(1)
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Morphologic evaluation can be approached by recognizing lineage-specific features and formulating a differential diagnosis for tumors in various lineage-nonspecific groups (Fig. 1.1).
Lineage-Specific Pattern
Determining cell lineage in poorly differentiated tumors is often the first diagnostic step. The general cytologic features of the tumors in the four lineages (i.e., “the Big 4 ”) have been outlined in Chap. 2. Identifying the subtype of a tumor in each lineage category is the second step, followed by detecting the primary origin (Fig. 1.9).
This chapter covers the general features of common subtypes of carcinoma, mesothelioma, and germ cell tumors. In the carcinoma category, the commonly encountered subtypes are adenocarcinoma, squamous carcinoma, neuroendocrine carcinoma, as well as renal cell carcinoma, hepatocellular carcinoma, urothelial carcinoma, and rarely, adrenal cortical carcinoma (Fig. 3.1). The general features of each are described below.
Fig. 3.1
A stepwise approach to cytologic diagnosis of metastatic carcinoma in fine needle aspiration sample: subtyping and primary site determination. Abbreviations: CA carcinoma, GI gastrointestinal, HCC hepatocellular carcinoma, H&N head and neck, RCC renal cell carcinoma, UC urothelial carcinoma
Adenocarcinoma
The individual cells of adenocarcinoma generally have delicate, finely vacuolated cytoplasm, open or vesicular chromatin pattern, and conspicuous or prominent nucleoli, in contrast with the dense cytoplasm and coarse chromatin with inconspicuous nucleoli that are commonly associated with squamous carcinoma. Although poorly differentiated adenocarcinomas often show disorganized groups and numerous isolated cells with no particular architectural pattern, better differentiated adenocarcinomas tend to show patterns suggesting a primary site. For example, the presence of atypical columnar cells in a necrotic background favors a colorectal origin; high-grade papillary carcinoma in an older woman suggests serous papillary carcinoma of gynecologic origin; and linear arrays or a single-file of plasmacytoid cells is typically seen in lobular breast carcinoma (Fig. 2.8). The five common patterns of adenocarcinoma and the possible primary origins are listed in Fig. 3.2.
Fig. 3.2
Five common patterns of adenocarcinoma and the common primary origins. Abbreviation: GI gastrointestinal
Glandular Pattern
Columnar cells with nuclear polarity (i.e., palisading or feathering) and a luminal edge (Fig. 3.3), with a hint of glandular or tubular formation. Smears of glandular structures often form cohesive flat sheets, and the size of the sheet is positively correlated with the size of gland (Fig. 3.4). Note: other types of carcinoma, such as hepatocellular carcinoma, may show glandular-like configurations (Fig. 3.5).
Fig. 3.3
Adenocarcinoma with glandular pattern (example 1): metastatic large duct carcinoma from the prostate showing columnar cells with nuclear palisading and sharp luminal edge (Papanicolaou stain)
Fig. 3.4
Adenocarcinoma with glandular pattern (example 2): endometrioid carcinoma showing tumor cells that retain nuclear polarity and form cohesive flat sheets. The larger the gland, the larger the sheet is (left, Papanicolaou stain; right, H&E-stained cell block)
Fig. 3.5
An example of diagnostic traps: hepatocellular carcinoma can form glandular-like cell groups, superficially resembling adenocarcinoma (left, Papanicolaou stain; right, H&E-stained cell block)
Papillary Pattern
Fingerlike projections with fibrovascular cores and epithelial lining (Figs. 3.6, 3.7, 3.8, and 3.9). Papillary thyroid carcinoma may show a flowerlike configuration (Fig. 3.8) or form flat cohesive sheets on thinner smears (Fig. 3.9). Micropapillary carcinoma usually does not have a true fibrovascular core but shows tight clusters of papillae or small groups (Fig. 3.10). Note: other malignant tumors can show true papillary features, such as mesothelioma. Some non-papillary tumors may yield papillary-like tissue fragments on smears if the tumor contains abundant delicate vascular networks, such as paraganglioma (Fig. 3.11).
Fig. 3.6
Adenocarcinoma with papillary pattern (example 1): metastatic adenocarcinoma from the pancreas with broad papillary fronds (Papanicolaou stain)
Fig. 3.7
Adenocarcinoma with papillary pattern (example 2): metastatic serious papillary carcinoma from the ovary with delicate papillary fronds and fibrovascular cores (left, Papanicolaou stain; right, H&E-stained cell block)
Fig. 3.8
Adenocarcinoma with papillary pattern (example 3): metastatic papillary thyroid carcinoma with large flowerlike papillary fronds and fibrovascular cores (Papanicolaou stain)
Fig. 3.9
Papillary thyroid carcinomas in thinner area of smear often show flat cohesive sheets. Cell block demonstrates diagnostic nuclear features (left, Papanicolaou stain; right, H&E-stained cell block)
Fig. 3.10
Micropapillary carcinoma usually demonstrates tight clusters of papillae without fibrovascular core. This is a metastatic micropapillary carcinoma from the breast (Papanicolaou stain)
Fig. 3.11
An example of diagnostic traps: a capillary-rich non-papillary tumor (paraganglioma) may yield papillary-like tissue fragments on smear, which can be mistaken for papillary tumor (left, Papanicolaou stain; right, H&E-stained cell block)
Microacinar Pattern
Small group of cells forming vague acinar or follicles. This pattern is typically seen in prostatic adenocarcinoma, thyroid follicular carcinoma, acinar cell carcinoma of the pancreas (Figs. 3.12, 3.13, and 3.14), and some salivary gland carcinomas. Note: non-adenocarcinomas, such as hepatocellular carcinoma and neuroendocrine carcinoma, may show a microacinar-like or rosette-like configuration (Figs. 3.15 and 3.16).
Fig. 3.12
Adenocarcinoma with microacinar pattern (example 1): metastatic prostate carcinoma (Papanicolaou stain)
Fig. 3.13
Adenocarcinoma with microacinar pattern (example 2): metastatic pancreatic acinar cell carcinoma (left, Diff-Quik stain; right, Papanicolaou stain)
Fig. 3.14
Adenocarcinoma with microacinar pattern (example 3): metastatic follicular thyroid carcinoma (Papanicolaou stain)
Fig. 3.15
An example of diagnostic traps: non-adenocarcinoma showing microacinar-like configuration as seen in the hepatocellular carcinoma. The hepatoid tumor cells wrapped by endothelial cells are characteristic (Papanicolaou stain; inset, H&E-stained cell block)
Fig. 3.16
An example of diagnostic traps: non-adenocarcinoma showing microacinar-like configuration as seen in the metastatic neuroendocrine carcinoma (left, Papanicolaou stain; right, H&E-stained cell block)
Mucinous Pattern
Tumor cells with cytoplasmic mucin, with or without background mucin (Figs. 3.17, 3.18, and 3.19). Note: if a lesion is sampled via endoscopic ultrasound-guided FNA, the background “lesional mucin” should be distinguished from inadvertently sampled mucin from the gastrointestinal tract.
Fig. 3.17
Adenocarcinoma with mucinous pattern (example 1): metastatic adenocarcinoma from the pancreas with evenly distributed intracytoplasmic mucin (Papanicolaou stain)
Fig. 3.18
Adenocarcinoma with mucinous pattern (example 2): metastatic adenocarcinoma from the lung with cytoplasmic mucin vacuoles in scattered cells of the cell group (Papanicolaou stain)
Fig. 3.19
Adenocarcinoma with mucinous pattern (example 3): metastatic mucinous carcinoma from the breast with abundant extracellular mucin in the background (left, Diff-Quik stain; right, Papanicolaou stain)
Signet Ring Cell Pattern
Tumor cells with a large cytoplasmic mucin vacuole that compresses the nucleus to one side of the cell (Fig. 3.20). Common primary sites include the stomach, breasts, and pancreas. Note: non-adenocarcinomas, such as vascular tumors and occasionally lymphoma, can show signet ring features (see section “Lineage-Nonspecific Pattern” and Fig. 1.10).
Fig. 3.20
An example of metastatic adenocarcinoma with signet ring cell pattern from breast showing large cytoplasmic mucin vacuole that compresses the nucleus to one side (left and right, Papanicolaou stain)
Squamous Carcinoma
Well to Moderately Differentiated Squamous Carcinoma (Fig. 3.21):
Fig. 3.21
An example of moderately differentiated squamous carcinoma showing bizarre keratinized cells with dense orangeophilic cytoplasm and pyknotic nuclei admixed with anucleate cells and necrotic debris (Papanicolaou stain)
Discohesive or single highly pleomorphic or bizarre-appearing (“tadpole”) cells
Keratinized cells: dyskeratotic cells with distinct cell borders, orangeophilic dense cytoplasm (seen in Papanicolaou stain), keratin pearls, and a low N/C ratio in some cells
Hyperchromatic or pyknotic chromatin and inconspicuous nucleoli
Anucleate cells and necrotic debris
Differential diagnosis: epidermal inclusion cyst and benign lesions with squamous metaplasia
Poorly Differentiated Squamous Carcinoma (Fig. 3.22):
Fig. 3.22
An example of poorly differentiated squamous carcinoma showing syncytial groups of carcinoma cells with smudging chromatin and inconspicuous nucleoli admixed with necrotic debris. There are no keratinized cells (Papanicolaou stain)
Large syncytial clusters without keratinized cells and less distinct cell borders compared to better differentiated squamous carcinoma; some tumor cells may have a basaloid appearance
Relatively uniform cells, higher N/C ratio, and less dense cytoplasm
Smudging or coarse chromatin with inconspicuous or conspicuous nucleoli
Necrotic background
Differential diagnosis: small cell carcinoma, basal cell adenocarcinoma, and basaloid carcinoma of the anal region
Neuroendocrine Carcinoma(See Chap. 4 for Immunophenotype and Differential Diagnosis of Neuroendocrine Tumors)
Low Grade (Carcinoid and Islet Cell Tumor) (Figs. 3.23 and 3.24):
Fig. 3.23
An example of low-grade neuroendocrine carcinoma: metastatic islet cell tumor from pancreas showing uniform, plasmacytoid cells with rosette arrangement. The cells have “salt-and-pepper” chromatin and inconspicuous nucleoli (left, Diff-Quik stain; right, Papanicolaou stain)
Fig. 3.24
An example of neuroendocrine carcinoma: medullary thyroid carcinoma showing uniform plasmacytoid cells with finely stippled chromatin and indistinct nucleoli. Small neurosecretory granules are seen in left panel (left, Diff-Quik stain; right, Papanicolaou stain)
Acinar, rosette-like, or trabecular arrangement, numerous loosely cohesive groups and isolated cells
Uniform round to plasmacytoid cells with eccentrically located nuclei; occasionally spindle cell type
Occasionally, tiny red cytoplasmic neurosecretory granules (better seen in Diff-Quik stain) and cytoplasmic vacuolization
Finely stippled chromatin with inconspicuous nucleoli (“salt-and-pepper” appearance) is characteristic. Background amyloid may be seen.
Increased mitotic figures indicate an higher grade (such as atypical carcinoid).
Differential diagnosis: tumors with plasmacytoid features (Table 2.3).
High Grade (Small Cell Carcinoma and Merkel Cell Carcinoma) (Fig. 3.25):
Fig. 3.25
An example of high-grade neuroendocrine carcinoma: metastatic small cell carcinoma from the lung showing small-to-intermediate oval cells with scant cytoplasm and nuclear molding, hyperchromatic but evenly distributed chromatin, and indistinct nucleoli (Papanicolaou stain)
Small- or intermediate-sized round-to-oval cells
Scant cytoplasm, high N/C ratio, and nuclear molding
Evenly dispersed chromatin and inconspicuous nucleoli
Frequent mitotic figures, apoptotic bodies, and crush artifacts (e.g., nuclear streaking)
Background necrosis
Differential diagnosis: poorly differentiated carcinoma and other small blue cell tumors (see section “Lineage-Nonspecific Pattern,” Fig. 1.10)
Urothelial Carcinoma, Renal Cell Carcinoma, Hepatocellular Carcinoma, and Adrenal Cortical Carcinoma
Urothelial Carcinoma (Fig. 3.26):
Fig. 3.26
An example of urothelial carcinoma showing loosely cohesive and isolated tumor cells with plasmacytoid features, occasional “cercariform” cells that have fishtail-like end (Papanicolaou stain)
Loosely cohesive cell groups or isolated cells
Epithelioid cells with plasmacytoid or polygonal appearance and scattered “cercariform” cells with a long slender cytoplasmic process and a blunt end
Occasionally sarcomatoid features
Differential diagnosis: squamous carcinoma and tumors with plasmacytoid features (Table 2.3)
Renal Cell Carcinoma (see Chap. 4 for Immunophenotype and Differential Diagnosis of Kidney Tumors)Cytologic features of renal cell carcinomas vary significantly depending on subtype. The most common subtypes are clear cell type and papillary type. Their common features include (Fig. 3.27):
Fig. 3.27
An example of clear cell renal cell carcinoma showing tumor cells with clear cytoplasm that often intertwine with capillaries in tight tissue fragments (Papanicolaou stain)
Tight cell clusters intertwined with capillaries (in clear cell type) or papillary groups (in papillary type), with scattered isolated tumor cells
Polygonal cells with a moderate to abundant amount of cytoplasm, with a multivacuolated or granular appearance
Low N/C ratio with abundant cytoplasm
Cytoplasmic hyaline globules may be seen
Depending on tumor grade, the nucleus ranges from bland or small round to bizarre or large pleomorphic and the nucleolus ranges from inconspicuous to prominent
Differential diagnosis: for clear cell renal cell carcinoma, renal parenchyma (glomeruli and proximal renal tubular cells), benign renal tumors (oncocytoma and angiomyolipoma), chromophobe renal cell carcinoma, adrenal cortical tumors, benign hepatocytes, and hepatocytic tumors; for papillary renal cell carcinoma, other papillary tumors
Chromophobe renal cell carcinoma is less commonly encountered and typically shows hyperchromatic chromatin and perinuclear pale zones. The differential diagnosis includes clear cell renal cell carcinoma and renal oncocytoma.
Collecting duct carcinoma and medullary carcinoma are rare and show high-grade cytologic features. Sarcomatoid component with high-grade spindle and pleomorphic cells can be seen in various proportions in a renal cell carcinoma. The differential diagnosis includes urothelial carcinoma in the renal pelvis and metastatic high-grade tumors.
Hepatocellular Carcinoma (Figs. 3.15 and 3.28):
Fig. 3.28
An example of well-differentiated hepatocellular carcinoma showing atypical hepatoid cells with moderate amount of granular cytoplasm. The cells form thick cords and nests that are wrapped by endothelial cells (left, Diff-Quik stain; right, Papanicolaou stain)
Cohesively and discohesively arranged hepatoid atypical cells.
Thick cords, nests, and acinar groups wrapped by endothelial cells or capillaries traversing tissue fragments are characteristic.
Individual hepatoid cells are polygonal with moderate to abundant granular cytoplasm, occasionally cytoplasmic bile pigments, and hyaline globules.
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