N	N	N	N
Ewing sarcoma/PNET	PN	N	N	N	N	PN	N	PN	P
Metastatic NE carcinomas	N	P	N	PN	N	PN	N	PN	PN
Metastatic neuroblastoma	PN	N	N	N	N	P	N	P	N

DES, Desmin; N, negative (<10% of cases); NE, neuroendocrine; P positive (>80% of cases); PK, pan-keratin; PN variably positive (10%-80% of cases); PNET primitive neuroectodermal tumor; S-100, S-100 protein; SYN synaptophysin; TTF1, thyroid transcription factor-1; VIM, vimentin.

Figure 18.54 (A) the fine-needle aspiration biopsy image of these tumors is comparable in primary and secondary lesions. (B) Hierarchical segregation of gene sets allows for diagnostic separation of primary from secondary squamous carcinomas in the lung.

Sostman and Matthay reported that uterine cervical SCCs spread to the lungs less frequently (4%) than cervical adenocarcinomas do (20%).²⁰⁹ In most cases, single or multiple lesions are present, and as with all SCCs, there is a tendency toward cavitation.^210,211 Metastatic cervical SCC also may involve pulmonary hilar or mediastinal lymph nodes, endobronchial mucosal sites,^212,213 or the intrapulmonary lymphatics.²⁹,²¹⁴

Gene profiling has also been used in this context to differentiate metastatic SCC from primary pulmonary SCC. Vachani and coworkers²¹⁵ used a selected 10-gene panel, achieving 96% accuracy among 122 cases. A hierarchical segregation of the genes in that data set is shown in Fig. 18.54. Girard and associates showed that the same end can be achieved by scrupulous histologic assessment, focusing on tumor grade, cytologic features, stromal patterns, and the extent of necrosis.²¹⁶ In that study, the concordance between histologic predictions and genomic profiling was approximately 90%.

In the setting of an intraoperative consultation, one is often asked to decide whether a solitary squamous lung tumor is primary or metastatic in a patient with a history of squamous carcinoma elsewhere. If the radiographic and macroscopic features of the lesion are indeterminate, it is the authors’ practice to defer the answer until later. The surgeon is then counseled to perform a procedure that is conservative but would be sufficient in the treatment of a primary lung carcinoma (e.g., wedge excision), with the working premise that the neoplasm is primary. If the neoplasm proves to be metastatic after further studies are obtained, no harm has been done to the patient. The same approach applies to tumors with nonsquamous lineages, especially if microscopic sections of previous malignancies are unavailable for comparison.

Metastatic melanoma has a myriad of histologic and cytologic appearances. For this reason, it may be considered in the differential diagnosis with selected adenocarcinomas, malignant small round cell tumors, spindle cell neoplasms, large polygonal cell malignancies, and even some SCCs. The appearance of single cells with metaplastic cytoplasm, large, often eccentric ovoid nuclei, and prominent nucleoli is common in the cytologic evaluation of malignant melanoma (Figs. 18.55 and 18.56). Melanin production is a helpful clue to the identity of this tumor (Fig. 18.57), but it may be confused with other pigments, such as hemosiderin, and it requires histochemical verification. A history of ocular, cutaneous, or mucosal melanoma is often known when that neoplasm involves the lungs metastatically. However, some metastatic melanomas represent the initial sign of that tumor.

Figure 18.55 Metastatic malignant melanoma in the lung parenchyma. The tumor is composed of large anaplastic polyhedral cells; melanin pigment is scarce.

Virtually all examples of melanoma in the lungs and pleura are metastatic; only anecdotal examples of primary pulmonary malignancies with melanocytic differentiation have been documented.²¹⁷ Metastatic melanomas usually involve multiple organs; DasGupta and Brasfield found that the lungs were involved in 70% of cases.²¹⁸ Secondary lesions usually have multiple intrapulmonary nodules, but solitary lesions, lymphangitic or miliary disease, or endobronchial implants may also be seen.^219-222 Balch and coworkers reported that a solitary pulmonary mass was the first evidence of metastatic disease in 38% of cases.²²³ Conversely, Pogrebniak and colleagues found that 33% of lung nodules in patients with melanoma were unrelated and benign.²²⁴

Metastatic urothelial (transitional cell) carcinomas (TCCs) of the urinary tract often have a squamoid cytoplasmic appearance, and true squamous differentiation also may be seen. Cytologic specimens show extensive cellular dyshesion and necrosis. Some authors have reported that cercariform cells containing nucleated globular bodies and bulbous cytoplasmic processes suggest metastatic TCC.^102,225 These tumors often form mass lesions in the lungs and also can spread lymphangitically.

Table 18.6 shows the immunopathologic profile of SCCs based on their sites of origin; the immunophenotypes of their morphologic mimics are also included. If metastatic melanoma is included in the differential diagnosis, it can be easily characterized by its reactivity for S-100 protein, HMB-45, MART-1, and tyrosinase.²²⁶ Urothelial carcinomas may label for cytokeratin 20 but are negative for cytokeratin 7 in some cases; this profile is the opposite of that seen in primary pulmonary adenocarci- noma.^150,227-229 Thrombomodulin (CD141) is potentially shared by both of the latter tumors, but it is more commonly present in TCC. Similarly, p63 protein is present in TCC but not in most adenocarcinomas. SCCs of all sites share with TCC the potential for thrombomodulin and p63 reactivity, but the two may be distinguished by selective immunoreactivity for uroplakin in TCC.²³⁰ Perhaps the best marker of urothelial origin is GATA-3.²³¹

Undifferentiated Large Polygonal Cell Malignancies

Undifferentiated large polygonal cell tumors of the lung include primary large cell carcinomas, malignant lymphomas, metastatic melanoma, metastatic germ cell tumors, metastatic pleomorphic undifferentiated sarcoma, metastatic epithelioid sarcoma, metastatic alveolar soft tissue sarcoma (ASPS), and metastatic adrenocortical carcinoma. The diagnostic difficulty related to this group of tumors is associated with their anaplastic appearance, which often defies a determination of basic lineage.

Table 18.6 Immunohistologic Differential Diagnosis of Squamous Cell Carcinomas and Their Potential Simulators

Tumor	Antiboc	<y
	TBM	CK5/6	S-100	EMA
Squamous cell carcinoma of lung	PN	P	N	PN
Squamous cell carcinoma of cervix	PN	P	N	PN
Squamous cell carcinoma of head and neck	PN	P	N	PN
Squamous cell carcinoma of esophagus	PN	P	N	PN
Melanoma	N	N	P	N
Transitional cell carcinoma	P	P	N	P
"Squamoid” hepatocellular carcinoma	N	N	N	N

CK5/6, Cytokeratin 5/6; EMA, epithelial membrane antigen; N, negative (<10% of cases); P positive (>80% of cases); PN, variably positive (10%-80% of cases); S-100, S-100 protein; TBM, thrombomodulin. I would split p63 from CK5/6 & add p40 to p63. Would add p16 which would be + on in cervical ca.

Ultrastructural studies have shown that primary large cell carcinomas of the lung often show squamous or, more often, glandular differentiation; these features may be seen focally in histologic or cytologic preparations. As their name implies, the cells that make up these tumors contain a relatively large amount of cytoplasm and correspondingly large nuclei. In cytologic specimens, some large cell carcinomas show significant cellular dyshesion (Fig. 18.58). Clinically, they are often bulky masses associated with mediastinal lymphadenopathy. Primary large cell carcinomas of the lung have an immunopathologic profile that is similar to that of other primary non-small cell carcinomas but are negative for TTF-1, napscin-A, p63, and p40.

Figure 18.57 (A) Melanin pigment is seen in this fine-needle aspirate of metastatic melanoma. (B) the tumor is amelanotic in the cytologic cell block preparation.

Many of the other neoplasms in the differential diagnosis were discussed previously. Sarcomas that imitate primary large cell carcinomas have an epithelioid appearance, but except for epithelioid sarcoma and epithelioid synovial sarcoma, they are nonreactive for keratin immunohistochemically.^230,232,233

Poorly differentiated adrenocortical carcinomas may show lipidized cytoplasm, which is an unusual feature in primary large cell carcinoma. The most common metastatic germ cell malignancies that simulate primary pulmonary large cell carcinoma are embryonal carcinoma (Fig. 18.59) and choriocarcinoma. When these neoplasms metastasize, they are often admixed with other germ cell components, such as seminoma or teratoma, features that help to distinguish them from other large polygonal cell tumors. The clinical history of patients with secondary germ cell lesions is often distinctive, vis-à-vis that which accompanies primary lung cancers. Metastatic germ cell cancers are most commonly seen in young individuals,²³⁴ whereas primary large cell carcinomas more often occur in older patients with a significant smoking history.^235,236

The histologic image of metastatic germ cell tumors is often sufficient for their definitive recognition, especially when it includes two or more morphologic subtypes of such lesions. Moreover, yolk sac tumor commonly shows distinctive intercellular and intracytoplasmic eosinophilic globules, and choriocarcinoma is singular in its biphasic composition by cytotrophoblastic and syncytiotrophoblastic elements (Fig. 18.60). Nevertheless, the existence of primary somatic carcinomas of the lung with areas resembling germ cell tumor confounds the evaluation of these lesions.²³⁷

Figure 18.58 (A) Primary large cell undifferentiated carcinoma of the lung showing sheets of anaplastic tumor cells with no distinguishing characteristics. (B) Fine-needle aspiration specimen in the same case shows no evidence of squamous or glandular differentiation.

Figure 18.59 (A) Chest radiograph showing metastatic solid embryonal carcinoma of the testis involving the lung. Findings on fine-needle aspiration (B) and subsequent biopsy (C) led to a diagnosis of metastatic embryonal carcinoma. The tumor is morphologically similar to that shown in Fig. 18.58, but immunoreactivity for alpha-fetoprotein (D) and the patient's history confirmed metastatic embryonal carcinoma.

Table 18.7 shows the immunopathologic profile of specific large polygonal cell tumors. The panel of antibody reagents is particularly helpful in distinguishing primary large cell carcinoma from its diagnostic alternatives. However, there may be antigen overlap. For example, placental-like alkaline phosphatase is seen in most germ cell tumors, and it is occasionally present in primary large cell carcinomas.²³⁸ CD117 and CD30 are also selective markers for seminoma and embryonal carcinoma, respectively (Fig. 18.61). Those lesions may be distinguished from somatic tumors by their differential expression of epithelial membrane antigen; it is present in primary lung cancers but not in germ cell malignancies.^89,238 CD45 is restricted to large cell lymphoma (Fig. 18.62). MART-1 is limited to melanoma and adrenocortical carcinoma, and except for epithelioid sarcoma and clear cell sarcoma, metastatic mesenchymal neoplasms are typified by positivity for vimentin but are devoid of keratin and melanocyte-related markers.

Other Adjunctive Pathologic Techniques for the Diagnosis of Metastatic Carcinoma

Although EM has been used less and less in recent years in the diagnosis of tumors in surgical pathology, it still has considerable value in that context. ’Hiere are several settings in the evaluation of possibly metastatic tumors in the lung where ultrastructural studies are useful.^239-249 Adenocarcinomas, including those arising in the pulmonary parenchyma, are characterized generically by short, nonbranched plasmalemmal microvilli with a length-to-diameter ratio of less than 10 : 1 (Figs. 18.63 and 18.64).^250-252 Specialized features of specific lesions in that category include laminated cytoplasmic granules (primitive surfactant bodies) in some examples of primary lung adenocarcinoma (Fig. 18.65); cytoplasmic mucin granules and terminal webs of intermediate filaments that insert into the microvilli in adenocarcinomas with enteric differentiation (Fig. 18.66); glycogen pools and lipid droplets in metastatic renal cell carcinomas (Fig. 18.67); and tubular cristae in the mitochondria of steroid-producing tumors, such as adrenocortical carcinoma (Fig. 18.68).^{242,243,247,248} Malignant mesothelioma is typified by elongated, bushy, branching microvilli with an length-to-diameter ratio of greater than 10 : 1, together with complex desmosomal complexes and cytoplasmic tonofilaments (Figs. 18.69 and 18.70).^250-252 Mucin granules and surfactant bodies are absent in mesotheliomas.

Figure 18.61 Immunoreactivity for CD30 (A) and OCT3/4 (B) in metastatic embryonal carcinoma of the testis involving the lung. These markers are not expected in primary pulmonary tumors.

Table 18.7 Immunohistologic Differential Diagnosis of Large Polygonal Cell Malignancies in the Lung

Tumor	Anti	body
	PK	VIM	CD45	EMA	MART	S-100	PLAP
Primary large cell carcinoma of lung	P	PN	N	P	N	PN	PN
Metastatic epithelioid sarcoma	P	P	N	P	PN	N	N
Large cell lymphoma	N	P	P	N	N	N	N
Metastatic melanoma	N	P	N	N	P	P	N
Metastatic embryonal carcinoma	P	PN	N	N	N	N	P
Metastatic PLUS	N	P	N	N	N	N	N
Metastatic adrenocortical carcinoma	N	PN	N	N	N	N	N
Metastatic hepatocellular carcinoma	P	N	N	N	N	N	N
Metastatic renal cell carcinoma	P	PN	N	P	N	N	N

EMA, Epithelial membrane antigen; MART, MART-1; Met., metastatic; N, negative (<10% of cases); P positive (>80% of cases); PK, pan-keratin; PLAP, placental-like alkaline phosphatase; PLUS, pleomorphic undifferentiated sarcoma; PN, variably positive (10%-80% of cases); S-100, S-100 protein; VIM, vimentin.

Neuroendocrine carcinomas may be identified with certainty because of their synthesis of dense-core (neurosecretory) granules measuring 150 to 400 nm in diameter. Those inclusions have peripheral zones of lucency and tend to be clustered in the cytoplasm (Fig. 18.71), often near the Golgi apparatus.^239-242 Macular intercellular junctional complexes are also evident in such lesions, and small whorls of perinuclear intermediate filaments are common. These characteristics are the same regardless of the site of origin of neuroendocrine tumors; thus EM cannot be used to distinguish primary pulmonary lesions from metastases.

Germ cell tumors exhibit ultrastructural characteristics that potentially simulate those of somatic carcinomas. Seminomas are undifferentiated at a fine structural level, showing only primitive appositional intercellular junctional complexes, prominent nucleoli, and the usual constituency of basic metabolic organelles (Fig. 18.72). One salient feature of these tumors is the presence of cytoplasmic glycogen pools, but those are shared by many nongerminal tumors.²⁴² Embryonal and yolk sac carcinomas largely resemble somatic adenocarcinomas, including the formation of plasmalemmal microvilli and intercellular gland-like spaces (Fig. 18.73). Choriocarcinomas are relatively distinctive ultrastructurally and show cytoplasmic tonofibrils reminiscent of those seen in squamous tumors.²⁴⁶

Figure 18.62 Immunoreactivity for CD45, a marker restricted to hematopoietic proliferations, in large cell non-Hodgkin lymphoma involving the lung.

Figure 18.63 Electron photomicrograph of primary pulmonary adenocarcinoma showing prominent intercellular junctions bordering a tumor gland microlumen. Short nonbranching plasmalemmal microvilli are also apparent.

Figure 18.64 Short cell surface microvilli and cytoplasmic mucin granules are seen in this metastatic adenocarcinoma with mucinous features arising in the breast.

Nonepithelial malignancies with specific electron microscopic attributes include RMS, LMS, ASPS, NB, melanoma (and clear cell sarcoma) (MEL), and angiosarcoma (AS).²⁵³ These neoplasms show primitive sarcomeric differentiation with thick and thin cytoplasmic myofilaments (RMS) (Fig. 18.74), cytoplasmic skeins of thin filaments punctuated by dense bodies (LMS), paracrystalline cytoplasmic inclusions (ASPS) (Fig. 18.75), complex interdigitating cytoplasmic extensions containing microtubules (NB) (Fig. 18.76), premelanosomes (MEL) (Fig. 18.77), and Weibel-Palade bodies (AS) (Fig. 18.78). All of these structures are absent in primary pulmonary tumors except for sarcomatoid carcinomas. These lesions show a mixture of cells with epithelial characteristics (e.g., intercellular junctions, tonofibrils, microvilli) and others with mesenchymal attributes (Figs. 18.79 and 18.80).^244,253

Figure 18.65 Lamellated "myelinoid” figures are seen in the cytoplasm of tumor cells in this primary pulmonary adenocarcinoma. These structures may represent primitive surfactant bodies.

Figure 18.66 A terminal web of thin filaments inserts into the plasmalemmal microvilli in the tumor cells of this metastatic colonic adenocarcinoma. This structure is highly suggestive of an enteric anatomic origin.

Hematopoietic proliferations are perhaps the most primitive at an electron microscopic level. They show only basic cytoplasmic constituents and often contain abundant dispersed ribosomes, with or without rough endoplasmic reticulum, but lack other distinguishing features (Fig. 18.81).²⁴⁸,²⁵⁴

Cytogenetic information is rapidly accumulating on a variety of tumor types, and it holds the promise of serving as helpful differential diagnostic data. For example, several neoplasms have unique chromosomal abnormalities that exclude other possibilities. These include deletions of the short arm of chromosome 3 in renal cell carcinoma, an unrelated deletion in the same chromosomal segment in primary SCCL, the t(11;22) translocation in primitive neuroectodermal tumor/ Ewing sarcoma, the t(1;13) or t(2;13) translocation in alveolar RMS, the t(12;22) translocation in clear cell sarcoma, the der(17)t(X;17) translocation in ASPS, the t(X;18) translocation in synovial sarcoma, isochromosome 12p in germ cell malignancies, and a group of semispecific or specific karyotypic abnormalities in malignant lymphomas and leukemias.^255-266 These markers are best assessed with fresh tissue, but assays based on polymerase chain reaction or fluorescent in situ hybridization studies are available for use in hospital practice and are more practical.

Figure 18.67 (A) Numerous lipid droplets are seen in the tumor cell cytoplasm in this metastatic renal cell carcinoma. (B) Another area of the same tumor shows abundant cytoplasmic glycogen.

Figure 18.68 Tubular mitochondrial cristae are seen in this metastatic adrenocortical carcinoma.

Figure 18.69 Electron photomicrograph of malignant mesothelioma of the pleura showing branching, bushy cell surface microvilli and elaborate, elongated intercellular junctional complexes.

Outcomes Analysis

Optimal diagnostic testing strategies, principally pertaining to the sequence of tests, are controversial regarding the assessment of patients with pulmonary lesions that are suspicious for metastases. In countries with available resources, a definitive diagnosis is usually based on the pathologic examination of tissue specimens. The methods used to obtain these specimens have been previously discussed, but several factors affect the choice of a subsequent diagnostic testing approach. They include the preferences of patients and physicians; cost; testing characteristics, such as sensitivity, specificity, rate, and complexity; and clinical attributes (e.g., radiologic findings, age, and general patient health).

Most decision-related analytic studies that have attempted to determine optimal testing strategies have focused on patients with solitary pulmonary nodules, and the authors generally have assumed that There was no known history of malignancy. In these publications, the optimal testing paradigm was also equated with the most cost-effective strategy, meaning that it resulted in the greatest increase in population-related life expectancy for the lowest cost. Evaluations of this type have reached contradictory conclusions, with some stating that open biopsy or excision is the procedure of choice and others suggesting that sputum cytology should precede other testing methods.^267-271

Figure 18.70 the branching nature of plasmalemmal microvilli in mesothelioma is well seen in an electron photomicrograph.

Figure 18.71 Numerous dense-core neurosecretory granules are dispersed throughout the cytoplasm in an electron photomicrograph of metastatic well-differentiated neuroendocrine carcinoma (carcinoid) from the ileum involving the lungs.

Figure 18.72 Electron photomicrograph of metastatic seminoma showing a complex nucleolar structure, abundant cytoplasmic glycogen, and macular-type intercellular junctions. Cytoplasmic organelles are otherwise rudimentary.

Figure 18.73 Metastatic embryonal carcinoma of the testis showing cell surface microvilli (lower right), simulating the appearance of a somatic adenocarcinoma at a fine structural level.

Figure 18.74 (A) Metastatic embryonal rhabdomyosarcoma in a fine-needle aspirate showing dyshesive cells with high nucleocytoplasmic ratios and naked nuclei. (B) An electron photomicrograph from a similar case shows cytoplasmic thin and thick filaments representing primitive sarcomeric differentiation.

Figure 18.75 (A) Metastatic alveolar soft tissue sarcoma presenting in the left lung (arrow) in an adolescent boy in the absence of a known soft tissue tumor. Fine-needle aspiration (B) and subsequent biopsy (C) confirmed the diagnosis. (D) An electron photomicrograph of the lesion shows characteristic paracrystalline cytoplasmic inclusions. A primary lesion was ultimately found in the right buttock.

Potential reasons for these disagreements include study bias, assumptions based on incomplete data, and the overall complexity of analytic modeling. One study that included theoretical patient preferences showed that the cost-effectiveness of testing strategies was variable, depending on patient values such as risk aversion (aversion to a false-negative diagnosis or a testing complication).^272-275 Although these factors have yet to be measured in practice, the results of the latter study showed that a single testing strategy may not apply for all patient populations, including those with potential metastatic disease in the lungs.

Raab et al. assessed the sensitivity and cost-effectiveness of percutaneous FNA in a group of patients with known extrapulmonary malignancies and solitary lung masses.²⁷⁶ Using data from two hospitals with active FNA programs, they showed that pathologists correctly classified 87% of the pulmonary lesions as primary or secondary malignancies. More than 90% were metastases, indicating that the probability of a primary lung tumor is low in this clinical setting. As mentioned earlier, the distinction of primary and secondary malignancies depended on light microscopic features; morphologic comparison with previous specimens, when available; and the judicious use of immunocytochemistry.

Figure 18.76 (A) Metastatic neuroblastoma involving the lungs of a child. (B) the tumor is represented by sheets of small round undifferentiated tumor cells. (C and D) Electron microscopy shows interdigitating cytoplasmic processes containing microtubules as well as dense-core granules.

Figure 18.77 (A) Electron photomicrograph of metastatic melanoma in the lung showing epithelioid tumor cells joined by primitive appositional plaques. (B) Characteristic premelanosomes were seen in the cytoplasm.

Figure 18.78 (A) Metastatic epithelioid angiosarcoma in the lung originating in the scalp in an elderly man. (B) A Weibel- Palade body is seen in a tumor cell, marking the proliferation as endothelial.

Figure 18.79 (A) Metastatic Wilms tumor showing primitive tubules that punctuate a small round cell (blastematous) background population of tumor cells. (B) Electron photomicrographs from the same case show a relatively nondescript population of cells joined by primitive appositional plaques and surrounded in part by basal lamina.

Figure 18.80 (A) Metastatic synovial sarcoma originating in the soft tissue of the arm, involving the lungs. (B) Electron microscopy of the lesion shows investment of the tumor cells by basal lamina and the presence of intercellular junctions. These ultrastructural features may be misinterpreted as those of a carcinoma.

Figure 18.81 (A) Computed tomogram of the chest (arrows) and photomicrographs (B and C) showing lesions of granulocytic sarcoma (tumefactive acute myelogenous leukemia) involving the lungs. (D) In an electron photomicrograph, the tumor cells contain only primitive organelles and are not distinctive ultrastructurally.

Raab and coworkers found that the latter method was needed in only 20% of cases, but it yielded a definitive diagnosis in 78% of cases in which it was used.²⁷⁶ the cost-effectiveness of percutaneous FNA— compared with bronchoscopy and thoracoscopy—depends on several factors, such as test sensitivity and the pre-FNA probability of malignancy. An underlying assumption is that patients with metastatic disease do not need pulmonary resection, although these procedures may be appropriate in some cases. At pre-FNA probability of malignancy of more than 50% and FNA sensitivity of greater than 75%, FNA was more cost-effective than thoracoscopy in the cited series.²⁷⁶ In most clinical scenarios, percutaneous FNA was also more cost-effective than bronchoscopy. Nonetheless, clinicians still tend to use a wide variety of testing strategies in the diagnostic evaluation of pulmonary masses.²⁷³

Another question of increasing importance is the utilitarian value of ancillary studies, such as immunopathology, in tumor subtyping. Raab showed that immunocytochemistry was cost-effective in three theoretical scenarios: increasing patient life expectancy, diagnostic certainty, and the ability to predict patient prognosis.²⁷⁶ However, as Wick and colleagues indicated, it has never been proven formally that the correct immunohistologic diagnosis of a specific tumor type, particularly concerning nonhematolymphoid malignancies, produces a benefit in patient outcome.¹⁹⁵ Accurate pathologic diagnosis is believed to be advantageous in some instances, such as those concerning small-cell pediatric malignancies. Nonetheless, for the most part, patient survival generally depends more on nonpathologic variables, such as tumor stage, patient age, and overall health.^275-279 the actual effect of accurate diagnosis was not reported in the latter study, which investigated the cost-effectiveness of FNA in evaluation of lung masses, but Imlay and Raab separately showed that the use of immunopathology had no effect on patient survival in reference to pleural fluid evaluation.⁴⁶

Some immunologic markers have a potentially predictive role in secondary pulmonary malignancies, such as estrogen receptor protein, progesterone receptor protein, and HER-2 in cases of metastatic breast cancer. Those determinants may forecast the clinical response to appropriate treatment regimens, the response to which, in turn, may be prognostic (indicative of overall patient survival).¹⁹⁵ the cost- effectiveness of most other markers of that type has not yet been thoroughly assessed.¹⁹⁵

Self-assessment questions related to this chapter can be found online at ExpertConsult.com.

References

1. Crow J, Slavin G, Kreel L. Pulmonary metastasis: a pathologic and radiologic study. Cancer. 1981;47:2595-2603.

2. Johnson RM, Lindskog GE. 100 cases of tumor metastatic to the lung and mediastinum. JAMA. 1967;202:94-98.

3. Abrams HJ, Spiro R, Goldstein N. Metastates in carcinoma, analysis of 1000 autopsied cases. Cancer. 1950;3:74-75.

4. Farrell JT Pulmonary metastasis: a pathologic, clinical, roentgenologic study based on 78 cases seen at necropsy. Radiology. 1935;24:444-451.

5. Matthay R, Coppage L, Shaw C. Filderman A. Malignancies metastatic to the pleura. Invest Radiol. 1990;25:601-619.

6. Filderman AE, Coppage L, Shaw C, Matthay RA. Pulmonary and pleural manifestations of extrathoracic malignancies. Clin Chest Med. 1989;10:747-807.

7. Fidler IJ. Review: biologic heterogeneity of cancer metastases. Breast Cancer Res Treat. 1987;17:17.

8. Fidler IJ. The evolution of biologic heterogeneity in metastatic neoplasms. In: Nicholson GL, Milas L, eds. Cancer Invasion and Metastases: Biologic and Therapeutic Aspects. New York: Raven Press; 1984:5.

9. Liotta LA. Editorial. H-ras p21 and the metastatic phenotype. J Natl Cancer Inst. 1988;80:468.

10. Cotran RS, Kumar V, Collins T, Robbins SL. Neoplasia. In: Kumar V, Abbas AK, Aster JC, eds. Robbins Pathologic Basis of Disease. Philadelphia: WB Saunders; 1999:241-304.

11. Braman SS, Whitcomb ME. Endobronchial metastasis. Arch Intern Med. 1975;135:543-547.

12. Winterbauer RH, Elfenbein IB Jr, Ball WC. Incidence and clinical significance of tumor embolization to the lungs. Am J Med. 1968;45:271-290.

13. Goldhaber SZ, Dricker E, Buring JE. Clinical suspicion of autopsy-proven thrombotic and tumor pulmonary embolism in cancer patients. Am Heart J. 1987;114:1432-1435.

14. Chan CK, Hutcheon MA, Hyland RH, et al. Pulmonary tumor embolism: a critical review of clinical, imaging, and hemodynamic features. J Thorac Imaging. 1987;2:4-14.

15. Gonzalez-Vitale JC, Garcia-Bunuel R. Pulmonary tumor emboli and cor pulmonale in primary carcinoma of the lung. Cancer. 1976;38:2105-2110.

16. Abbondanzo SL, Klappenbach RS, Tsou E. Tumor cell embolism to pulmonary alveolar capillaries. Arch Pathol Lab Med. 1986;110:1197-1198.

17. Kane RD, Hawkins HK, Miller JA. Microscopic pulmonaiy tumor emboli associated with dyspnea. Cancer. 1975;36:1473-1482.

18. Pinckard JK, Wick MR. Tumor-related thrombotic pulmona^ microangiopathy: review of pathologic findings and pathophysiologic mechanisms. Ann Diagn Pathol. 2000;4:154-157.

19. Soares FA, Landell GAM. deOliveira JAM. Pulmona^ tumor embolism to alveolar septal capillaries: a prospective study of 12 cases. Arch Pathol Lab Med. 1991;115:127-130.

20. Scholten ET, Kreel L. Distribution of lung metastases in the axial plane. Radiol Clin North Am. 1977;46:248-265.

21. Steele JD. The solitary pulmonary nodule. J Thorac Cardiovasc Surg. 1963;46:21-39.

22. Toomes H, Delphendahl A, Manke H, Vogt-Moykopf I. The coin lesion of the lung: a review of 955 resected coin lesions. Cancer. 1983;51:534-537.

23. Viggiano RW, Swensen SJ, Rosenow EC. Evaluation and management of solitary and multiple pulmonary nodules. Clin Chest Med. 1992;13:83-95.

24. Quint LE, Park CH, Iannettoni MD. Solitary pulmonary nodules in patients with extrapulmonary neoplasms. Radiology. 2000;217:257-261.

25. Dodd GD, Boyle JJ. Excavating pulmonary metastases. Am J Roentgenol. 1961;85:277-293.

26. D'Angio GJ, Iannaccone G. Spontaneous pneumothorax as a complication of pulmonary metastases in malignant tumors of childhood. Am J Roentgenol. 1961;86:1092-1102.

27. Fichera G, Hagerstrand I. The small lymph vessels of the lungs in lymphangiosis carcinomatosa. Acta Pathol Microbiol Scand. 1965;65:505-513.

28. Harold JT Lymphangitis carcinomatosa of the lungs. Q J Med. 1952;21:353-360.

29. Yang SP, Lin CC. Lymphangitic carcinomatosis of the lungs: the clinical significance of its roentgenologic classification. Chest. 1972;62:179-187.

30. Trapnell DH. The radiological appearance of lymphangitic carcinomatosa of the lung. Thorax. 1964;19:251-260.

31. Winterbauer RH, Belic N, Moores KD. A clinical interpretation of bilateral hilar adenopathy. Ann Intern Med. 1973;78:65-71.

32. Janower ML, Blennerhassett JB. Lymphangitic spread of metastatic cancer to the lung: a radiologic-pathologic classification. Radiology. 1971;101:267-273.

33. Goldsmith HS, Bailey HD, Callahan EL, Beattie EJ. Pulmonary lymphangitic metastases from breast cancer. Arch Surg. 1967;94:483-488.

34. Thurlbeck WM. Neoplasia of the pulmonary vascular bed. In: Moser KM, ed. Pulmonary Vascular Disease. New York: Marcel Dekker; 1979:629-649.

35. Geisinger KR, Levine EA, Shen P, Bradley RF. Pleuropulmonary involvement in pseudomyxoma peritonei: morphologic assessment and literature review. Am J Clin Pathol. 2007;127:135-143.

36. Canto-Armengod A. Macroscopic characteristics of pleural metastases arising from the breast and observed by diagnostic thorascopy. Am Rev Respir Dis. 1990;142:616-618.

37. Hsu C. Cytologic detection of malignancy in pleural effusion: review of 5,255 samples from 3,811 patients. Diagn Cytopathol. 1987;3:8-12.

38. Johnson WW. The malignant pleural effusion: a review of cytopathologic diagnoses of 584 specimens from 472 consecutive patients. Cancer. 1985;56:905-909.

39. Venrick MG, Sidaway MK. Cytologic evaluation of serous effusions: processing techniques and optimal number of smears for routine preparation. Am J Clin Pathol. 1993;99: 182-186.

40. DeMay RM. Fluids. In: DeMay RM, ed. The Art and Science of Cytopathology. Chicago: ASCP Press; 1996:257-325.

41. Chernow B, Sahn SA. Carcinomatous involvement of the pleura: an analysis of 96 patients. Am J Med. 1977;63:695-702.

42. Edoute Y, Kuten A, Ben-Haim SA. Symptomatic pericardial effusion in breast cancer patients: the role of fluid cytology. J Surg Oncol. 1990;45:265-269.

43. Sahn SA. Malignant pleural effusions. Semin Respir Med. 1987;9:43-53.

44. Canto A, Ferrer G, Romagosa V, Moya J, Bernat R. Lung cancer and pleural effusion. Clinical significance and study of pleural metastatic locations. Chest. 1985;87:649-852.

45. DiBonito L, Falconieri G, Colautti I. Cytopathology of malignant mesothelioma: a study of its patterns and histological bases. Diagn Cytopathol. 1993;9:25-31.

46. Imlay SP, Raab SS. Pleural fluid cytology: immunocytochemistry usage patterns and significance of nondefinitive diagnosis. Diagn Cytopathol. 1999;22:281-285.

47. VandeMolengraft FJJM, Vooijs GP. Survival of patients with malignancy-associated effusions. Acta Cytol. 1989;33:911-916.

48. Chretien J, Jaubert F. Pleural responses in malignant metastatic tumors. In: Chretien J, Bignon J, Hirsch A, eds. The Pleura in Health and Disease. New York: Marcel Dekker; 1985:489-505.

49. Sahn SA. Malignant pleural effusion. In: Fishman AP, ed. Pulmonary Diseases and Disorders. 2nd ed. New York: McGraw-Hill; 1988:2159-2169.

50. Spriggs AI. Malignant cells in serous effusions complicating bronchial carcinoma. Thorax. 1954;9:26-34.

51. Smith-Purslow MJ, Kini SR, Naylor B. Cells of squamous cell carcinoma in pleural, peritoneal and pericardial fluids: origina and morphology. Acta Cytol. 1989;84:125-128.

52. Light RW. Pleural Diseases. 5th ed. Philadelphia: Lippencott Williams and Wilkins; 2007.

53. Bourke SA, Henderson AF, Stevenson RD, Banham SW. Endobronchial metastases simulating primary carcinoma of the lung. Respir Med. 1989;83:151-152.

54. King DS, Castleman B. Bronchial involvement in metastatic pulmonary malignancy. J Thorac Surg. 1943;12:305-315.

55. Katsimbri PP, Bamias AT, Froudarakis ME, et al. Endobronchial metastases secondary to solid tumors: report of eight cases and review of the literature. Lung Cancer. 2000;28:163-170.

56. Casino AR, Bellmunt J, Salud A, et al. Endobronchial metastases in colorectal adenocarcinoma. Tumori. 1992;78:270-273.

57. Schoenbaum S, Viamonte M. Subepithelial endobronchial metastases. Diagn Radiol. 1971;101:63-69.

58. Fitzgerald RH. Endobronchial metastases. South Med J. 1977;79:440-443.

59. Heitmiller R, Marasco W, Hruban R, Marsh B. Endobronchial metastasis. J Thorac Cardiovasc Surg. 1993;106:537-542.

60. Argyros G, Torrington K. Fiberoptic bronchoscopy in the evaluation of carcinoma metastatic to the lung. Chest 1994;105:454-457.

61. Wang YH, Wong SL, Lai YF, Lin AS, Chang HW. Endobronchial metastatic disease. Chang Keng I Hsueh Tsa Chih. 1999;22:240-245.

62. Salud A, Porcel JM, Rovirosa A, Bellmunt J. Endobronchial metastatic disease: analysis of 32 cases. J Surg Oncol. 1996;62:249-252.

63. Mehta AC, Marty JJ, Lee FWY. Sputum cytology. Lung Cancer. 1993;14:36-85.

64. Koss L, Melamed M, Goodner J. Pulmonary cytology: a brief survey of diagnostic results from July 1st, 1952 until December 31st, 1960. Acta Cytol. 1964;8:104-113.

65. Arroliga A, Matthay R. The role of bronchoscopy in lung cancer. Lung Cancer. 1993;14:87-98.

66. Harrow EM, Wang KP. The staging of lung cancer by bronchoscopic transbronchial needle aspiration. Chest Surg Clin North Am. 1996;6:223-235.

67. Wang KP. Transbronchial needle aspiration and percutaneous needle aspiration for staging and diagnosis of lung cancer. Clin Chest Med. 1995;16:535-552.

68. Salazar A, Westcott J. The role of thoracic needle biopsy for the diagnosis and staging of lung cancer. Lung Cancer. 1993;14:99-110.

69. Garcia RF, Lobato SD, Pino JM. Value of CT-guided fine needle aspiration in solitary pulmonary nodules with negative fiberoptic bronchoscopy. Acta Radiol. 1994;35:478-480.

70. Sonett J. Pulmonary metastases: biologic and historical justification for VATS. Video assisted thoracic surgery. Eur J Cardiothorac Surg. 1999;16(suppl):S13-S15.

71. Coosemans W, Lerut T, Raemdonck DV. Thoracoscopic surgery: the Belgian experience. Ann Thorac Surg. 1993;56:621-660.

72. Miller J. The present role and future considerations of video-assisted thorascopy in general thoracic surgery. Ann Thorac Surg. 1993;56:804-806.

73. Nathan M, Colloing V, Adams R. Differentiation of benign and malignant pulmonary nodules by growth rate. Radiology. 1962;79:221-232.

74. Nathan M. Management of solitary pulmonary nodules: an organized approach based on growth rate and statistics. JAMA. 1974;227:1141-1144.

75. Godwin JP, Speckman JM, Fram EK. Distinguishing benign from malignant pulmonary nodules by computed tomography. Radiology. 1982;144:349-352.

76. Layfield LJ, Coogan A, Johnston WW, Patz EF Transthoracic fine needle aspiration biopsy. Sensitivity in relation to guidance technique and lesion size and location. Acta Cytol. 1996;40:687-690.

77. Pilotti S, Rilke F, Gribaudi G, Damascelli B. Fine needle aspiration biopsy cytology of primary and metastatic pulmonary tumors. Acta Cytol. 1982;26:661-666.

78. Zarbo R, Fenoglio-Preiser C. Interinstitutional database for comparison of performance in lung fine-needle aspiration cytology. A College of American Pathologists Q-Probe Study of 5264 cases with histologic correlation. Arch Pathol Lab Med. 1992;116:463-470.

79. Al-Jaghbeer M, Marcus M, Durkin M, McGuire FR, Iftikhar IH. Diagnostic yield of electromagnetic navigational bronchoscopy. Ther Adv Resp Dis. 2016;10:295-299.

80. Kern WH, Schweizer CW. Sputum cytology of metastatic carcinoma of the lung. Acta Cytol. 1976;20:514-520.

81. Perchalski JE, Hall KL, Dewar MA. Metastasis of unknown orgin. Care. 1992;19:747-757.

82. Fizazi K, Culine S. Metastatic carcinoma of unknown origin. Bull Cancer. 1998;85:609-617.

83. Schapira DV, Jerrett AR. The need to consider survival, outcome, and expense when evaluating and treating patients with unknown primary carcinoma. Arch Intern Med. 1995;155:2050-2054.

84. Heim S, Mitleman F. Solid tumors. In: Heim S, Mitelman F, eds. Cancer Cytogenetics. New York: Alan R Liss; 1987:227-261.

85. Papec R. Distant metastases from head and neck. Cancer. 1984;53:342-345.

86. Probert J, Thompson R, Bagshaw M. Patterns of spread of distant metastases in head and neck cancer. Cancer. 1974;33:127-133.

87. Raab SS, Oweity T, Hughes JH, et al. The effect of clinical history on diagnostic accuracy in the interpretation of bronchial brush specimens. Am J Clin Pathol. 2000;114:78-83.

88. 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;6:244-285.

89. DeYoung BR, Wick MR. Immunohistologic evaluation of metastatic carcinomas by unknown origin: an algorithmic approach. Semin Diagn Pathol. 2000;17:184-193.

90. Silver SS, Askin FB. True papillary carcinoma of the lung. A distinct clinicopathologic entity. Am J Surg Pathol. 1997;21:43-51.

91. Nakamura S, Koshikawa T, Sato T, Hayashi K, Suchi T Extremely well differentiated papillary adenocarcinoma of the lung with prominent cilia formation. Acta Pathol Jpn. 1992;42:745-750.

92. Salisbury JR, Darby AJ, Whimster WF Papillary adenocarcinoma of lung with psammoma bodies: report of a case derived from type II pneumocytes. Histopathology. 1986;10:877-884.

93. Massin J-P, Savoie J-C, Garnier H, Guiraudon G, Leger FA. Bacourt. Pulmonary metastases in differentiated thyroid carcinoma. Study of 58 cases with implications for the primary tumor treatment. Cancer. 1984;53:982-992.

94. Samaan NA, Schultz PN, Haynie TP, Ordonez NG. Pulmonary metastasis of differential thyroid carcinoma: treatment results in 101 patients. J Clin Endocrinol Metab. 1985;60:376-380.

95. Venkatesh YSS, Ordonez NG, Schultz PN, et al. Anaplastic carcinoma of the thyroid: a clinicopathologic study of 121 cases. Cancer. 1990;66:321-330.

96. Shepherd MP. Endobronchial metastatic disease. Thorax. 1982;37:362-365.

97. Kerr VE, Cadman E. Pulmonary metastases in ovarian cancer. Cancer. 1985;56:1209-1213.

98. Dvoretsky PM, Richards KA, Angel C. Distribution of disease at autopsy in 100 women with ovarian cancer. Hum Pathol. 1988;19:57-63.

99. Oosterlee J. Peritoneovenous shunting for ascites in cancer patients. Br J Surg. 1980;67:663-666.

100. Fildes J, Narvarez GP, Baig KA, Pai N, Gerst PH. Pulmonary tumor embolization after perito- neovenous shunting for malignant ascites. Cancer. 1988;61:1973-1976.

101. Werner M, Chott A, Fabiano A, Battifora H. Effect of formalin tissue fixation and processing on immunohistochemistry. Am J Surg Pathol. 2000;24:1016-1019.

102. Renshaw AA, Dean BR, Antman KH, Sugarbaker DJ, Cibas ES. The role of cytologic evaluation of pleural fluid in the diagnosis of malignant mesothelioma. Chest 1997;111:106-109.

103. Moran CA, Wick MR, Suster S. The role of immunohistochemistry in the diagnosis of malignant mesothelioma. Semin Diagn Pathol. 2000;17:178-183.

104. Moch H, Oberholzer M, Dalquen P. Diagnostic tools for differentiating between pleural mesothelioma and lung adenocarcinoma in paraffin embedded tissue. Virch Arch A. 1993; 423:19-27.

105. Moch H, Oberholzer M, Christen H. Diagnostic tools for differentiating plural mesothelioma from lung adenocarcinoma in paraffin embedded tissue. Part II. Virch Arch A. 1993;423:493-496.

106. Wang N-S. Electron microscopy in the diagnosis of pleural mesotheloma. Cancer. 1973;31:1046-1054.

107. Batiffora H, Kopinski MI. Distinction of mesothelioma from adenocarcinoma. An immunohistochemical approach. Cancer. 1985;55:655-662.

108. Strickler JG, Hemdier BG, Rouse RV Immunohistochemical staining in malignant mesotheliomas. Am J Clin Pathol. 1987;88:610-614.

109. Gaffey M, Mills S, Askin F, et al. Clear cell tumor of the lung. A clinicopathologic, immunohistochemical, and ultrastructural study of eight cases. Am J Surg Pathol. 1990;14:248-259.

110. Greenberg BE, Young JM. Pulmonary metastasis from occult primary sites resembling bronchogenic carcinoma. Dis Chest. 1958;33:496-505.

111. Hughes JH, Jensen CS, Donnelly AD, et al. The role of fine-needle aspiration cytology in the evaluation of metastatic clear cell tumors. Cancer. 1999;87:380-389.

112. Saitoh H. Distant metastasis of renal adenocarcinoma in patients with a tumor thrombus in the renal vein and/or vena cava. J Urol. 1982;127:652-653.

113. Latour A, Shulman HS. Thoracic manifestations of renal cell carcinoma. Radiology. 1976;121: 43-48.

114. Coppage L, Shaw C, Curtis AM. Metastatic disease to the chest in patients with extrathoracic malignancy. J Thorac Imag. 1987;2:24-37.

115. Gerle R, Felson B. Metastatic endobronchial hypernephroma. Dis Chest 1963;44:225-233.

116. Noy S, Michowitz M, Lazebnik N, Baratz M. Endobronchial metastasis of renal cell carcinoma. J Surg Oncol. 1986;31:268-270.

117. Amer E, Guy J, Vaze B. Endobronchial metastasis from renal adenocarcinoma simulating a foreign body. Thorax. 1981;36:183-184.

118. King TE, Fisher J, Schwarz MI, Patzelt LH. Bilateral hilar adenopathy: an unusual presentation of renal cell carcinoma. Thorax. 1982;37:317-318.

119. Katzenstein A-LA, Purvis RW, Gmelich JT, Askin FB. Pulmonary resection for metastatic renal adenocarcinoma. Cancer. 1978;41:712-723.

120. Chu P, Arber DA. Paraffin section detection of CD10 in 505 nonhematopoietic neoplasms: frequent expression in renal cell carcinoma and endometrial stromal sarcoma. Am J Clin Pathol. 2000;113:374-382.

121. Scarpatetti M, Tsybrovskyy O, Popper HH. Cytokeratin typing as an aid in the differential diagnosis of primary versus metastatic lung carcinoma, and comparison with normal lung. Virchows Arch. 2002;440:70-76.

122. Avery AK, Beckstead J, Renshaw AA, Corless CL. Use of antibodies to RCC and CD10 in the differential diagnosis of renal neoplasms. Am J Surg Pathol. 2000;24:203-210.

123. Ostler DA, Prieto VG, Reed JA, et al. Adipophilin expression in sebaceous tumors and other cutaneous lesions with clear-cell histology: an immunohistochemical study of 117 cases. Mod Pathol. 2010;23:567-573.

124. Lisa JR, Trinidad S, Rosenblatt MB. Pulmonary manifestations of carcinoma of the pancreas. Cancer. 1964;17:395-401.

125. Cutler SJ, Asire AJ, Taylor SG. Classification of patients with disseminated cancer of the breast. Cancer. 1969;24:861-869.

126. DeBeer RA, Garcia RL, Alexander SC. Endobronchial metastasis from cancer of the breast. Chest. 1978;73:94-96.

127. Winchester DP, Sener SF, Khandekar JD. Symptomatology as an indicator of recurrent or metastatic breast cancer. Cancer. 1979;43:956-960.

128. Casey JJ, Stempel BG, Scanlon EF, Fry WA. The solitary pulmonary nodule in the patient with breast cancer. Surgery. 1984;96:801-805.

129. Fracchia AA, Knapper WH, Carey JT Intrapleural chemotherapy for effusion from metastatic breast carcinoma. Cancer. 1970;26:626-629.

130. Raab SS, Berg LC, Swanson PE, Wick MR. Adenocarcinoma in the lung in patients with breast cancer. A prospective analysis of the discriminatory value of immunohistology. Am J Clin Pathol. 1993;100:27-35.

131. Dabbs DJ, Landreneau RJ, Liu Y, et al. Detection of estrogen receptor by immunohistochemistry in pulmonary adenocarcinoma. Ann Thorac Surg. 2002;73:403-406.

132. Wang Z, Spaulding B, Sienko A, et al. Mammaglobin: a valuable diagnostic marker for metastatic breast carcinoma. Int J Clin Exp Pathol. 2009;2:384-389.

133. Kandalaft PL, Simon RA, Isacson C, Gown AM. Comparative sensitivities and specificities of antibodies to breast markers GCDFP-15, mammoglobin A, and different clones of GATA-3: a study of 338 tumors using whole sections. Appl Immunohistochem Mol Morphol. 2016;24: 609-614.

134. MacDonald RA. Primary carcinoma of the liver. A clinicopathologic study of one hundred eight cases. Arch Intern Med. 1957;99:266-279.

135. Katyal S, Oliver JH, Peterson MS, et al. Extrahepatic metastases of hepatocellular carcinoma. Radiology. 2000;216:698-703.

136. Patton RB, Horn RC. Primary liver carcinoma. Autopsy study of 60 cases. Cancer. 1964;17:757-768.

137. Tsai GL, Liu JD, Siauw CP, Chen PA. Thoracic roentgenologic manifestations in primary carcinoma of the liver. Chest. 1984;86:430-434.

138. Levy JI, Geddes EW, Kew MC. The chest radiograph in primary liver cancer. An analysis of 449 cases. S Afr Med J. 1976;50:1323-1326.

139. Cohen MB, Haber MM, Holly EA, et al. Cytologic criteria to distinguish hepatocellular carcinoma from nonneoplastic liver. Am J Clin Pathol. 1991;95:125-130.

140. Wieczorek TJ, Pinkus JL, Glickman JN, Pinkus GS. Comparison of thyroid transcription factor-1 and hepatocyte antigen immunohistochemical analysis in the differential diagnosis of hepatocellular carcinoma, metastatic adenocarcinoma, renal cell carcinoma, and adrenal cortical carcinoma. Am J Clin Pathol. 2002;118:911-921.

141. Parks GE, Perkins LA, Zagoria RJ, et al. Benefits of a combined approach to sampling of renal neoplasms as demonstrated in a series of 351 cases. Am J Surg Pathol. 2011;35:827-835.

142. August DA, Ottow RT, Sugarbaker PH. Clinical perspective of human colorectal cancer metastasis. Cancer Metastasis Rev. 1984;5:303-324.

143. Dionne L. The pattern of blood-borne metastasis from carcinoma of rectum. Cancer. 1965;18:775-781.

144. Taylor FW. Cancer of the colon and rectum: a study of routes of metastases and death. Surgery. 1962;52:302-308.

145. Langer B. Managing distant metastases. Can J Surg. 1985;28:419-421.

146. McCormack PM, Attiyeh FF Resected pulmonary metastases from colorectal cancer. Dis Colon Rectum. 1979;22:553-556.

147. Flint A, Lloyd RV. Colon carcinoma metastatic to the lung. Cytologic manifestations and distinction from primary pulmonary adenocarcinoma. Acta Cytol. 1992;36:230-235.

148. Harlamert HA, Mira J, Bejarano PA. Thyroid transcription factor-1 and cytokeratins 7 and 20 in pulmonary and breast carcinoma. Acta Cytol. 1998;42:1382-1388.

149. Bohinski RJ, Bejarano PA, Balko G. Determination of lung as the primary site of cerebral metastatic adenocarcinomas using monoclonal antibody to thyroid transcription factor-1. J Neurooncol. 1998;40:227-231.

150. Wauters CC, Smedts F, Gerrits LG, Bosman FT, Ramaekers FC. Keratins 7 and 20 as diagnostic markers of carcinomas metastatic to the ovary. Hum Pathol. 1995;26:852-855.

151. Tsao MS, Fraser RS. Primary pulmonary adenocarcinoma with enteric differentiation. Cancer. 1991;68:1754-1757.

152. Bacchi CE, Gown AM. Distribution and pattern of expression of villin, a gastrointestinal-associated cytoskeletal protein, in human carcinomas: a study employing paraffin-embedded tissue. Lab Invest. 1991;64:418-424.

153. Gatalica Z, Miettinen M. Distribution of carcinoma antigens CA19-9 and CA15-3: an immunohistochemical study of 400 tumors. Appl Immunohistochem. 1994;2:205-211.

154. Saad RS, Silverman JF, Khalifa MA, Rowsell C. CDX2, cytokeratin 7 and 20 immunoreactivity in rectal adenocarcinoma. Appl Immunohistochem Mol Morphol. 2009;17:196-201.

155. Moran CA, Hocchholzer L, Fishback N, Travis WD, Koss MN. Mucinous (so-called colloid) carcinomas of lung. Mod Pathol. 1992;5:634-638.

156. Cathro HP, Stoler MH. Expression of cytokeratins 7 and 20 in ovarian neoplasia. Am J Clin Pathol. 2002;117:944-951.

157. Ware JL. Prostate tumor progression and metastasis. Biochim Biophys Acta. 1987;907:279-298.

158. Ballon SC, Donaldson RC, Growdon WA. Pulmonary metastases in endometrial carcinoma. In: Weiss L, Gilbert HW, eds. Pulmonary Metastasis. Boston: GK Hall; 1978.

159. Mintz ER, Smith GG. Autopsy finding in 100 cases of prostatic cancer. N Engl J Med. 1934;211:479-487.

160. Elkin M, Mueller HP. Metastasis from cancer of the prostate: autopsy and roentgenological findings. Cancer. 1954;7:1246-1248.

161. Kume H, Takai K, Kameyama S, Kawabe K. Multiple pulmonary metastasis of prostatic carcinoma with little or no bone or lymph node metastasis. Report of two cases and review of the literature. Urol Int. 1999;62:44-47.

162. Scherz H, Schmidt JD. Endobronchial metastasis from prostate carcinoma. Prostate. 1986;8:319-324.

163. Legge DA, Good CA, Ludwig J. Roentgenologic features of pulmonary carcinomatosis from carcinoma of the prostate. Am J Roentgenol Radium Ther Nucl Med. 1971;111:360-364.

164. Apple JS, Paulson DF, Baber C, Putman CE. Advanced prostatic carcinoma: pulmonary manifestations. Radiology. 1985;54:601-604.

165. Miller GJ. The use of histochemistry and immunohistochemistry in evaluating prostatic neoplasia. Prog Surg Pathol. 1982;5:115-126.

166. Suster S. Recent advances in the application of immunohistochemical markers for the diagnosis of soft tissue tumors. Semin Diagn Pathol. 2000;17:225-235.

167. Lewis J, Brennan M. Soft tissue sarcomas. Curr Probl Surg. 1996;33:817-872.

168. Scranton PE, DeCicco FA, Totten RS. Prognostic factors in osteosarcoma. A review of 20 year's experience at the University of Pittsburgh Health Center Hospitals. Cancer. 1975;36:2179-2191.

169. Vezeridis MP, Moore R, Karakousis CP. Metastatic patterns in soft-tissue sarcomas. Arch Surg. 1983;118:915-918.

170. Flynn KJ, Kim HS. Endobronchial metastasis of uterine leiomyosarcoma. JAMA. 1978;240:2080.

171. Aronchick JM, Palevsky HI, Miller WT. Cavitary pulmonary metastases in angiosarcoma. Diagnosis by trans-thoracic needle aspiration. Am Rev Respir Dis. 1989;139:252-253.

172. Shaw AB. Spontaneous pneumothorax from seconda^ sarcoma of lung. Br Med J. 1951;1:278-280.

173. Spittle MF, Heal J, Harmer C, White WF. The association of spontaneous pneumothorax with pulmonary metastases in bone tumors of children. Clin Radiol. 1968;19:400-403.

174. Lodmell EA, Capps SC. Spontaneous pneumothorax associated with metastatic sarcoma. Radiology. 1949;52:88-93.

175. Dines DE, Cortese DA, Brennan MD, Hahn RG, Payne WS. Malignant pulmonary neoplasms predisposing to spontaneous pneumothorax. Mayo Clin Proc. 1973;48:541-544.

176. Brooks JJ. The significance of double phenotypic patterns and markers in human sarcomas: a new model of mesenchymal differentiation. Am J Pathol. 1986;125:113-123.

177. Gal AA, Brooks JSJ, Pietra GG. Leiomyomatous neoplasms of the lung: a clinical, histologic and immunohistochemical study. Mod Pathol. 1989;2:209-216.

178. Cho KR, Woodrumm JD, Epstein JI. Leiomyoma of the uterus with multiple extrauterine smooth muscle tumors: a case report suggesting multifocal orgin. Hum Pathol. 1989;20:80-83.

179. Miller J, Shoni M, Siegert C, et al. Benign metastasizing leiyomyosarcoma to the lungs: an institutional case series and review of the recent literature. Ann Thorac Surg. 2016;102:253-258.

180. Sherman RS, Brant EE. An x-ray of spontaneous pneumothorax due to cancer metastases to the lungs. Chest. 1954;26:328-337.

181. Lipton JH, Fong TC, Burgess KR. Miliary pattern as presentation of leiomyomatosis of the lung. Chest. 1987;91:781-782.

182. Wolff M, Kaye G, Silva F. Pulmonary metastases (with admixed epithelial elements) from smooth muscle neoplasms. Report of nine cases, including three males. Am J Surg Pathol. 1979;3:325-342.

183. Horstmann JP, Pietra GG, Harman JA. Spontaneous regression of pulmonary leiomyomas during pregnancy. Cancer. 1977;39:314-321.

184. Kaplan C, Katoh A, Shamoto M. Multiple leiomyomas of the lung: benign or malignant. Am Rev Respir Dis. 1973;108:656-659.

185. Norris HJ, Parmley T. Mesenchymal tumors of the uterus.V: intravenous leiomyomatosis. A clinical and pathologic study of 14 cases. Cancer. 1975;36:2164-2178.

186. Bachman D, Wolff M. Pulmonary metastases from benign smooth muscle tumors of the uterus.

AJR Am J Roentgenol. 1976;127:441-446.

187. Patton KT, Cheng L, Papavero V, et al. Benign metastasizing leiomyoma: clonality, telomere length, and clinicopathologic analysis. Mod Pathol. 2006;19:130-140.

188. Devoe K, Weidner N. Immunohistochemistry of small round-cell tumors. Semin Diagn Pathol. 2000;17:216-224.

189. Meis-Kindblom JM, Stenman G, Kindblom LG. Differential diagnosis of small round cell tumors. Semin Diagn Pathol. 1996;13:213-241.

190. Byrd-Gloster AL, Khoor A, Glass LF, et al. Differential expression for thyroid transcription factor 1 in small cell lung carcinoma and Merkel cell tumor. Hum Pathol. 2000;31:58-62.

191. Wang W, Epstein JI. Small cell carcinomas of the prostate. A morphologic and immunohistochemical study of 95 cases. Am J Surg Pathol. 2008;32:65-71.

192. Moll R, Lower A, Laufer J. Cytokeratin 20 in human carcinomas. A new histodiagnostic marker detected by monoclonal antibodies. Am J Pathol. 1992;140:427-447.

193. Schmidt U, Muller U, Metz KA. Cytokeratin and neurofilament protein staining in Merkel cell carcinoma and of the small cell type and small cell carcinoma of the lung. Am J Dermatopathol. 1998;20:346-351.

194. Wick MR. Immunohistology of neuroendocrine and neuroectodermal tumors. Semin Diagn Pathol. 2000;17:194-203.

195. Wick MR, Ritter JH, Swanson PE. The impact of diagnostic immunohistochemistry on patient outcomes. Clin Lab Med. 1999;19:797-814.

196. Oliveira AM, Tazelaar HD, Myers JL, Erickson LA, Lloyd RV Thyroid transcription factor-1 distinguishes metastatic pulmonary from well-differentiated neuroendocrine tumors of other sites. Am J Surg Pathol. 2001;25:815-819.

197. Corrin B. Lung endocrine tumors. Invest Cell Pathol. 1980;3:195-206.

198. Ikeda K, Tate G, Suzuki T, Mitsuya T. Cytologic comparison of a primary parathyroid cancer and its metastatic lesions: a case report. Diagn Cytopathol. 2005;34:50-55.

199. Iihara M, Okamoto T, Suzuki R, et al. Functional parathyroid carcinoma: long-term treatment outcome and risk factor analysis. Surgery. 2007;142:936-943.

200. Juhl J. Tumors of the lungs and bronchi. In: Crummy AB, Kuhlman MD, eds. Paul and Juhls Essentials of Radiologic Imaging. Philadelphia: Lippincott-Raven; 1998:1-95.

201. Colby TV, Carrington CB. Malignant lymphoma simulating lymphomatoid granulomatosis. Am J Surg Pathol. 1982;6:19-32.

202. Colby TV, Carrington CB. Lymphoreticular tumors and infiltrates of the lung. Pathol Annu. 1983;18:27-70.

203. Melamed MR. The cytological presentation of malignant lymphomas and related diseases in effusions. Cancer. 1963;16:413-431.

204. Meda BA, Buss DH, Woodruff RD, et al. Diagnosis and subclassification of primary and recurrent lymphoma. The usefulness and limitations of combined fine-needle aspiration cytomorphology and flow cytometry. Am J Clin Pathol. 2000;113:688-689.

205. Demington M, Carter D, Meyers A. Distant metastases in head and neck epidermoid carcinoma. Laryngoscope. 1980;90:196-201.

206. O'Brien PH, Carlson R. Steubner EA. Distant metastases in epidermoid cell carcinoma of the head and neck. Cancer. 1971;27:204-307.

207. Malefetto JP, Kasimis BS, Moran EM, Wuerker RB, Stein JJ. The clinical significance of radiographically detected pulmonary neoplastic lesions in patients with head and neck cancer. J Clin Oncol. 1984;2:625-630.

208. Leon X, Quer M, Diez S, et al. Second neoplasm in patients with head and neck cancer. Head Neck. 1999;21:204-210.

209. Sostman HD, Matthay RA. Thoracic metastases from cervical carcinoma: current status. Invest Radiol. 1980;15:113-119.

210. D'Orsi CJ, Bruckman J, Mauch P, Smith EH. Lung metastases in cervical and endometrial carcinoma. Am J Roentgenol. 1979;133:719-722.

211. Kirubakaran MG, Pulimood BM, Ray D. Excavating pulmonary metastases in carcinoma of the cervix. Postgrad Med J. 1975;51:243-245.

212. Scott I, Bergin CJ, Muller NL. Mediastinal and hilar lymphadenopathy as the only manifestation of metastatic carcinoma of the cervix. J Can Assoc Radiol. 1986;37:52-53.

213. King TE, Neff TA, Ziporin P. Endobronchial metastasis from the uterine cervix: presentation as primary lung abscess. JAMA. 1979;242:1651-1652.

214. Buchsbaum HJ. Lymphangitis carcinomatosis secondary to carcinoma of cervix. Obstet Gynecol. 1970;36:850-860.

215. Vachani A, Nebozhyn M, Singhal S, et al. A 10-gene classifier for distinguishing head and neck squamous cell carcinoma and lung squamous cell carcinoma. Clin Cancer Res. 2007;13:2905-2915.

216. Girard N, Deshpande C, Lau C, et al. Comprehensive histologic assessment helps to differentiate multiple lung primary non-small cell carcinomas from metastases. Am J Surg Pathol. 2009;33:1752-1764.

217. Wilson RW, Moran CA. Primary melanoma of the lung: a clinicopathologic and immunohistochemical study of eight cases. Am J Surg Pathol. 1997;21:1196-1202.

218. DasGupta T, Brasfield R. Metastatic melanoma: a clinicopathological study. Cancer. 1964;17: 1323-1339.

219. Harpole DH, Johnson CM, Wolfe WG, George SL, Seigler HF. Analysis of 945 cases of pulmonary metastatic melanoma. J Thorac Cardiovasc Surg. 1992;103:743-750.

220. Chen JTT, Dahmash NS, Ravin CE. Metastatic melanoma to the thorax: report of 130 patients. Am J Roentgenol. 1981;137:293-298.

221. Dwyer AJ, Reichert CM, Woltering EA, Flye MW. Diffuse pulmonary metastasis in melanoma: radiographic-pathologic correlation. Am J Roentgenol. 1984;143:983-984.

222. Webb WR, Gamsu G. Thoracic metastasis in malignant melanoma. Chest. 1977;71:176-181.

223. Balch CM, Soong SJ, Murad TM, et al. A multifactorial analysis of melanoma: prognostic factors in 200 melanoma patients with distant metastases. J Clin Oncol. 1983;1:126-134.

224. Pogrebniak HW, Stovroff M, Roth JA, Pass HI. Resection of pulmonary metastases from malignant melanoma: results of a 16-year experience. Ann Thorac Surg. 1988;46:20-23.

225. Renshaw A, Madge R. Cercariform cells for helping distinguish transitional cell carcinoma from non-small cell lung carcinoma in fine needle aspirates. Acta Cytol. 1997;41: 999-1007.

226. Gown AM, Vogel AM, Hoak D, Gough F, McNutt MA. Monoclonal antibodies specific for melanocytic tumors distinguish subpopulations of melanocytes. Am J Pathol. 1986; 123: 195-203.

227. Wang NP, Zee S, Zarbo RJ, et al. Coordinate expression of cytokeratins 7 and 20 defines unique subsets of carcinomas. Appl Immunohistochem. 1995;3:99-107.

228. Baars JH, DeRuijter JL, Smedts F, et al. The applicability of a keratin 7 monoclonal antibody in routinely Papanicolaou-stained cytologic specimens for the differential diagnosis of carcinomas. Am J Clin Pathol. 1994;101:257-261.

229. Sack MJ, Roberts SA. Cytokeratins 20 and 7 in the differential diagnosis of metastatic carcinoma in cytologic specimens. Diagn Cytopathol. 1997;16:132-136.

230. Lotan TL, Ye H, Melamed J, et al. Immunohistochemical panel to identify the primary site of invasive micropapillary carcinoma. Am J Surg Pathol. 2009;33:1037-1041.

231. Liang Y, Heitzman J, Kamat AM, et al. Differential expression of GATA 3 in urothelial carcinoma variants. Hum Pathol. 2014;45:1466-1472.

232. Munk PL, Connell DG, Muller NL, Lentle BC. Alveolar soft parts sarcoma with pulmonary metastases. Skeletal Radiol. 1988;17:454-457.

233. Weiss SW, Enzinger FM. Malignant fibrous histiocytoma: an analysis of 200 cases. Cancer. 1978;41:2250-2266.

234. Hendin AS. Gestational trophoblastic tumors metastatic to the lungs. Cancer. 1984;53:58-61.

235. Hatch KD, Shingleton HM, Gore H, Younger B, Boots LR. Human chorionic gonadotropin-secreting large cell carcinoma of the lung detected during follow-up of a patient previously treated for gestational trophoblastic disease. Gynecol Oncol. 1980;10:98-104.

236. Kumar J, Ilancheran A, Ratnam SS. Pulmonary metastases in gestational trophoblastic disease: a review of 97 cases. Br J Obstet Gynecol. 1988;95:70-74.

237. Siegel RJ, Bueso-Ramos C, Cohen C, Koss M. Pulmonary blastoma with germ cell (yolk sac) differentiation: report of two cases. Mod Pathol. 1991;4:566-570.

238. Wick MR, Swanson PE, Manivel JC. Placenta-like alkaline phosphatase reactivity in human tumors: an immunohistochemical study of 520 cases. Hum Pathol. 1987;18:946-954.

239. Hammar S. The use of electron microscopy and immunohistochemistry in the diagnosis and understanding of lung neoplasms. Clin Lab Med. 1987;7:1-30.

240. Hammar SP, Bolen JW, Bockus D, Remington F, Friedman S. Ultrastructural and immunohistochemical features of common lung tumors: an overview. Ultrastruct Pathol. 1985;9:283-318.

241. Mennemeyer R, Hammar SP, Bauermeister DE, et al. Cytologic, histologic, and electron microscopic correlations in poorly-differentiated primary lung carcinoma: a study of 43 cases. Acta Cytol. 1979;23:297-302.

242. Mackay B, Silva EG. Diagnostic electron microscopy in oncology. Pathol Annu. 1980;15(Pt II):241-270.

243. Tucker JA. The continuing value of electron microscopy in surgical pathology. Ultrastruct Pathol. 2000;24:383-389.

244. Mierau GW, Berry PJ, Malott RL, Weeks DA. Appraisal of the comparative utility of immu- nohistochemistry and electron microscopy in the diagnosis of childhood round cell tumors. Ultrastruct Pathol. 1996;20:507-517.

245. Erlandson RA, Rosai J. A realistic approach to the use of electron microscopy and other ancillary diagnostic techniques in surgical pathology. Am J Surg Pathol. 1995;19:247-250.

246. Lombardi L, Orazi A. Electron microscopy in an oncologic institution: diagnostic usefulness in surgical pathology. Tumori. 1988;74:531-535.

247. Williams MJ, Uzman BG. Uses and contributions of diagnostic electron microscopy in surgical pathology: a study of 20 Veterans Administration hospitals. Hum Pathol. 1984;15:738-745.

248. Azar HA, Espinoza CG, Richman AV, Saba SR, Wang T "Undifferentiated" large cell malignancies: an ultrastructural and immunocytochemical study. Hum Pathol. 1982;13:323-333.

249. Seymour AE, Henderson DW. Electron microscopy in surgical pathology: a selective review. Pathology. 1981;13:111-135.

250. Warhol MJ, Corson JM. An ultrastructural comparison of mesotheliomas with adenocarcinomas of the lung and breast. Hum Pathol. 1985;16:50-55.

251. Warhol MJ, Hickey WF, Corson JM. Malignant mesothelioma: ultrastructural distinction from adenocarcinoma. Am J Surg Pathol. 1982;6:307-314.

252. Warhol MJ, Hunter NJ, Corson JM. An ultrastructural comparison of mesotheliomas and adenocarcinoma of the ovary and endometrium. Int J Gynecol Pathol. 1982;1:125-134.

253. Wick MR, Swanson PE, Manivel JC. Immunohistochemical analysis of soft tissue sarcomas. Comparisons with electron microscopy. Appl Pathol. 1988;6:169-196.

254. Gonzalez-Crussi F, Mangkornkanok M, Hsueh W. Large-cell lymphoma: diagnostic difficulties and case study. Am J Surg Pathol. 1987;11:59-65.

255. Weinstein MH, Dal Cin P. Genetics of epithelial tumors of the renal parenchyma in adults and renal cell carcinoma in children. Anal Quant Cytol Histol. 2001;23:362-372.

256. Argani P, Antonescu CR, Illei PB, et al. Primary renal neoplasms with the ASPL-TFE3 gene fusion of alveolar soft parts sarcoma: a distinctive tumor entity previously included among renal cell carcinomas of children and adolescents. Am J Pathol. 2001;159:179-192.

257. Cerasoli S, Spada F, Buda R, Turci A, Giangaspero F. Cytogenetic analysis of 19 renal cell tumors. Pathologica. 2001;93:118-123.

258. Dennis TR, Stock AD. A molecular cytogenetic study of chromosome 3 rearrangements in small cell lung cancer: consistent involvement of chromosome band 3q13.2. Cancer Genet Cytogenet. 1999;113:134-140.

259. Onuki N, Wistuba II, Travis WD, et al. Genetic changes in the spectrum of neuroendocrine lung tumors. Cancer. 1999;85:600-607.

260. Kovatich A, Friedland DM, Druck T, et al. Molecular alterations to human chromosome 3p loci in neuroendocrine lung tumors. Cancer. 1998;83:1109-1117.

261. Sandberg AA. Cytogenetics and molecular genetics of bone and soft-tissue tumors. Am J Med Genet 2002;115:189-193.

262. Parham DM. Neuroectodermal and neuroendocrine tumors principally seen in children. Am J Clin Pathol. 2001;115(suppl):S113-S128.

263. Summersgill B, Goker H, Osin P, et al. Establishing germ cell origin of undifferentiated tumors by identifying gains of 12p material using comparative genomic hybridization analysis of paraffin-embedded samples. Diagn Mol Pathol. 1998;7:260-266.

264. Ahmed S, Siddiqui AK, Rai KR. Low-grade B-cell bronchial associated lymphoid tissue (BALT) lymphoma. Cancer Invest 2002;20:1059-1068.

265. Hedvat CV, Hegde A, Chaganti RS, et al. Application of tissue microarray technology to the study of non-Hodgkin's and Hodgkin's lymphoma. Hum Pathol. 2002;33:968-974.

266. Mehra S, Messner H, Minden M, Chaganti RS. Molecular cytogenetic characterization of non-Hodgkin lymphoma cell lines. Genes Chromosomes Cancer. 2002;33:225-234.

267. Minna JD. Neoplasms of the lung. In: Favei AS, Braunwald E, Isselbacher KJ, eds. Harrison's Principles of Internal Medicine. New York: McGraw-Hill; 1998:552-562.

268. Snyder CL, Saltzman DA, Ferrell KL, Thompson RC, Leonard AS. A new approach to the resection of pulmonary osteosarcoma metastases. Results of aggressive metastasectomy. Clin Orthop. 1991;270:247-253.

269. Todd TR. The surgical treatment of pulmonary metastases. Chest. 1997;112:287S-290S.

270. Downey RJ. Surgical treatment of pulmonaiy metastases. Surg Oncol Clin North Am. 1999;8:341.

271. Raab SS, Hornberger J, Raffin T. The importance of sputum cytology in the diagnosis of lung cancer. A cost-effectiveness analysis. Chest. 1997;112:937-945.

272. Barlow PB, Beck JR. The solitary pulmonary nodule: a decision analysis [Abstract]. Chest. 1985;88:45S.

273. Cummings SR, Lillington GA, Richards RJ. Managing solitary pulmonary nodules: the choice of strategy is a "close call. Am Rev Respir Dis. 1986;134:453-460.

274. Kunstaetter R, Wolkove N, Kreisman H, Cohen C, Frank H. The solitary pulmonary nodule: decision analysis. Med Decis Making. 1985;5:61-75.

275. Raab SS, Hornberger J. The effect of a patient's risk-taking attitude on the cost effectiveness of testing strategies in the evaluation of pulmonary lesions. Chest. 1997;111:1583-1590.

276. Raab SS, Slagel DD, Hughes JH, Thomas PA, Silverman JF. Sensitivity and cost-effectiveness of fine needle aspiration with immunocytochemistry in the evaluation of patients with a pulmonary malignancy and a history of cancer. Arch Pathol Lab Med. 1997;121:695-700.

277. Raab S, Gross T, Grzybicki D, Silverman J. Clinical perception of the utility of sputa and other tests in patients with lung masses. Mod Pathol. 1999;12:188A.

278. Raab SS. The cost-effectiveness of immunohistochemistry. Arch Pathol Lab Med. 2000;124:1185-1191.

279. Alberts AS, Falkson G, Falkson HC, Merwe MP Treatment and prognosis of metastatic carcinoma of unknown primary: analysis of 100 patients. Med Pediatr Oncol. 1989;17:188-192.

Multiple Choice Questions

1. Which ONE of the following statements concerning metastatic tumors in the lung is TRUE?

A. Primary lung malignancies outnumber metastases by a ratio of 2:1.

B. Less than 10% of metastatic carcinomas involve only the lungs.

C. Tumors that spread via the lymphatics do not involve the lungs.

D. Conceptually, all malignancies that metastasize to the lungs comprise a single clone of neoplastic cells.

E. The rate at which primary tumors develop the ability to metastasize varies substantially.

ANSWER: E

2. Which ONE of the following statements is FALSE?

A. Lung metastases are always symptomatic.

B. Metastases to the lung may be nodular masses or diffuse infiltrates.

C. Pulmonary infarcts may result from metastasis to the lung.

D. Tumor-related thrombotic microangiopathy can produce pulmonary hypertension and cor pulmonale.

E. Arterially mediated metastases to the lung occur via bronchial arteries.

ANSWER: A

3. Which of the following statements about hematogenous metastases to the lungs is/are TRUE?

A. Involvement of the middle to lower lung fields is predominant.

B. A subpleural location is common.

C. They grow more rapidly than do primary lung carcinomas.

D. The presence of a solitary intrap arenchymal nodule does not exclude the possibility of metastasis.

E. All of the above

ANSWER: E

4. The most common source of a solitary metastatic tumor in the lung that measures more than 5 cm in diameter is the:

A. Breast

B. Larynx

C. Colon

D. Prostate

E. Pancreas

ANSWER: A

5. The radiographic appearances of lymphangitic tumors in the lung include:

A. Multiple bilateral linear infiltrates with no lymph node enlargement

B. Hilar masses with centripetal parenchymal extension

C. Focal linear infiltration of the parenchyma adjacent to a mass

D. Stellate parenchymal radiations from a peripheral mass

E. All of the above

ANSWER: E

6. Which ONE of the following statements concerning malignant pleural effusions is TRUE?

A. They are more common than effusions related to cardiac failure.

B. They typically measure no more than 500 mL and are serous.

C. Ninety percent or more can be diagnosed by thoracentesis cytology.

D. They are seen in virtually all cases of metastatic pleural sarcoma.

E. Those caused by lymphoma are particularly ominous prognostically.

ANSWER: C

7. Metastatic endobronchial tumors:

A. May present with symptoms and signs of adult asthma

B. Are not associated with renal cell carcinomas

C. Are strictly hematogenous in nature

D. Are caused by secondary sarcoma in 75% of cases

E. Typically occur within 1 year after diagnosis of the primary tumor

ANSWER: A

8. The accuracy of clinicopathologic sampling methods that are used to identify intrapulmonary metastases:

A. Is dependent on location(s) of the lesion(s)

B. Is much less than that associated with primary lung cancers

C. Is less than 50% with regard to computed tomography-guided transthoracic fine-needle aspiration

D. Has no relationship whatsoever to the experience of the operator

E. All of the above ANSWER: A

9. Which of the following sources of information are useful in determining the nature and source of a solitary tumor in the lung?

A. Its radiographic appearance

B. Its histologic appearance

C. Clinical history of the patient

D. Molecular (e.g., gene chip) analyses

E. All of the above

ANSWER: E

10. Intrapulmonary adenocarcinomas with a papillary appearance commonly originate in the:

A. Kidney

B. Colon

C. Prostate

D. Oropharynx

E. Stomach

ANSWER: A

11. Among all metastatic malignancies that can assume a polygonal clear cell appearance, the ONE that also contains microscopic blood “lakes” is:

A. Clear cell ovarian carcinoma

B. Clear cell breast carcinoma

C. “Balloon cell” melanoma

D. Renal cell carcinoma

E. Clear cell (“mesonephroid”) bladder carcinoma

ANSWER: D

12. Which ONE of the following markers is associated with metastatic breast carcinoma in the lung rather than primary bronchogenic carcinoma?

A. CDX2

B. Thyroid transcription factor-1

C. Napsin-A

D. Gross cystic disease fluid protein-15

E. CD138

ANSWER: D

13. Fine-needle aspiration biopsies that are aimed at sampling lesions in the basal lower lobe of the right lung can yield a misdiagnosis of well-differentiated oncocytic adenocarcinoma because of sampling the:

A. Kidney

B. Liver

C. Adrenal gland

D. Gallbladder

E. All of the above

ANSWER: B

14. Metastatic carcinomas in the lung that may show obvious central necrosis include:

A. Colorectal adenocarcinoma

B. Renal cell carcinoma

C. Esophageal adenocarcinoma

D. Ductal breast adenocarcinoma

E. All of the above

ANSWER: E

15. The single most important characteristic of gene chip analyses of metastatic tumors in the lung is the:

A. Size of the lesion that was sampled

B. pH at which the analysis is performed

C. Age of the patient

D. Type of chemical material that was used to construct the chip

E. Size and diversity of the tumor cohort population

ANSWER: E

16. The great majority of metastatic spindle cell tumors of the lung are:

A. Sarcomatoid melanomas

B. Sarcomatoid carcinomas

C. Sarcomas

D. Metastasizing leiomyomas

E. Anaplastic large cell lymphomas

ANSWER: C

17. Which of the following cell lineages may pertain to small cell metastatic tumors in the lung?

A. Melanocytic

B. Muscular

C. Chondroid

D. Neuritic

E. All of the above

ANSWER: E

18. Gene profiling to separate primary from secondary squamous carcinomas in the lung is associated with an accuracy of:

A. 10%

B. 25%

C. 50%

D. 75%

E. 95%

ANSWER: E

19. Which ONE of the following markers can be useful in diagnostically separating metastatic germ cell tumors from primary pulmonary adenocarcinomas?

A. CK20

B. PNL2

C. Titin

D. CD30

E. MIC2

ANSWER: D

20. Which ONE of the following tumors shows paracrystalline cytoplasmic inclusions by electron microscopy?

A. Melanoma

B. Rhabdomyosarcoma

C. Pancreatic adenocarcinoma

D. Alveolar soft part sarcoma

E. Adrenocortical carcinoma

ANSWER: D