Avoiding Underdiagnosis, Overdiagnosis, and Misdiagnosis of Lung Carcinoma

Written By: Sam Savage

Published Date: July 16, 2008 Last Edited: July 16, 2008

By Butnor, Kelly J

* Context.-Given the magnitude of the therapeutic and prognostic implications, it is critical that pathologists diagnose lung cancer accurately. This can sometimes be a formidable challenge, as a number of benign entities mimic lung carcinoma and vice versa. Objective.-To present strategies for recognizing benign entities likely to be confused with lung carcinoma, malignancies of the lung prone to misinterpretation as benign, and commonly misclassified pulmonary neoplasms.

Data Sources.-The medical literature and experience from consultative and surgical practice.

Conclusions.-In addition to understanding the clinical context in which a lung biopsy is procured and the radiographic findings, appreciating the histologic distribution of disease and what, if any, pathologic features are present in the background can go a long way toward averting a mis-diagnosis of lung cancer. Recognizing the limitations posed by small samples and communicating clearly to clinicians the level of diagnostic uncertainty are equally as important for establishing an accurate diagnosis of lung cancer.

(Arch Pathol Lab Med. 2008;132:1118-1132)

Call it anything you like; just don’t call it cancer.

Anonymous

The pathology literature is replete with reports of benign entities mimicking lung carcinoma. Because lung cancer is a disease with remarkably poor overall survival that often entails treatment with both surgery and chemotherapy/radiotherapy, the stakes are high to avoid not only overdiagnosis but also underdiagnosis of lung carcinoma. A false-positive diagnosis of lung cancer may result in inappropriately aggressive treatment with attendant risks of morbidity and toxicity that are not inconsequential. Failure to recognize carcinoma of the lung is likely to result in suboptimal treatment and/or treatment delay. It is just as important not to misclassify malignancies involving the lung, as the therapy and prognosis for primary and metastatic pulmonary malignancies and even different histologic types of lung carcinoma substantially differ.

It would be nearly impossible to catalog all of the entities that cause diagnostic confusion in the realm of pulmonary neoplasia. The following sections highlight benign conditions that simulate lung carcinoma, malignant pulmonary tumors mistaken for benign lesions, and malignancies of the lung that mimic one another, which are likely to be encountered in routine surgical pathology practice and how to avoid misdiagnosing them.

OVERDIAGNOSIS OF LUNG CANCER

“Pseudomalignancies” of the lung fall into 2 general categories: reactive processes misinterpreted as cancerous and benign tumors mistaken for malignancy. An adequate clinical history and understanding of the radiologic findings is helpful in the evaluation of any surgical lung biopsy but is of paramount importance when dealing with reactive/benign pulmonary processes. Such information often provides the keys to avoiding an overdiagnosis of malignancy. Questions to consider include the following: What were the presenting signs and symptoms? What has been the time course of disease? Is the patient immunosuppressed? Does he or she show any signs/symptoms of infection? Is there a history of lung or extrapulmonary malignancy and if so, how long ago was it and did the patient receive chemotherapy and/or radiation? Is there a radiographically discrete lesion or is the process diffuse? If a mass lesion is present, what are its contours and does the surrounding lung show any abnormalities?

Another key to avoiding an overdiagnosis of malignancy relates to understanding the limitations of small specimens, such as transbronchial and needle core biopsies. Although it has been estimated that the overall diagnostic yield from transbronchial biopsies is anywhere from 31% to 67%, the rate is exquisitely dependent on a myriad of factors, including the skill of the bronchoscopist; the prebiopsy probability that the pathologic process is malignant; the number, size, and quality of the tissue fragments obtained; and the pathologist’s experience in interpreting small lung biopsies.1-3 Clinicians often place considerable pressure on the pathologist to render a definitive diagnosis on specimens obtained by minimally invasive means. Although no one would argue that having a patient go through multiple procedures to obtain a diagnosis is desirable, in some instances, whether because of inadequate tissue, inappropriate technique/handling resulting in obscuring artifact, or failure to sample the diagnostically informative portion of the lesion, a malignant diagnosis cannot be made with a reasonable level of certainty. In such circumstances, it is entirely appropriate to render a descriptive diagnosis, provided that the reasons for doing so are also commented on. Necessitating a second diagnostic procedure does far less harm to the patient than an overdiagnosis of malignancy.

What follows are selected benign/reactive conditions that simulate malignancy. The reader is referred to other sources for a more detailed examination of such entities.4,5

Squamous Metaplasia Overdiagnosed as Squamous Cell Carcinoma

Squamous metaplasia is a reactive phenomenon that can involve the bronchial and bronchiolar epithelium, as is not infrequently seen in cigarette smokers or in chronic airway inflammatory conditions. It may also develop around healing mucosal ulcers/erosions or involve honeycomb cysts of end-stage lung. The setting in which squamous metaplasia is most apt to be confused with squamous cell carcinoma is in diffuse alveolar damage.6 Squamous metaplasia of the bronchiolar epithelium and/or alveolar ducts in diffuse alveolar damage occurs during the proliferative (organizing) phase around 1 to 2 weeks following the inciting injury (Figure 1, A).7 In some cases, the degree of cytologic atypia can be quite striking (Figure 1, B). Atypical mitoses and infiltrative growth should not be present. Avoiding an overdiagnosis of squamous cell carcinoma rests on the recognition that the squamous atypia is part of an acute lung injury pattern in which other supporting features, such as hyaline membranes, organizing pneumonia, interstitial edema with fibroblastic expansion, and/or type 2 pneumocyte hyperplasia are also seen (Figure 1, C).

Bronchial/Peribronchiolar Metaplasia Overdiagnosed as Adenocarcinoma

Bronchial metaplasia arises in honeycomb cysts of advanced interstitial lung disease, most typically in usual interstitial pneumonia. To those unaccustomed to evaluating end-stage interstitial lung disease or when dealing with small biopsies, the closely apposed cysts set in a background of dense fibrosis in end- stage lung bear some resemblance to the acinar subtype of lung carcinoma (Figure 2, A and B). In contrast to the angulated infiltrative acini of carcinoma, the cysts in honeycomb lung have generally rounded contours. The benign nature of the metaplastic epithelium in honeycomb cysts is confirmed by the presence of cilia, which are usually readily identified at high magnification (Figure 2, A, inset). Another distinguishing feature that may be appreciated in wedge biopsies or larger specimens is the abrupt transition between honeycombed and relatively normal lung in usual interstitial pneumonia (Figure 2, C). By comparison, adenocarcinoma tends to gradually merge with nonneoplastic lung, often exhibiting a bronchioloalveolar carcinoma (BAC)-like growth pattern at its periphery (Figure 2, D).

Peribronchiolar metaplasia (PBM), alternatively referred to as Lambertosis, can be found incidentally in association with an underlying interstitial lung disease or as the sole manifestation of interstitial lung disease.8 In PBM, the lining of the peribronchiolar alveoli are replaced by metaplasia epithelium. Peribronchiolar metaplasia has some similarities to adenocarcinoma and BAC, in particular. The epithelium in PBM ranges from low cuboidal to ciliated columnar (Figure 2, E). Finding the latter is certainly helpful to not overdiagnose PBM as malignancy. In biopsies that are of sufficient size, the exquisitely peribronchiolar location of PBM is also a useful discriminator from BAC, which tends to be more randomly distributed (Figure 2, F).

Reactive Pneumocyte Hyperplasia Overdiagnosed as Adenocarcinoma

Normally, alveoli are lined predominantly by type I pneumocytes but may become populated by hyperplastic type II pneumocytes under a variety of circumstances, including the proliferative (organizing phase) of diffuse alveolar damage, radiation or drug-related toxicity, infection, and various inflammatory/fibrosing conditions.7 The prominence of hyperplastic type II pneumocytes, as compared with type I cells, which are typically inconspicuous, can be concerning for BAC.

Reactive type II pneumocytes are cuboidal to hobnailshaped (Figure 3, A). The degree of atypia they exhibit, particularly in organizing diffuse alveolar damage, is sometimes quite striking. This “too atypical to be malignant” appearance contrasts with the relative cytologic blandness exhibited by many BACs (Figure 3, B). Unlike solitary BACs, which are typically discrete lesions surrounded by unremarkable lung parenchyma, reactive pneumocyte hyperplasia is generally a diffuse process (Figure 3, C). Even BACs with a diffuse pneumonia-like radiographic appearance usually exhibit discontinuous growth along the alveolar septa (Figure 3, D). Other findings related to the underlying condition in which reactive pneumocyte hyperplasia is a feature, whether it be resolving acute lung injury, fibrosis, or inflammation, typically not only accompany but often overshadow reactive pneumocyte hyperplasia. Atypical Adenomatous Hyperplasia Overdiagnosed as Adenocarcinoma

Atypical adenomatous hyperplasia (AAH) is a localized preinvasive proliferation of neoplastic rounded to low columnar nonciliated cells lining alveoli and on occasion respiratory bronchioles (Figure 4, A). Atypical adenomatous hyperplasia is most often an incidental finding in specimens procured for other reasons, found in as many as 19% of men and 30% of women with resected pulmonary adenocarcinomas. 9 Inflammation and fibrosis is usually absent or no more than minimal in AAH.

In simplistic terms, AAH can be likened to atypical ductal hyperplasia of the breast in that it shares some of the genetic alterations present in pulmonary adenocarcinoma, but its histologic features fall short of a diagnosis of malignancy. 10 However, in contrast to preinvasive neoplastic lesions of the breast, the definition of AAH, and for that matter BAC, is a moving target that is neither universally recognized nor uniformly applied. Formerly, AAH was limited to 5 mm or less.11 The current World Health Organization classification has no size restriction but instead defines AAH as a focal lesion that is usually less than 5 mm in diameter, whereas BAC is generally larger than 10 mm.12 Qualitative criteria for AAH are also somewhat vague. Atypical adenomatous hyperplasia exhibits only mild to moderate cytologic atypia and no more than one of the following: marked cellular stratification, high cell density and marked nuclear overlap, coarse chromatin with nucleoli, columnar cell change with cellular crowding, or micropapillary tufting.12 If severe cytologic atypia is present and/ or 2 or more of the previous features are present, BAC should be considered (Figure 4, B).12

The distinction between AAH and BAC is by no means trivial, particularly in cases in which the specimen contains a separate bona fide BAC. Diagnosing an atypical focus as BAC rather than AAH in a lobe that also harbors what would otherwise be a T1 BAC increases the T category to T4 and, in the absence of nodal or distant metastases, elevates the stage from IA to IIIB.13 If a second focus is present in a different lobe of the same lung as the primary BAC, under current American Joint Commission on Cancer guidelines, the patient is categorized as having M1, stage IV disease, which is generally considered inoperable.13,14

Perhaps in the not too distant future sufficient prognostic data will have been acquired to permit the formulation of a classification scheme akin to that used in breast neoplasia, wherein the term BAC is replaced by a strictly defined entity designated as in situ adenocarcinoma.

With the cytomorphologic similarities between AAH and BAC, it is not difficult to see how AAH can be overdiagnosed as BAC in biopsies that do not encompass the entire lesion. Definitive diagnosis of AAH, as well as BAC, should not be rendered on small samples, such as transbronchial biopsies or transthoracic needle core biopsies. In such circumstances, the use of a descriptive term such as atypical pneumocyte proliferation with a comment addressing the problems posed by incompletely sampled lesions that have features of BAC would be appropriate.

Pulmonary Hamartoma Overdiagnosed as Chondrosarcoma

Pulmonary hamartoma can be confused with metastatic chondrosarcoma or other mesenchymal malignancies, especially in small biopsies. Although all of the elements may not be represented in a small sample, hamartomas contain at least 2 mesenchymal components, such as cartilage and fat, with the former typically predominating. Essential to avoiding an overdiagnosis is the recognition that the mesenchymal elements in hamartomas are mature. Unlike chondrosarcoma, the cartilage in pulmonary hamartoma lacks cytologic atypia (Figure 5, A). The typically well-circumscribed, nodular appearance of metastatic chondrosarcoma is similar to hamartoma, but it is unusual for pulmonary metastases to be the first manifestation of disease in chondrosarcoma.15 An awareness that benign respiratory epithelium entrapped in cleftlike spaces, or in endobronchial lesions, overlying squamous metaplasia and/or hyperplasia, are frequent findings in hamartoma will lessen concerns over a biphasic neoplasm(Figure 5, B and C).

Inflammatory Myofibroblastic Tumor Overdiagnosed as Undifferentiated Pleomorphic Sarcoma or Spindle Cell Carcinoma

Inflammatory myofibroblastic tumor (IMT) is a term used to refer to a cadre of pulmonary lesions that have gone under such disparate appellations as inflammatory pseudotumor, plasma cell granuloma, xanthogranuloma, and fibrous histiocytoma. There continues to be debate as to whether IMT represents a reactive/inflammatory lesion or a low-grade mesenchymal malignancy.16 Although these tumors are defined as having myofibroblastic differentiation in common, recent investigations suggest that at least a subset do not show immunohistochemical evidence of myofibroblastic differentiation and are instead comprised predominantly of cells of macrophage- dendritic cell origin.17

Inflammatory myofibroblastic tumors consist of variable proportions of spindle cells in a storiform or fascicular arrangement admixed with collagen and inflammatory cells. Inflammatory cells in IMT can be quite prominent and include lymphocytes, histiocytes, which sometimes take the form of Touton- type giant cells or foamy macrophages, and plasma cells (Figure 6, A). Although the spindle cells in IMT are generally cytologically bland, an intense inflammatory infiltrate may cause them to appear more concerning. The heterogeneous appearance of IMT, coupled with its destruction of the underlying alveolar architecture and capacity to invade extrapulmonary structures, contribute to IMT being mistaken for spindle cell carcinoma or undifferentiated pleomorphic sarcoma, referred to in the past as malignant fibrous histiocytoma. Careful inspection of the spindle cells in IMT will usually disclose a lack of nuclear pleomorphism, bizarre giant cells, and atypical mitoses that typify malignant fibrous histiocytoma (Figure 6, B). As compared with malignant fibrous histiocytoma, when necrosis is present in IMT, it is usually scant, and the mitotic rate is low (

Keratin staining should be interpreted with caution when attempting to distinguish IMT from spindle cell carcinoma of the lung. Cytokeratin immunoreactivity can be notoriously patchy in spindle cell carcinoma, whereas about 30% of IMTs show focal positivity.18 As with malignant fibrous histiocytoma, spindle cell carcinoma typically has a substantially greater degree of nuclear pleomorphism and mitotic activity than IMT. Rather than being interspersed throughout the tumor as in IMT, in spindle cell carcinomas of the lung with a prominent inflammatory infiltrate, the inflammatory cells are often localized to the periphery of the tumor. When positive, ALK1 can be helpful in confirming IMT, but this marker is negative in about 50% to 60% of cases.12,17

Alveolar Adenoma, Papillary Adenoma, and Mucous Gland Adenoma Overdiagnosed as Adenocarcinoma

Alveolar adenoma, papillary adenoma, and mucous gland adenoma are rare benign pulmonary neoplasms that may be mistaken for adenocarcinoma. The first 2 are well-circumscribed parenchymal lesions, whereas the latter is an exophytic endobronchial tumor. Alveolar adenoma is composed of cytokeratin-positive, flattened to hobnail cells lining variably ectatic spaces that often contain eosinophilic material (Figure 7).19 Papillary adenoma is a branching papillary proliferation of cuboidal to columnar cells with fibrovascular cores.20 In addition to their circumscription, alveolar adenoma and papillary adenoma are distinguished from BAC by the absence of cytologic atypia, micropapillary tufting, and discontinuous growth that characterizes BAC.12

With its closely packed glands and mucus-filled cysts, mucous gland adenoma bears a superficial resemblance to adenocarcinoma.21 Aside from a having a typically more peripheral location than mucous gland adenoma, invasive adenocarcinoma features infiltrative glands composed of cytologically atypical, mitotically active cells. Mucous gland adenoma can also be misinterpreted as mucoepidermoid carcinoma, but in addition to mucus cells, the latter features squamous differentiation and intermediate cells.

Sclerosing Hemangioma Overdiagnosed as Adenocarcinoma

Sclerosing hemangioma (SH) can exhibit a variety of growth patterns that often appear in combination in the same lesion. The papillary pattern of SH is most apt to be confused with BACs with papillary features. A distinctive feature of SH is its dual population of bland cuboidal surface cells and round stromal cells within variably sclerotic papillary structures.

Unlike SH, which obliterates the underlying architecture, the overall structure of the parenchyma is preserved in BAC. Immunohistochemically, the neoplastic cells in BAC stain intensely with cytokeratins, but while the surface cells of SH are keratin- positive, the round stromal cells are negative for this marker.22

Carcinoid Tumorlet Overdiagnosed as Carcinoid Tumor

Although a carcinoid tumorlet could conceivably be sampled by a fortuitously placed transbronchial or needle core biopsy, it is most often detected incidentally in wedge biopsies or larger specimens that have been obtained for other reasons. Tumorlets have histologic features identical to those seen in carcinoid tumor, including bland polygonal to spindled cells with finely granular chromatin, scant cytoplasm, absent necrosis, and low mitotic activity (

Meningothelial-like Nodules Overdiagnosed as Carcinoid Tumor

A typically incidental lesion that can be confused with carcinoid tumors or tumorlets, particularly in small biopsies, is a meningothelial-like nodule (MLN), formerly called chemodectoma.24 The current designation refers to the ultrastructural resemblance of MLN cells to meningothelial cells. Usually subcentimeter in size, MLNs are composed of bland cells with more cytoplasm than is found in carcinoids and tumorlets. Like meningothelial cells, MLNs may exhibit a whorled arrangement and nuclear pseudoinclusions. Location is a key feature for separating these lesions. Whereas carcinoids and tumorlets arise adjacent to airways, MLNs are found within the interstitium, typically in a perivenular distribution (Figure 9, A and B). Their identity can be confirmed by immunohistochemistry. Meningothelial-like nodules stain positively for vimentin and are variably positive for epithelial membrane antigen and in contrast to carcinoids and tumorlets, are negative for cytokeratin and neuroendocrine markers.25,26

Crushed Lymphocytes Overdiagnosed as Small Cell Carcinoma

Like the cells in small cell lung carcinoma (SCLC), lymphocytes are fragile and prone to crush artifact. This type of artifact is a frequent problem in transbronchial biopsies (Figure 10, A). Because of the gravity of the diagnosis, when SCLC is being considered in small biopsies that show substantial crush artifact, it is prudent to immunohistochemically exclude lymphocytes as the origin of the crushed cells. This can be accomplished with a limited panel of markers that includes a cocktail of high- and low-molecular-weight cytokeratins, such as AE1/AE3 and CAM 5.2, and leukocyte common antigen. Cytokeratins typically stain SCLC in a finely granular rim and perinuclear dotlike distribution (Figure 10, B). Strong circumferential cytoplasmic and/or membranous staining should prompt a consideration of non-small cell carcinoma (see “Basaloid Carcinoma Misdiagnosed as SCLC” and “Large Cell Neuroendocrine Carcinoma Misdiagnosed as SCLC”). Rarely, particularly poorly preserved SCLCs fail to immunoreact with cytokeratins. Positive staining for leukocyte common antigen, combined with a complete absence of cytokeratin immunoreactivity, is not seen in SCLC and confirms the lymphoid nature of the infiltrate.

Depending on the extent of crush artifact, it may be difficult to determine whether a lymphoid infiltrate appears reactive or is morphologically atypical. In some cases, immunostaining for CD3 and CD20 permits the discrimination of a mixed lymphoid infiltrate from a B- or T-cell predominant population. In samples that appear to show a B- or T-cell predominance but are severely crushed, a descriptive diagnosis of “atypical lymphoid infiltrate” with a comment suggesting additional sampling with submission of fresh tissue for flow cytometric analysis to further evaluate the possibility of lymphoma is reasonable.

An algorithm for evaluating hyperchromatic crushed infiltrates, where limited tissue is almost always an issue, is presented in Figure 11.

Carcinoid Overdiagnosed as SCLC

Albeit at opposite ends of the spectrum in terms of aggressiveness, carcinoid tumor and SCLC are both neuroendocrine tumors that share a propensity to exhibit crush artifact in transbronchial biopsies. Morphologic features that distinguish SCLC from carcinoid tumor, such as necrosis and abundant mitotic figures (usually >60/2 mm^sup 2^) may be difficult to discern in extensively crushed specimens (Figure 12, A and B).12 This problem, coupled with the immunohistochemical overlap in staining for cytokeratins and neuroendocrine markers, are factors that contribute to carcinoid being mistaken for SCLC.

The proliferation marker MIB-1 (Ki-67) can be useful in the evaluation of neuroendocrine tumors with prominent crush artifact.27,28 Even extensively crushed SCLCs typically show a high proliferation index, as evidence by diffuse (>40%-50%) staining for MIB-1 (Figure 11). Sparse (

UNDERDIAGNOSIS OF LUNG CANCER

Not recognizing relatively bland proliferations as malignant, small quantities of malignant cells, or malignant cells growing in an unfamiliar pattern are but a few of the reasons lung cancer is underdiagnosed in pathology specimens. Studies examining how delays in recognizing the symptoms of lung cancer or referring patients suspected to have lung cancer for biopsy adversely affect survival are beginning to appear in the literature.29,30 The frequency and degree to which false-negative pathologic diagnoses impact the prognosis of patients with subsequently confirmed lung cancer has yet to be established.

Adenocarcinoma Underdiagnosed as Desquamative Interstitial Pneumonia

Adenocarcinoma of the lung can occasionally exhibit a growth pattern that mimics other cellular alveolar filling processes (Figure 13, A). There have been cases in which adenocarcinoma is underdiagnosed as desquamative interstitial pneumonia.31 Despite adenocarcinoma occasionally exhibiting a growth pattern similar to desquamative interstitial pneumonia, these entities have important morphologic differences. The nuclear-cytoplasmic ratio in most adenocarcinomas is comparatively high and nucleoli are often apparent. Desquamative interstitial pneumonia, which is a misnomer because the cells that fill alveoli are macrophages rather than sloughed pneumocytes as was originally believed, is characterized by cells with abundant eosinophilic to finely pigmented light brown cytoplasm, small nuclei, and inconspicuous nucleoli (Figure 13, B).32 The macrophages in desquamative interstitial pneumonia are truly intra-alveolar, distinct from the pneumocytes that line the alveolar septa. In adenocarcinoma with a prominent alveolar growth pattern, in addition to filling the alveolar spaces, malignant cells also grow along the alveolar septa replacing normal pneumocytes. Immunohistochemistry can be used in equivocal cases. The macrophages in desquamative interstitial pneumonia stain positively for CD68 and are negative for cytokeratins, whereas the opposite staining profile is observed in adenocarcinoma.

Atypical Carcinoid Underdiagnosed as Typical Carcinoid

Although typical carcinoid (TC) is closer to atypical carcinoid (AC) along the spectrum of neuroendocrine malignancies of the lung than it is to SCLC, there are prognostic differences between TC and AC. The overall 10-year survival rate for AC (35%-59%) is significantly worse than TC (82%-95%).33-35 Not recognizing the histologic features that separate AC from TC when they are present results in the underdiagnosis of AC. Atypical carcinoid is distinguished from TC by the presence of foci of necrosis and/or increased mitoses (2-10/2 mm^sup 2^) as compared with less than 2 mitoses per 2 mm^sup 2^ in TC. By comparison, SCLC typically exhibits more than 60 mitoses per 2 mm^sup 2^ and is more likely to show extensive necrosis. Reliable distinction between AC and TC is dependent on the size and preservation quality of the sample. Distinguishing TC from AC may be difficult on small specimens, which are prone to crush artifact. MIB-1 staining, which is significantly increased in SCLC as compared with TC and AC, cannot be used to differentiate TC from AC because their rates of MIB-1 staining do not significantly differ.28

BAC Underdiagnosed as Reactive Pneumocyte Hyperplasia

The overdiagnosis of reactive pneumocyte hyperplasia as BAC has already been discussed. Its reversal, underdiagnosing BAC as reactive pneumocyte hyperplasia, is also a problem in pulmonary pathology. Although the cells in BAC are usually more cytologically atypical than those seen in AAH, in the spectrum of pulmonary neoplasia, BAC cells can be rather banal-appearing and are paradoxically often blander than reactive pneumocytes.

A helpful feature in recognizing BAC is the discontinuous growth along alveolar septa, termed lepidic spread. Even in cytologically bland cases, the cells in BAC usually contrast sharply with adjacent pneumocytes (Figure 3, D). This is in contradistinction to reactive pneumocyte hyperplasia, which is generally a diffuse process without intervening normal pneumocytes (Figure 3, C).

Intravascular Tumor Underdiagnosed as Thromboemboli

Intravascular tumor can be underdiagnosed by failing to recognize that an abnormality within the pulmonary vasculature is present or by mistaking intravascular tumor for organizing thromboemboli. Pulmonary tumor microemboli, which are reportedly present in as many as one quarter of patients with solid tumors at autopsy, are only rarely detected antemortem.36 In some cases, there is an antecedent history of carcinoma, but on occasion, symptoms related to pulmonary tumor microemboli are the initial manifestation of malignancy. Metastatic breast, lung, and gastric carcinoma account for the majority of reported cases.37 Patients may come to biopsy because of progressive dyspnea or unexplained pulmonary hypertension.37 Apart from the occlusion of small pulmonary arteries, arterioles, and/or alveolar septal capillaries by emboli comprised of neoplastic cells, the lung tissue in patients with pulmonary tumor microemboli may be relatively normal (Figure 14, A). Because there is a general tendency to focus on the airways, alveoli, and interstitium when evaluating lung biopsies, tumor microemboli can be all too easily overlooked. Before reporting that there are no pathologic findings in a lung biopsy, it is crucial to look carefully at the vessels. Uncertainty regarding the nature of the cells comprising a thrombus can be resolved by staining for cytokeratins. The same approach applies to recognizing pulmonary lymphatic carcinomatosis, a condition in which metastatic tumor diffusely involves the lymphatic channels of the lung.38

Intravascular malignancies, especially sarcomas such as pulmonary artery sarcoma, can be mistaken for organizing thromboemboli. Recanalized thrombi often accompany pulmonary artery sarcomas and can cause diagnostic confusion (Figure 14, B).12 Although organizing thromboemboli can exhibit quite cellular foci and areas within pulmonary sarcoma can be hypocellular and collagenized, with proper sampling, frankly sarcomatous growth is evident in the latter (Figure 14, C).

Marginal Zone Lymphoma Underdiagnosed as Nodular Lymphoid Hyperplasia

Although a comprehensive discussion of this topic is beyond the scope of this article, excellent reviews may be found elsewhere.39 Marginal zone lymphoma of the mucosa-associated lymphoid tissue (MALT lymphoma) has some striking similarities to nodular lymphoid hyperplasia (NLHP) of the lung that predispose this low-grade malignancy to underdiagnosis (Figure 15, A and B). Like MALT lymphoma, NLHP may obliterate the underlying lung parenchyma. The presence of reactive germinal centers is also not a distinguishing feature. Although reactive germinal centers are more typically associated with reactive conditions, they may be seen in up to 85% of MALT lymphomas.40 A peculiar feature present in as many as one half of MALT lymphomas of the lung, multinucleated giant cells and/ or sarcoidlike granulomas can also be seen in nodular lymphoid hyperplasia (Figure 15, C).40 Lymphoepithelial lesions, which are characterized by airway epithelial invasion by lymphoid cells, are almost invariably present in MALT lymphomas but are reportedly also found in up to 60% of cases of NLHP (Figure 15, D).41 Plasma cells may be intimately admixed with neoplastic cells in MALT lymphoma, further confounding accurate diagnosis.

A feature that can be helpful in separating MALT lymphoma from NLHP, but is only reliably appreciated in wedge biopsies or larger specimens, is the overall disease distribution. MALT lymphoma of the lung exhibits a lymphangitic growth pattern and has a tendency to spread to the pleura in a plaquelike manner, as well as invade the bronchial cartilage (Figure 15, E and F). The presence of any of these features argues against a diagnosis of NLHP.

Unlike NLHP, which is composed of a polymorphous mixture of B and T lymphocytes arranged in a distribution typically seen in and around reactive follicles, the neoplastic small lymphocytes that surround germinal centers in MALT lymphoma are monoclonal B cells that are CD20 positive, typically Bcl-2 positive, and often aberrantly coexpress CD43.41

The immunohistochemical demonstration of monoclonality by way of kappa or lambda light chain restriction can sometimes be vexingly difficult on formalin-fixed, paraffin-embedded tissue. Molecular analysis using polymerase chain reaction is usually successful in showing clonal rearrangement of the immunoglobulin heavy chain gene in paraffin sections.42 The occasional case that is histologically suspicious for MALT lymphoma but in which clonality cannot be definitively established is probably best handled with the input of one’s hematopathologist colleagues.

Mucinous (“Colloid”) Adenocarcinoma Underdiagnosed as Mucostasis

Mucinous (“colloid”) adenocarcinomas of the lung (MCA) share the same diagnostic difficulties as their histologic equivalents in other sites, such as the breast and gastrointestinal tract. Two factors that contribute to the underdiagnosis of MCA are the paucity of neoplastic cells and the typically well-differentiated nature of such tumors. Relative to the copious pools of mucin seen in most MCAs, tumor cells are often quite sparse and at low magnification can be rather inconspicuous (Figure 16, A). Even when the columnar mucinous epithelium that comprises most MCAs is detected, the diagnosis of malignancy is sometimes called into question by the cytologic blandness of the neoplastic cells (Figure 16, B).43

Whether it is because tumor cells are simply not present in the sample, a problem that increases in likelihood with decreasing specimen size, tumor cells are present but are not detected, or tumor cells are not recognized as being malignant, MCA can be mistaken for nonneoplastic disorders that cause excess mucus production and/or deposition in the lung, such as mucostasis. Mucostasis can be seen in a number of conditions, most commonly distal to bronchiectasis or as a feature of various forms of bronchiolitis (Figure 16, C). Abnormal airways filled with mucus that spills out into the surrounding airspaces is certainly helpful if found, but the proximate cause of mucostasis is not always histologically apparent, particularly in small biopsies. Typically, the only type of cells present in mucus resulting from stasis are inflammatory, most common among which are macrophages. The identification of cytokeratin-positive cells in mucin that are not obviously benign bronchial or bronchiolar epithelial cells should prompt thorough sampling to search for additional columnar and/or goblet cells suspended in mucin and/or focally adherent to alveolar walls that would help to establish a diagnosis of malignancy.

MISDIAGNOSIS OF LUNG CANCER

In this era of targeted drug therapy, it is more crucial than ever to correctly identify histologic type in lung carcinoma. Not only do treatment regimens for primary lung cancers and metastases drastically differ, with the development of tyrosine kinase inhibitors that exploit epidermal growth factor receptor mutations in some pulmonary adenocarcinomas, so also does present day management of different histologic types of lung carcinoma.

As important as it is to classify lung carcinomas accurately, it should nonetheless be remembered that lung cancers can exhibit considerable heterogeneity. When sampled extensively, more than one histologic type can be identified in 45% of lung carcinomas.44

Basaloid Carcinoma Misdiagnosed as SCLC

The histologic features of basaloid carcinoma (BC) and the basaloid and small cell variants of squamous cell carcinoma are such that these types of non-small cell lung carcinoma have a notorious propensity for being misdiagnosed as SCLC, especially in small biopsies. Classified as a type of large cell carcinoma, BC is characterized by relatively small cells with hyperchromatic nuclei, inconspicuous nucleoli, and scant cytoplasm, growing as solid nodules or trabeculae with abundant mitoses and prominent peripheral palisading (Figure 17, A).45 Occasional rosettes can be seen and central comedonecrosis is not uncommon. Nuclear molding is said to be absent in BC.12 The basaloid variant of squamous cell carcinoma is a poorly differentiated form of squamous cell carcinoma that has histologic features similar to basaloid carcinoma but also shows at least focal squamous differentiation.46 Both BC and basaloid variant of squamous cell carcinoma, as well as the small cell variant of squamous cell carcinoma, purportedly have a lower nuclear- cytoplasmic ratio and coarser, more vesicular chromatin than SCLC.12

Immunohistochemistry can be extremely helpful in distinguishing SCLC from BC and poorly differentiated variants of squamous cell carcinoma. In contrast to SCLC, which typically shows weak to moderate intensity staining in a perinuclear rim and dotlike pattern for cytokeratins AE1/AE3 and CAM 5.2, the variants of non-small cell lung carcinoma most apt to be confused with SCLC typically demonstrate strong circumferential cytoplasmic and membranous staining (Figure 17, B). Thyroid transcription factor 1 (TTF-1) and cytokeratin 34betaE12 provide additional information. Although about 10% to 25% of SCLCs are TTF-1 negative, nearly all BCs and poorly differentiated squamous cell carcinoma do not express TTF-1.47 The opposite staining results are seen with cytokeratin 34betaE12. Nearly all BCs and poorly differentiated squamous cell carcinomas are cytokeratin 34betaE12 positive, whereas almost all SCLCs are nonimmunoreactive for this marker (Figure 11).47-49 p63, like cytokeratin 34betaE12, stains poorly differentiated squamous cell carcinomas but is negative in SCLC.49 p16Ink4a has also recently been investigated as a discriminatory marker and was found to be nearly always expressed in SCLC but only variably positive in non- small cell lung carcinoma.49

Because of the limited amount of tissue in many cases and the specificity of TTF-1 and cytokeratin 34betaE12, staining for neuroendocrine markers is usually not necessary for distinguishing BC or poorly differentiated squamous cell carcinoma from SCLC and can even be misleading. Up to 25% of SCLCs are negative for neuroendocrine markers, whereas at least focal staining for chromogranin, synaptophysin, and/or other neuroendocrine markers is occasionally seen in non-small cell lung carcinomas, including BC.47

Large Cell Neuroendocrine Carcinoma Misdiagnosed as SCLC

Judging solely on the basis of their names, it would seem that distinguishing large cell neuroendocrine carcinoma (LCNEC) from SCLC is straightforward. However, as both of these tumors are part of the spectrum of neuroendocrine malignancies of the lung, making this distinction can sometimes be difficult. Unlike distinguishing BC from SCLC, which is greatly aided by immunohistochemistry, the separation of LCNEC from SCLC is primarily dependent on morphologic features. Apart from exhibiting more diffuse staining for cytokeratins AE1/AE3 and CAM 5.2 and a somewhat lower frequency of TTF-1 positivity than SCLC, LCNEC is similar to SCLC with respect to positivity for neuroendocrine markers and absent staining for cytokeratin 34betaE12.47 In a recent study that attempted to discriminate LCNEC from SCLC using a large panel of antibodies, only cytokeratin (CK) 18 and E-cadherin demonstrated significantly higher rates of staining in LCNEC than SCLC.50 Despite the statistical differences in staining between LCNEC and SCLC, a substantial proportion of SCLCs were immunoreactive for these markers and thus their clinical utility appears limited. Typically, tumor cells in LCNEC are 3 times larger than a small resting lymphocyte and have a relatively low nuclear-cytoplasmic ratio, vesicular chromatin, and conspicuous nucleoli, whereas SCLC is composed of small cells with a high nuclear-cytoplasmic ratio and finely granular chromatin (Figure 18, A and B). In a small proportion of cases of SCLC, the tumor cells are somewhat larger and exhibit more cytoplasm than is typically expected in SCLC and may even show slightly vesicular chromatin and occasional nucleoli (Figure 18, C). Such features, which are apt to cause confusion with LCNEC, are most likely to be seen in resection specimens, which generally show better preservation and less crush artifact than biopsies obtained bronchoscopically.51

In rare instances, it may not be possible to confidently categorize a tumor with neuroendocrine differentiation as LCNEC or SCLC, particularly in small biopsies in which the morphologic features are obscured by crush artifact. Under such circumstances, it is entirely acceptable to diagnose “neuroendocrine carcinoma, not further classified” and suggest additional sampling or if applicable, refer to concurrent cytologic samples that may contain better quality diagnostic material.

For tumors that show features not classic for SCLC, ancillary findings can be helpful. Nuclear molding and basophilic staining of vessels and stroma, know as the Azzopardi effect, are seldom seen in LCNEC but are not uncommon in SCLC (Figure 18, D and E). Occasional larger cells scattered among smaller cells with typical SCLC features should in no way obviate a diagnosis of SCLC. However, if the proportion of large cells with prominent nucleoli admixed with small cells reaches 10%, combined small cell/large cell carcinoma should be considered.51

Metastatic Prostatic Adenocarcinoma Misdiagnosed as Primary Lung Adenocarcinoma

Although it is rare for prostatic adenocarcinoma lung metastases (PALM) to come to clinical attention before the primary tumor is detected, it is important to be familiar with the most common patterns of PALM, as the extent to which they mimic primary pulmonary carcinoma is underappreciated. The architectural patterns seen most frequently in PALM are microacinar, tubulopapillary, and carcinoid-like.52 The microacinar pattern is characterized by small acinar proliferations of minimally pleomorphic tumor cells with eosinophilic cytoplasm, conspicuous nucleoli, and occasional intraluminal blue mucin (Figure 19, A). The tubulopapillary pattern of PALM, with its stratified tumor cells, prominent nucleoli, and comedonecrosis, resembles metastatic colorectal adenocarcinoma. PALM can also show a nested arrangement reminiscent of carcinoid tumor but, unlike carcinoid, reportedly does not feature finely granular chromatin.52 Neuroendocrine markers can be misleading, as they stain upward of half of prostatic adenocarcinomas.53 Fortunately, nearly all PALMs stain with prostate-specific antigen and prostate acid phophatase.52 The use of prostate markers should be considered in males with TTF-1-negative adenocarcinoma involving the lung. Other findings that may prompt consideration of PALM include a lymphangitic distribution, along with a low degree of nuclear pleomorphism, prominent round nucleoli, distinct cell borders, and a lack of desmoplastic stromal response (Figure 19, B).52

Pulmonary Intestinal-Type Adenocarcinoma Misdiagnosed as Metastatic Colorectal Adenocarcinoma

The array of histologic patterns primary pulmonary adenocarcinoma can manifest is nothing short of remarkable. Uncommonly, primary lung adenocarcinoma can appear morphologically identical to metastatic colorectal adenocarcinoma. Dubbed pulmonary intestinal- type adenocarcinoma, these primary lung carcinomas are apt to be mistaken for metastases if immunohistochemical studies are not performed.54 Pulmonary intestinal-type adenocarcinomas demonstrate stratified columnar cells in a garlandlike arrangement with cribriforming and central “dirty” necrosis (Figure 20, A and B). They often elicit an exuberant host response, as well as a pronounced desmoplastic stromal reaction. Adding to the confusion with colorectal carcinoma is the lack of lepidic growth at the periphery of pulmonary intestinal-type adenocarcinomas. However, in contrast to metastatic colorectal adenocarcinoma, pulmonary intestinal-type adenocarcinoma retains a pulmonary immunophenotype by displaying a TTF-1-positive, CK7-positive, CK20-negative, and CDX- 2-negative staining pattern (Figure 20, C).54

Mucin-Rich Pulmonary Carcinomas Misdiagnosed as Metastatic Mucinous Adenocarcinoma

Mucin-rich primary lung carcinomas are quite a heterogeneous group of tumors that includes mucinous cystoadenocarcinoma, mucinous (“colloid”) adenocarcinoma, signet ring adenocarcinoma, and mucinous BAC. These tumors have disparate immunohistochemical staining profiles, which often do not clearly point to a respiratory or extrapulmonary origin.

Primary mucinous adenocarcinomas of the lung that are comprised of neoplastic goblet cells frequently exhibit staining for markers typically associated with enteric differentiation, including CDX-2, MUC2, and in about half of cases, CK20 (Table).55 A sizable proportion of these tumors (~18%) are CK7 negative.55 Only about 73% are immunoreactive for TTF-1 and in cases that are TTF-1 positive, staining is usually patchy.55 In contrast, the CK7-positive, TTF-1- positive, CDX-2-negative, MUC2-negative staining pattern exhibited by signet ring adenocarcinoma of the lung typifies the immunophenotype seen in most adenocarcinomas of pulmonary origin. Although mucinous BACs are frequently CK20 positive (~80%-90%) and TTF-1 negative (~70%-80%), they reportedly uniformly express CK7, do not stain with CDX-2 or MUC2, and only rarely show weak cytoplasmic villin immunoreactivity.55-57 Although so-called pulmonary adenocarcinomas with enteric differentiation variably stain for markers typically associated with a colorectal origin, like mucinous BAC, pulmonary adenocarcinomas with enteric differentiation are uniformly positive for CK7.58

Thyroid transcription factor 1 positivity in mucin-rich adenocarcinomas that involve the lung supports a pulmonary origin. For TTF-1-negative tumors, which often express a phenotypically confusing array of immunohistochemical markers, the separation of primary mucin-rich lung adenocarcinoma from metastatic mucinous adenocarcinomas originating in the gastrointestinal or pancreaticobiliary tracts, ovary, or breast is most reliably accomplished through the integration of the clinical details and the radiographic distribution of disease.

Mixed Subtype Adenocarcinoma Misdiagnosed as Nonmucinous BAC

Data from the Early Lung Cancer Action Program, a study in which asymptomatic patients undergo computed tomography screening for lung cancer, suggests that BAC is overdiagnosed.14 Of cases submitted by the contributing pathologists as BAC, more than three quarters were reclassified by the Early Lung Cancer Action Program pathology review panel as invasive adenocarcinoma, mixed subtype, on the basis of identifying stromal invasion. The inaccurate diagnosis of BAC is undoubtedly related at least in part to the evolving definition of BAC. Initially described as a well-differentiated adenocarcinoma in the periphery of the lung with a tendency to spread aerogenously and by lymphatic routes, the definition of BAC has since been restricted to what essentially amounts to in situ carcinoma. Bronchioloalveolar carcinoma is currently defined as the growth of neoplastic cells along preexisting alveolar structures (lepidic growth) without evidence of stromal, vascular, or pleural invasion.11,12,59

Whether it is because of a delay in accepting the stringent definition of BAC that was instituted in 1999, a failure to implement it, or a lack of understanding what constitutes stromal invasion by the pathology community, one thing has become certain- misdiagnosing mixed subtype adenocarcinoma as BAC has important prognostic implications. Whereas BAC, as strictly defined by currentWorld Health Organization criteria, has a 100% 5-year survival for tumors 2 cm or less in diameter, the 5-year survival rate for similar size carcinomas that exhibit unequivocal central stromal invasion is only 60%.60 Other studies have demonstrated similar results. Noguchi and colleagues61 showed that patients with pure BAC had 100% 5-year survival, whereas 48% of those with poorly differentiated invasive adenocarcinoma were dead of disease within 5 years.

It is not uncommon for invasive adenocarcinomas to demonstrate a BAC growth pattern at their periphery, small biopsies of which may entirely miss the invasive component (Figure 21, A and B). For this reason, it is inappropriate to make a definitive diagnosis of BAC in biopsies that do not encompass the entire lesion.62 Bronchioloalveolar carcinoma has a tendency to undergo central collapse, a phenomenon that is accompanied by alveolar septal thickening (Figure 21, C). Distinguishing sclerosing BAC from mixed subtype invasive adenocarcinoma with a prominent BAC component can be challenging. Aside from overt obliteration of the alveolar architecture, other features that are helpful in distinguishing invasive adenocarcinoma from BAC include foci of acinar growth, tubulopapillary structures, a fibroblastic stromal reaction, and/or solid nests of tumor cells (Figure 21, D).12,60 Some investigators have advocated the use of elastin stains to highlight disruption of the pulmonary interstitial elastic framework in areas of invasion.60,63

CONCLUDING REMARKS

There is a multitude of other ways in which lung cancer can be underdiagnosed, overdiagnosed, or misdiagnosed, including mistaking reactive atypia in the setting of pneumothorax for adenocarcinoma,64 misinterpreting extensively necrotic squamous cell carcinoma as abscess, failing to detect carcinoma in usual interstitial pneumonia,65misidentifying sarcomatoid carcinoma as sarcoma, overinterpreting florid reactive stromal processes such as organizing pneumonia as malignant, confusing malignant melanoma in all of its various guises as carcinoma, and erroneously interpreting extrapulmonary thoracic malignancies that invade the lung as primary lung carcinoma. The examples presented herein will hopefully provide a framework for recognizing when things are not as they appear in pathologic proliferations of the lung.

I would like to thank Mary Beth Beasley, MD, Thomas Colby, MD, Anthony Gal, MD, Kevin Leslie, MD, Victor Roggli, MD, and Henry Tazelaar, MD, for their insightful suggestions.

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Kelly J. Butnor, MD

Accepted for publication November 7, 2007.

From the Department of Pathology, University of Vermont/Fletcher Allen Health Care, Burlington.

The author has no relevant financial interest in the products or companies described in this article.

Reprints: Kelly J. Butnor, MD, Department of Pathology, University of Vermont/Fletcher Allen Health Care, ACC Building, EP2- 120, 111 Colchester Ave, Burlington, VT 05401 (e-mail: [email protected]).

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