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Figure 7.1a — Fetal Adenocarcinoma, Fine Needle Aspiration [Pap Stain; Low Power]. Fetal adenocarcinoma is a peripherally based lung adenocarcinoma composed of tubular and cribriform structures often in a complex back-to-back arrangement histologically mimicking the appearance of fetal lung between 10 and 16 weeks gestation. Both low-grade and high-grade variants exist, with the former arising in the fourth to fifth decade of life, and the latter about 2 decades later. Interposed between glandular structures are small solid so-called “morular” nests of cytologically bland cells as seen jutting from the top and in the center of this microfragment. Cellular smears contain densely clustered aggregates that show thin papillary strands projecting from the fragment edge.

Figure 7.1b — Fetal Adenocarcinoma, Fine Needle Aspiration [Pap Stain; Medium Power]. Three-dimensional microfragments may show peripheral palisading (arrow). The glands in both low and high-grade subtypes contain glycogen-rich cells with cytoplasmic vacuoles imitating secretory endometrium. Although subnuclear or supranuclear vacuoles may be seen in Romanowsky-stained slides, they are rarely visible in alcohol-fixed preparations. A well-formed squamous “morule” composed of cytologically uniform cells with banal nuclei is seen in the inset. There is no specific immunohistochemical profile for fetal adenocarcinoma; however, these neoplasms show diffuse TTF-1 staining as well as aberrant nuclear staining with β-catenin, which can be diagnostically helpful. Since a high percentage express synaptophysin and chromogranin A, these aspirates may be mistaken for carcinoid tumor. Other entities in the differential diagnosis include endometriosis, well-differentiated adenocarcinoma not otherwise specified, and pulmonary blastoma.

Figure 7.1c — Fetal Adenocarcinoma, Fine Needle Aspiration [Diff-Quik Stain; High Power]. One of the more striking features of fetal adenocarcinoma is the presence of dense hyaline globules with sharp, smooth borders somewhat evocative of adenoid cystic carcinoma. These globules are pale in Papanicolaou-stained slides, and densely metachromatic as illustrated in this Romanowsky-stained smear. Surrounding these globules, cells have a basaloid appearance with overlapping nuclei and nuclear molding. Smear background is typically clean in fetal adenocarcinoma lacking the tumor diathesis so regularly encountered in small cell neuroendocrine carcinoma. A “tigroid” background characterized by linear strips of detached cytoplasmic material has been reported in some instances of fetal adenocarcinoma. However, a “tigroid” background (initially promulgated as characteristic of seminoma) is not unusual in any neoplasm with high cytoplasmic glycogen content.

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Figure 7.1d — Fetal Adenocarcinoma, Lobectomy [H&E Stain; High Power]. This low-grade fetal adenocarcinoma resembles the pseudoglandular phase of fetal lung development, with sub- and supranuclear glycogen-rich (i.e., Periodic acid-Schiff-positive, diastase-sensitive) vacuoles within uniform tall columnar nonciliated cells, with small, uniform, low-grade nuclei. TTF-1 will routinely be positive. This example contains prominent squamoid morules. Low-grade tumors have pure fetal morphology and typically affect young smokers, while high-grade variants are more often found in elderly male smokers. High-grade tumors have at least 50% fetal morphology, but also contain more common adenocarcinoma patterns, often with foci of necrosis, and lack morules. Unlike their low-grade counterparts, high-grade lesions may express AFP, glypican-3, and SALL4.

Figure 7.2 — Lymphoepithelioma-Like Carcinoma, Lobectomy [H&E Stain; High Power]. This tumor is composed of anastomosing syncytia of undifferentiated malignant epithelial cells, extensively infiltrated and often obscured by a dense reactive lymphoid infiltrate (CD3/CD8+ and CD20+). The neoplastic cells are large, with round to oval vesicular nuclei with irregular nuclear membranes and prominent eosinophilic nucleoli. In some cases, the tumor cells are more spindled. Immunohistochemical stains usually show expression of CK5/6, p40, and p63, suggesting squamous differentiation. Evaluation for the presence of Epstein–Barr virus by immunohistochemistry or in situ hybridization is routinely positive in the neoplastic cells. Differential diagnostic considerations include metastatic nasopharyngeal carcinoma (distinction requires history and/or imaging) and lymphocyte-rich thymoma (Epstein–Barr virus-negative; characteristic imaging). Granulomatous inflammation can be excluded with immunohistochemical staining for keratins and CD68.

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Figure 7.3a — Adenoid Cystic Carcinoma, Fine Needle Aspiration [Pap Stain; Medium Power]. Multiple finger-like bulbous papillae project from a scant amount of basal lamina producing a “fir tree” configuration in this image. Because adenoid cystic carcinoma of the lung commonly involves large airways, an endobronchial component resulting in a papillary architecture is not unusual, and can be potentially mistaken for squamous papilloma. Cell nuclei are typically small, isomorphic, and basaloid with much less cytoplasm than seen in the exfoliated squames from squamous papilloma. Within the tracheobronchial tree, adenoid cystic carcinoma is the most common salivary gland-type neoplasm, accounting for 70 % to 80% of cases.

Figure 7.3b — Adenoid Cystic Carcinoma, Fine Needle Aspiration [Pap Stain; High Power]. Smoothly contoured papillary fronds and microacini contain a monotonous basaloid population with indistinct cell borders and a meager amount of cytoplasm. Nuclear chromatin is evenly dispersed, and unlike many small cell/basaloid neoplasms of the lung, nuclear molding is largely absent. The classic cribriform/“Swiss-cheese” architecture containing translucent globules is not always present. Unlike squamous papilloma or small cell carcinoma, single cells are largely absent in adenoid cystic carcinoma smears.

Figure 7.3c — Adenoid Cystic Carcinoma, Fine Needle Aspiration [Pap Stain; Medium Power]. A sharp smooth-edged “double-contour” configuration results from the 3-dimensional nature of this single microacinar fragment. Fine focusing on this cluster is required to appreciate any cells or stroma that may be in the center of this microacinus. The clean smear background lacking a tumor diathesis helps distinguish this basaloid neoplasm from more common entities such as small cell carcinoma. Immunostains from a cell block show positive myoepithelial marker (e.g., p63, smooth muscle actin, calponin, S100, and SOX-10) that help to distinguish adenoid cystic carcinoma from other basaloid malignancies.

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Figure 7.4a — Adenoid Cystic Carcinoma, Fine Needle Aspiration [Diff-Quik Stain; High Power]. This field provides an example of the classic appearance of adenoid cystic carcinoma–note the oval, magenta-colored globules with smooth borders ringed by basaloid cells. This is a contrast to the “inside out” pattern of pleomorphic adenoma, in which cells are imbedded in magenta-colored stroma that engulfs the neoplastic cells. While adenoid cystic carcinoma may be primary to the lung, which contains salivary tissue, there have been reported instances in which adenoid cystic carcinoma invades from a distant site along a nerve.

Figure 7.4b — Adenoid Cystic Carcinoma, Fine Needle Aspiration [Pap Stain; High Power]. On the Pap stain, the globular material of adenoid cystic carcinoma is not as obvious but still detectable. The neoplastic cells appear smaller, but are more visible throughout the surface of the globules rather than simply at the edges. Because the structures are symmetrical, they may be initially ignored on a Pap stain preparation if not present in great numbers.

Figure 7.4c — Metastatic Adenoid Cystic Carcinoma, Biopsy [H&E Stain; Low Power]. This metastatic lesion shows the classic low power pattern of adenoid cystic carcinoma, with irregular cribriform, tubular, and solid nests of tumor cells, embedded in a myxohyaline stroma. The tumor infiltrates adjacent normal lung parenchyma, including a bronchovascular bundle, at the bottom of the image. Primary adenoid cystic carcinomas are histologically indistinguishable from metastatic lesions, but arise centrally from the seromucinous glands of the bronchi; the peripheral intraparenchymal location of this lesion is characteristic of a metastasis. This patient had a documented history of adenoid cystic carcinoma of the parotid gland.

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Figure 7.4d — Metastatic Adenoid Cystic Carcinoma, Biopsy [H&E Stain; High Power]. The glands of adenoid cystic carcinoma are lined by a dual layer of cells: a luminal cuboidal surface cell and a spindled, myoepithelial-type cell peripherally. The lumens contain a core of myxoid or hyalinized matrix.

Figure 7.5a — Mucoepidermoid Carcinoma, Fine Needle Aspiration [H&E Stain; High Power]. If cell block material is created, a mucicarmine stain can be used to verify the presence of mucin with gland-like spaces. Mucoepidermoid carcinoma typically affects young patients and is found within large airway spaces. If patients have the tumor surgically resected, the prognosis is excellent. While immunohistochemical studies performed on tissue biopsies may help exclude a classic lung adenocarcinoma or squamous cell carcinoma, the interpretation is substantially more difficult on cell block material.

Figure 7.5b — Mucoepidermoid Carcinoma, Fine Needle Aspiration [Pap Stain; High Power]. These cells contain mucinous vacuoles, form a glandular space, and have hyperchromatic nuclei with irregular nuclear borders and distinct nucleoli. The intracytoplasmic vacuoles have the bubbly appearance suggestive of mucinous contents. A squamous component is not readily apparent. The background contains granular debris, which may be necrotic material or degenerated mucin. While mucoepidermoid carcinomas can be low or high grade, the majority are low-grade carcinomas. However, grading of mucoepidermoid carcinoma on cytologic material is not usually possible.

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Figure 7.5c — Mucoepidermoid Carcinoma, Fine Needle Aspiration [Diff-Quik Stain; High Power]. This fragment contains a mixture of cell types, including squamoid cells with prominent nucleoli and spindled morphology, as well as vacuolated histiocytic-like, clear mucinous cells. The cells seen here are overtly malignant, with greatly enlarged nuclei, anisonucleosis, and a disorganized arrangement within the fragment.

Figure 7.5d — Mucoepidermoid Carcinoma, Fine Needle Aspiration [Diff-Quik Stain; High Power]. Mucoepidermoid carcinoma may develop in the lung salivary tissue. Mucoepidermoid carcinoma is a diagnostic challenge because it contains both malignant squamoid and glandular elements. If only one element is sampled, such as the glandular component seen here, it may raise concern for either an adenocarcinoma or a squamous cell carcinoma. If both glandular and squamous components are seen, the differential includes an adenosquamous carcinoma of the lung.

Figure 7.6a — Metastatic Mucoepidermoid Carcinoma, Biopsy [H&E Stain; Low Power]. At low power, nests of malignant squamous (“epidermoid”) tumor cells are seen spreading through air spaces at the periphery of this metastasis. Non-small cell carcinoma is a consideration, and history is of critical importance in establishing the correct diagnosis. This patient had a documented history of mucoepidermoid carcinoma of the parotid gland.

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Figure 7.6b — Metastatic Mucoepidermoid Carcinoma, Biopsy [H&E Stain; High Power]. At high power, both components of this neoplasm can be appreciated. The squamous component dominates, and is at the upper left, while a mucin vacuole is present at the bottom, right of center. Mucicarmine staining and/or immunostaining for CK7 or EMA can be used to highlight the glandular component, which may be subtle on hematoxylin and eosin stain. The squamous nests express p40/p63 as well as CK5/6. Primary adenosquamous carcinoma of the lung may be difficult to exclude with certainty, especially in the absence of a clear history of a prior salivary lesion.

Figure 7.7a — Meningioma, Fine Needle Aspiration [Diff-Quik Stain; Low Power]. Primary pulmonary meningiomas are exceptionally rare. Metastatic deposits to the lung from intracranial neoplasms are also very uncommon. Meningiomas presumably derive from pluripotent cells, ectopic embryonic arachnoid cells, or from meningothelial nodules. A wide age range has been reported with most patients being of middle age. Most examples are single, incidentally encountered, well-demarcated nodules in the lung periphery. Aspirates are highly cellular, composed primarily of syncytial aggregates with few single forms. The smear background is clean.

Figure 7.7b — Meningioma, Fine Needle Aspiration [Diff-Quik Stain; High Power]. Upon closer inspection, cells within these loose syncytial aggregates appear identical to one another with rounded to oval smoothly contoured nuclei, indistinct nucleoli, occasional nuclear grooves, and intranuclear cytoplasmic invaginations (absent here). Some cells have eccentrically placed nuclei, giving them a plasmacytoid “look.” The moderate to abundant wispy cytoplasm interconnects among cells without sharp cell borders. Cell cytoplasm projects from single cells in long tapering strands. In contrast to this meningothelial variant, cells in the fibrous variant are also cytologically bland, but spindle shaped and mimic a mesenchymal neoplasm.

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Figure 7.7c — Meningioma, Fine Needle Aspiration [Pap Stain; High Power]. Cells of meningioma may be arranged in well-formed whorled nests, particularly in the meningothelial variant. In many instances, however, this concentric cellular arrangement is incomplete, and instead cells form a smooth bulbous contour but lack well-developed circumferential streaming (lower left). Depending on the histologic subtype, psammoma bodies may be encountered in aspirate smears, but are usually infrequent. Note the absence of mitotic figures and individual cell necrosis in these images of meningioma.

Figure 7.7d — Meningioma, Core Needle Biopsy [H&E Stain; Medium Power]. Meningioma of the lung is histologically indistinguishable from its meningeal counterpart. This example shows the classic multinodular whorled pattern, with spindled to epithelioid cells with abundant eosinophilic cytoplasm and open chromatin with punctate nucleoli. Psammoma bodies may be present. Immunohistochemical stains for EMA, vimentin, and progesterone receptor are routinely positive, while keratin stains are negative. In the lung, this rare tumor is more often a metastasis from a meningeal primary than a primary neoplasm. In small biopsies, the features may suggest solitary fibrous tumor (STAT6-positive, EMA-negative), synovial sarcoma (CD99+, bcl-2+, EMA+), or a granuloma (CD68+; negative for EMA and PR).

Figure 7.8a — Solitary Fibrous Tumor, Fine Needle Aspiration [Diff-Quik Stain; Low Power]. In the thoracic cavity, solitary fibrous tumor most commonly arises from the visceral pleura, and has been described in the mediastinum and trachea, but only very infrequently within the lung parenchyma proper. Solitary fibrous tumor varies greatly in size from a few centimeters to greater than 15 cm, and occurs over a broad age range; most occur in the sixth to seventh decade. In addition to being discovered incidentally, patients may present with nonspecific symptoms. Since the histopathology contains hyper- and hypocellular zones, aspiration smears vary in cellularity from only modestly cellular to containing 3-dimensional hypercellular clusters imitating a sarcoma. The ropy collagen that is often present in tissue can sometimes be captured in cytologic smears. Metachromatic collagen fibers intersect among a uniform population of cells in these two clusters. Single cells with rounded nuclei containing only wispy strands of cytoplasm are dispersed in a clean smear background.

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Figure 7.8b — Solitary Fibrous Tumor, Fine Needle Aspiration [Pap Stain; Low Power]. Oval nuclei show extreme uniformity and hypochromasia with some having incomplete nuclear grooves. Cell cytoplasm is barely perceptible. Small lymphocytes are scattered among these fibroblastic cells. Malignant solitary fibrous tumor is defined primarily by mitotic activity. Since accurate mitotic counts are not possible cytologically, definitive statements regarding malignancy for solitary fibrous tumor are not possible. Cytologic images such as this one are easily confused for synovial sarcoma, malignant peripheral nerve sheath tumor, and desmoplastic round cell tumor.

Figure 7.8c — Solitary Fibrous Tumor, Core Needle Biopsy [H&E Stain; Medium Power]. Stromal collagen is evident in this pleural core needle biopsy. Aspirates from these foci of extensive hyalinization are hypocellular due to the inability of a fine needle to extract cells from this matrix. Note that the uniform hypochromic nuclei mirror their appearance in the prior cytologic image. The branching vascular pattern (so-called hemangiopericytomatous), which is so helpful in recognizing solitary fibrous tumor, is absent from cytologic smears. Solitary fibrous tumor has been more readily recognizable in recent years due to the relatively high sensitivity (greater than 95% positive staining) and specificity of STAT6 immunostaining. These neoplasms are also CD34, bcl-2, and CD99 positive.