Seminars in Diagnostic Pathology xxx (xxxx) XXX-XXX
ELSEVIER
Contents lists available at ScienceDirect
Seminars in Diagnostic Pathology
journal homepage: www.elsevier.com/locate/semdp
$
Seminars in Diagnostic Pathology
MARK R. WICK, MD
A Festschrift for Dr. Juan Rosai Mark. F. Wck. MD
Review article
Primary lesions that may imitate metastatic tumors histologically: A selective review
Mark R. Wick
Division of Surgical Pathology & Cytopathology, University of Virginia Medical Center, Room 3020, 1215 Lee St., Charlottesville, VA 22908-0214, USA
ARTICLE INFO
Keywords: Microscopic simulants of metastasis Metastatic neoplasms Histologic mimics
ABSTRACT
Several primary pathologic entities in diverse anatomic locations have the potential to simulate metastatic neoplasms histologically. Their misinterpretation as such may result in needless and extensive clinical evalua- tions that are intended to detect a presumed malignancy at another site. More importantly, mistakes of this type can deprive patients of surgical excisions that could be curative. This presentation considers a review of selected primary lesions that can simulate metastases. They include hemangioblastoma, glioblastoma and meningioma with epithelial metaplasia, choroid plexus carcinomas, primary neuroendocrine carcinomas in unusual locations, special forms of sinonasal and salivary glandular adenocarcinoma, clear-cell thyroid carcinomas, unusual mi- croscopic subtypes of pulmonary adenocarcinoma, epithelioid myomelanocytomas (“sugar tumors”), mesothe- liomas, primary thymic carcinomas, endodermal choristomas of the interatrial myocardium, peripheral cho- langiocarcinoma, adrenocortical carcinoma, adenocarcinomas of the urinary bladder, mucinous and “rhabdoid” tumors of the ovaries, rete testis adenocarcinomas, interdigitating dendritic-cell sarcoma of lymph nodes, se- lected sweat gland carcinomas, cutaneous Merkel cell carcinoma, primary dermal and subcutaneous melanoma, mucosal and visceral melanomas, epithelioid sarcoma, clear-cell sarcoma, and adamantinoma of long bones. Differential diagnostic observations are emphasized in reference to those lesions.
The ability of neoplastic proliferations to imitate one another morphologically is well-known to all anatomic pathologists. That ca- pacity is best recognized in regard to cytologically-undifferentiated tumors, among which carcinomas, melanomas, lymphomas, and sar- comas can all potentially look alike under the microscope, as stained with hematoxylin & eosin (H&E). However, other images may also prove to be closely similar among different disease entities, given spe- cific anatomic locations and clinical circumstances for them.
This discussion focuses on selected primary neoplasms that can potentially be confused pathologically with metastatic tumors. That circumstance is compelling in both directions. Patients may be assigned an adverse prognosis and deprived of effective surgery, if a truly pri- mary lesion is felt to be a metastasis, or they may be subjected to un- necessary resections if the converse situation applies. Sometimes, ad- junctive studies can be employed to help make the necessary distinction between primary and secondary tumors, but that eventuality is not universal.
Tumors of the nervous system that can imitate metastases
Hemangioblastoma
Hemangioblastoma (HBL) is an unusual neoplasm that most often arises in the cerebellum, but it can be seen in the supratentorial brain or spinal cord as well, and even in extraneural locations.1 This lesion comprises a mixture of endothelial cells, stromal cells, and vascular pericytes, and the second of those elements usually demonstrates at least partial cytoplasmic clarity histologically.2 That is a particularly troublesome feature of the tumor because it is sometimes seen in pa- tients with the von Hippel-Lindau (VHL) syndrome, who also may de- velop clear-cell renal cell carcinomas (RCCs). In that scenario, HBL and metastatic RCC can be difficult to separate from one another morpho- logically.3
Dysfunctional VHL protein may accumulate in the lesional cells of HBL, as a consequence of VHL gene mutation or gene silencing.2 The protein normally serves to inhibit hypoxia-inducible factor-1a (HIF- 1a), but its abnormal form is incapable of doing so. Intracellular accrual of HIF-1a leads to the overproduction of vascular endothelial growth factor, platelet-derived growth factor-ß, and transforming growth factor-a. They mediate cellular proliferation in HBL.
https://doi.org/10.1053/j.semdp.2017.11.010
0740-2570/ @ 2017 Elsevier Inc. All rights reserved.
Fortunately, several points of immunohistological difference exist between HBL and metastatic clear cell carcinoma of the kidney. The stromal cells of HBL are immunoreactive for a-inhibin and brachyury (Fig. 1), but they lack keratin and epithelial membrane antigen, both of which are typically seen in RCC. On the other hand, both tumor types may potentially express vimentin, PAX8, and carbonic anhydrase-IX (CA9).4-9
Glioblastoma & meningioma with divergent epithelial differentiation
Rare examples of both glioblastoma (GBM; grade IV astrocytoma) and meningioma are capable of showing divergent epithelial differ- entiation, manifested by the histologic presence of gland-like structures, squamous foci, clear-cell or rhabdoid features, or signet ring-cell change10-13 (Figs. 2 and 3). Inasmuch as GBMs and malignant me- ningiomas are often highly-anaplastic and undifferentiated neoplasms, those findings could erroneously lead one to make a diagnosis of me- tastatic carcinoma in a brain biopsy of such tumors. That problem is abetted by the fact that epithelial foci in neural neoplasms can be im- munoreactive for keratin, epithelial membrane antigen (EMA), p40, p63, and E-cadherin.14-20 Podoplanin expression is relatively non- specific regarding cellular lineage, but it appears to be present in vir- tually all meningiomas and it is absent in many carcinomas.21 Im- munoreactivity for glial fibrillary acidic protein (GFAP) is expected in GBMs, but not in metastatic carcinomas.14 Fluorescent or chromogenic in-situ hybridization studies can be useful in the recognition of meta- plastic meningiomas, because both the epithelial and meningothelial
tumoral elements show potential losses of chromosomes 1p, 14q, and 22q.19 Nevertheless, some anaplastic metastatic carcinomas may de- monstrate similar cytogenetic aberrations.22
These data point out the challenges presented by divergent malig- nant neural neoplasms, concerning their diagnostic distinction from metastases. Integration of radiological, pathological, and surgical findings is usually necessary to reach a final conclusion in such cases.
Primary intracranial neuroendocrine carcinomas
Several cases have been documented in which primary neu- roendocrine carcinomas (NECs) arose in the sellar area of the brain in adults, possibly centered in the pineal gland.23,24 They showed the ty- pical organoid growth, dispersed nuclear chromatin, and mitotic ac- tivity of neuroendocrine tumors, and no extracranial neoplasms were apparent. Moreover, immunostains supported a primary neuroepithe- lial lesion in each case, showing reactivity for pankeratin and sy- naptophysin or chromogranin. There were no markers of pulmonary or enteric origin. On the other hand, solitary brain metastases from visc- eral NECs would usually be expected to demonstrate such determinants immunohistochemically.25
Choroid plexus carcinomas
Neural tumors that are centered in the cerebral ventricles include meningiomas, choroid plexus neoplasms (papillomas and carcinomas), and metastatic carcinoma or melanoma.26 Among those, the potential
morphological similarities between choroid plexus carcinoma (CPC) and metastatic carcinoma (MC) are several. Papillary, gland-forming, and solid trabecular patterns of growth may be evidence in either tumor type, with nuclear atypicality and mitotic activity.27-29 Likewise, im- munoreactivity for pankeratin, CK7, EMA, S100 protein, and carci- noembryonic antigen (CEA) is possible in either CPC or MC.30-32 However, two other markers-GFAP and Kir7.1-are indeed dis- criminatory, because labeling for either one of them supports the di- agnosis of CPC.33 Another important point is that CPC arises principally in pediatric-age patients, whereas MC is a disease of adults.27
Adenocarcinoma of the ocular ciliary epithelium
Primary carcinomas within the ocular globe are principally re- presented by those arising in the non-pigmented ciliary epithelium.3 Those lesions are seen in adults, who may present with secondary cataracts, lens subluxation, or signs of intraocular inflammation. The tumors are amelanotic and demonstrate the invasive growth of cyto- logically-atypical glandular cells into the tissue around the ciliary body (Fig. 4). Immunoreactivity for pankeratin and EMA is typical. Most examples of ciliary adenocarcinoma have a favorable prognosis, and do not require enucleation or exenteration.34,35 Mistakenly labeling such tumors as metastases would be unfortunate, and it is worth noting that the most common sources of secondary carcinomas in the eye include the breasts, lungs, and gastrointestinal tract.36 Therefore, im- munohistologic evaluation of intraocular carcinomas for such markers as TTF-1, napsin-A, mammaglobin, GATA3, CDX2, and SATB2 is
advisable.
Sinonasal & salivary gland tumors that can mimic metastases Enteric-type sinonasal adenocarcinoma (ETSA)
Adenocarcinomas of the nose and paranasal sinuses are uncommon tumors,37 but a particularly important one is that which shows enteric (intestinal-type) differentiation.38-41 ETSA is typically seen in adult patients, many of whom have had occupational exposure to inhaled organic dusts (mainly wood and leather).41 The neoplasm shows a composition by atypical glandular cells with polarized nuclei, “dirty” necrosis, and infiltrative growth, and it is virtually indistinguishable from colorectal carcinoma in H&E stains.37 Nevertheless, the likelihood is remote that a carcinoma in the alimentary tract would selectively metastasize to the upper airway.
Resto et al. compared the immunophenotypes of ETSAs and color- ectal carcinomas.42 They found that the former neoplasms were best supported diagnostically by an immunoprofile that included cor- eactivity for CK7, CK20, and MUC2. In contrast, lesions that lacked CK7 were potentially metastatic. Skalova & colleagues also reported uniform immunoreactivity for CDX2 and SATB2 in ETSA, in likeness to color- ectal carcinomas. 43 In the final analysis, the integration of clinical and radiological information with pathologic findings is again the best in- terpretative approach to ETSA.
Sinonasal renal cell-like carcinoma (SRCLC)
In 2002, Zur et al. described a newly-recognized form of primary sinonasal adenocarcinoma that strongly resembled clear-cell RCC his- tologically.44 This lesion favors adult women between the ages of 20 and 80 years, who present with epistaxis or nasal obstruction. It has been observed in the nasal cavity, paranasal sinuses, and nasopharynx. Microscopically, SRCLC comprises sheets, follicles, and nests of large polygonal cells with cytoplasmic clarity and relatively low nucleocy- toplasmic ratios. In likeness to RCC, intratumoral hemorrhage with formation of blood “lakes” is common.45 Fortunately, SRCLC differs conclusively from RCC at an immunohistologic level. The first of those tumors is reactive for pankeratin, CK7, and EMA, but it lacks PAX8, RCC-antigen, and vimentin.46 At least one of the last three markers is expected in cases of metastatic clear-cell RCC.47,48 Another point of difference is the immunoreactivity of SRCLC for DOG1 and SOX1045,49; those determinants are not seen in RCCs.
In aggregate, Kubik et al. concluded that SRCLC had a “ser- omucinous” immunophenotype.45 The behavior of that neoplasm has been indolent, with a good prognosis, compared with the dire outlook of patients with metastatic RCC.
Clear-cell acinic cell carcinoma of salivary glands
Another tumor of the head and neck that can simulate RCC histo- logically is salivary glandular acinic cell carcinoma (ACC). This neo- plasm most often arises in the parotid glands (Fig. 5). Several histologic growth patterns may be encountered in ACC, including serous-acinar, solid, tubular, papillary, cystic, follicular, and clear-cell variants.5 Approximately 1% of these lesions exclusively comprise tumor cells with lucent cytoplasm.51-53 In contrast to metastatic RCC, ACC often contains an admixture of lymphoid aggregates, as well as cytoplasmic granules that are reactive with the digested periodic acid-Schiff stain.50 Moreover, ACC is potentially immunoreactive for S100 protein and the DOG1 antigen,54 whereas RCC is not. On the other hand, the expression of PAX8 in RCC is not shared by ACC. 46
Mammary analogue secretory carcinoma of salivary glands
In the past, some publications remarked on the histologic similarity between some examples of salivary glandular “acinic cell carcinoma” and secretory carcinoma of the breast (SCB).55,56 Subsequently, a re- producible rearrangement of the ETV6 gene was identified in the second of those lesions, but it was not seen in acinic cell tumors.57 That divergent observation, as well as additional information indicating an immunohistological synonymity between SCB and microscopically-
similar salivary gland lesions (with reactivity for mammaglobin, GATA3, EMA, CK7, & gross cystic disease fluid protein-15),58-60 led to the conclusion that a homologue of SCB existed in the salivary glands. It was named mammary analogue secretory carcinoma (MASC) (Fig. 6).
Patients with MASC include both adolescents and adults, with a mean age of 45 years. They have slowly-growing masses, which usually arise in the parotid or submandibular glands. Only a few affect minor salivary gland sites.61
Histologically, one sees an unencapsulated proliferation of compact polygonal cells, potentially assuming solid, microcystic, papillocystic, tubular, or cribriform growth patterns. Microcysts and tubules in the lesion are filled with colloid-like or frothy secretion, which can be la- beled with the digested periodic acid-Schiff stain.6º Mitotic activity is rare, and necrosis is rarely observed.62 Like SCB, MASC is a “triple negative” tumor, lacking immunoreactivity for estrogen receptor pro- tein, progesterone receptor protein, and HER2 protein. Both of those neoplasms also demonstrate a t(12.15)(p13.q25) chromosomal trans- location, producing an ETV6-NTRK3 gene fusion transcript that can be detected using in-situ hybridization or the polymerase chain reaction.60
Despite the virtual pathologic identity of MASC with SCB, it is un- likely that the second of those tumors would selectively metastasize to the salivary glands because SCB is typically a low-grade adenocarci- noma with a favorable clinical course.55 Nevertheless, imaging studies of the breasts are appropriate before making a definitive interpretation of MASC.
Salivary duct adenocarcinoma
In the early 1980s, a singular form of salivary glandular adeno- carcinoma was recognized that had theretofore been categorized as “adenocarcinoma, not further specified”.63 That lesion bore a striking morphological homology to invasive ductal carcinoma of the breast of the “usual” type (UDCB), and likewise demonstrated a potential asso- ciation with intrasalivary ductal carcinoma in-situ. Accordingly, it was designated as “salivary duct adenocarcinoma” (SDA). That tumor ty- pically behaves in an aggressive fashion, with potential metastasis to regional lymph nodes and viscera. 64,65
SDA comprises randomly-disposed solid nests or tubule-forming aggregates of cytologically-atypical epithelial cells, set in a fibrous stroma (Fig. 7). Mitotic activity is easily identified, and perineural and lymphatic invasion are common. Immunohistochemically, this neo- plasm is potentially reactive for mammaglobin, gross cystic disease fluid protein-15, estrogen receptor protein, progesterone receptor pro- tein, androgen receptor protein, epidermal growth factor receptor, keratin 5/6, GATA3, and HER2.66-71 That immunophenotype is super- imposable on that of UDCB.66 Indeed, Di Palma & colleagues found that
A
Fig. 6. Mammary analogue secretory carcinoma may take the form of an intraoral, minor salivary glandular mass (top, left). It has a multilobular growth pattern (top, right), and comprises gland-forming nests of epithelioid cells that are associated with secretory material (bottom, left). A fluorescent in-situ hybridiza- tion study with an ETV6 breakapart probe shows chromosomal rearrangement involving that gene (bottom, right).
luminal, HER2-positive, and basal-like subtypes of SDA can be deli- neated, as true of ductal breast cancers.70
Cases have been described in which UDCB selectively metastasized to a major salivary gland,72,73 and, conversely, SDA may metastasize to the breast.74 Inasmuch as immunohistochemical analysis is unhelpful in separating those tumors, clinical and radiographic information is again critical to a final diagnostic interpretation.
Thyroid neoplasms that may imitate metastases
Thyroid carcinomas containing clear cells
Primary thyroid carcinomas that comprise a majority of cells with clear cytoplasm constitute < 1% of all malignant neoplasms in that gland.75,76 “Clear cell carcinoma” of the thyroid (CCCT) does not ap- pear to represent a uniform group of lesions, encompassing tumors with partial papillary, follicular, “insular,” medullary, and anaplastic mor- phologic features.76 Carcangiu et al. found that the causes of cyto- plasmic lucency in this group also were variable, including intracellular vesicle formation, glycogen accumulation, and excess thyroglobulin synthesis.75 In a study of CCT by Cipriani & colleagues, molecular findings were heterogeneous as well, including RAS gene mutation, PAX8-PPAR- Y translocation, p53 mutation, AML4-ALK translocation, and TFG-MET translocation.76 Concurrent immunoreactivity is expected in CCCT for TTF1, PAX8, and thyroglobulin, and some cases with pa- pillary features also exhibit labeling for the BRAF-V600E mutant pro- tein.51,77 Clear-cell medullary carcinoma is reactive for chromogranin-
A, carcinoembryonic antigen (CEA), and calcitonin. The principal di- agnostic alternative, metastatic clear-cell renal cell carcinoma,78 is also potentially PAX8-positive, but additionally expresses adipophilin and RCC-antigen. The latter two markers are not expected in CCCT.79 Moreover, the presence of intratumoral “blood lakes” is typical of RCC, but not CCCT.
Primary thyroidal mammary analogue secretory carcinoma
As described above in reference to the salivary glands, MASC may rarely present as a primary intrathyroidal neoplasm.80 Its pathologic features are identical to those of salivary tumors.
Multifocal medullary thyroid carcinoma, imitating metastatic neuroendocrine carcinoma
Particularly in patients with multiple endocrine neoplasia, type 2, multiple independent foci of medullary (primary neuroendocrine) car- cinoma may arise in the thyroid81 (Fig. 8). As such, they can simulate secondary involvement of the gland by metastatic neuroendocrine carcinoma (MNC), usually originating in the lungs.82-84 Conventional histologic examination is insufficient to make a distinction between the two possibilities, because the generic appearance of a neuroendocrine tumor is seen in both instances. Tumor cells are arranged in an organoid pattern, with dispersed nuclear chromatin and variable mitotic activity. Amyloid deposits are potentially seen in either primary medullary thyroid carcinoma or MNC.81 Matias-Guiu et al. found that a
predominantly-interstitial growth pattern of tumor in the thyroid fa- vored metastasis, as did formation of cellular rosettes, folliculotropism, and an absence of immunoreactivity for CEA, calcitonin and PAX8.82 Those markers are seen in the majority of medullary carcinomas. La- beling for TTF-1 can be seen in either group of lesions.
Primary pleuropulmonary tumors that may simulate metastases Clear-cell carcinomas of the lung
“Primary clear cell carcinoma of the lung” (CCCL) likely is com- posed of tumors with squamous, glandular, and “null-cell” fine struc- tural differentiation.85 In addition to those lesions, other primary in- trapulmonary clear cell neoplasms, including some “carcinoids”86 and the so-called “sugar tumor” (myomelanocytoma)87 also must be sepa- rated diagnostically from solitary metastases of renal cell carcinoma, “balloon cell” melanoma, and clear-cell adenocarcinomas of genitour- inary origin. This can be accomplished by a combination of radio- graphic and immunohistologic evaluations, which should be done re- flexively in each instance79 (Fig. 9). The overall clinicopathologic attributes of primary CCCL are comparable to those of “large-cell un- differentiated” carcinomas of the lung.85
A more specific form of pulmonary clear-cell carcinoma is re- presented by clear-cell acinic cell carcinoma (Fechner’s tumor).88 Its pathologic characteristics have been described above, in reference to salivary gland lesions of that type.
Special subtypes of primary pulmonary adenocarcinoma
In some cases of intrapulmonary adenocarcinoma, substantial morphologic overlap exists between these primary tumors and the ap- pearances of metastatic adenocarcinomas in the lung. Needless to say, in cases featuring multifocal adenocarcinoma in more than one lobe, this problem is especially troublesome. Morphologic mimicry is parti- cularly applicable to primary enteric adenocarcinoma, mucinous (“colloid”) carcinoma (Fig. 10), and signet-ring-cell carcinoma of the lung, which can closely imitate the attributes of metastatic gastric or colorectal carcinomas.89 Psammoma bodies can also be seen in primary papillary adenocarcinomas of the lung, and these structures therefore raise the question of whether one is instead viewing a solitary metas- tasis from an occult tumor of the thyroid, ovary, or other locations wherein psammomatous carcinomas are potentially found.90,91 Im- munohistologic studies are often used in an attempt to resolve this differential diagnosis. However, it must be realized that primary lung tumors that manifest enteric-type morphotypes also may have enteric immunoprofiles, rather than bronchial-epithelial or pneumocytic staining patterns.92 Ultimately, diagnostic decisions in this specific context may rest on such banal characteristics as peritumoral fibrosis and inflammation, which are generally more common in primary pul- monary lesions than in metastases.
-
-
Clear-cell Carcinoma, Uncertain Whether Primary or Metastatic
PAX8
-
+
Metastatic Renal Cell Carcinoma
CA-125
+
Metastatic Clear-cell Carcinoma of Non-Renal Origin
-
CGA
+
Carcinoid with Clear-cell Features
-
P63
+
Primary Squamous Cell Carcinoma of Lung
+
TTF-1
+
Primary Clear-cell Adenocarcinoma of Lung
Pankeratin
+
Metastatic “Balloon-cell” Melanoma
-
S100
Either One +
“Sugar Tumor” (Myomelanocytoma)
-
MSA & HMB45
-
Non-Epithelial Clear-cell Tumor of Uncertain Cellular Lineage
Fig. 10. Primary mucinous adenocarcinoma of the lung (MEL) is seen as a peripheral intraparenchymal mass in a computed to- mogram (left panel). Microscopically, it demonstrates numerous mucin pools in which groups of relatively-bland polygonal cells are suspended (top right & first bottom right panels). A fine needle aspirate from another case of MEL shows im- munoreactivity for thyroid transcription factor-1 (second bottom right panel).
Epithelioid myomelanocytoma (sugar tumor; PEComa)
The clear-cell “sugar” tumor of the lung (STL) is a purely epithelioid lesion, which is probably best regarded as a biologically “borderline” neoplasm. It was first described noncommittally as “clear cell tumor of the lung” by Liebow and Castleman over 50 years ago as an asympto- matic nodule in the peripheral lung fields, typically in patients over 40 years old.93,94
Histologic examination discloses two general growth patterns in STLs.85,87,95,96 The first is organoid, with broad cords and rounded nests of cells being separated by a variably prominent fibrovascular stroma. The second configuration is a medullary image, showing sheets of epithelioid cells with little internal clustering. Small bronchi and bronchioles are often entrapped by the neoplastic cells. Nuclei are round with small nucleoli; intranuclear invaginations of cytoplasm also may be apparent, but mitotic figures are usually difficult to find. Cy- toplasm is clear or lightly eosinophilic, and may be finely granular. Histochemical evaluation with the undigested periodic acid-Schiff method usually shows intense cytoplasmic labeling for glycogen in the tumor cells.96
Immunohistologically, STL manifests a uniform lack of reactivity for epithelial markers, but it is consistently positive for vimentin, CD117, collagen type IV, HMB-45, SOX10, and microphthalmia transcription factor. Inconsistent but generally positive results are also obtained for muscle-specific actin, alpha-isoform (“smooth-muscle”) actin, and neuron-specific enolase.87,97 Those findings overlap in part with the immunoprofile of metastatic melanoma, but the presence of muscle- related markers favors a diagnosis of STL. In addition, MUM1 is present in the majority of metastatic melanomas98 but is only seen in a minority of “sugar” tumors.
Primary pulmonary salivary duct adenocarcinoma
In keeping with the concept that bronchial glands are salivary homologues, it is to be expected that salivary gland-type neoplasms may be seen primarily in the lungs. That premise has already been al- luded-to in this discussion. As described above, salivary duct adeno- carcinoma has been reported rarely as a primary pulmonary tumor.99,100 Its pathologic features are covered in the previous section on salivary gland lesions; lesions of this type have identical character- istics in either anatomic site.
Pleural mesotheliomas
Several forms of epithelioid malignant mesothelioma (EMM) of the pleura can imitate the histologic images of metastatic carcinomas.10
They include “type ordinaire” EMM, as well as clear-cell, rhabdoid, and small-cell variants. On the other hand, sarcomatoid (spindle-cell) me- sothelioma (SM) has a potential microscopic resemblance to metastatic sarcomatoid carcinomas, sarcomatoid melanomas, and sarcomas. It comprises fusiform cells with variable degrees of atypia and pleo- morphism. These may be arranged in fascicles, storiform arrays, or random configurations. Indeed, a special variant of SM shows divergent differentiation into “heterologous” mesenchymal tissues such as os- teoid, cartilage, and striated muscle. Mesotheliomas with angio- sarcoma-like appearances also exist.101 Some observers have anecdo- tally suggested that all pleural neoplasms with monomorphic sarcoma- like features should be classified as mesothelioma, even if they are immunohistologically-negative for keratin. I cannot agree with that supposition, because my experience is that SMs express keratin in vir- tually every case.
The separation of EMM from metastatic adenocarcinomas in the pleura was based historically on histochemical results.102 The capacity for the latter tumor group to synthesize epithelial mucin has been well- recognized for many years, and it is also known that mesotheliomas do not possess that ability. Conversely, EMMs manufacture stromal mucin - which was labeled by the colloidal iron or alcian blue methods at pH 2.5 - and prior treatment of tissue sections with hyaluronidase remove that substance. Those observations are much less helpful if the differ- ential diagnosis is that of SM versus spindle cell carcinoma or true sarcoma, because the histochemical profiles of all of those lesions overlap.
With respect to immunohistology, one might assume that the pro- portion of mesotheliomas which can be recognized confidently would have a direct relationship to the number of antibodies used to study the case. In contrast, Ordonez103 has recommended that:
” … the best discriminators among the antibodies considered to be negative markers for [epithelioid] mesothelioma are CEA, MOC-31, Ber-EP4, BG8, and B72.3. A panel of four markers (two positive and two negative) selected based upon availability and which ones yield good staining results in a given laboratory is recommended. Because of their specificity and sensitivity for mesotheliomas, the best combination appears to be calretinin and cytokeratin 5/6 (or WT1 [or podoplanin] [sic]) for the positive markers and CEA and MOC-31 (or B72.3, Ber-EP4, or BG-8) for the negative markers.”
Using logic-regression analysis of 12 markers, Yaziji & coworkers104 concluded that a 3-marker panel (calretinin, MOC31, and BG8) was diagnostically-sufficient and accurate in separating adenocarcinoma from EMM. Marchevsky & Wick,105 Kushitani & colleagues,106 and King et al.107 have reached similar conclusions.
Malignant thymic neoplasms that may imitate metastases
Virtually all of the malignant neoplasms that arise in the thymus have histologic patterns that are also seen in primary tumors of other organs, especially the lungs. These include keratinizing & non-kerati- nizing squamous, lymphoepithelioma-like, adenosquamous, clear-cell, papillary (Fig. 11), mucinous, mucoepidermoid, sarcomatoid, rhabdoid, micronodular & lymphoid-rich, and anaplastic morphotypes.108-111 Many-but not all-thymic carcinomas are immunoreactive for both p63 and PAX8, unlike their extrathymic counterparts.112,113 The tumors that lack one or the other of those markers cannot be distinguished from metastatic lesions immunohistochemically. Accordingly, thorough radiological examination is necessary before a final diagnosis can be made.
Another group of potentially-intrathymic malignancies is re- presented by extragonadal germ cell tumors. All of them, including seminoma, embryonal carcinoma, yolk sac carcinoma, chor- iocarcinoma, or malignant mixed germ cell tumors, can arise within the confines of the thymus gland.114 They can be distinguished from pri- mary thymic epithelial neoplasms by their lack of immunostaining for EMA and PAX8, and only choriocarcinoma has the capacity for p63- positivity, like that expected in thymic carcinomas. On the other hand, germ cell tumors may be labeled for placental alkaline phosphatase, CD117, podoplanin, CD30, glypican-3, SALL4, and beta-human chor- ionic gonadotrophin.114 There are no consistent phenotypic or im- munohistologic differences between gonadal and intrathymic germ cell tumors.115 Hence, clinical evaluation of the testes and ovaries is ne- cessary in this setting.
Endodermal choristoma (formerly “mesothelioma”) of the interatrial cardiac septum
Several reports have been made of a fascinating lesion of the in- teratrial septum in the region of the atrioventricular (AV) node. It was initially felt to be a form of “mesothelioma” and, if it is identified at all macroscopically, it usually comprises an agglomeration of minuscule cysts.116,117 Patients with this abnormality have spanned all age groups. Symptoms from “mesothelioma of the AV node” (MAV) are typically related to abnormalities in cardiac conduction, manifested by syncope, bradycardia, or sudden death, and these problems usually become
evident early in life. 118-121
Histologically, MAV comprises variably-sized nests of polygonal cells in the interatrial myocardium. Many of the cellular aggregates contain central lumina, whereas others exhibit a squamoid appearance or are solid. The cell nests are usually grouped in an organoid fashion, but occasionally they may also demonstrate a more random archi- tecture. Nuclei are compact with dispersed chromatin, and cytoplasm is amphophilic or eosinophilic and relatively abundant (Fig. 12). There is only modest nuclear atypia and mitotic activity is typically ab- sent. 116,121
Immunohistochemical studies have shown that MAV does not, in fact, have the phenotype of mesothelial cells. Instead, it exhibits re- activity for carcinoembryonic antigen (CEA) and tumor-associated glycoprotein-72 (TAG-72 [also known as CA72.4]; recognized by the monoclonal antibody B72.3), as seen in activated or neoplastic gland- ular epithelial cells.119,121 Thus, on the whole, it would appear best to relabel MAV as an “intracardiac endodermal choristoma.”
Differential diagnosis concerns the exclusion of metastatic adeno- carcinoma. This is facilitated by attention to the rather bland cytologic attributes of MAV, as well as the fact that most affected individuals are young and therefore unlikely to have an epithelial malignancy. Furthermore, metastatic carcinoma in the myocardium manifests grossly-visible nodules, in contrast to the macroscopically-unobtrusive nature of MAV. Carcinomas also show a greater degree of nuclear atypicality.
Hepatic neoplasms that may simulate metastases
Primary intrahepatic neuroendocrine carcinoma
In 1958, Edmondson proposed the existence of primary neu- roendocrine carcinomas (NECs) in the liver.122 The premise that such lesions do, in fact, exist is still questioned, because of the problem of excluding the possibility of metastasis to the liver from an occult pri- mary NEC elsewhere in the body.123-126 A prototypically organoid growth pattern and the spectrum of cytological appearances of neu- roendocrine tumors (Fig. 13) are potentially common to lesions arising in the lung, alimentary tract, pancreas, and other sites. Therefore, non- morphological methods must be employed in attempts to determine the primary site of a possibly-metastatic NEC.
Several authors have employed selected panels of antibody reagents and gene-set analyses to further that goal. In particular, im- munoreactivity for CDX2 is fairly restricted to intestinal NECs, but it only labels around one-half of them.127 TTF-1 positivity is weighted towards pulmonary NECs, with a greater number of high-grade tumors being labeled.128 However, that marker has also been observed in pri- mary NECs of the thyroid, urinary bladder, intestine, and gynecological tract.128,129 CK20 is present in 85-90% of Merkel cell (primary cuta- neous neuroendocrine) carcinomas and a majority of salivary glandular small-cell carcinomas, but can also be seen in NECs of the gut and pancreas. Neuroendocrine secretory protein-55 (NESP55) is a relatively specific but insensitive indicator of pancreatic origin for NECs.130 Pancreatic & duodenal homeobox-1 (PDX1) expression is common to pancreatic and rectal NECs,131 whereas prostatic acid phosphatase is seemingly restricted to intestinal neuroendocrine tumors.130 Using the quantitative polymerase chain reaction to assess the expression of 4 genes (bombesin-like receptor 3; opioid receptor kappa-1; oxytocin receptor; secretin receptor), Maxwell et al. were successful in identi- fying bowel-derived and pancreas-derived metastases of NECs in 89% of cases, using that approach. 132,133
The information just considered applies only indirectly to the di- agnosis of primary NECs in the liver. No first-hand im- munohistochemical or molecular data apply to the non-morphological profiles of those tumors, because none is represented in the published literature. However, if one were to demonstrate, in a solitary liver mass, the presence of an immunophenotype or genotype that is known to be associated with metastatic NECs from other organs, the diagnosis of
primary hepatic NEC would essentially be precluded.
Peripheral cholangiocarcinoma
Soliary peripheral cholangiocarcinomas (SPCs) that arise in the proximal, intrahepatic portions of the biliary tree (Fig. 14) may be extremely difficult to distinguish from metastatic carcinoma on radi- ological and pathological grounds.134,135 In particular, in solitary form, metastatic ductal pancreatic adenocarcinoma in the liver can simulate the appearance of SPC virtually perfectly.
This general problem has been addressed by several authors, using immunohistochemistry. Results have shown that SPC differs from me- tastatic colorectal cancer (MCRC) because it has a CK7 +/CK20- im- munophenotype whereas colonic carcinoma is positive only for the latter of those markers.136 Similarly, SPC demonstrates a lack of cell- membrane labeling for CD15 and CA72.4, in contrast to its presence in MCRC.137 Both tumor types express MOC-31.138
As mentioned earlier, a much more difficult problem is the se- paration of SPC from metastatic ductal pancreatic adenocarcinoma (MDPA). In fact, those two neoplasms can be virtually identical mor- phologically and immunohistochemically. They are both typified by potential reactivity for CK7, CD5, CD7, S100P, CA19-9, and DUPAN- 2.139-142 As expected, focused imaging of the pancreas is indicated before making a definitive diagnosis of SPC.
Fig. 14. Peripheral cholangiocarcinoma may assume a multifocal growth pattern, as seen in a computed tomogram (top left) or by gross examination (top right). This tumor is constituted by in- teranastomosing glandular profiles that comprise atypical, low- columnar or cuboidal epithelioid cells (bottom panels). The his- tologic image is similar to that of metastatic pancreatic adeno- carcinoma in many cases.
Adrenocortical carcinoma imitating a unifocal metastasis
Several forms of visceral carcinoma manifest a tendency to metas- tasize to the adrenal glands, and they may do so in a selective fashion. These include tumors originating in the lungs, breasts, liver, and kid- neys, among others.143 Metastatic melanoma also may have a com- parable clinicopathologic profile. Each of those neoplasms has the ca- pacity to assume an undifferentiated large-cell growth pattern, with or without oncocytic or clear-cell features, and the same is true of primary adrenocortical carcinoma (ACC) (Fig. 15). If multiple nodules of tumor are seen in one or both adrenals, metastatic disease is overwhelmingly likely. However, solitary lesions may well represent either primary ACC or a single implant of a secondary tumor.
Histochemical studies for glycogen (with the undigested periodic acid-Schiff [UPAS] method) or mucin (with the digested PAS (DPAS) technique) can be helpful in separating primary ACC-which is typi- cally negative for both-from metastatic carcinomas, which are often positive with one or the other.144 Melanoma is typically PAS-negative, but, in addition, it often labels with the Fontana-Masson or Schmorl techniques for melanin. 145
A more definitive approach is based on immunohistochemical eva- luation. Even though it is undeniably epithelial in nature, ACC has such a low density of intracellular keratin in paraffin sections that it is fre- quently negative for that marker.146 Moreover, it lacks EMA, CEA, MOC-31, glypican-3, arginase-1, thyroid transcription factor-1 (TTF1), napsin-A, PAX8, carbonic anhydrase IX, S100 protein, and SOX10. One or several of those determinants is expected in metastatic carcinomas or
melanomas.79,147,148
In contrast, ACC is often paradoxically labeled for melan-A (usually used as a melanocytic marker), often accompanied by staining for steroidogenic factor-1, inhibin, calretinin, or steroid receptor coacti- vator-1.149 This profile differs from that of metastatic carcinomas and melanomas.
Carcinomas of the urinary bladder that may simulate metastases
Three forms of primary carcinoma in the urinary bladder may as- sume microscopic images that imitate those of metastatic tumors.150-155 They include clear-cell adenocarcinoma (CCA) (Fig. 16), enteric-type (colorectal-like) adenocarcinomas (ETAs), and NECs. As true of clear- cell lung carcinomas (see above), primary CCAs in the bladder comprise a heterogeneous group of lesions. These include primary urothelial carcinoma with clear-cell attributes, Mullerian-type clear-cell carci- noma, and CCA with a combination of Mullerian, urothelial, and enteric features.156 Urothelial CCA expresses p63 and GATA3, with or without CD10, E-cadherin, and CK7.156 Mullerian-type CCA is reactive for CA- 125, PAX8, and napsin-A.155,157 Hybrid CCA may express any of the markers seen in urothelial or Mullerian-type lesions, as well as hepa- tocyte nuclear factor 1-beta, CA19-9, CEA, and MUC1.158-160 Hence, the immunophenotypes of primary Mullerian-type and hybrid CCA s of the bladder may overlap substantially with those of metastatic clear cell carcinomas from the gynecologic tract and gut. Clinical attention to the latter anatomic sites is necessary before a final clinicopathologic in- terpretation can be made.
A
ETAs of the bladder have morphological appearances which are identical to those of the various forms of colorectal carcinoma and gastric carcinoma, including tumors comprising signet-ring-cells. In keeping with their histologic attributes, the immunohistologic features of ETAs are also comparable to primary neoplasms of the alimentary tract. They include the coexpression of CK7 and CK20 and potential reactivity for CEA, CDX2, SATB2, and CA19-9.161 In light of that profile, careful clinical examination of the gut-particularly the rectum-must precede a pathologic diagnosis of primary vesical ETA.
The pathologic approach to possibly-primary NEC of the bladder is essentially the same as that described above in reference to hepatic neuroendocrine tumors. A potentially confounding finding in vesical NECs is that they have the ability for aberrant TTF-1 expression.
Carcinomas of the gonads that may imitate metastases
Ovarian tumors
One of the most problematic issues in ovarian tumor pathology is the diagnostic separation of primary mucinous neoplasms from metas- tases to the gonads.162,163 Substantial information can often be gar- nered by attention to the gross characteristics of lesions in this category. Primary ovarian mucinous tumors (POMTs) are typically solitary and unilateral, whereas metastases from the pancreas or intestines tend to be multifocal and bilateral.164 The spectrum of histologic findings in POMTs includes borderline lesions that are relatively bland on the one hand, and anaplastic tumors that may contain signet ring-cell forms on the other.162,165,166 McCluggage & Young found that high-grade pri- mary mucinous neoplasms were often composite lesions that included adenofibromatous or cystadenomatous areas, aiding in their recogni- tion as native ovarian tumors.166 Immunohistology has limited value in this context, because of shared phenotypes with metastatic enteric tu- mors. Both lesional groups may express CK7, CK20, CEA, CA-125, CA19-9, and CDX2.162,167 Because of that fact, Kubecek et al.164 have suggested that gene expression profiling may be necessary to confirm the primacy of some mucinous tumors in the ovary. Once again, clinical evaluation of the alimentary tract and pancreas is mandatory if me- tastasis is considered a possibility.
A second group of primary ovarian tumors that can imitate metas- tases histologically are the “rhabdoid” carcinomas that were formerly known as small-cell hypercalcemic tumors (SCHTs)168 (Fig. 17). The latter designation is inaccurate, because the lesional cells in SCHTs are not small. Instead, they are polygonal, often with prominent nucleoli, eccentric nuclei, and densely eosinophilic cytoplasm.169-171 They are cytologically identical to the constituents of pediatric renal rhabdoid tumors, neural teratoid-rhabdoid neoplasms, and rhabdoid carcinomas
of the lung and other organs.172 Therefore, metastases from tumors in other sites may closely imitate SCHT of the ovary, as may secondary deposits of amelanotic melanoma.173 The first of those two groups has immunohistologic features that are interchangeable regardless of the anatomic origins of the lesions. All rhabdoid tumors are hetero- geneously reactive for keratin, EMA, vimentin, and neuroendocrine markers, and they all show deletion of INI1 or SMARCA4-related in- tranuclear proteins.172 Metastatic melanoma of the rhabdoid type may show a lack of immunoreactivity for common melanocytic markers such as S100 protein, melan-A, HMB-45, PNL-2, MITF, and tyrosinase. However, they do not manifest abnormalities of INI1 or SMARCA4 polypeptide expression.174
Thirdly, small-cell NEC may be a primary neoplasm of the ovary as well.175 Once more, the diagnostic evaluation of this lesion for its se- paration from metastatic NECs is comparable to that presented earlier in this discussion, concerning hepatic tumors.
Testicular tumors
Primary testicular neoplasms that may imitate metastases include NECs (typically low-grade)176 and adenocarcinomas of the rete testis (ARTs).177 The second of those lesions may assume acinar, serous-pa- pillary, or clear-cell histologic configurations (Fig. 18). The criteria for making that diagnosis were advanced over 30 years ago by Nochomo- vitz & Orenstein.181 They include the absence of any histologically-si- milar extrascrotal or intratesticular neoplasms; an intact parietal tunica vaginalis; an epicenter of the tumor in the testicular hilum; and a his- tologic transition from normal to neoplastic rete epithelium. All of those stipulations are important, because the pathologic features of ARTs are otherwise rather non-discriminating. They demonstrate im- munoreactivity for keratin and EMA, and selected examples also have labeled for CEA, CD10, and RCC-antigen. 177-180
Low-grade primary NEC of the testis (“classical carcinoid”) is seen in adult men between the ages of 25 and 70 yrs., and it may assume in- sular, acinar, solid, or trabecular growth patterns.182-186 As true of primary hepatic NECs, there are no publications that concern the comparative immunophenotypes or genetic profiles of primary and metastatic testicular NECs.
A study by Ulbright & Young on metastatic carcinomas in the testis is noteworthy, because it emphasized a lack of pathologic features that are usually associated with secondary tumors in general.187 Metastases to the testis originated in the prostate, kidney; intestines; bladder, lungs, or esophagus, but the primary tumors were clinically-occult in over 60% of cases. Moreover, only 8% of metastatic tumors involved both testes, and 65% showed a lack of mulinodular growth. Hence, those authors concluded that “metastatic carcinomas to the testis are
Fig. 17. Rhabdoid (formerly “small-cell hypercalcemic”) carci- noma of the ovary replaces the gonadal parenchyma and contains areas of hemorrhage and necrosis. The tumor cells are often ar- ranged in cords (top right) and they have an anaplastic epithelioid appearance (bottom right). This lesion may simulate metastatic ovarian involvement by rhabdoid carcinomas of other organs.
usually solitary, unilateral tumors that may simulate primary neoplasms, including rete adenocarcinoma.”
Primary lymph nodal neoplasms that may imitate metastases Interdigitating dendritic-cell sarcoma
Intranodal spindle cell lesions on biopsy are problematic for a sur- gical pathologist, often requiring an extensive immunohistochemical evaluation with variable and frequently unsatisfactory results. In the absence of a history of malignancy, the differential diagnosis of a cy- tologically-atypical intranodal spindle cell tumor must include both a primary proliferation and a metastatic process.188,189 Particularly challenging are those lesions that share morphologic and im- munohistochemical features; spindle cell melanomas (SCM) and inter- digitating dendritic cell sarcomas (IDCS) (Fig. 19) belong to that cate- gory.190,191 Electron microscopy has been proposed as an effective method for separation of the two entities,190 but that assertion is questionable.
A study by Stowman et al. compared the histologic and im- munohistological features of SCM and IDCS.192 The two tumor types were morphologically comparable, and they demonstrated virtually equivalent staining profiles for MUM-1, beta-catenin, SOX-10, MiTF, and p75. Those authors concluded that IDCS is, in fact, very likely an intranodal melanocytic proliferation rather than a neoplastic entity which is distinct from metastatic SCM. That conclusion is further sup- ported by several other reports demonstrating identical V600E
mutations in the BRAF gene in both IDCS and SCM.193-195 These find- ings make it impossible to distinguish between IDCS and metastatic SCM in lymph node biopsies; indeed, I consider them both to be forms of melanoma.
Primary intranodal “Merkel cell carcinoma”
In 1992, Eusebi et al. described 8 cases of neuroendocrine carci- noma that was found in lymph nodes in the inguinal, axillary, and submandibular areas, with no definable primary tumor elsewhere.196 Those lesions had histologic and immunohistochemical features that were comparable to those of “Merkel cell” (primary neuroendocrine) carcinoma of the skin (MCC) (Fig. 20). However, the affected patients had no history of cutaneous lesions. Recurrences of the tumors were seen in 3 cases but were still localized to lymph nodes, and none of the patients manifested any evidence of visceral tumors during a surveil- lance period of up to 26 months.196
Several other examples of this phenomenon have been reported in the intervening 25 years.197 In each instance, the intranodal neoplasms have been immunoreactive for chromogranin-A, synaptophysin, and/or CD56, and they have shown perinuclear “dot-like” reactivity for pan- keratin and CK20. Those characteristics mirror the profile of MCC.198,199
Eusebi & colleagues acknowledged that the tumors in question could have represented metastases from totally-regressed lesions of the skin,196 and it is additionally known that MCC may rarely involute completely and spontaneously.200 Nevertheless, an alternative
explanation is that neuroendocrine epithelial cell rests may sometimes reside in lymph nodes and undergo neoplastic transformation. That same occurrence has been seen in reference to intranodal tumors with salivary glandular, thyroid, mammary, and mullerian features.201-203
From a practical perspective, the presence of intranodal MCC in the absence of a known skin tumor must always prompt a thorough sys- temic evaluation clinically, to search for another possible source of the lesion. If none is found and subsequent surveillance also fails to reveal one, a retrospective diagnosis of primary intranodal MCC can be made.
Cutaneous carcinomas & melanocytic lesions that may simulate metastases
Selected sweat gland carcinomas
A relatively common form of sweat gland carcinoma is known as ductal eccrine carcinoma (DEC), a lesion that bears a striking structural homology to ductal adenocarcinoma of the breast and salivary duct carcinoma66 (Fig. 21). As such, DEC comprises epithelioid cells ar- ranged in tubules or solid nests and cords, with at least modest nuclear atypia and randomly-disposed infiltrative growth throughout a fibrotic dermis. The peripheral borders of such tumors are irregular and per- meative; abnormal mitotic figures and foci of spontaneous necrosis are often found as well.204 There are no immunohistochemical features of DEC that may be used to separate it definitively from metastatic mammary carcinoma.205,206 Several authors have proposed using the markers p63, podoplanin, and keratin 5/6 to address that problem,
averring that immunoreactivity for any of those determinants argues for primacy of a malignant glandular skin tumor.207-210 That conclusion is generally valid, but, in my experience, a substantial number of DECs lack all 3 markers. Thus, careful examination of the breasts and thor- ough history-taking are paramount in resolving this differential diag- nosis.
Another form of sweat gland carcinoma that may simulate metas- tases is the mucinous eccrine (primary “colloid”) carcinoma (MEC). That neoplasm shares the same relatedness to mammary tumors that was mentioned above in connection with DEC. Accordingly, MEC shows cords and nests of relatively uniform polygonal cells that are suspended in pools of epithelial mucin. The latter material stains with the periodic- acid-Schiff and mucicarmine methods, and is resistant to diastase di- gestion.211 Nests of neoplastic cells usually infiltrate the dermis and subcutis irregularly at the advancing edges of MEC. The degree of nu- clear atypia is typically slight, and mitotic figures are limited in scope. Some examples of MEC contain an admixture of more solidly-cellular tissue that resembles DEC. That type of “hybrid” tumor is also en- countered in the breast. Immunohistology does aid in the elimination of skin metastasis from enteric mucinous carcinoma, because MEC lacks such markers as CDX2, SATB2, and CA19-9.212
Apocrine sweat gland carcinomas (ACs) are largely confined to the eyelids, axillae, and genitoperineal region, where apocrine glands are found in the highest density. Their cytoarchitectural features are similar to those of DEC, with some salient modifications. ACs additionally ex- hibit the variable formation of tumoral micropapillae. The cytoplasm in that tumor is relatively copious and obviously eosinophilic with fine
granularity. Tubular profiles of the neoplastic cells commonly show decapitation secretion with the elaboration of luminal “snouts”.213 Signet-ring-cell AC is seen almost exclusively in the eyelids, and it may be bilateral.214 Those characteristics commonly engender concern over the possibility of metastasis from a lobular breast carcinoma.215 To make matters worse, the immunophenotypes of the two tumor types are virtually identical.
Clear-cell sweat gland carcinoma bears a microscopic resemblance to metastatic RCC, but it lacks the vascularity (with formation of “blood lakes”) that is seen in the latter neoplasm.216 Furthermore, RCC is ty- pified by immunoreactivity for PAX8, RCC-antigen, and vimentin, whereas clear-cell cutaneous adnexal carcinomas lack those markers.
In considering the other side of the problem-the recognition of metastatic carcinoma in the skin-many visceral tumors are capable of dissemination to secondary cutaneous sites. Cancers of the breast, lung, gastrointestinal tract, and oropharynx are most commonly implicated, in respective order.217,218 Accordingly, adenocarcinomas are more frequently observed than neoplasms with squamous or transitional cell differentiation.
Metastasis to the skin is usually observed in the context of wide- spread disease when the primary site of growth has already been well documented.217 Hence, one must analyze malignant neoplasms in in- ternal organs from another perspective, to gain insights on those that most commonly simulate primary cutaneous carcinomas. Lookingbill et al. analyzed visceral neoplasms with the unusual capacity for “herald metastasis,” wherein skin involvement is the initial manifestation of an internal malignancy.219 They found that the most frequent sites of origin were the lung, kidney, stomach, and internal female genitals; other studies have reached similar conclusions. Fortunately, in light of the microscopic similarities between sweat gland carcinomas and breast cancer, the mammary glands relatively rarely give rise to distant, ex- trathoracic cutaneous metastases in the absence of obvious primary breast disease.218
The clinical history given by the patient is often the most valuable piece of information in this context, provided it is reliable. Sweat gland carcinomas are solitary masses in almost all cases and have been pre- sent for at least six months, with gradual enlargement. In contrast, metastatic tumors are rapidly-growing lesions, even when they are so- litary.220 Even though only one secondary skin lesion may be noted initially, the usual evolution of such cases is typified by the appearance of several additional tumors within a short time after presentation.
Pragmatically speaking, if the identity of a cutaneous adenocarci- noma is uncertain as primary or secondary, complete but conservative excision of the lesion can be advised. The subsequent biological evo- lution of the case will then help establish a final interpretation.
Merkel cell (primary cutaneous neuroendocrine) carcinoma
MCC of the skin is a high-grade neuroendocrine epithelial tumor that principally arises in elderly adults, in sun-exposed skin areas.198,199,221 Despite its undifferentiated microscopic appear- ance-comparable to that of small-cell neuroendocrine carcinomas (SCNCs) in other sites (especially the lungs)- this tumor has typically been present in solitary form for at least six months.222,223 That fact has the same pertinence to the primacy of the lesion as it does for sweat gland carcinomas.
Fortunately, the differential diagnosis between MCC and metastatic SCNC of the lung can be usually accomplished with im- munohistochemistry. MCC shows reactivity for pankeratin, CD56, and other neuroendocrine markers. CK20 is present in 85 to 90% of cases, manifested as “dot-like” cytoplasmic labeling of the tumor cells.198,222 A unique virus-Merkel cell carcinoma polyomavirus virus-is present in the lesional cells in 55 to 60% of cases.224,225 In contrast, MCC is non- reactive for TTF-1, CDX2, PDX-1, and CEA, which represent determi- nants that are seen in metastases from visceral SCNCs in the skin.127
Primary dermal or subcutaneous melanomas
Roughly 20 years ago, a form of primary cutaneous melanoma was recognized that had theretofore been confused with metastatic disease; namely, primary melanoma located in the deep dermis or subcutis, with no intraepidermal component whatsoever.226,227 It is rare, and in the experience of Bowen et al., primary dermal/subcuticular melanoma (PDSM) accounted for only 0.61% of melanomas seen at the University of Michigan Medical Center.226 This tumor type was identified because of its unexpectedly favorable behavior. In contrast to “usual” cutaneous melanomas that grow deeply into the subjacent tissue, with a 5-18% 5- year survival, > 80% of patients with PDSM are alive at the same point in time. 228,229
The immunohistochemical profile of PDSM is like that of melanoma in general. However, Cassarino et al. found that the former of those tumor types demonstrates lesser labeling for mutant p53 protein and cyclin-D1, a lower Ki-67 index, and less angiolymphatic invasion as seen with stains for podoplanin (D2-40).228 Nevertheless, the pro- spective recognition of PDSM depends on an integration of clinical in- formation (indicating the presence of a solitary, slowly-evolving deep cutaneous nodule) and results of pathologic evaluation.
Primary mucosal or visceral melanomas
Primary mucosal or visceral melanomas (PMVMs) can arise in the ocular uveal tract or conjunctiva, the leptomeninges, or the mucosal
surfaces of the alimentary and biliary tracts, vulva, vagina, penis, re- spiratory tract, and urinary bladder.230-233 They have no etiological relationship to sun damage, as conventional cutaneous melanoma does, and PMVM manifests a set of genetic mutations which differs from those of primary melanoma in the skin.230
Histopathologic evaluation is a key to the recognition of PMVM, to distinguish it from metastatic melanoma involving the mucosae or the viscera. Primary mucosal and visceral neoplasms demonstrate the pre- sence of an atypical intraepithelial melanocytic proliferation that is as- sociated with an invasive component,230 whereas metastases do not show that feature.
Selected tenosynovial sarcomas
Two forms of sarcoma that preferentially affect tendons and syno- vial surfaces may conceivably be confused with metastases. Those le- sions are represented by epithelioid sarcoma (EPS) and clear-cell sar- coma (CCS).
EPS was initially described by Enzinger in 1970,234 as “a sarcoma simulating a granuloma or a carcinoma.” Because that tumor arises in the soft tissues primarily, it may simulate a metastatic lesion.235 Indeed,
Plaza et al. found that poorly-differentiated carcinomas from a variety of visceral sources could spread secondarily to the soft tissues.236
EPS is constituted by nests, cords, and sheets of polygonal cells with atypical nuclear features. It most often arises in the soft tissues of the extremities, where it has “proximal” and “distal” microscopic forms. The first of them features the presence of rhabdoid cytomorphological characteristics, and the second comprises more nondescript epithelioid cells. Zones of spontaneous tumor necrosis are common to both, as well as discontinuous spread along fascial planes or tendons.237 Im- munohistologically, EPS shows reactivity for keratin and vimentin in > 90% of cases, and it may also express CK5/6, CK20, p63, EMA, CD34, and calretinin.238 The definitive method for pathologic identifi- cation of EPS is based on confirmation of its epithelial nature gener- ically, and then assessing the status of the intranuclear INI1 gene pro- duct. The latter protein is absent in EPS in both the proximal and distal forms of the tumor, in > 90% of cases. In contrast, all metastatic car- cinomas show positive nuclear INI1 staining.23
CCS was also first documented by Enzinger in 1965240 (Fig. 22). He noted that it showed cytologic and histologic similarities to cutaneous melanoma, as well as the potential to synthesize melanin pigment in a minority of cases. The gross growth patterns of CCS and EPS were
comparable, and both tended to arise in young or middle-aged adults on the extremities. Because of its likeness to melanoma and the observa- tion that it was immunoreactive for S100 protein, CCS was subse- quently called “melanoma of soft parts” by Chung & Enzinger in 1983.241 Further studies demonstrated a general immunohistologic synonymity between CCS and melanoma.242-244
With the availability of molecular genetic analyses in the early 1990s, a recurring chromosomal translocation [t(12;22)(q13.q12) was recognized in CCS that is not shared by cutaneous, mucosal, or visceral melanomas. The translocation creates a chimeric EWSR1/ATF1 gene that can be demonstrated by in-situ hybridization or the polymerase chain reaction.242,245 Hence, CCS and melanoma are separate and dis- tinct disease entities, despite many shared pathologic features.
Adamantinoma of bone
Adamantinoma (ADA) is a primary low-grade malignant intraoss- eous neoplasm that typically affects the tibial diaphysis along its anterior surface246 (Fig. 23). Most ADAs are intracortical, although medullocentric proliferations have also been described. They are usually confined by the periosteum, and those lesions with extraosseous extension are more prone to local recurrence and metastasis. Young adults are usually affected.247 A singular feature of ADA is its epithelial lineage.248,249 The histologic appearance of this tumor encompasses collections of spindle cells, aggregates of basaloid cells, and glandular or tubular structures, potentially simulating metastatic carcinoma. The first of those patterns may also imitate a fibroblastic or fibrohistiocytic proliferation.250 Irrespective of their cytological appearances, ADAs are immunoreactive for pankeratin and may also express epithelial mem- brane antigen, p63, or carcinoembryonic antigen.247,248,251 In some instances, osteofibrous elements similar to those of cortical osteofibrous dysplasia (COD; Campanacci disease) are clearly admixed with the neoplastic cells of ADA.247 Podoplanin immunoreactivity is common to both COD and ADA, further solidifying the interrelationship between those conditions. Importantly, that marker is not seen in metastatic carcinomas in bone, making it a valuable discriminant between those lesions and ADA. 252
References
1. Radner H, Katenkamp D, Reifenberger G, Deckert M, Pietsch T, Wiestler OD. New developments in the pathology of skull base tumors. Virchows Arch. 2001;438:321-335.
2. Gökden M, Roth KA, Carroll SL, Wick MR, Schmidt RE. Clear cell neoplasms and pseudoneoplastic lesions of the central nervous system. Semin Diagn Pathol. 1997;14:253-269.
3. Polydorides AD, Rosenblum MK, Edgar MA. Metastatic renal cell carcinoma to he- mangioblastoma in von Hippel-Lindau disease. Arch Pathol Lab Med. 2007;131:641-645.
4. Barresi V, Ieni A, Branca G, Tuccari G. Brachyury: a diagnostic marker for the dif- ferential diagnosis of chordoma and hemangioblastoma versus neoplastic histologic mimickers. Dis Markers. 2014;2014:514753 [E-publication] [PMID: 24591762].
5. Takei H, Powell SZ. Novel immunohistochemical markers in the diagnosis of non- glial tumors of the nervous system. Adv Anat Pathol. 2010;17:150-153.
6. Takei H, Bhattacharjee MB, Rivera A, Dancer Y, Powell SZ. New im- munohistochemical markers in the evaluation of central nervous system tumors: a review of 7 selected adult and pediatric brain tumors. Arch Pathol Lab Med. 2007;131:234-241.
7. Frank TS, Trojanowski JQ, Roberts SA, Brooks JJ. A detailed immunohistochemical analysis of cerebellar hemangioblastoma: an undifferentiated mesenchymal tumor. Mod Pathol. 1989;2:638-651.
8. Kuroda N, Agatsuma Y, Tamura M, Martinek P, Hes O, Michal M. Sporadic renal hemangioblastoma with CA9, PAX2, and PAX8 expression: diagnostic pitfall in the differential diagnosis from clear cell renal cell carcinoma. Int J Clin Exp Pathol. 2015;8:2131-2138.
9. Schaller T, Bode M, Berlis A, et al. Specific immunohistochemical pattern of car- bonic anhydrase IX is helpful for the diagnosis of CNS hemangioblastoma. Pathol Res Pract. 2015;211:513-520.
10. Gill SK, Padmanabhan V, Hickey WF, Marotti JD. Glioblastoma multiforme with epithelial differentiation: a potential diagnostic pitfall in cerebrospinal fluid cy- tology. Diagn Cytopathol. 2015;43:638-641.
11. Krishnamoorthy N, Veldore V, Sridhar PS, et al. Glioblastoma with signet ring-cell morphology: a diagnostic challenge. Asian J Neurosurg. 2016;11:319-320.
12. Takayama Y, Nobusawa S, Ochiai I, et al. Malignant meningioma with adeno- carcinoma-like metaplasia: demonstration of an intestinal phenotype. Neuropathology. 2015;35:158-164.
13. Patil S, Scheithauer BW, Strom RG, Mafra M, Chicoine MR, Perry A. Malignant meningiomas with epithelial (adenocarcinoma-like) metaplasia: a study of 3 cases. Neurosurgery. 2011;69:884-892.
14. Oh D, Prayson RA. Evaluation of epithelial and keratin markers in glioblastoma multiforme: an immunohistochemical study. Arch Pathol Lab Med. 1999;123:917-920.
15. Neelima R, Gopalakrishnan CV, Thomas B, Radhakrishnan VV. Glioblastoma mul- tiforme with epithelial differentiation. Neurol India. 2011;59:918-920.
16. Guadagno E, Del Basso-De Caro M, Pignatiello S, et al. Expression ofp40 (Np63) protein in meningiomas, an unexpected finding: immunohistochemical study and evaluation of its possible prognostic role. J Neurooncol. 2016;129:405-413.
17. England B, Huang T, Karsy M. Current understanding of the role and targeting of tumor suppressor p53 in glioblastoma multiforme. Tumour Biol. 2013;34:2063-2074.
18. Marguet F, Proust F, Crahes M, et al. Malignant meningioma with adenocarcinoma- like metaplasia: a rare entity not to be misdiagnosed. Ann Pathol. 2014;34:223-227.
19. Miettinen M, Paetau A. Mapping of the keratin polypeptides in meningiomas of different types: an immunohistochemical analysis of 463 cases. Hum Pathol. 2002;33:590-598.
20. Mrachek EK, Davis D, Kleinschmidt-DeMasters BK. Dual use of E-cadherin and D2- 40 immunostaining in unusual meningioma subtypes. Am J Clin Pathol. 2015;144:923-934.
21. Shintaku M, Honda T, Sakai T. Expression of podoplanin and calretinin in me- ningioma: an immunohistochemical study. Brain Tumor Pathol. 2010;27:23-27.
22. Bi M, Zhao S, Said JW, et al. Genomic characterization of sarcomatoid transfor- mation in clear-cell renal cell carcinoma. Proc Natl Acad Sci USA. 2016;113:2170-2715.
23. Hakar M, Chandler JP, Bigio EH, Mao Q. Neuroendocrine carcinoma of the pinel parenchyma: the first reported case. J Clin Neurosci. 2017;35:68-70.
24. Liu H, Wang H, Qi X, Yu C. Primary intracranial neuroendocrine tumor: two case reports. World J Surg Oncol. 2016;14:138.
25. Terada T. Pulmonary large-cell neuroendocrine carcinoma diagnosed in a brain metastasis. Int J Clin Exp Pathol. 2012;5:159-162.
26. Koeller KK, Sandberg GD. From the archives of the AFIP: cerebral intraventricular neoplasms-radiologic-pathologic correlation. Radiographics. 2002;22:1473-1505.
27. Bahar M, Hashem H, Tekautz T, et al. Choroid plexus tumors in adult and pediatric populations: the Cleveland Clinic and University Hospitals experience. J Neurooncol. 2017;132:427-432.
28. Sun MZ, Oh MC, Ivan ME, et al. Current management of choroid plexus carcinomas. Neurosurg Rev. 2014;37:179-192.
29. Geerts Y, Gabreels F, Lippens R, Merx H, Wesseling P. Choroid plexus carcinoma: a report of two cases and review of the literature. Neuropediatrics. 1996;27:143-148.
30. Gopal P, Parker JR, Debski R, Parker Jr JC. Choroid plexus carcinoma. Arch Pathol Lab Med. 2008;132:1350-1354.
31. Coffin CM, Wick MR, Braun JT, Dehner LP. Choroid plexus neoplasms: clin- icopathologic and immunohistochemical studies. Am J Surg Pathol. 1986;10:394-404.
32. Radotra BD, Joshi K, Kak VK, Banerjee AK. Choroid plexus tumors-an im- munohistochemical analysis with review of literature. Indian J Pathol Microbiol. 1994;37:9-19.
33. Schittenhelm J, Nagel C, Meyermann R, Beschorner R. Atypical teratoid/rhabdoid tumors may show morphological and immunohistochemical features seen in choroid plexus tumors. Neuropathology. 2011;31:461-467.
34. Terasaki H, Nagasaka T, Arai M, Harada T, Miyake Y. Adenocarcinoma of the nonpigmented ciliary epithelium: report of two cases with immunohistochemical findings. Graefes Arch Clin Exp Ophthalmol. 2001;239:876-881.
35. Shields JA, Eagle Jr RC, Shields CL, De Potter P. Acquired neoplasms of the non- pigmented ciliary epithelium (adenoma and adenocarcinoma). Ophthalmology. 1996;103:2007-2016.
36. De Potter P, Disneur D, Levecq L, Snyers B. Ocular manifestations of cancer. J Fr Ophthalmol. 2002;25:194-202.
37. Stelow EB, Mills SE, Jo VY, Carlson DL. Adenocarcinoma of the upper aerodigestive tract. Adv Anat Pathol. 2010;17:262-269.
38. Stelow EB. Glandular neoplasia of the sinonasal tract. Surg Pathol Clin. 2017;10:89-102.
39. Hoeben A, van de Winkel L, Hoebers F, et al. Intestinal-type sinonasal adeno- carcinomas: the road to molecular diagnosis and personalized treatment. Head Neck. 2016;38:1564-1570.
40. Leivo I. Sinonasal adenocarcinoma: update on classification, immunophenotype, and molecular features. Head Neck Pathol. 2016;10:68-74.
41. Thompson LD. Intestinal-type sinonasal adenocarcinoma. Ear Nose Throat J. 2010;89:16-18.
42. Resto VA, Krane JF, Faquin WC, Lin DT. Immunohistochemical distinction of in- testinal-type sinonasal adenocarcinoma from metastatic adenocarcinoma of in- testinal origin. Ann Otol Rhinol Laryngol. 2006;115:59-64.
43. Skalova A, Sar A, Laco J, et al. The role of SATB2 as a diagnostic marker of sinonasal intestinal-type adenocarcinoma. Appl Immunohistochem Mol Morphol. 2016 [June 2, 2016 E-publication] [PMID: 27258560].
44. Zur KB, Brandwein M, Wang B, Som P, Gordon R, Urken ML. Primary description of a new entity, renal cell-like carcinoma of the nasal cavity. Arch Otolaryngol Head Neck Surg. 2002;128:441-447.
45. Kubik M, Barasch N, Choby G, Seethala R, Snyderman C. Sinonasal renal cell-like carcinoma: case report and review of the literature. Head Neck Pathol. 2016 [E-
publication, Dec. 28, 2016] [PMID: 28032289].
46. Butler RT, Alderman MA, Thompson LD, McHugh JB. Evaluation of PAX2 and PAX8 expression in salivary gland neoplasms. Head Neck Pathol. 2015;9:47-50.
47. Majewska H, Skalova A, Badecka K, et al. Renal clear cell carcinoma metastasis to salivary glands-a series of 9 cases: clinicopathological study. Pol J Pathol. 2016;67:39-45.
48. Seifert G, Hennings K, Caselitz J. Metastatic tumors to the parotid and sub- mandibular glands-analysis and differential diagnosis of 108 cases. Pathol Res Pract. 1986;181:684-692.
49. Hsieh MS, Lee YH, Chang YL. SOX10-positive salivary gland tumors: a growing list, including mammary analogue secretory carcinoma of the salivary glands, sialo- blastoma, low-grade salivary duct carcinoma, basal cell adenoma/adenocarcinoma, and a subgroup of mucoepidermoid carcinomas. Hum Pathol. 2016;56:134-142.
50. Vander Poorten V, Triantafyllou A, Thompson LD, et al. Salivary acinic cell carci- noma: reappraisal and update. Eur Arch Otorhinolaryngol. 2016;273:3511-3531.
51. Said-Al-Naief N, Klein MJ. Clear cell entities of the head and neck: a selective review of clear cell tumors of the salivary glands. Head Neck Pathol. 2008;2:111-115.
52. Ellis GL. Clear cell neoplasms in salivary glands: clearly a diagnostic challenge. Ann Diagn Pathol. 1998;2:61-78.
53. Maiorano E, Altini M, Favia G. Clear cell tumors of the salivary glands, jaws, and oral mucosa. Semin Diagn Pathol. 1997;14:203-212.
54. Canberk S, Onenerk M, Sayman E, et al. Is DOG1 really useful in the diagnosis of salivary gland acinic cell carcinoma? A DOG1 (clon K9) analysis in fine needle aspiration cell blocks and the review of the literature. CytoJournal. 2015;12:18 [E- publication Aug. 13, 2015] [PMID: 26425134].
55. Hirokawa M, Sugihara K, Sai T, et al. Secretory carcinoma of the breast: a tumour analogous to salivary gland acinic cell carcinoma? Histopathology. 2002;40:223-229.
56. Reis-Filho JS, Natrajan R, Vatcheva R, et al. Is acinic cell carcinoma a variant of secretory carcinoma? A FISH study using ETV6’split apart’ probes. Histopathology. 2008;52:840-846.
57. Majewska H, Skálová A, Stodulski D, et al. Mammary analogue secretory carcinoma of salivary glands: a new entity associated with ETV6 gene rearrangement. Virchows Arch. 2015;466:245-254.
58. Bishop JA, Yonescu R, Batista D, Begum S, Eisele DW, Westra WH. Utility of mammaglobin immunohistochemistry as a proxy marker for the ETV6-NTRK3 translocation in the diagnosis of salivary mammary analogue secretory carcinoma. Hum Pathol. 2013;44:1982-1988.
59. Skalova A. Mammary analogue secretory carcinoma of salivary gland origin: an update and expanded morphologic and immunohistochemical spectrum of recently described entity. Head Neck Pathol. 2013;7(Suppl 1):S30-S36.
60. Stevens TM, Parekh V. Mammary analogue secretory carcinoma. Arch Pathol Lab Med. 2016;140:997-1001.
61. Chiosea SI, Griffith C, Assaad A, Seethala RR. Clinicopathological characterization of mammary analogue secretory carcinoma of salivary glands. Histopathology. 2012;61:387-394.
62. Del Castillo M, Chibon F, Arnould L, et al. Secretory breast carcinoma: a histo- pathologic and genomic spectrum characterized by a joint specific ETV6-NTRK3 gene fusion. Am J Surg Pathol. 2015;39:1458-1467.
63. Garland TA, Innes Jr DJ, Fechner RE. Salivary duct carcinoma: an analysis of four cases with review of literature. Am J Clin Pathol. 1984;81:436-441.
64. Gilbert MR, Sharma A, Schmitt NC, et al. A 20-year review of 75 cases of salivary duct carcinoma. JAMA Otolaryngeol Head Neck Surg. 2016;142:489-495.
65. McHugh JB, Visscher DW, Barnes EL. Update on selected salivary gland neoplasms. Arch Pathol Lab Med. 2009;133:1763-1774.
66. Wick MR, Ockner DM, Mills SE, Ritter JH, Swanson PE. Homologous carcinomas of the breasts, skin, and salivary glands. A histologic and immunohistochemical comparison of ductal mammary carcinoma, ductal sweat gland carcinoma, and salivary duct carcinoma. Am J Clin Pathol. 1998;109:75-84.
67. Lewis JE, Mckinney BC, Weiland LH, Ferreiro JA, Olsen KD. Salivary duct carci- noma: clinicopathologic and immunohistochemical review of 26 cases. Cancer. 1996;77:223-230.
68. Schwartz LE, Begum S, Westra WH, Bishop JA. GATA3 immunohistochemical ex- pression in salivary gland neoplasms. Head Neck Pathol. 2013;7:311-315.
69. Nabili V, Tan JW, Bhuta S, Sercarz JA, Head CS. Salivary duct carcinoma: a clinical and histologic review with implications for trastuzumab therapy. Head Neck. 2007;29:907-912.
70. Di Palma S, Simpson RH, Marchio C, et al. Salivary duct carcinomas can be clas- sified into luminal androgen receptor-positive, HER2, and basal-like phenotypes. Histopathology. 2012;61:629-643.
71. Udager AM, Chiosea SI. Salivary duct carcinoma: an update on morphologic mimics and diagnostic use of androgen receptor immunohistochemistry. Head Neck Pathol. 2017 [E-publication, March 20, 2017][, PMID: 28321773].
72. Erra S, Costamagna D. Breast cancer metastatic to the submandibular gland: case report. G Chir. 2011;32:194-198.
73. Laforga JB, Gasent JM. Mammary invasive duct carcinoma metastatic to parotid gland: report of a case diagnosed by fine-needle aspiration. Diagn Cytopathol. 2009;37:154-158.
74. Khazai L, Falcon S, Rosa M. Metastatic salivary duct carcinoma to the breast. Breast J. 2016;22:461-463.
75. Carcangiu ML, Sibley RK, Rosai J. Clear cell change in primary thyroid tumors: a study of 38 cases. Am J Surg Pathol. 1985;9:705-722.
76. Cipriani NA, Agarwal S, Dias-Santagata D, Faquin WC, Sadow PM. Clear cell change in thyroid carcinoma: a clinicopathologic and molecular study with identification of variable genetic anomalies. Thyroid. 2017;27:819-824.
77. Nonaka D, Tang Y, Chiriboga L, Rivera M, Ghossein R. Diagnostic utility of thyroid
transcription factors PAX8 and TTF-2 (FoxE1) in thyroid epithelial neoplasms. Mod Pathol. 2008;21:192-200.
78. Di Furia M, Della Penna A, Salvatorelli A, Clementi M, Guadagni S. A single thyroid nodule revealing early metastases from clear cell renal carcinoma: case report and review of literature. Int J Surg Case Rep. 2017;34:96-99.
79. Mentrikoski MJ, Wendroth SM, Wick MR. Immunohistochemical distinction of renal cell carcinoma from other carcinomas with clear-cell histomorphology: utility of CD10 and CA-125 in addition to PAX2, PAX8, RCCma, and adipophilin. Appl Immunohistochem Mol Morphol. 2014;22:635-641.
80. Dettloff J, Seethala RR, Stevens TM, et al. Mammary analogue secretory carcinoma (MASC) involving the thyroid gland: a report of the first 3 cases. Head Neck Pathol. 2017;11:124-130.
81. Baloch ZW, LiVolsi VA. Neuroendocrine tumors of the thyroid gland. Am J Clin Pathol. 2001;115(Suppl):S56-S67.
82. Matias-Guiu X, LaGuette J, Puras-Gil AM, Rosai J. Metastatic neuroendocrine tu- mors to the thyroid gland mimicking medullary carcinoma: a pathologic and im- munohistochemical study of six cases. Am J Surg Pathol. 1997;21:754-762.
83. Yamada H, Hasegawa Y, Mitsudomi T, Nakashima T, Yatabe Y. Neuroendocrine tumor metastasis to the thyroid gland. Int J Clin Oncol. 2007;12:63-67.
84. Sivrikoz E, Ozbey NC, Kaya B, et al. Neuroendocrine tumors presenting with thyroid gland metastasis: a case series. J Med Case Rep. 2012;6:73-77.
85. Gaffey MJ, Mills SE, Ritter JH. Clear cell tumors of the lower respiratory tract. Semin Diagn Pathol. 1997;14:222-232.
86. Gaffey MJ, Mills SE, Frierson Jr HF, Askin FB, Maygarden SJ. Pulmonary clear cell carcinoid tumor: another entity in the differential diagnosis of pulmonary clear cell neoplasia. Am J Surg Pathol. 1998;22:1020-1025.
87. Gaffey MJ, Mills SE, Zarbo RJ, Weiss LM, Gown AM. Clear cell tumor of the lung: immunohistochemical and ultrastructural evidence of melanogenesis. Am J Surg Pathol. 1991;15:644-653.
88. Moran CA, Suster S, Koss MN. Acinic cell carcinoma of the lung (“Fechner tumor”): a clinicopathologic, immunohistochemical, and ultrastructural study of five cases. Am J Surg Pathol. 1992;16:1039-1050.
89. Moran CA. Pulmonary adenocarcinoma: the expanding spectrum of histologic var- iants. Arch Pathol Lab Med. 2006;130:958-962.
90. Silver SA, Askin FB. True papillary carcinoma of the lung: a distinct clin- icopathologic entity. Am J Surg Pathol. 1997;21:43-51.
91. Amin MB, Tamboli P, Merchant SH, et al. Micropapillary component in lung ade- nocarcinoma: a distinctive histologic feature with possible prognostic significance. Am J Surg Pathol. 2002;26:358-364.
92. Ritter JH, Boucher LD, Wick MR. Peripheral pulmonary adenocarcinomas with bronchioloalveolar features: immunophenotypes correlate with histologic patterns. Mod Pathol. 1998;11:566-572.
93. Liebow AA, Castleman B. Benign clear cell tumors of the lung. Am J Pathol. 1963;43:13-14.
94. Liebow AA, Castleman B. Benign clear cell (sugar) tumors of the lung. Yale J Biol Med. 1971;43:213-222.
95. Slodkowska J, Suilkowska-Rowinska A, Dorosz P, Radomski P, Wasiutynshi A. Benign clear cell tumor of the lung (sugar tumor): morphologic, im- munohistochemical, and ultastructural evaluation. Pneumonol Allergol Pol. 2000;68:60-64.
96. Andiron A, Mazzucco G, Gugliotta P, Monga G. Benign clear-cell (sugar) tumor of the lung: a light microscopic, histochemical, and ultrastructural study with a review of the literature. Cancer. 1985;56:2657-2663.
97. Gal AA, Koss MN, Hochholzer L, Chejfec G. An immunohistochemical study of be- nign clear-cell (sugar) tumor of the lung. Arch Pathol Lab Med. 1991;115:1034-1038.
98. Sundram U, Harvell JD, Rouse RV, Nathunam Y. Expression of the B-cell pro- liferation marker MUM1 by melanocytic lesions and comparison with S100, gp100 (HMB45), and melan-A. Mod Pathol. 2003;16:802-810.
99. Fishbein GA, Grimes BS, Xian RR, Lee JM, Barjaktarevic I, Xu H. Primary salivary duct carcinoma of the lung, mucin-rich variant. Hum Pathol. 2016;47:150-156.
100. Lee CL, Wang TY, Tzen CY, Chen CK. Primary high-grade salivary-type duct car- cinoma of the lung: a case report. Int J Surg Pathol. 2014;22:536-539.
101. Husain AN, Colby TV, Ordonez NG, et al. Guidelines for pathologic diagnosis of malignant mesothelioma: 2012 update of the consensus statement from the International Mesothelioma Interest Group. Arch Pathol Lab Med. 2013;137:647-667.
102. Wick MR, Loy T, Mills SE, Legier JF, Manivel JC. Malignant epithelioid pleural mesothelioma versus peripheral pulmonary adenocarcinoma: a histochemical, ul- trastructural, and immunohistologic study of 103 cases. Hum Pathol. 1990;21:759-766.
103. Ordonez NG. The immunohistochemical diagnosis of mesothelioma: a comparative study of epithelioid mesothelioma and lung adenocarcinoma. Am J Surg Pathol. 2003;27:1031-1051.
104. Yaziji H, Battifora H, Barry TS, et al. Evaluation of 12 antibodies for distinguishing epithelioid mesothelioma from adenocarcinoma: identification of a three-antibody immunohistochemical panel with maximal sensitivity and specificity. Mod Pathol. 2006;19:514-523.
105. Marchevsky AM, Wick MR. Evidence-based guidelines for the utilization of im- munostains in diagnostic pathology: pulmonary adenocarcinoma versus mesothe- lioma. Appl Immunohistochem Mol Morphol. 2007;15:140-144.
106. Kushitani K, Takeshima Y, Amatya VJ, Furonaka O, Sakatani A, Inai K. Immunohistochemical marker panels for distinguishing between epithelioid me- sothelioma and lung adenocarcinoma. Pathol Int. 2007;57:190-199.
107. King JE, Thatcher N, Pickering CA, Hasleton PS. Sensitivity and specificity of im- munohistochemical markers used in the diagnosis of epithelioid mesothelioma: a
detailed systematic analysis using published data. Histopathology. 2006;48:223-232.
108. Moran CA, Suster S. Thymic carcinoma: current concepts and histologic features. Hematol Oncol Clin North Am. 2008;22:393-407.
109. Kwon AY, Han J, Chu J, et al. Histologic characteristics of thymic adenocarcinomas: clinicopathologic study of a nine-case series and a review of the literature. Pathol Res Pract. 2017;213:106-112.
110. Weissferdt A, Moran CA. Thymic carcinoma associated with multilocular thymic cyst: a clinicopathologic study of 7 cases. Am J Surg Pathol. 2011;35:1074-1079.
111. Weissferdt A, Moran CA. Anaplastic thymic carcinoma: a clinicopathologic and immunohistochemical study of 6 cases. Hum Pathol. 2012;43:874-877.
112. Weissferdt A, Moran CA. PAX8 expression in thymic epithelial neoplasms: an im- munohistochemical analysis. Am J Surg Pathol. 2011;35:1305-1310.
113. Weissferdt A, Moran CA. Thymic carcinoma, part 1: a clinicopathologic and im- munohistochemical study of 65 cases. Am J Clin Pathol. 2012;138:103-114.
114. Moran CA, Suster S. Germ-cell tumors of the mediastinum. Adv Anat Pathol. 1998;5:1-15.
115. Weissferdt A, Rodriguez-Canales J, Liu H, Fujimoto J, Wistuba II, Moran CA :. Primary mediastinal seminomas: a comprehensive immunohistochemical study with a focus on novel markers. Hum Pathol. 2015;46:376-383.
116. Fine G, Morales AR. Mesothelioma of the atrioventricular node. Arch Pathol. 1971;92:402-408.
117. Fenoglio Jr JJ, Jacobs DW, McAllister Jr HA. Ultrastructure of the mesothelioma of the atrioventricular node. Cancer. 1977;40:721-727.
118. Manion WC, Nelson WP, Hall RJ, Brierty RE. Benign tumor of the heart causing complete heart block. Am Heart J. 1972;83:535-542.
119. Burke AP, Anderson PG, Virmani R, James TN, Herrera GA, Ceballos R. Tumor of the atrioventricular nodal region: a clinical and immunohistochemical study. Arch Pathol Lab Med. 1990;114:1057-1062.
120. Balasundaram S, Halees SA, Duran C. Mesothelioma of the atrioventricular node: first successful followup after excision. Eur Heart J. 1992;13:718-719.
121. Monzon-Munoz FJ, Aguilera-Tapia B, Martinez-Penuela-Virseda JM, Oliva-Aldamiz H. Polycystic endodermal heterotopia of the atrioventricular node. Med Clin. 1995;104:257-261.
122. Edmonson HA. Tumors of the Liver & Intrahepatic Bile Ducts. [In: Atlas of Tumor Pathology, Series 1, Fascicle 25]. Washington, DC: Armed Forces Institute of Pathology; 1958:105-106.
123. Fenwick SW, Wyatt JI, Toogood GJ, Lodge JP. Hepatic resection and transplanta- tion for primary carcinoid tumors of the liver. Ann Surg. 2004;239:210-219.
124. Fenoglio LM, Severini S, Ferrigno D, et al. Primary hepatic carcinoid: a case report and literature review. World J Gastroenterol. 2009;15:2418-2422.
125. Donadon M, Torzilli G, Palmisano A, et al. Liver resection for primary hepatic neuroendocrine tumors: report of three cases and review of the literature. Eur J Surg Oncol. 2006;32:325-328.
126. Yang K, Cheng YS, Yang JJ, Jiang X, Guo JX. Primary hepatic neuroendocrine tu- mors: multimodal imaging features with pathological correlations. Cancer Imaging. 2017;17:20-26.
127. Lin X, Saad RS, Luckasevic TM, Silverman JF, Liu Y. Diagnostic value of CDX2 and TTF-1 expressions in separating metastatic neuroendocrine neoplasms of unknown origin. Appl Immunohistochem Mol Morphol. 2007;16:407-414.
128. Ordonez NG. Value of thyroid transcription factor-1 immunostaining in distin- guishing small cell lung carcinomas from other small cell carcinomas. Am J Surg Pathol. 2000;24:1217-1223.
129. Siami K, McCluggage WG, Ordonez NG, et al. Thyroid transcription factor-1 ex- pression in endometrial and endocervical adenocarcinomas. Am J Surg Pathol. 2007;31:1759-1763.
130. Bellizzi AM. Assigning site of origin in metastatic neuroendocrine neoplasms: a clinically significant application of diagnostic immunohistochemistry. Adv Anat Pathol. 2013;20:285-314.
131. Chan ES, Alexander J, Swanson PE, Jain D, Yeh MM. PDX-1, CDX-2, TTF-1, and CK7: a reliable immunohistochemical panel for pancreatic neuroendocrine neo- plasms. Am J Surg Pathol. 2012;36:737-743.
132. Maxwell JE, Sherman SK, Stashek KM, O’Dorisio TM, Bellizzi AM, Howe JR. A practical method to determine the site of unknown primary in metastatic neu- roendocrine tumors. Surgery. 2014;156:1359-1365.
133. Sherman SK, Maxwell JE, Carr JC, et al. Gene expression accurately distinguishes liver metastases of small bowel and pancreas neuroendocrine tumors. Clin Exp Metastas -. 2014;31:935-944.
134. Apisarnthanarak P, Pansri C, Maungsomboon K, Thamtorawat S. The CT appear- ances for differentiating of peripheral mass-forming cholangiocarcinoma and liver metastases from colorectal adenocarcinoma. J Med Assoc Thai. 2014;97:415-422.
135. Koea J, Taylor G, Miller M, Rodgers M, McCall J. Solitary necrotic nodule of the liver: a riddle that is difficult to answer. J Gastrointest Surg. 2003;7:627-630.
136. Rullier A, Le Bail B, Fawaz R, Blanc JF, Saric J, Bioulac-Sage P. Cytokeratin 7 and 20 expression in cholangiocarcinoma varies along the biliary tract but still differs from that in colorectal carcinoma metastasis. Am J Surg Pathol. 2000;24:870-876.
137. Fucich LF, Cheles MK, Thung SN, Gerber MA, Marrogi AJ. Primary vs. metastatic hepatic carcinoma: an immunohistochemical study of 34 cases. Arch Pathol Lab Med. 1994;118:927-930.
138. Proca DM, Niemann TH, Porcell AI, DeYoung BR. MOC31 immunoreactivity in primary and metastatic carcinoma of the liver: report of findings and review of other utilized markers. Appl Immunohistochem Mol Morphol. 2000;8:120-125.
139. Chu PG, Arber DA, Weiss LM. Expression of T/NK-cell and plasma cell antigens in nonhematopoietic epithelioid neoplasms: an immunohistochemical study of 447 cases. Am J Clin Pathol. 2003;120:64-70.
140. Tsai JH, Huang WC, Kuo KT, Yuan RH, Chen YL, Jeng YM. S100P immunostaining
identifies a subset of peripheral-type intrahepatic cholangiocarcinomas with mor- phological and molecular features similar to those of perihilar and extrahepatic cholangiocarcinomas. Histopathology. 2012;61:1106-1116.
141. Ohshio G, Ogawa K, Kudo H, et al. Immunohistochemical studies on the localization of cancer associated antigens DU-PAN-2 and CA19-9 in carcinomas of the digestive tract. J Gastroenterol Hepatol. 1990;5:25-31.
142. Ji YF, Huang H, Jiang F, Ni RZ, Xiao MB. S100 family signaling network and related proteins in pancreatic cancer. Int J Mol Med. 2014;33:769-776.
143. Duregon E, Volante M, Bollito E, et al. Pitfalls in the diagnosis of adrenocortical tumors: a lesson from 300 consultation cases. Hum Pathol. 2015;46:1799-1807.
144. Lewinsky BS, Grigor KM, Symington T, Neville AM. The clinical and pathologic features of non-hormonal adrenocortical tumors: report of twenty new cases and review of the literature. Cancer. 1974;33:778-790.
145. Wick MR, Patterson JW. Multimodal pathologic diagnosis of malignant melanoma: integration of morphology, histochemistry, immunohistology, and electron micro- scopy. J Histotechnol. 2003;26:253-258.
146. Gaffey MJ, Traweek ST, Mills SE, et al. Cytokeratin expression in adrenocortical neoplasia: an immunonhistochemical and biochemical study with implications for the differential diagnosis of adrenocortical, hepatocellular, and renal cell carci- noma. Hum Pathol. 1992;23:144-153.
147. Sangoi AR, Fujiwara M, West RB, et al. Immunohistochemical distinction of primary adrenal cortical lesions from metastatic clear cell renal cell carcinoma: a study of 248 cases. Am J Surg Pathol. 2011;35:678-686.
148. Li H, Hes O, MacLennan GT, Eastwood DC, Iczkowski KA. Immunohistochemical distinction of metastases of renal cell carcinoma to the adrenal from primary adrenal nodules, including oncocytic tumors. Virchows Arch. 2015;466:581-588.
149. Nakamura YK, Yamazaki Y, Felizola SJ, et al. Adrenocortical carcinoma: review of the pathologic features, production of adrenal steroids, and molecular pathogenesis. Endocrinol Metab Clin North Am. 2015;44:399-410.
150. Ward AM. Glandular neoplasia within the urinary tract: the etiology of adeno- carcinoma of the urothelium with a review of the literature. Virchows Arch A Pathol Pathol Anat. 1971;352:1296-1311.
151. Grignon DJ, Ro JY, Ayala AG, Johnson DE. Primary signet-ring-cell carcinoma of the urinary bladder. Am J Clin Pathol. 1991;95:13-20.
152. Kamat MR, Kulkarni JN, Tongaonkar HB. Adenocarcinoma of the bladder: study of 14 cases and review of the literature. Br J Urol. 1991;68:254-257.
153. Young RH, Eble JN. Unusual forms of carcinoma of the urinary bladder. Hum Pathol. 1991;22:948-965.
154. Young RH, Scully RE. Clear cell adenocarcinoma of the bladder and uretha: a report of three cases and review of the literature. Am J Surg Pathol. 1985;9:816-826.
155. Adeniran AJ, Tamboli P. Clear cell adenocarcinoma of the urinary bladder: a short review. Arch Pathol Lab Med. 2009;133:987-991.
156. Knez VM, Barrow W, Lucia MS, Wilson S, La Rosa FG. Clear cell urothelial carci- noma of the urinary bladder: a case report and review of the literature. J Med Case Rep. 2014;8:275-279.
157. Terada T. An autopsy case of clear cell adenocarcinoma of the urinary bladder. Appl Immunohistochem Mol Morphol. 2013;21:371-375.
158. Ellis CL, Chang AG, Cimino-Mathews A, et al. GATA-3 immunohistochemistry in the differential diagnosis of adenocarcinoma of the urinary bladder. Am J Surg Pathol. 2013;37:1756-1760.
159. Hanley KZ, Cohen C, Osunkoya AO. Hepatocyte nuclear factor-1-beta expression in clear cell renal cell carcinoma and urothelial carcinoma with clear-cell features: a potential diagnostic pitfall. Appl Immunohistochem Mol Morphol. 2017;25:134-138.
160. Oliva E, Amin MB, Jimenez R, Young RH. Clear cell carcinoma of the urinary bladder: a report and comparison of four tumors of mullerian origin and nine of probable urothelial origin with discussion of histogenesis and diagnostic problems. Am J Surg Pathol. 2002;26:190-197.
161. Giannico GA, Gown AM, Epstein JI, Revetta F, Bishop JA. Role of SATB2 in dis- tinguishing the site of origin in glandular lesions of the bladder/urinary tract. Hum Pathol. 2017 [E-publication July 12, 2017] [PMID: 28711650].
162. Young RH. From Krukenberg to today: the ever present problems posed by meta- static tumors in the ovary. Part I: historical perspective, general principles, and mucinous tumors, including the Krukenberg tumor. Adv Anat Pathol. 2006;13:205-227.
163. Young RH. From Krukenberg to today: the ever present problems posed by meta- static tumors in the ovary. Part II. Adv Anat Pathol. 2007;14:149-177.
164. Kubecek O, Laco J, Spacek J, et al. The pathogenesis, diagnosis, and management of metastatic tumors to the ovary: a comprehensive review. Clin Exp Metastas -. 2017 [E-publication, July 20, 2017] [PMID: 28730323].
165. Kiyokawa T, Young RH, Scully RE. Krukenberg tumors of the ovary: a clin- icopathologic analysis of 120 cases with emphasis on their variable pathologic manifestations. Am J Surg Pathol. 2006;30:277-299.
166. McCluggage WG, Young RH. Primary ovarian mucinous tumors with signet ring cells: report of 3 cases with discussion of so-called primary Krukenberg tumor. Am J Surg Pathol. 2008;32:1373-1379.
167. Cathro HP, Stoler MH. Expression of cytokeratins 7 and 20 in ovarian neoplasia. Am J Clin Pathol. 2002;117:944-951.
168. Karanian-Philippe M, Velasco V, Longy M, et al. SMARCA4 (BRG1) loss of expres- sion is a useful marker for the diagnosis of ovarian small cell carcinoma of the hypercalcemic type (ovarian rhabdoid tumor): a comprehensive analysis of 116 rare gynecologic tumors, 9 soft tissue tumors, and 9 melanomas. Am J Surg Pathol. 2015;39:1197-1205.
169. Kupryjańczyk J, Dansonka-Mieszkowska A, Moes-Sosnowska J, et al. Ovarian small cell carcinoma of hypercalcemic type - evidence of germline origin and SMARCA4 gene inactivation. a pilot study. Pol J Pathol. 2013;64:238-246.
170. Foulkes WD, Clarke BA, Hasselblatt M, Majewski J, Albrecht S, McCluggage WG. No
small surprise - small cell carcinoma of the ovary, hypercalcaemic type, is a ma- lignant rhabdoid tumour. J Pathol. 2014;233:209-214.
171. Conlon N, Silva A, Guerra E, et al. Loss of SMARCA4 expression is both sensitive and specific for the diagnosis of small cell carcinoma of ovary, hypercalcemic type. Am J Surg Pathol. 2016;40:395-403.
172. Fuller CE. All things rhabdoid and SMARC: an enigmatic exploration with Dr. Louis P. Dehner. Semin Diagn Pathol. 2016;33:427-440.
173. Chang ES, Wick MR, Swanson PE, Dehner LP. Metastatic malignant melanoma with “rhabdoid” features. Am J Clin Pathol. 1994;102:426-431.
174. Gavino AC, Gillies EM. Metastatic rhabdoid melanoma: report of a case with a comparative review of the literature. J Cutan Pathol. 2008;35:337-342.
175. Howitt BE, Kelly P, McCluggage WG. Pathology of neuroendocrine tumors of the female genital tract. Curr Oncol Rep. 2017;19:59-69.
176. Lu C, Zhang Z, Jiang Y, et al. Primary pure carcinoid tumors of the testis: clin- icopathological and immunophenotypical characteristics of 11 cases. Oncol Lett. 2015;9:2017-2022.
177. Amin MB. Selected other problematic testicular and paratesticular lesions: rete testis neoplasms and pseudotumors, mesothelial lesions, and secondary tumors. Mod Pathol. 2005;18 [Suppl: S131-Suppl: S145].
178. Ballotta MR, Borghi L, Barucchello G. Adenocarcinoma of the rete testis: report of two cases. Adv Clin Pathol. 2000;4:169-173.
179. Mermershtain W, Vardi N, Gusakova I, Klein J. Serous papillary adenocarcinoma of the rete testis: unusual ultrasonography and pathological findings. J Cancer Res Ther. 2007;3:37-39.
180. Huang PW, Chang KM. Adenocarcinoma of the rete testis with prominent papillary structure and clear neoplastic cells: morphologic and immunohistochemical find- ings and differential diagnosis. Indian J Pathol Microbiol. 2015;58:232-234.
181. Nochomovitz LE, Orenstein JM. Adenocarcinoma of the rete testis: case report, ultrastructural observations, and clinicopathologic correlates. Am J Surg Pathol. 1984;8:625-634.
182. Kato N, Motoyama T, Kameda N, et al. Primary carcinoid tumor of the testis: im- munohistochemical, ultrastructural and FISH analysis with review of the literature. Pathol Int. 2003;53:680-685.
183. Reyes A, Moran CA, Suster S, Michal M, Dominguez H. Neuroendocrine carcinomas (carcinoid tumor) of the testis: a clinicopathologic and immunohistochemical study of ten cases. Am J Clin Pathol. 2003;120:182-187.
184. Wang WP, Guo C, Berney DM, et al. Primary carcinoid tumors of the testis: a clinicopathologic study of 29 cases. Am J Surg Pathol. 2010;34:519-524.
185. Hayashi T, Iida S, Taguchi J, et al. Primary carcinoid of the testis associated with carcinoid syndrome. Int J Urol. 2001;8:522-524.
186. Haupt HM, Mann RB, Trump DL, Abeloff MD. Metastatic carcinoma involving the testis: clinical and pathologic distinction from primary testicular neoplasms. Cancer. 1984;54:709-714.
187. Ulbright TM, Young RH. Metastatic carcinoma to the testis: a clinicopathologic analysis of 26 nonincidental cases with emphasis on deceptive features. Am J Surg Pathol. 2008;32:1683-1693.
188. Bhullar JS, Varshney N, Dubay L. Intranodal palisaded myofibroblastoma: a review of the literature. Int J Surg Pathol. 2013;21:337-341.
189. Black JO, Zhai QJ, Varona OB, Ordonez NG, Luna MA. Primary schwannoma in a cervical lymph node. Head Neck. 2010;32:964-969.
190. Ohtake H, Yamakawa M. Interdigitating dendritic cell sarcoma and follicular den- dritic cell sarcoma: histopathological findings for differential diagnosis. J Clin Exp Hematop. 2013;53:179-184.
191. Perkins SM, Shinohara ET. Interdigitating and follicular dendritic cell sarcomas: a SEER analysis. Am J Clin Oncol. 2013;36:395-398.
192. Stowman AM, Mills SE, Wick MR. Spindle cell melanoma and interdigitating den- dritic cell sarcoma: do they represent the same process? Am J Surg Pathol. 2016;40:1270-1279.
193. Di Liso E, Pennelli N, Lodovichetti G, et al. BRAF mutation in interdigitating den- dritic cell sarcoma: a case report and review of the literature. Cancer Biol Ther. 2015;16:1128-1135.
194. O’Malley DP, Agrawal R, Grimm KE, et al. Evidence of BRAF V600E in in- determinate cell tumor and interdigitating dendritic cell sarcoma. Ann Diagn Pathol. 2015;19:113-116.
195. Go H, Jeon YK, Huh J, et al. Frequent detection of BRAF V600E mutations in his- tiocytic and dendritic cell neoplasms. Histopathology. 2014;65:261-272.
196. Eusebi V, Capella C, Cossu A, Rosai J. Neuroendocrine carcinoma within lymph nodes in the absence of a primary tumor, with special reference to Merkel cell carcinoma. Am J Surg Pathol. 1992;16:658-666.
197. Boghossian V, Owen ID, Nuli B, Xiao PQ. Neuroendocrine (Merkel cell) carcinoma of the retroperitoneum with no identifiable primary site. World J Surg Oncol. 2007;5:117-120.
198. Llombart B, Requena C, Cruz J. Update on Merkel cell carcinoma: epidemiology, etiopathogenesis, clinical features, diagnosis, and staging. Actas Dermosifiliogr. 2017;108:108-119.
199. Harms PW. Update on Merkel cell carcinoma. Clin Lab Med. 2017;37:485-501.
200. Connelly TJ, Cribier B, Brown TJ, Yanguas I. Complete spontaneous regression of Merkel cell carcinoma: a review of the 10 reported cases. Dermatol Surg. 2000;26:853-856.
201. Layfield LJ, Mooney E. Hetertopic epithelium in an intramammary lymph node. Breast J. 2000;6:63-67.
202. Yoo J, Choi HJ, Kang SJ. Mullerian-type gland inclusions in pelvic lymph nodes, mimicking metastasis: a case report and review of the literature. Cancer Res Treat. 2003;35:165-167.
203. Luna MA, Tortoledo ME, Allen M. Salivary dermal analogue tumors arising in lymph nodes. Cancer. 1987;59:1165-1169.
204. Martinez SR, Barr KL, Canter RJ. Rare tumors through the looking glass: an ex- amination of malignant cutaneous adnexal tumors. Arch Dermatol. 2011;147:1058-1062.
205. Wallace ML, Longacre TA, Smoller BR. Estrogen and progesterone receptors and anti-gross cystic disease fluid protein-15 (BRST-2) fail to distinguish metastatic breast carcinoma from eccrine neoplasms. Mod Pathol. 1995;8:897-901.
206. Mentrikoski MJ, Wick MR. Immunohistochemical distinction of primary sweat gland carcinoma and metastatic breast carcinoma: can it always be accomplished reliably? Am J Clin Pathol. 2015;143:430-436.
207. Plaza JA, Ortega PF, Stockman DL, Suster S. Value of p63 and podoplanin (D2-40) immunoreactivity in the distinction between primary cutaneous tumors and ade- nocarcinomas metastatic to the skin: a clinicopathological and im- munohistochemical study of 79 cases. J Cutan Pathol. 2010;37:403-410.
208. Rollins-Raval M, Chivukula M, Tseng GC, Jukic D, Dabbs DJ. An im- munohistochemical panel to differentiate metastatic breast carcinoma to skin from primary sweat gland carcinomas with a review of the literature. Arch Pathol Lab Med. 2011;135:975-983.
209. Mahalingam M, Nguyen LP, Richards JE, Muzikansky A, Hoang MP. The diagnostic utility of immunohistochemistry in distinguishing primary skin adnexal carcinomas from metastatic adenocarcinoma to skin: an immunohistochemical reappraisal using cytokeratin 15, nestin, p63, D2-40, and calretinin. Mod Pathol. 2010;23:713-719.
210. Lee JJ, Mochel MC, Piris A, Boussahmain C, Mahalingam M, Hoang MP. p40 ex- hibits better specificity than p63 in distinguishing primary skin adnexal carcinoma from cutaneous metastases. Hum Pathol. 2014;45:1078-1083.
211. Kazakov DV, Suster S, LeBoit PE, et al. Mucinous carcinoma of the skin, primary, and secondary: a clinicopathologic study of 63 cases with emphasis on the mor- phologic spectrum of primary cutaneous forms: homologies with mucinous lesions in the breast. Am J Surg Pathol. 2005;29:764-782.
212. Rekhi B, Deodhar KK, Laskar SG, D’Cruz A. Fine-needle aspiration cytology in a rare case of recurrent mucinous carcinoma of skin, displaying psammoma bodies on smears. Diagn Cytopathol. 2015;43:937-940.
213. Warkel RL. Selected apocrine neoplasms. J Cutan Pathol. 1984;11:437-449.
214. Requena L, Prieto VG, Requena C, et al. Primary signet-ring cell/histiocytoid car- cinoma of the eyelid: a clinicopathologic study of 5 cases and review of the lit- erature. Am J Surg Pathol. 2011;35:378-391.
215. Langel DJ, Yeatts RP, White WL. Primary signet ring cell carcinoma of the eyelid: report of a case demonstrating further analogy to lobular carcinoma of the breast with a literature review. Am J Dermatopathol. 2001;23:444-449.
216. Gauerke S, Driscoll JJ. Hidradenocarcinomas: a brief review and future directions. Arch Pathol Lab Med. 2010;134:781-785.
217. Hu SC, Chen GS, Wu CS, Chai CY, Chen WT, Lan CC. Rates of cutaneous metastases from different internal malignancies: experience from a Taiwanese medical center. J Am Acad Dermatol. 2009;60:379-387.
218. Fernandez-Flores A. Cutaneous metastases: a study of 78 biopsies from 69 patients. Am J Dermatopathol. 2010;32:222-239.
219. Lookingbill DP, Spangler N, Sexton FM. Skin involvement as the presenting sign of internal carcinoma: a retrospective study of 7316 cancer patients. J Am Acad Dermatol. 1990;22:19-26.
220. Riahi RR, Cohen PR. Clinical manifestations of cutaneous metastases: a review with special emphasis on cutaneous metastases mimicking keratoacanthoma. Am J Clin Dermatol. 2012;13:103-112.
221. Andea AA, Coit DG, Amin B, Busam KJ. Merkel cell carcinoma: histologic features and prognosis. Cancer. 2008;113:2549-2558.
222. Wong HH, Wang J. Merkel cell carcinoma. Arch Pathol Lab Med. 2010;134:1711-1716.
223. Wang TS, Byrne PJ, Jacobs LK, Taube JM. Merkel cell carcinoma: update and re- view. Semin Cutan Med Surg. 2011;30:48-56.
224. Harms PW, Patel RM, Verhaegen ME, et al. Distinct gene expression profiles of viral- and nonviral-associated Merkel cell carcinoma revealed by transcriptome analysis. J Invest Dermatol. 2013;133:936-945.
225. Leroux-Kozal V, Lévêque N, Brodard V, et al. Merkel cell carcinoma: histopathologic and prognostic features according to the immunohistochemical expression of Merkel cell polyomavirus large T antigen correlated with viral load. Hum Pathol. 2015;46:443-453.
226. Bowen GM, Chang AE, Lowe L, Hamilton T, Patel R, Johnson TM. Solitary mela- noma confined to the dermal and/or subcutaneous tissue: evidence for revisiting the staging classification. Arch Dermatol. 2000;136:1397-1399.
227. Swetter SM, Ecker PM, Johnson DL, Harvell JD. Primary dermal melanoma: a dis- tinct subtype of melanoma. Arch Dermatol. 2004;140:99-103.
228. Cassarino DS, Cabral ES, Kartha RV, Swetter SM. Primary dermal melanoma: dis- tinct immunohistochemical findings and clinical outcome compared with nodular and metastatic melanoma. Arch Dermatol. 2008;144:49-56.
229. Plaza JA, Torres-Cabala C, Evans H, Diwan HA, Suster S, Prieto VG. Cutaneous metastases of malignant melanoma: a clinicopathologic study of 192 cases with emphasis on the morphologic spectrum. Am J Dermatopathol. 2010;32:129-136.
230. Dominiak NR, Wick MR, Smith MT. Mucosal melanomas: site-specific information, comparisons with cutaneous tumors, and differential diagnosis. Semin Diagn Pathol. 2016;33:191-197.
231. Keraliya AR, Krajewski KM, Braschi-Amirfarzan M, et al. Extracutaneous mela- nomas: a primer for the radiologist. Insights Imaging. 2015;6:707-717.
232. Haiducu ML, Hinek A, Astanehe A, Lee TK, Kalia S. Extracutaneous melanoma epidemiology in British Columbia. Melanoma Res. 2014;24:377-380.
233. Hussein MR. Extracutaneous malignant melanomas. Cancer Invest. 2008;26:516-534.
234. Enzinger FM. Epithelioid sarcoma: a sarcoma simulating a granuloma or a
carcinoma. Cancer. 1970;26:1029-1041.
235. Chase DR, Enzinger FM. Epithelioid sarcoma: diagnosis, prognostic indicators, and treatment. Am J Surg Pathol. 1985;9:241-263.
236. Plaza JA, Perez-Montiel D, Mayerson J, Morrison C, Suster S. Metastases to soft tissue: a review of 118 cases over a 30-year period. Cancer. 2008;112:193-203.
237. Chbani L, Guillou L, Terrier P, et al. Epithelioid sarcoma: a clinicopathologic and immunohistochemical analysis of 106 cases from the French sarcoma group. Am J Clin Pathol. 2009;131:222-227.
238. Thway K, Jones RL, Noujaim J, Fisher C. Epithelioid sarcoma: diagnostic features and genetics. Adv Anat Pathol. 2016;23:41-49.
239. Hornick JL, Dal Cin P, Fletcher CDM. Loss of INI1 expression is characteristic of both conventional and proximal-type epithelioid sarcoma. Am J Surg Pathol. 2009;33:542-550.
240. Enzinger FM. Clear cell sarcoma of tendons and aponeuroses: an analysis of 21 cases. Cancer. 1965;18:1163-1174.
241. Chung EB, Enzinger FM. Malignant melanoma of soft parts: a reassessment of clear cell sarcoma. Am J Surg Pathol. 1983;7:405-413.
242. Dim DC, Cooley LD, Miranda RN. Clear cell sarcoma of tendons and aponeuroses: a review. Arch Pathol Lab Med. 2007;131:152-156.
243. Ferenczi K, Lastra RR, Farkas T, et al. MUM-1 expression differentiates tumors in the PEComa family from clear cell sarcoma and melanoma. Int J Surg Pathol. 2012;20:29-36.
244. Pletneva MA, Andea A, Palanisamy N, et al. Clear cell melanoma: a cutaneous clear cell malignancy. Arch Pathol Lab Med. 2014;138:1328-1336.
245. Hantschke M, Mentzel T, Rütten A, et al. Cutaneous clear cell sarcoma: a clin- icopathologic, immunohistochemical, and molecular analysis of 12 cases empha- sizing its distinction from dermal melanoma. Am J Surg Pathol. 2010;34:216-222.
246. Jain D, Jain VK, Vasishta RK, Ranjan P, Kumar Y. Adamantinoma: a clin- icopathological review and update. Diagn Pathol. 2008;3:8-18.
247. Kahn LB. Adamantinoma, osteofibrous dysplasia, and differentiated adamantinoma. Skelet Radiol. 2003;32:245-258.
248. Rosai J, Pinkus GS. Immunohistochemical demonstration of epithelial differentia- tion in adamantinoma of the tibia. Am J Surg Pathol. 1982;6:427-434.
249. Knapp RH, Wick MR, Scheithauer BW, Unni KK. Adamantinoma of bone. An elec- tron microscopic and immunohistochemical study. Virchows Arch A Pathol Anat Histopathol. 1982;398:75-86.
250. Jundt G, Remberger K, Roessner A, Schulz A, Bohndorf K. Adamantinoma of long bones. A histopathological and immunohistochemical study of 23 cases. Pathol Res Pract. 1995;191:112-120.
251. Dickson BC, Gortzak Y, Bell RS, et al. p63 expression in adamantinoma. Virchows Arch. 2011;459:109-113.
252. Kashima TG, Dongre A, Flanagan AM, Hogendoorn PC, Taylor R, Athanasou NA. Podoplanin expression in adamantinoma of long bones and osteofibrous dysplasia. Virchows Arch. 2011;459:41-46.