Context.—The diagnosis of the site of origin of metastatic neoplasms often poses a challenge to practicing pathologists. A variety of immunohistochemical and molecular tests have been proposed for the identification of tumor site of origin, but these methods are no substitute for careful attention to the pathologic features of tumors and their correlation with imaging findings and other clinical data. The current trend in anatomic pathology is to overly rely on immunohistochemical and molecular tests to identify the site of origin of metastatic neoplasms, but this “shotgun approach” is often costly and can result in contradictory and even erroneous conclusions about the site of origin of a metastatic neoplasm.

Objective.—To describe the use of a systematic approach to the evaluation of metastatic neoplasms.

Data Sources.—Literature review and personal experience.

Conclusions.—A systematic approach can frequently help to narrow down differential diagnoses for a patient to a few likely tumor sites of origin that can be confirmed or excluded with the use of selected immunohistochemistry and/or molecular tests. This approach involves the qualitative evaluation of the “pretest and posttest probabilities” of various diagnoses before the immunohistochemical and molecular tests are ordered. Pretest probabilities are qualitatively estimated for each individual by taking into consideration the patient's age, sex, clinical history, imaging findings, and location of the metastases. This estimate is further narrowed by qualitatively evaluating, through careful observation of a variety of gross pathology and histopathologic features, the posttest probabilities of the most likely tumor sites of origin. Multiple examples of the use of this systematic approach for the evaluation of metastatic lesions are discussed.

Identification of the site of origin of metastatic neoplasms frequently poses a difficult challenge to practicing pathologists and may remain elusive at times, even in the era of advanced imaging techniques, immunohistochemistry, and molecular tests.16 In addition, it is often difficult to determine, for patients with a previous history of malignancy, whether a lesion represents a metastasis or a new primary neoplasm.714 The need to diagnose the site of origin of metastatic neoplasms has stimulated the proliferation of a variety of immunohistochemistry tests and molecular methods, described in other articles in this issue. However, these ancillary methods cannot entirely substitute the information provided by careful examination of hematoxylin-eosin–stained histologic slides and, very importantly, correlation of the pathologic changes with the clinical and imaging data.15,16 Indeed, overreliance on the results of multiple immunohistochemical and molecular tests is costly and can result in contradictory and even erroneous estimates of the site of origin of a metastatic neoplasm.17,18 For example, we recently evaluated a subcutaneous nodule composed of epithelioid cells that were immunoreactive for keratin AE1/AE3 and calretinin and exhibited negative immunoreactivity for thyroid transcription factor 1, CD15, and carcinoembryonic antigen. The contributing pathologist suggested a diagnosis of metastatic malignant mesothelioma but recognized that it was an unusual metastatic site for this neoplasm. As unusual events tend to occur rarely, we decided to phone the patient's pulmonologist, who readily described the presence of a large perihilar lung mass and the absence of pleural effusion or other imaging findings suggestive of malignant mesothelioma. The patient also had brain metastasis and was thought to suffer from metastatic non–small cell lung carcinoma (NSCLC). In this case, the “pretest probability” of NSCLC provided by the clinical data was probably higher than the “posttest probability” provided by immunostaining. Indeed, negative results with immunostains are not particularly helpful for excluding diagnoses, and calretinin immunoreactivity has been described in NSCLC and several neoplasms other than malignant mesothelioma.1921 

The time-tested truism that the pathologic findings need to be correlated with the clinical history and with the information available from previous pathology specimens and relevant imaging studies is all too frequently forgotten by pathology residents and even experienced practitioners during the evaluation of metastastic tumors, as illustrated in the previous example. In contrast, it is often useful to follow the systematic approach shown in Table 1 for the evaluation of metastases before proceeding with the selection of a targeted immunostain panel and/or molecular studies. The following example of a 60-year-old male patient who presented with metastatic nodules to the spine briefly illustrates the application of this systematic approach for the identification of the primary site of origin of a metastatic neoplasm. The metastatic tumor location and the patient's age and sex suggested the following as the most probable diagnoses in our patient population: metastatic prostatic, pulmonary, or pancreatic carcinoma.8,15,22,23 This differential diagnosis did not entirely exclude other less likely possibilities. The differential diagnosis of 3 probable sites for the primary neoplasm can be further narrowed if the clinical history describes the presence of signs and symptoms associated with the respiratory tract, abdomen, or urinary tract and/or if the prostate-specific antigen levels are elevated and/or if the imaging findings describe the presence of mass in any of these 3 organs. Examination of biopsy specimens from the bony lesions will likely narrow the differential diagnosis further. For example, in the presence of a squamous cell carcinoma, the diagnosis of metastatic lung cancer would become the most likely. In contrast, if the metastatic tumor is an adenocarcinoma, the pathologist would then have to search for the presence of additional histopathologic findings that could help narrow the differential diagnosis further, such as the presence of small glands lined by tumor cells exhibiting prominent nucleoli and a vacuolated cytoplasm, features favoring a metastastic prostatic adenocarcinoma (Figure 1); or of larger glands, papillary structures, or mucin secretion, features supporting the diagnosis of metastatic lung or pancreatic lesions (Figure 2, A and B). Thereafter, the use of a few immunostains such as prostate-specific antigen and androgen receptor, thyroid transcription factor 1, napsin A, and perhaps CA 19.9 would likely confirm the most likely site of origin of the metastatic adenocarcinoma.2426 

Figure 1.

Metastatic tumor in the femur demonstrates small glands lined by tumor cells exhibiting a vacuolated cytoplasm and prominent nucleoli, features favoring a metastastic prostatic adenocarcinoma (hematoxylin-eosin, original magnification ×100).

Figure 1.

Metastatic tumor in the femur demonstrates small glands lined by tumor cells exhibiting a vacuolated cytoplasm and prominent nucleoli, features favoring a metastastic prostatic adenocarcinoma (hematoxylin-eosin, original magnification ×100).

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Figure 2.

Metastatic tumors depicted in A and B support the diagnosis of metastatic lung or pancreatic carcinoma. A, Metastatic tumor composed of large glands with central necrosis. B, Metastatic tumor composed of papillary structures (hematoxylin-eosin, original magnifications ×200).

Figure 3. Diagnostic criteria identified by posttest odds ratio calculations that were most likely to provide an accurate diagnosis of primary lung adenocarcinoma. A, Glandular formation. B, Lepidic growth features. C, Nuclear pseudoinclusions. D, Scar (hematoxylin-eosin, original magnifications ×100 [A and B], ×400 [C], and ×40 [D]).

Figure 2.

Metastatic tumors depicted in A and B support the diagnosis of metastatic lung or pancreatic carcinoma. A, Metastatic tumor composed of large glands with central necrosis. B, Metastatic tumor composed of papillary structures (hematoxylin-eosin, original magnifications ×200).

Figure 3. Diagnostic criteria identified by posttest odds ratio calculations that were most likely to provide an accurate diagnosis of primary lung adenocarcinoma. A, Glandular formation. B, Lepidic growth features. C, Nuclear pseudoinclusions. D, Scar (hematoxylin-eosin, original magnifications ×100 [A and B], ×400 [C], and ×40 [D]).

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Table 1

Systematic Approach to the Evaluation of Metastatic Neoplasms

Systematic Approach to the Evaluation of Metastatic Neoplasms
Systematic Approach to the Evaluation of Metastatic Neoplasms

Clinical pathologists, internists, and other specialists are more familiar with the concepts of pretest and posttest probabilities than are anatomic pathologists; they use them to evaluate the results of laboratory tests “in context,” by considering the prevalence of a particular disease, sensitivity and specificity of the test, and other parameters.2729 Pretest probabilities offer a metric of the “likelihood” of a disease being diagnosed before a particular laboratory test is performed.3032 Posttest probabilities show the improvement in diagnostic accuracy resulting from the test results.33 Recent studies from our laboratory9,34,35 have shown the potential value of using similar probabilistic concepts to identify diagnostic features in surgical pathology and/or in select immunohistochemistry tests. These studies demonstrated that antibody panels composed of a few selected immunostains often yield better odd ratios and diagnostic probabilities than the use of many immunohistochemistry tests. Indeed, the use of a large number of immunostains or other ancillary methods frequently yields overlapping results that only add uncertainty to the interpretation of a case. This approach can also be helpful for the stratification of the clinical applicability of selected histopathologic features in selected differential diagnoses. For example, using pretest probability calculations, we determined that, in our patient population, a woman with a solitary lung nodule and a previous history of breast cancer was 2.6 times more likely to have a new lung carcinoma than a metastasis from the breast. Posttest odds ratio calculations identified glandular formation, lepidic growth features, nuclear pseudoinclusions, and scar as the diagnostic criteria that were most likely to provide an accurate diagnosis of primary lung adenocarcinoma35 (Figure 3, A through D). In contrast, the presence of solid nests, comedonecrosis, trabecular architecture, and cribriform growth favored the diagnosis of metastastic breast cancer9 (Figure 4, A through D).

Figure 4.

Diagnostic criteria identified by posttest odds ratio calculations that were most likely to provide an accurate diagnosis of metastatic carcinoma from the breast. A, Solid nests. B, Comedonecrosis. C, Trabecular architecture. D, Cribriform growth pattern (hematoxylin-eosin, original magnifications ×100 [A and C] and ×40 [B and D]).

Figure 4.

Diagnostic criteria identified by posttest odds ratio calculations that were most likely to provide an accurate diagnosis of metastatic carcinoma from the breast. A, Solid nests. B, Comedonecrosis. C, Trabecular architecture. D, Cribriform growth pattern (hematoxylin-eosin, original magnifications ×100 [A and C] and ×40 [B and D]).

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This discussion does not intend to propose that practicing pathologists should start using Bayesian statistics for diagnostic purposes in daily practice; instead, it emphasizes the importance of interpreting the pathologic findings by using probabilistic thinking that considers their association with other available clinical and imaging data.

In patients without a previous history of malignancy and/or particular imaging findings, it is often useful to consider the individual's age and sex and the location of metastases in the estimation of probable primary sites of origin before pathologic evaluation.36  Table 2 shows our anecdotal experience with the most frequent sources of lymph node metastases listed by the location of the lymph nodes and the patient's age and sex. Table 3 shows our anecdotal experience with the most likely sources of metastases in solid organs, by patient's age and sex.

Table 2

Origin of a Lymph Node Metastasis: Most Likely Sites of the Primary Tumor by Location and Patient's Age and Sex

Origin of a Lymph Node Metastasis: Most Likely Sites of the Primary Tumor by Location and Patient's Age and Sex
Origin of a Lymph Node Metastasis: Most Likely Sites of the Primary Tumor by Location and Patient's Age and Sex
Table 3

Most Likely Sites of the Primary Tumor by Location and Patient's Age and Sex

Most Likely Sites of the Primary Tumor by Location and Patient's Age and Sex
Most Likely Sites of the Primary Tumor by Location and Patient's Age and Sex

Evaluation of the gross appearance of metastatic lesions can reveal the presence of several features that can help identify probable tumor sites of origin.36 In our experience, evaluation of the gross features of metastatic lesions is particularly useful during intraoperative consultations. However, many metastases are currently being diagnosed with needle biopsy specimens, where the gross features of a lesion cannot be adequately assessed.

Color and Growth Features of Metastases

Careful evaluation of the gross appearance of a metastatic tumor, including its color, texture, consistency, and growth features can provide clues to its classification and probable site of origin. For example, the presence of a golden-yellow tumor surface in a metastasis can be a nonspecific finding resulting from tumor necrosis, but it is often present in prominently lipidized or glycogenated tumors, such as renal cell carcinomas (RCCs) (Figure 5, A), adrenal cortical neoplasms, sex cord–stromal tumors, liposarcomas, and others.3740 A dark brown to black tumor surface is seen in neoplasms exhibiting melanocytic differentiation, such as melanoma, melanotic schwannoma, and pigmented paraganglioma41,42 (Figure 5, B). The presence of a golden-brown to red tumor surface can result from nonspecific hemorrhage but, when it appears as a prominent gross feature, may suggest the diagnosis of a neoplasm such as angiosarcoma and Kaposi sarcoma and of neoplasms that can exhibit extensive hemorrhage or hemorrhagic necrosis, such as choriocarcinoma, leiomyosarcoma, paraganglioma, and gastrointestinal stromal tumors40,4347 Interestingly, melanoma, papillary thyroid carcinoma, and lung carcinoma tend to induce prominent hemorrhage only in selected anatomic locations such as the brain.48,49 In contrast, RCCs and thyroid follicular carcinoma tend to appear as very hemorrhagic metastatic bone metastases.50 

Figure 5.

A, Metastatic deposit of renal cell carcinoma that exhibits a golden-yellow tumor surface as a result of prominently glycogenated tumor cells. It can also be observed in tumors with prominently lipidized cells such as adrenal cortical neoplasms, sex cord–stromal tumors, and liposarcomas. B, Metastatic melanoma with a dark brown to black cut surface. Similar appearance can be seen in other neoplasms exhibiting melanocytic differentiation, such as melanotic schwannoma and pigmented paraganglioma. C, Fish-flesh appearance in a synovial sarcoma metastatic to the lung. D, Multiple tumor nodules in a metastasis to the kidney.

Figure 5.

A, Metastatic deposit of renal cell carcinoma that exhibits a golden-yellow tumor surface as a result of prominently glycogenated tumor cells. It can also be observed in tumors with prominently lipidized cells such as adrenal cortical neoplasms, sex cord–stromal tumors, and liposarcomas. B, Metastatic melanoma with a dark brown to black cut surface. Similar appearance can be seen in other neoplasms exhibiting melanocytic differentiation, such as melanotic schwannoma and pigmented paraganglioma. C, Fish-flesh appearance in a synovial sarcoma metastatic to the lung. D, Multiple tumor nodules in a metastasis to the kidney.

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Gross Tumor Texture of Metastases

Evaluation of the tumor surface texture can provide valuable information for the estimation of the likely source of a metastasis. For example, a variegated texture including soft and firm areas and solid and cystic components can raise the possibility of a metastatic germ cell tumor with teratomatous and/or yolk sac elements arising from the gonads, retroperitoneum, mediastinum, or skull.40,51 Tumors that exhibit a “fish-flesh” texture are often sarcomas or lymphomas (Figure 5, C). Neoplasms that exhibit a glistening or mucoid tumor surface texture are frequently metastatic, mucin-secreting adenocarcinomas arising from the gastrointestinal tract or myxoid sarcomas, particularly myxoid liposarcoma, myxofibrosarcoma, and myxoid malignant fibrous histiocytomas arising from the extremities, retroperitoneum, and other locations.40,51 

Consistency of Metastases

A metastasis with a firm or hard consistency, resembling that of bone or cartilage, often suggests the diagnostic possibility of osteosarcoma, chondrosarcoma, and other matrix-producing tumors, such as ossifying myxoid tumor of soft parts, teratoma, and carcinosarcoma arising in long bones or other skeletal primary sites.40,51 Occasionally, metastatic deposits can feel firm and exhibit a gritty surface due to the presence of numerous psammomatous calcifications, suggesting the possibility of a metastatic carcinoma arising in the ovary or papillary thyroid carcinoma.

Growth Features of Metastases

Most metastatic tumors appear as well-circumscribed, single or multiple nodules (Figure 5, D), but some neoplasms, such as lobular carcinoma of the breast and signet ring adenocarcinoma, tend to present as ill-circumscribed, firm areas that are almost invisible to the naked eye.

Histopathology usually provides more detailed information than gross pathology for estimating the likely source of a metastatic tumor. It allows for the classification of type and the identification of particular morphologic features that are characteristic of certain neoplasms. For the purposes of this discussion, metastatic neoplasms can be broadly divided into 2 categories: (1) tumors showing a combination of cell type and microscopic features that often suggest likely sites of origin; and (2) other tumors with morphologic features that offer only limited information regarding their likely site of origin.

Metastatic Adenocarcinomas With Microscopic Features Suggestive of a Particular Site of Origin

Adenocarcinomas can present with a large variety of microscopic features, such as the formation of acinar, papillary, and/or other structures that are shared by neoplasms arising in multiple locations. However, experienced pathologists can often suggest with considerable accuracy the origin of an adenocarcinoma, even in the absence of appropriate clinical history, by the combination of the patient's age and sex and the presence of selected histopathologic features. In our experience, it is often helpful to consider the relative incidences of primary adenocarcinomas in various organs by patient's age and sex and to evaluate the metastases microscopically for the presence of histopathologic features such as glandular and papillary features, solid nests, trabecular growth pattern, clear cells, so-called dirty necrosis, mucin secretion, and colloid material (Table 4). For example, in a metastatic lesion, the presence of solid nests and trabeculae composed of tumor cells with limited nuclear pleomorphism, punctate areas of necrosis suggestive of comedocarcinoma, or trabeculae composed of small hyperchromatic tumor cells strongly suggests the possibility of a breast origin, particularly in a female patient9 (Figure 4, A through D). In contrast, the presence of prominent glandular formation in a metastatic tumor to bone or brain suggests the possibility of a pulmonary origin for the lesion3 (Figure 2, A). Other microscopic features in metastatic adenocarcinomas that help identify probable primary sites include the presence of small, fairly uniform glandular spaces lined by malignant tumor cells exhibiting prominent nucleoli, bubbly cytoplasm, and lack of cytoplasmic mucin, suggestive of prostatic adenocarcinoma (Figure 1); glandular spaces lined by pseudostratified cells that exhibit elongated nuclei (so-called cigar-type nuclei) and extensive necrosis with karyorrhectic debris (so-called dirty necrosis), suggestive of colonic or rectal adenocarcinoma (Figure 6, A); extensive mucin secretion suggestive of gastrointestinal tract and pancreatic origin; colloid within follicles, characteristic of metastatic thyroid carcinoma, and a papillary morphology suggestive of neoplasms of thyroid (Figure 6, B), gynecologic, or pulmonary origin.3,16,23,52,53 Lastly, colloid carcinoma is another example of metastatic adenocarcinoma with unique histologic features that suggest a particular differential diagnosis of primary site. These lesions, characterized by the presence of well-circumscribed pools of mucin containing detached floating epithelial elements and/or glands that exhibit limited cytologic atypia, often arise from the pancreas, gastrointestinal tract, or, less likely, the breast40 (Figure 6, C).

Figure 6.

A, Metastatic colorectal adenocarcinoma exhibiting glandular spaces lined by pseudostratified cells with elongated cigar-shaped nuclei and extensive “dirty”-appearing necrosis due to the presence of karyorrhectic debris. B, Metastatic deposit of papillary carcinoma of the thyroid to the kidney exhibiting papillary morphology and colloid within the follicles. C, Metastatic colloid carcinoma from the gastrointestinal tract exhibiting well-delineated pools of mucin containing detached floating epithelial elements and/or glands with limited cytologic atypia (hematoxylin-eosin, original magnifications ×200 [A], ×40 [B], and ×100 [C]).

Figure 6.

A, Metastatic colorectal adenocarcinoma exhibiting glandular spaces lined by pseudostratified cells with elongated cigar-shaped nuclei and extensive “dirty”-appearing necrosis due to the presence of karyorrhectic debris. B, Metastatic deposit of papillary carcinoma of the thyroid to the kidney exhibiting papillary morphology and colloid within the follicles. C, Metastatic colloid carcinoma from the gastrointestinal tract exhibiting well-delineated pools of mucin containing detached floating epithelial elements and/or glands with limited cytologic atypia (hematoxylin-eosin, original magnifications ×200 [A], ×40 [B], and ×100 [C]).

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Table 4

Histopathologic Features in Metastatic Adenocarcinomas That Favor Certain Sites of Origin

Histopathologic Features in Metastatic Adenocarcinomas That Favor Certain Sites of Origin
Histopathologic Features in Metastatic Adenocarcinomas That Favor Certain Sites of Origin

Metastatic Carcinomas Other Than Adenocarcinomas With Morphologic Features Frequently Associated With Particular Sites of Origin

Certain carcinomas other than adenocarcinomas exhibit distinctive histopathologic features that are characteristic of an origin in selected primary sites (Table 5). For example, adenoid cystic carcinoma or mucoepidermoid carcinomas are other examples of tumors with characteristic histopathologic features that point toward likely primary sites; these diagnoses suggest an origin from a major or minor salivary gland and, less likely, lung/aerodigestive tract, breast, lacrimal gland, and skin1,53,54 (Figure 7, A). Metastatic clear cell carcinoma encompasses a collection of lesions composed of cells that exhibit a clear or glycogenated cytoplasm and commonly arises in 2 sites, the kidney and the gynecologic tract, including the ovary and endometrium.51 The clear cell variant of RCC metastasizes to unusual sites, including skin, soft tissue, bone, and brain.40,51 Renal cell carcinoma metastases frequently exhibit characteristic histopathologic features such as the presence of nests or lobules divided by a highly vascular network and composed of cells with sharp cytoplasmic borders, clear cytoplasm, hyperchromatic nuclei, and prominent nucleoli37 (Figure 7, B). In contrast, metastatic clear cell carcinomas from the gynecologic tract, including primary ovarian surface epithelial carcinomas and endometrial clear cell carcinomas, tend to spread primarily in the abdominal cavity with involvement of abdominal organs.55,56 These metastases show a distinctive histologic appearance from RCC, with arrangement of the clear cells in tubules or microcysts rather than solid nests and the presence of “hobnail” cells with nucleus standing on a cytoplasmic stalk.57 Metastatic clear cell carcinomas arising from the müllerian and gynecologic tract can also show other patterns of differentiation, such as squamous, endometrioid, and papillary serous features, which are typically absent in metastatic RCC.51 

Figure 7.

A, Metastatic adenoid cystic carcinoma of the parotid gland in the lung exhibits distinctive morphology with cribriform proliferation of small, dark basaloid cells. Basement membrane–type material is present within some of the cribriform nests. B, Lymphovascular embolus of metastatic renal cell carcinoma exhibits characteristic nests and lobules composed of cells with sharp cytoplasmic borders, clear cytoplasm, hyperchromatic nuclei, and prominent nucleoli in pulmonary parenchyma (hematoxylin-eosin, original magnifications ×100 [A] and ×40 [B]).

Figure 8. Metastasis of goblet cell carcinoid of the appendix to the testis. The tumor exhibits both neuroendocrine and adenocarcinoma features: nests and glands lined by endocrine cells and by goblet cells are present (hematoxylin-eosin, original magnification ×40).

Figure 9. Metastatic small cell carcinoma from the prostate. The tumor shows cells with hyperchromatic nuclei and scanty cytoplasm. Necrosis and apoptosis are present (hematoxylin-eosin, original magnification ×100).

Figure 10. A, Lymph node metastasis of a mixed müllerian tumor. B, The biphasic morphology comprising both adenocarcinoma and sarcoma is present at the metastatic site (hematoxylin-eosin, original magnifications ×40 [A] and ×200 [B]).

Figure 7.

A, Metastatic adenoid cystic carcinoma of the parotid gland in the lung exhibits distinctive morphology with cribriform proliferation of small, dark basaloid cells. Basement membrane–type material is present within some of the cribriform nests. B, Lymphovascular embolus of metastatic renal cell carcinoma exhibits characteristic nests and lobules composed of cells with sharp cytoplasmic borders, clear cytoplasm, hyperchromatic nuclei, and prominent nucleoli in pulmonary parenchyma (hematoxylin-eosin, original magnifications ×100 [A] and ×40 [B]).

Figure 8. Metastasis of goblet cell carcinoid of the appendix to the testis. The tumor exhibits both neuroendocrine and adenocarcinoma features: nests and glands lined by endocrine cells and by goblet cells are present (hematoxylin-eosin, original magnification ×40).

Figure 9. Metastatic small cell carcinoma from the prostate. The tumor shows cells with hyperchromatic nuclei and scanty cytoplasm. Necrosis and apoptosis are present (hematoxylin-eosin, original magnification ×100).

Figure 10. A, Lymph node metastasis of a mixed müllerian tumor. B, The biphasic morphology comprising both adenocarcinoma and sarcoma is present at the metastatic site (hematoxylin-eosin, original magnifications ×40 [A] and ×200 [B]).

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Table 5

Histopathologic Features in Carcinomas That Favor Selected Primary Sites

Histopathologic Features in Carcinomas That Favor Selected Primary Sites
Histopathologic Features in Carcinomas That Favor Selected Primary Sites

Metastatic Neuroendocrine Lesions

Neuroendocrine lesions include typical and atypical carcinoid tumors and high-grade neuroendocrine carcinomas such as small cell carcinoma and large cell neuroendocrine carcinoma.58 Recognition of neuroendocrine morphologic features in a metastatic neoplasm suggests the diagnoses of typical and atypical carcinoid tumors and high-grade neuroendocrine carcinoma, and it provides limited clues as to the probable site of origin of the neoplasm. Indeed, in these neoplasms the pretest probability provided by the clinical data is often more helpful than the results of immunostaining and other information provided by ancillary tests.58 For example, it is well known that these neoplasms usually arise in the gastrointestinal tract and the lungs. The site of the metastasis can help narrow down this information to estimate likely sites of tumor site origin. For example, gastrointestinal neuroendocrine neoplasms have a propensity to metastasize to the liver, peritoneum, and lungs, whereas pulmonary neoplasms tend to metastasize to mediastinal lymph nodes, liver, brain, and other locations. Goblet cell carcinoid is a neuroendocrine malignancy with a unique appearance, characterized by the presence of both nests and glands lined by endocrine cells and by goblet cells. This diagnosis in a metastasis strongly suggests the possibility of an appendiceal primary tumor59 (Figure 8).

The diagnosis of a metastastic small cell carcinoma strongly suggests the possibility of a pulmonary primary lesion, although lesions with this morphology can develop in a variety of other primary sites such as the upper airways, gynecologic tract, urinary tract, and others60 (Figure 9).

Metastastic Sarcomatoid Carcinomas and Biphasic Neoplasms

Sarcomatoid carcinomas are neoplasms composed of fascicles of spindle cells admixed with solid sheets of undifferentiated epithelioid cells with pleomorphic nuclei and other features of high-grade malignancy. The diagnosis of metastastic sarcomatoid carcinoma suggests an origin from a pulmonary, gynecologic (uterus and ovary), and genitourinary (kidney and bladder) origin.40,51 

Biphasic neoplasms are lesions that exhibit histopathologic features of combined epithelial and stromal differentiation. They include adenosarcoma, carcinosarcoma, malignant mixed müllerian tumor, pulmonary blastomas, and biphasic mesotheliomas.40,51 The presence of histopathologic features of a biphasic malignancy in a metastasis suggests an origin from a gynecologic tract, lung, or breast, as other primary sites are unusual.61 Metastases with histopathologic features of biphasic differentiation are unusual, as these neoplasms tend to metastasize usually as carcinomas or, less frequently, sarcomas rather than as biphasic malignancies.62 However, occasional biphasic metastasis from a carcinosarcoma can be observed62,63 (Figure 10, A and B).

Adenosarcoma is an unusual biphasic malignancy that arises in the uterus, and less frequently, in the ovaries and peritoneum. It is composed of epithelial elements that do not exhibit morphologic features of malignancy, admixed with sarcomatous elements. The presence of a metastatic intra-abdominal adenosarcoma, for example involving bowel serosa or peritoneal surfaces or even ovary, strongly raises the possibility of metastatic spread from the uterus, as origin from an extrauterine site is unusual.64 

Malignant mesothelioma uncommonly exhibits biphasic morphology and it is impossible to distinguish it with certainty from carcinosarcoma or other biphasic neoplasms, such as synovial sarcoma, without the use of immunostains.65 Clinical information regarding the presence of pleural effusion or ascites, calcified pleural plaques, and/or history of exposure to amphibole asbestos can help suggest this diagnosis in patients with metastatic biphasic lesions to mediastinal lymph nodes.21 

Metastatic Matrix-Producing Neoplasms

Metastases from matrix-producing neoplasms include a variety of lesions that can produce osteoid and/or chondroid matrices (Figure 11, A and B). The tumor cell type combined with the patient's age can provide clues as to the probable origin of the metastases, but these issues can only be resolved with appropriate clinical information and correlation with imaging studies. For example, in lung metastasis from an osteosarcoma in a child or adolescent, the possibility of a neoplasm arising in long bones is most likely, but the possibility of other primary sites cannot be excluded.66,67 Likewise, a metastatic chondrosarcoma in an older adult raises the question of a pelvic primary tumor, although an origin from other primary sites of chondrosarcoma in other locations cannot be excluded.67 

Figure 11.

Metastases from matrix-producing malignancies. A, Metastatic osteosarcoma with osteoid production. B, Metastatic chondrosarcoma with chondroid production (hematoxylin-eosin, original magnifications ×100).

Figure 12. Metastasis from (A) embryonal rhabdomyosarcoma, (B) synovial sarcoma with biphasic morphology, (C) Ewing sarcoma with prominent pseudorosettes, and (D) alveolar soft part sarcoma (hematoxylin-eosin, original magnifications ×100 [A and D] and ×40 [B and C]).

Figure 11.

Metastases from matrix-producing malignancies. A, Metastatic osteosarcoma with osteoid production. B, Metastatic chondrosarcoma with chondroid production (hematoxylin-eosin, original magnifications ×100).

Figure 12. Metastasis from (A) embryonal rhabdomyosarcoma, (B) synovial sarcoma with biphasic morphology, (C) Ewing sarcoma with prominent pseudorosettes, and (D) alveolar soft part sarcoma (hematoxylin-eosin, original magnifications ×100 [A and D] and ×40 [B and C]).

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Metastatic neoplasms with osteosarcoma and/or chondrosarcoma differentiation need to be examined carefully for the presence of focal epithelial elements. Such carcinoma elements are seen in metastatic carcinosarcomas with heterologous elements arising from the gynecologic tract, metaplastic carcinomas of the breast, and other unusual biphasic neoplasms.

Sarcoma Cell Type as a Feature to Suggest the Likely Primary Site of Metastatic Lesions

Sarcomas include a broad range of neoplasms that can arise in multiple locations. A large variety of sarcoma cell types exist, many of which cannot be easily diagnosed without the aid of clinicopathologic correlation, immunostains, and other ancillary studies. However, a few cell sarcomas exhibit characteristic morphologic features on hematoxylin-eosin–stained sections; this information can be used to suggest probable sites of origin through pretest information derived from primary sites where those lesions are more frequent. For example, for a metastatic leiomyosarcoma, an origin from the uterus, gastrointestinal tract, or prostate is to be considered most likely. In contrast, the diagnosis of metastatic liposarcoma raises the possibility of a primary lesion in the retroperitoneum. Other sarcomas that tend to develop more frequently in certain locations include embryonal rhabdomyosarcoma developing in the head and neck and genitourinary area of children; synovial sarcoma arising from extremities and head and neck area; and epithelioid sarcoma, Ewing sarcoma/primitive neuroectodermal tumor, alveolar soft part sarcoma, and other lesions that usually arise from the extremities68 (Figure 12, A through D).

Metastatic Germ Cell Tumors

Germ cell tumors (Figure 13, A through C) are uncommon neoplasms that usually develop in pediatric and young adult patients and have a propensity to metastasize to the retroperitoneum and the lungs.69 Their diagnosis suggests the need to exclude primary lesions in the gonads, mediastinum, and central nervous system.70,71 

Figure 13.

Metastatic germ cell tumor. A, Teratoma. B, Embryonal carcinoma (arrowhead) and yolk sac tumor (arrow). C, Lymphovascular invasion by choriocarcinoma with syncytiotrophoblasts and cytotrophoblasts (hematoxylin-eosin, original magnifications ×200).

Figure 14. Metastatic melanoma with scanty melanin production and prominent nucleoli (hematoxylin-eosin, original magnification ×400).

Figure 13.

Metastatic germ cell tumor. A, Teratoma. B, Embryonal carcinoma (arrowhead) and yolk sac tumor (arrow). C, Lymphovascular invasion by choriocarcinoma with syncytiotrophoblasts and cytotrophoblasts (hematoxylin-eosin, original magnifications ×200).

Figure 14. Metastatic melanoma with scanty melanin production and prominent nucleoli (hematoxylin-eosin, original magnification ×400).

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Unfortunately, many neoplasms exhibit a cell type and/or other histopathologic features that provide limited information regarding their likely site of origin. The origin of these lesions can only be established with the aid of clinicopathologic information and ancillary studies such as immunostaining and molecular methods. For example, it is not possible to determine the site of origin of a metastatic squamous cell carcinoma by evaluation of its histopathologic features, but the patient's age and sex and the location of the metastasis frequently provide valuable clues for identifying the primary site. For example, the presence of metastastic squamous cell carcinoma in a neck lymph node of an adult patient strongly suggests the possibility of a head and neck or pulmonary primary tumor, while presence of such a tumor in the inguinal lymph node of a woman would suggest an origin from the gynecologic tract. Another example would be metastatic melanoma. Melanomas are known for their propensity to metastasize to any organ and to exhibit diverse histomorphologic features. They are also known to present with metastasis after regression at the primary site. These characteristics of melanoma make it mandatory to consider these malignancies in the differential diagnoses during evaluation of metastatic disease72,73 (Figure 14).

Histochemistry has a very limited role in the era of immunohistochemistry and molecular pathology. Mucicarmine and periodic acid–Schiff diastase stains can be helpful to exclude, in most cases, neoplasms of renal, prostatic, or thyroid origin. They can also be used in the differential diagnosis of a poorly differentiated neoplasm with signet ring morphology. Melanin and Fontana-Masson stains, in combination with iron stains, although rarely considered, can be useful with neoplasms that contain pigment to determine whether the pigment is melanin or iron/hemosiderin-based pigment.

The authors have no relevant financial interest in the products or companies described in this article.

The authors wish to thank David Frishberg, MD, director of Surgical Pathology, Cedars-Sinai Medical Center, for a critical review of the manuscript.

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Author notes

From the Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California.