|Year : 2016 | Volume
| Issue : 2 | Page : 73-82
The diagnostic utility of pan-cytokeratin, CK19, CEA, CD10, and p63 in differentiating clear cell odontogenic carcinoma from hyalinizing clear cell carcinoma
Omneya M Wahba
Department of Oral Pathology, Faculty of Dentistry, Tanta University, Tanta, Egypt
|Date of Submission||08-Mar-2016|
|Date of Acceptance||15-Apr-2016|
|Date of Web Publication||23-Aug-2016|
Omneya M Wahba
Department of Oral Pathology, Faculty of Dentistry, Tanta University, Tanta
Source of Support: None, Conflict of Interest: None
Clear cell carcinoma (CCC), or hyalinizing CCC, and clear cell odontogenic carcinoma (CCOC) are rare and typically indolent malignancies that can be diagnostically challenging.
The aim of this study was to determine the diagnostic utility of p63, carcinoembryonic antigen (CEA), CD10, pan-cytokeratin (pan-CK), and cytokeratin 19 (CK19) in the diagnosis of CCOC and hyalinizing CCC.
Material and Methods
The study groups comprised patients with CCOC (n = 15) and CCC (n = 10). The blocks of CCOC and CCCs were prepared for immunohistochemical staining for p63, CEA, CD10, pan-CK, and CK19.
The results of this study revealed significant differences between the expression of pan-CK, CK19, and CEA between CCOC and hyalinizing CCC, with no significant value of p63 and CD10 expression. In conclusion, CCOC and hyalinizing CCC are malignant, locally aggressive tumors with the capacity to metastasize.
Based on the current observations and immunostains, it can be concluded that they are difficult, and, in some cases, impossible to distinguish morphologically and immunohistochemically despite a different cell of origin. Pan-CK, CK19, and CEA may have slight significant difference between CCOC and hyalinizing CCC but the diagnosis of these tumors mainly depends on the exclusion of other tumors. In addition, histological and immunohistochemical analyses of neoplasm features have limited value.
Keywords: clear cell carcinoma, clear cell odontogenic carcinoma, pan-cytokeratin
|How to cite this article:|
Wahba OM. The diagnostic utility of pan-cytokeratin, CK19, CEA, CD10, and p63 in differentiating clear cell odontogenic carcinoma from hyalinizing clear cell carcinoma. Tanta Dent J 2016;13:73-82
|How to cite this URL:|
Wahba OM. The diagnostic utility of pan-cytokeratin, CK19, CEA, CD10, and p63 in differentiating clear cell odontogenic carcinoma from hyalinizing clear cell carcinoma. Tanta Dent J [serial online] 2016 [cited 2018 Nov 20];13:73-82. Available from: http://www.tmj.eg.net/text.asp?2016/13/2/73/188907
| Introduction|| |
Clear cells may be found in many tumor types. They are a result of fixation defects, intracellular storage of some substances (such as glycogen, lipid, mucin), or paucity of organelles. In the head and neck region, clear cell tumors usually are odontogenic  or salivary in origin, although metastatic tumors need to be considered .
Odontogenic neoplasms, which are composed predominantly of clear cells, are almost rare . Examples include the clear cell subtype of Pindborg tumor (calcifying epithelial odontogenic tumor), and of ameloblastoma ,, and clear cell odontogenic carcinoma (CCOC) . The latter has a high rate of recurrence and tendency to metastasize to regional nodes and distant sites .
CCOC is considered a rare odontogenic tumor associated with aggressive clinical behavior, metastasis, and low survival rate. CCOCs were called clear cell ameloblastoma or clear cell odontogenic tumors and were considered benign in the WHO classification . Because these tumors have an aggressive behavior and may metastasize to lymph node and distant organs, the 2005 WHO classification classified them as carcinomas characterized by sheets and islands of vacuolated and clear cells .
Clear cell carcinoma (CCC) is a malignancy that arises from the salivary glands, especially within the palate, the tongue, the hypopharynx, nasopharynx, subglottic larynx, parotid, and lacrimal gland ,,,. Although CCC is considered a low-grade malignant tumor, 25% of its patients have been reported to have metastases and 12% have local recurrence ,. Metastases usually involve the lung, bones, and the regional lymph nodes .
p63 is considered a member of the p53 family. During early development of embryo, it is important for the specialization of several epithelia . The p63-deficient mice are characterized by abnormalities of stratified squamous epithelia and their derivatives, including sebaceous, salivary, and mammary glands, and defects in the craniofacial structures and limbs. Thus, it has been concluded that p63 plays a key role in regulating epithelial proliferation and differentiation processes ,.
In addition, p63 expression may be used as a special marker for some epithelial progenitor cells in the esophagus, including mucosal gland ducts . In a recent study, p63 protein has been detected in some human normal tissues: breast, larynx, bladder, kidney esophagus, tonsil, lung, and skin . Furthermore, p63 is considered a selective nuclear marker of the myoepithelial cells in the human breast tissue, as shown by Barbareschi et al. .
p63 is not a classical tumor-suppressor gene . Several researchers have demonstrated high levels of p63 protein in squamous cell carcinomas of the gastrointestinal tract . p63 expression has also been observed through immunohistochemistry in lung, skin, and cervical squamous cell carcinomas . In addition, by screening a large number and variety of neoplasms, Di Como et al.  have detected p63 protein in non-Hodgkin lymphomas urothelial carcinomas and thymomas. They found p63 expression in four pleomorphic adenomas and two of the four carcinomas of the salivary glands.
Carcinoembryonic antigen (CEA) is considered as a sum of related glycoproteins involved in cell–cell adhesion. CEA is normally produced during fetal development in the gastrointestinal tissue, but the production stops just before birth. Therefore, CEA is usually present only at low levels in the blood of healthy persons. However, the serum levels are also raised in some types of cancer, which means that it may be used as a tumor marker in clinical tests .
Serum CEA measurements in patient with colorectal cancer is useful in the management ,. In addition, CEA has been evaluated in some types of malignancies, including breast cancer . In their study, Kochi et al.  concluded that high levels of CEA provide additional prognostic value in patients with primary gastric cancer.
CD10 (common acute lymphoblastic leukemia or neutral) is a cell surface glycoprotein present in a variety of healthy cells and, acting as an enzyme, can hydrolyze peptide bonds, thus decreasing the cellular response to local peptide hormones. CD10 is strongly and diffusely expressed by clear cells in healthy kidney and in renal cell carcinoma .
CD10 is expressed in different types of cancers, cutaneous neoplasms , mesotheliomas , hemangioendotheliomas , ovarian carcinomas , urothelial carcinomas, prostatic adenocarcinomas, pancreatic adenocarcinomas, colonic adenocarcinomas, melanomas, spindle cell sarcomas, ovarian carcinomas, hepatocellular carcinomas, endometrial stromal sarcomas, lung carcinomas, and pancreatic solid pseudopapillary tumors .
Cytokeratins (CKs) are intermediate filaments: type I and type II ,. In their study, Moll et al.  classified 19 human epithelial keratins with different molecular weights within the 40–70 kDa range, and an additional keratin was identified, CK20. They can be classified according to their molecular weights (low and high), and as acidic or basic. Pan-cytokeratin (pan-CK), which is a blend of CK, is common to most epithelial tissues but not all of them, and is characterized by the antibody AE1/AE3 . CK19 is type I keratin; it is the smallest one and it is exceptional because it lacks the typical domain (no α helix) . It is expressed in most simple epithelia: ductal, intestinal, gastric epithelia, and in the mesothelium. Moreover, it is present in urothelial cells, nonkeratinized stratified squamous epithelium, and pseudostratified epithelia .
In thyroid pathology, CK19 can facilitate the differential diagnosis between papillary carcinoma with strong and diffuse staining and other thyroid cancers with weak and focal staining . CK19 is detected in the epithelium near squamous cells carcinomas, which suggests that it could be used as a fundamental biological agent of the malignant progression .
Given the changes in the expression of CK19 in the inner enamel epithelium, some researchers have suggested that CK19 could be considered as an effective marker of ameloblast differentiation .
These considerable histologic similarities may result in difficulty in differentiating CCC from CCOC in the maxillary or mandibular region. Adding, the description of a 'central hyalinizing clear cell carcinoma' involving the jawbones on the basis of histologic criteria. Finally, the importance of this distinction is not particularly clear at this point. In a recent study, a comparison was carried out between the immunohistochemical profile of CCC and that of CCOC in an attempt to resolve this diagnostic challenge.
The aim of this study was to determine the diagnostic utility of p63, CEA, CD10, pan-CK, and CK19 in the diagnosis of CCOC and hyalinizing CCC.
| Materials and Methods|| |
A total of 25 cases were used in this study, including the diagnosed cases that were retrieved from archives of the Department of Oral Pathology, Faculty of Dentistry, Tanta University. The study groups comprised patients with CCOC (n = 15) and CCC (n = 10).
To confirm the diagnosis of the samples in the study, first, 5 μm sections were prepared and were stained using the hematoxylin and eosin staining protocol. The diagnosis was then confirmed by two pathologists. Sections with sufficient tissue with proper fixation were selected, and those with inflammation and hemorrhage, insufficient tissue, and incisional biopsy were excluded from the study. Afterward, the blocks of CCOC and CCC were prepared for immunohistochemical staining for p63, CEA, CD10, pan-CK, and CK19.
For immunohistochemical staining, 4 μm sections were prepared from each paraffin block and were deparaffinized in the xylene solution and then dehydrated in a graded alcohol series. To block the internal peroxidase activity, hydrogen peroxide (3%) in a phosphate buffer solution was used. Then, antigen retrieval was carried out in a microwave oven (Panasonic 1380W, USA) for 10 minutes, under the pressure of almost 2 atm at 120°C. Further incubations using prediluted ready-to-use primary mouse monoclonal antibody anti-p63 (clone 4A4; Sigma-Aldrich Inc., USA), 2 mg/ml; anti-CEA (Biocare Medical, Concord, California, USA), dilution 1: 200; anti-CD10 (Dako, Denmark, USA) dilution 1: 40; pan-CK (AE1/AE3) (Biocare Medical), 10 mg/ml; and anti-human CK19 (Dako), dilution 1: 50 were used as the primary antibodies for 30 min and were incubated in a moist chamber in room temperature for 1 day, followed by the application of secondary antibody (for 15 min), DAB (producing brown staining), and Meyer's hematoxylin (for background staining). The samples were placed in PBS immediately after each of the above-mentioned steps. Prostate, small intestine, kidney, skin, and thyroid gland, respectively, were positive according to the manufacturer's instructions. The negative control was prepared by the replacement of primary antibody with PBS.
Assessment of immunohistochemistry stained sections
Presence of brown-colored reaction nuclear (p63), membranous (CD10) or cytoplasmic (CEA, pan-CK and CK19), was considered as positive reaction. The assessment of intensity of the immunostaining was classified as negative (no tumor cells showed positivity), weak (less than 25% of tumor cells showed positivity), moderate (25–50% of tumor cells were positive), or strong (more than 50% of tumor cells were positive) from three fields using a blinded analysis obtained by two independent pathologists using a conventional diagnostic microscope (Eclipse 80i; Nikon, Tokyo, Japan), and a further image analysis was carried out by using the Image J software, version 4.10.03 (Nikon).
For statistical analysis, all measured data were expressed as mean±SD. All statistical analyses were performed using the one-way analysis of variance followed by Dunnett's post-hoc test to reveal the statistical significance of the difference. Values of P less than 0.05 indicated a statistically significant difference.
| Results|| |
CCOC revealed sheets or nests of different sized epithelial cells with clear eosinophilic cytoplasm separated with fibrovascular septa ([Figure 1]). The cells adjacent to the fibrovascular septa were cuboidal or columnar, showing high nuclear/cytoplasmic ratio and eosinophilic cytoplasm, whereas those in the center of the nests were larger and polygonal, with abundant clear cytoplasm ([Figure 2]). Each cell had a single nucleus with fine chromatin and prominent eosinophilic nucleolus. The cells at the periphery occasionally demonstrated nuclear palisading away from the basement membrane, i.e., reverse nuclear polarity. These peripheral cells also showed occasional mitoses. Dense strands of hyalinized connective tissue separated the clear cell nests. Presence of small cords of hyperchromatic basaloid epithelial cells in-between the hyalinized stroma.
|Figure 1: Hematoxylin and eosin-stained tissue sections showing nests of clear cells separated by fibrovascular septa (original magnification: ×100).|
Click here to view
|Figure 2: Hematoxylin and eosin-stained tissue sections showing large polygonal cells with abundant clear cytoplasm (original magnification: ×200).|
Click here to view
CCC showed nearby similarity to CCOC. Histologically, all tumors were predominantly composed of round or polygonal cells with cytoplasmic clearing arranged in various combinations of solid, nested, and infiltrative patterns ([Figure 3]). Admixed with the clear cells, there were cells with granular eosinophillic cytoplasm ([Figure 4]). Some nests were separated by hyalinized fibrous septa. Pleomorphism was occasionally apparent, but mitoses were rare; only 10% of the cases showed increased mitotic activity.
|Figure 3: Hematoxylin and eosin-stained tissue sections showing diffuse infiltration of clear cells (original magnification: ×100).|
Click here to view
|Figure 4: Hematoxylin and eosin-stained tissue sections showing pleomorphism and hyperchromatism of clear cells (original magnification: ×200).|
Click here to view
Immunoprofile of clear cell odontogenic carcinoma
All the stained tumors were positive for pan-CK. Strong cytoplasmic staining was seen within the nests of clear cells in CCOC ([Figure 5]a and [Figure 5]b), moderate nuclear staining was seen for the clear cells of CCOC to p63 ([Figure 5]c and [Figure 5]d), and weak cytoplasmic staining was seen for the clear cells of CCOC to CK19 and CEA ([Figure 5]e and [Figure 5]f, respectively). In addition, weak to negative membranous staining was seen for the clear cells of CCOC to CD10 ([Figure 5]g and [Figure 5]h).
|Figure 5: Immunoprofile of CCOC: (a) Pan-cytokeratin; (b) pan-cytokeratin; (c) p63; (d) p63; (e) cytokeratin 19; (f) carcinoembryonic antigen; (g) CD10; (h) CD10. Original magnification: ×100. CCOC, clear cell odontogenic carcinoma.|
Click here to view
Immunoprofile of clear cell carcinoma
There was a moderate staining to pan-CK for clear cells in CCC ([Figure 6]a), and strong to moderate nuclear staining was seen for clear cells of CCC to p63 ([Figure 6]b). Some clear cells showed weak cytoplasmic staining against p63 ([Figure 6]c). Furthermore, there was a negative staining to CK19 CEA and CD10 ([Figure 6]d,[Figure 6]e,[Figure 6]f).
|Figure 6: Immunoprofile of CCC: (a) Pan-cytokeratin; (b) p63; (c) p63; (d) cytokeratin 19; (e) carcinoembryonic antigen; (f) CD10. Original magnification: ×100. CCC, clear cell carcinoma.|
Click here to view
Statistical analysis of pan-CK, p63, CK19, CEA, and CD10 between CCOC and CCC is illustrated in [Figure 7].
|Figure 7: Histogram showing mean values of area percentage of expression of pan-cytokeratin, p63, CK19, CEA, and CD10 in CCOC and CCC. CCC, clear cell carcinoma; CCOC, clear cell odontogenic carcinoma; CEA, carcinoembryonic antigen; CK, cytokeratin.|
Click here to view
From the results of the statistical analysis, a significant difference was found between CCOC and CCC as regards pan-CK (P = 0.009), CK19 (P = 0.036), and CEA (P = 0.011). But the expressions of p63 and CD10 in CCOC and CCC were not significant (P = 0.646 and 0.524, respectively).
| Discussion|| |
This study was carried out to elucidate the diagnostic challenge between CCC and CCOC via the immunohustochemical expression of pan-CK, CK19, CEA, p63, and CD10.
Clear cell transdifferentiation is not restricted to a certain type of tumor. The presence of palisading cells may support the odontogenic nature of such lesions, especially when accompanied by inductive fibrohyalinization of the stroma. But still, CCC and CCOC show such a degree of histopathological overlap that makes distinction impossible .
In the present study, all cases of CCOC showed strong to moderate nuclear staining to p63, which was in agreement with the results obtained by Signoretti et al. , who found that the expression of p63 in myoepithelial and basal epithelial cells has a diagnostic value, and p63 could be used to verify or to exclude invasion in breast and prostate carcinomas.
p63 is not considered a classical tumor-suppressor gene. The data are most consistent with supporting the concept that ΔNp63 isoforms have oncogenic properties, but that TAp63 isoforms have tumor-suppressive properties . In the present study, ΔNp63 isoforms showed oncogenic properties as the p63 expression was increased in both CCC and CCOC, with no obvious significance between them (P = 0.646). In contrast, Salvesen et al.  found that the loss of p63 immunostaining expression was associated with high-grade malignancy and with reduced patient survival.
The present study showed that the clear cells of CCC had cytoplasmic reactivity to p63. This is in agreement with Edwards et al. , who reported that p63 is expressed in some salivary gland tumors. The expression was strong in basal cell adenoma, in adenoid cystic carcinoma, and in polymorphous low-grade adenocarcinoma, and negative in canalicular adenoma. In addition, Emanuel et al.  found p63 positivity in adenoid cystic carcinoma so that p63-positive cells may comprise a stem cell compartment that drives the growth of this neoplasm.
In general, the myoepithelial cells present in epithelial–myoepithelial carcinoma have a characteristic clear-stained cytoplasm of polygonal cells that showed expression of p63. Therefore, the expression of p63 may be important in the diagnosis of salivary gland tumors with myoepithelial differentiation .
Of interest, in this present study, there was a shift in p63 expression in the majority of the cells of CCC that showed cytoplasmic staining of p63 instead of nuclear. This was in agreement with Fabbro and Henderson , who reported the same result. They suggested that p63 is a transcription factor involved in apoptosis, transactivation, and proliferation, and essentially stains the nucleus. They also concluded that p63 has an altered and potentially oncogenic function for the mislocalized protein in the progression and survival in prostate cancer. Furthermore, Dhillon et al.  concluded that higher levels of cytoplasmic p63 were significantly associated with an increased proliferative activity (Ki-67) expression and lower levels of apoptosis, which may suggest an effective oncogenic role in prostate cancer progression.
CEA shows a limited tissue expression in normal adult tissue. It is present in mucous cells and pyloric mucous cells in the stomach, columnar epithelial cells and goblet cells in the colon, in squamous epithelial cells of the tongue, cervix, and esophagus, in secretory epithelia and duct cells of sweat glands, and in epithelial cells of the prostate ,.
American Joint Committee on Cancer at a recent consensus conference suggested that CEA be added to the TNM staging system for scoring colorectal cancer . After successful surgical removal of colorectal cancer, an increased CEA concentration must return to the normal level within 4–6 weeks. Failure of an increased preoperative value to decrease to normal concentrations within 6 weeks after surgery is mostly associated with recurrent disease . Multiple studies have shown that patients with high preoperative concentrations of CEA have worse outcome, and thus CEA has also been found to be prognostic in patients who have liver metastasis following resection for colorectal cancer .
In the present study, CCC showed negativity to CEA. This finding was in agreement with those obtained by Tsutsumi et al.  and Shi et al.  who showed negative staining of CEA in squamous cell carcinoma, thyroid carcinoma, hepatocellular carcinoma, nasopharyngeal carcinoma, melanoma, and different sarcomas. In contrast, CCOC showed weak positivity to CEA, with a mean of 0.87 ± 0.83, which was in agreement with Thompson et al. , who showed 10–50% of patients of breast carcinoma and serous ovarian carcinoma, respectively, to be positive.
In the present study, the clear cells of CCC containing glycogen showed negative cytoplasmic staining to CEA, which is in contrast to Deba et al. , who found that the clear cells detected in eccrine hidroadenocarcinma showed positivity to CEA. In contrast, the clear cells of trichilemmal carcinoma and also of metastatic renal cell carcinoma showed CEA negativity.
According to Kulpa et al.  and Nisman et al. , pretreatment of the CEA concentrations have an important prognostic value, but the studies by Shinkai et al.  and Buccheri et al.  do not confirm these data. In nonsmall cell lung cancer, high detectable tumor CEA expression might be an adverse prognostic factor. Patients with elevated expression of CEA may benefit from adjuvant therapy; but further series with longer follow-ups are needed for the establishment of a safe and effective management plan .
In addition, immunohistochemistry for markers to differentiate epithelial tumors may be helpful, and sometimes is critical, especially on small specimens. CKs are a family of water-insoluble proteins forming an essential part of the cytoskeleton of epithelial cells, and thus forms an important aid in the classification of epithelial neoplasm .
CK AE1/AE3 is a mixture of two different types of clones of anti-CK monoclonal antibodies, AE1 and AE3. AE1 detects the high molecular weight CKs 10, 14, 15, and 16. Clone AE3 detects the high molecular weight CKs 1, 2, 3, 4, 5, and 6, and the low molecular weight CKs 7 and 8. A broad spectrum of reactivity against both high and low molecular weight CKs is obtained. Because of the high reactivity, CK AE1/AE3 has been referred to as a 'pan-cytokeratin'. It can be used as an important 'epithelial screen' to search all epithelial differentiation .
Expression of pan-CK had been detected in various odontogenic lesions , and CK19 has also been found in all kinds of odontogenic epithelial cells ,. In salivary glands and their derivative tumors, only ductal epithelial cells exhibit the focal expression of CK19 . In their study, Li et al.  noticed that the tumor-clear cells of CCOC showed positive staining for pan-CK.
In the present study, all clear cells in CCOC and some sporadic cells in CCC showed positivity to pan-CK. These findings were in agreement with Pal and Chowdhury  and Patne et al. , who detected positivity in renal CCC of the prostate. In contrast, Singh et al.  and Wang and Xue  showed negative reactivity.
In contrast to the concept that CKs are produced in fragmented forms only by epithelial cells (due to apoptosis), Catherine et al.  reported a release of full-length CK19 by tumor cells, and they suggested that the release of CK19 was an essential active process and not simply a consequence of apoptosis, and that the viable tumor cells can secret CK19, which may contribute to the metastatic process among breast cancer patients. They also added that CK19 may be an indicator of aggressive behavior of disseminated breast cancer cells. Increase in the expression of CK19 may be a more accurate indicator for clinical outcome and prognostic marker in human oral squamous cell carcinoma and important molecular event in pathogenesis of oral carcinoma .
De Matos et al.  found negative CK19 staining in benign thyroid lesions, which is in contrast to Cheung et al. , Debdas et al. , and Nasr et al. , who showed positive expression of CK19 in goiter (20, 50, and 68%, respectively). The sensitivity and the specificity as regards CK19 in distinguishing benign from malignant were 78 and 45%, respectively. It has been suggested that CK19 may be used as a useful marker for differentiating papillary thyroid carcinoma from papillary hyperplasia .
Immunohistochemical studies of various antibodies to CKs have been performed to distinguish papillary from follicular thyroid tumors and to differentiate the former from non-neoplastic lesions through the differential expression of this marker in normal and neoplastic follicular cells . Sunati et al.  found diffuse and strong staining of CK19 in almost all cases of papillary thyroid carcinoma, regardless of their subtypes. In contrast, according to the findings of Kragsterman et al. , CK19 is of limited value as a marker for the definite diagnosis of thyroid tumors.
Moreover, according to a study by Schmitt et al. , CK19 should be included in routine diagnostic methods for pancreatic neuroendocrine tumors, because it improves the prognostic value of the WHO 2004 classification. In this study, CK19 reactivity was well correlated with histopathologic factors like mitoses, vascular invasion, necrosis, solid histological pattern, and Ki-67 labeling index. In their study, Charitini et al.  added that CK19 might represent an important sign of stem cell capabilities of some cells and could be indicative of ductal differentiation.
In oral squamous cell carcinoma, CK19 expression has been found to correlate significantly with the grade of pathological differentiation . Similarly, Chen et al.  observed a significant overexpression of CK19 in cutaneous squamous cell carcinoma. In contrast, Ossama et al.  found no significant differences in CK19 expression between actinic keratosis, carcinoma in situ, and squamous cell carcinoma.
Expression of CK has been studied in various types of odontogenic lesions . In the present study, the tumor cells of CCOC showed positivity to CK19. This is in agreement with Li et al. , who concluded that CK19 has been shown to react with all kinds of odontogenic epithelial cells. Thus, the immunocytochemical profile of the CCOC suggests that they are of odontogenic epithelial origin.
In this study, not all cells of CCC showed CK19 positivity; only some ductal cells showed reaction to CK19. This is in line with Li et al. , who concluded that only ductal cells exhibit focal expression of CK19.
CD10 is a zinc-dependent metalloendoprotease that can cleave signaling peptides ,. CD10 is expressed in various normal cell types, and being an essential tissue stem cell marker of the bone marrow , adipose tissue , lungs , and breasts , CD10 is also expressed in some types of cancers, such as the kidney, liver, skin, cervix, prostate, lung, breast, pancreas, stomach, and bladder . In head and neck squamous cell carcinoma, the role of CD10 in tumor growth and differentiation is important ; however, the underlying mechanism is not clear.
CD10 is associated with growth and differentiation of neoplastic cells, and its expression increases with an increase in tumor malignancy. In their study, Ogawa et al.  found that there was a negativity of CD10 in the stromal cells of normal colorectal tissue, but the presence of CD10+ stromal cells was increasing in dysplastic lesions and maximally found in the stroma adjacent to invasive carcinoma .
Marc et al.  found that patients with primary tumors expressing high levels of CD10 were more likely to have lymph node metastasis; in contrast, Osman et al.  proposed that loss of CD10 expression was associated with an unfavorable patient outcome. In addition, immunodetection of CD10 can be used to distinguish parotid metastasis of renal cell carcinoma from other CCC variants of the parotid gland .
Sayed et al.  concluded that Bcl-2, CD10, and CD34 are useful markers in differentiating between basal cell carcinoma and trichoepithelioma. Positive immunostaining for CD10 in stromal cells around basaloid nests favors trichoepithelioma over basal cell carcinoma. These findings may prove to be of diagnostic help in distinguishing borderline cases, and also offer some possible explanations for the biological differences between these neoplasms.
In the present study, CCC and CCOC showed 10 and 20% positive staining to CD10, respectively; this finding was in agreement with Ogawa et al. , who studied the expression of CD10 in colorectal carcinoma and did not find any expression of this marker, and with Saleh et al. , who showed negativity to both CCC and CCOT against CD10. In contrast, Fujimoto et al.  identified a strong expression of CD10 in patients with higher degree of metastases, which was also observed by Yao et al.  and Ohji et al. .
| Conclusion|| |
CCC and CCOC are malignant, locally aggressive tumors with the capacity to metastasize. Based on current observations and immunostains, they are difficult, and in some cases impossible to distinguish morphologically and immunohistochemically despite a different cell of origin. Pan-CK, CK19, and CEA may have slightly significant difference between CCC and CCOC, but based on published data and the clinical experience, the diagnosis of these tumors mainly depends on the exclusion of other tumors. Moreover, histological and immunohistochemical analyses of neoplasm features have limited value.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Batsakis JG. Clear cell tumors of salivary glands. Ann Otol Rhinol Laryngol 1980; 89(Pt 1):196–197.
Seifert G. Classification and differential diagnosis of clear and basal cell tumors of the salivary glands. Semin Diagn Pathol 1996; 13:95–103.
Hirshberg A, Leibovich P, Buchner A. Metastatic tumors to the jawbones: analysis of 390 cases. J Oral Pathol Med 1994; 23:337–341.
Maiorano E, Altini M, Favia G. Clear cell tumors of the salivary glands, jaws, and oral mucosa. Semin Diagn Pathol 1997; 14:203–212.
Schmidt-Westhausen A, Philipsen HP, Reichart PA. Clear cell calcifying epithelial odontogenic tumor. A case report. Int J Oral Maxillofac Surg 1992; 21:47–49.
Hicks MJ, Flaitz CM, Wong ME, McDaniel RK, Cagle PT. Clear cell variant of calcifying epithelial odontogenic tumor: case report and review of the literature. Head Neck 1994; 16:272–277.
Muller H, Slootweg P. Clear cell differentiation in an ameloblastoma. J Maxillofac Surg 1986; 14:158–160.
Ng KH, Siar CH. Peripheral ameloblastoma with clear cell differentiation. Oral Surg Oral Med Oral Pathol 1990; 70:210–213.
Odukoya O, Arole O. Clear-cell ameloblastoma of the mandible (a case report). Int J Oral Maxillofac Surg 1992; 21:358–359.
Eversole LR, Duffey DC, Powell NB. Clear cell odontogenic carcinoma. A clinicopathologic analysis. Arch Otolaryngol Head Neck Surg 1995; 121:685–689.
Bang G, Koppang H, Hansen L. Clear cell odontogenic carcinoma: report of three cases with pulmonary and lymph node metastases. J Oral Pathol Med 1989; 18:113–118.
Kramer I, Pindborg J, Shear M. WHO histological typing of odontogenic tumor 2
. Berlin, Germany: Springer Verlag; 1992. 320–322.
Barned L, Everson JW, Reichart P, Sidransky D. World Health Organization Classification of Tumours. Pathology and genetics of head and neck tumors
. Lyon, France: IARC Press; 2005. 410–412.
Yang S, Zhang J, Xinming C. Clear cell carcinoma, not otherwise specified, of salivary glands: a clinicopathologic study of 4 cases and review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008; 106:712–720.
Milchgrub S, Gnepp DR, Vuitch F, Delgado R, Albores-Saavedra J. Hyalinizing clear cell carcinoma of salivary gland. Am J Surg Pathol 1994; 18:74–82.
Solar AA, Schmidt BL, Jordan RC. Hyalinizing clear cell carcinoma: case series and comprehensive review of the literature. Cancer 2009; 115:75–83.
O'Sullivan-Mejia ED, Massey HD, Faquin WC, Powers CN. Hyalinizing clear cell carcinoma: report of eight cases and a review of literature. Head Neck Pathol 2009; 3:179–185.
O'Regan E, Shandilya M, Gnepp DR, Timon C, Toner M. Hyalinizing clear cell carcinoma of salivary gland: an aggressive variant. Oral Oncol 2004; 40:348–352.
Shih IM, Kurman RJ. p63 expression is useful in the distinction of epithelioid trophoblastic and placental site trophoblastic tumors by profiling trophoblastic subpopulations. Am J Surg Pathol 2004; 28:1177–1183.
Mills AA, Zheng B, Wang XJ, Vogel H, Roop DR, Bradley A. p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature 1999; 398:708–713.
Yang A, Schweitzer R, Sun D, Kaghad M, Walker N, Bronson RT, et al
. p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature 1999; 398:714–718.
Glickman JN, Yang A, Shahsafaei A, McKeon F, Odze RD. Expression of p53-related protein p63 in the gastrointestinal tract and in esophageal metaplastic and neoplastic disorders. Hum Pathol 2001; 32:1157–1165.
Di Como CJ, Urist MJ, Babayan I, Drobnjak M, Hedvat CV, Teruya-Feldstein J, et al.
p63 expression profiles in human normal and tumor tissues. Clin Cancer Res 2002; 8:494–501.
Barbareschi M, Pecciarini L, Cangi MG, Macrì E, Rizzo A, Viale G, Doglioni C p63, a p53 homologue, is a selective nuclear marker of myoepithelial cells of the human breast. Am J Surg Pathol 2001; 25:1054–1060.
Yang A, Kaghad M, Caput D, McKeon F, On the shoulders of giants: p63, p73 and the rise of p53. Trends Genet 2002; 18:90–95.
Choi HR, Batsakis JG, Zhan F, Sturgis E, Luna MA, El-Naggar AK. Differential expression of p53 gene family members p63 and p73 in head and neck squamous tumorigenesis. Hum Pathol 2002; 33:158–164.
Quade BJ, Yang A, Wang Y, Sun D, Park J, Sheets EE, et al
. Expression of the p53 homologue p63 in early cervical neoplasia. Gynecol Oncol 2001; 80:24–29.
Di Como CJ, Urist MJ, Babayan I, Drobnjak M, Hedvat CV, Teruya-Feldstein J, et al
. p63 expression profiles in human normal and tumor tissues. Clin Cancer Res 2002; 8:494–501.
Boehm MK, Perkins SJ. Structural models for carcinoembryonic antigen and its complex with the single-chain Fv antibody molecule MFE23. FEBS Lett 2000; 475:11–16.
Rogers GT. Carcinoembryonic antigens and related glycoproteins. Molecular aspects and specificity. Biochim Biophys Acta 1983; 695:227–249.
Fletcher RH. Carcinoembryonic antigen. Ann Intern Med 1986; 104:66–73.
Lang BA, Kocent A, Nekulová M, Hlávková J. Three-year follow-up of carcinoembryonal antigen levels in the serum of patients with breast cancer. Neoplasma 1984; 31:79–87.
Kochi M, Fujii M, Kanamori N, Kaiga T, Kawakami T, Aizaki K, et al
. Evaluation of serum CEA and CA19-9 levels as prognostic factors in patients with gastric cancer. Gastric Cancer 2000; 3:177–186.
Luan D, Steven S. Immunohistochemical diagnosis of renal neoplasms. Arch Pathol Lab Med 2011; 135:92–109.
Bahrami S, Malone JC, Lear S, Martin AW. CD10 expression in cutaneous adnexal neoplasms and a potential role for differentiating cutaneous metastatic renal cell carcinoma. Arch Pathol Lab Med 2006; 130:1315–1319.
Butnor KJ, Nicholson AG, Allred DC, Zander DS, Henderson DW, Barrios R, et al
. Expression of renal cell carcinoma-associated markers erythropoietin, CD10, and renal cell carcinoma marker in diffuse malignant mesothelioma and metastatic renal cell carcinoma. Arch Pathol Lab Med 2006; 130:823–827.
Weinreb I, Cunningham KS, Perez-Ordoñez B, Hwang DM. CD10 is expressed in most epithelioid hemangioendotheliomas: a potential diagnostic pitfall. Arch Pathol Lab Med 2009; 133:1965–1968.
Ohta Y, Suzuki T, Shiokawa A, Mitsuya T, Ota H. Expression of CD10 and cytokeratins in ovarian and renal clear cell carcinoma. Int J Gynecol Pathol 2005; 24:239–245.
Chu P, Arber D. Paraffin-section detection of CD10 in 505 nonhematopoietic neoplasms. Frequent expression in renal cell carcinoma and endometrial stromal sarcoma. Am J Clin Pathol 2000; 113:374–382.
Chu PG, Weiss LM. Keratin expression in human tissues and neoplasms. Histopathology 2002; 40:403–439.
Chung B, Rotty J, Coulombe P. Networking galore: intermediate filaments and cell migration. Curr Opi Cell Biol 2013; 25:600–612.
Moll R, Franke W, Schiller D, Geiger B, Krepler R. The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells. Cell 1982; 31:11–24.
Bader B, Magin T, Hatzfeld M, Franke W. Amino acid sequence and gene organization of cytokeratin no. 19, an exceptional tail-less intermediate filament protein. EMBO J 1986; 5:1865–1875.
Isic Dencic T, Cvejic D, Paunovic I, Tatic S, Havelka M, Savin S. Cytokeratin19 expression discriminates papillary thyroid carcinoma from other thyroid lesions and predicts its aggressive behavior. Med Oncol 2013; 30:362.
Crivelini M, de Araújo V, de Sousa S, de Araújo N. Cytokeratins in epithelia of odontogenic neoplasms. Oral Dis 2003; 9:1–6.
Signoretti S, Waltregny D, Dilks J, Isaac B, Lin D, Garraway L, et al
. p63 is a prostate basal cell marker and is required for prostate development. Am J Pathol 2000; 157:1769–1775.
Salvesen HB, Iversen OE, Akslen LA. Prognostic significance of angiogenesis and Ki-67, p53, and p21 expression: a population-based endometrial carcinoma study. J Clin Oncol 1999; 17:1382–1390.
Edwards PC, Bhuiya T, Kelsch RD. Assessment of p63 expression in the salivary gland neoplasms adenoid cystic carcinoma, polymorphous low-grade adenocarcinoma, and basal cell and canalicular adenomas. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2004; 97:613–619.
Emanuel P, Wang B, Wu M, Burstein DE. p63 immunohistochemistry in the distinction of adenoid cystic carcinoma from basaloid squamous cell carcinoma. Mod Pathol 2005; 18:645–650.
Akihiko K, Hiroshi H, Toshiro Y, Masayoshi K. P63 expression of clear myoepithelial cells in epithelial-myoepithelial carcinoma of the salivary gland. Cancer 2005; 105:204–205.
Fabbro M, Henderson BR. Regulation of tumor suppressors by nuclear-cytoplasmic shuttling. Exp Cell Res 2003; 282:59–69.
Dhillon PK, Barry M, Stampfer MJ, Perner S, Fiorentino M, Fornari A, et al
. Aberrant cytoplasmic expression of p63 and prostate cancer mortality. Cancer Epidemiol Biomarkers Prev 2009; 18:595–600.
Hammarstrom S, Olsen A, Teglund S, Baranov V. The nature and expression of the human CEA family, in cell adhesion and communication mediated by the CEA family. Basic Clin Perspect 1997; 12:1–30.
Nap M, Mollgard K, Burtin P, Fleuren GJ. Immunohistochemistry of carcino-embryonic antigen in the embryo, fetus and adult. Tumour Biol 1988; 9:145–153.
Compton C, Fenoglio-Preiser CM, Pettigrew N, Fielding LP. American Joint Committee on Cancer Prognostic Factors Consensus Conference: Colorectal Working Group. Cancer 2000; 88:1739–1757.
Filella X, Molina R, Piqué JM, Grau JJ, Garcia-Valdecasas JC, Biete A, et al
. CEA as a prognostic factor in colorectal cancer. Anticancer Res 1994; 14:705–708.
Wagner JS, Adson MA, van Heerden JA, Adson MH, Ilstrup DM. The natural history of hepatic metastases from colorectal cancer. A comparison with resective treatment. Ann Surg 1984; 199:502–508.
Tsutsumi Y, Onoda N, Misawa M, Kuroki M, Matsuoka Y. Immunohistochemical demonstration of non-specific crossreacting antigen in normal and neoplastic human tissues using a monoclonal antibody. Comparison with carcinoembryonic antigen localization. Acta Pathol Jpn 1990; 40:85–97.
Shi ZR, Tacha D, Itzkowitz SH. Monoclonal antibody COL-1 reacts with restricted epitopes on carcinoembryonic antigen: an immunohistochemical study. J Histochem Cytochem 1994; 42:1215–1219.
Thompson J, Zimmermann W, Nollau P, Neumaier M, Weber-Arden J, Schrewe H, et al.
CGM2, a member of the carcinoembryonic antigen gene family is down-regulated in colorectal carcinomas. J Biol Chem 1994; 269:32924–32931.
Deba P, Daniel O, Jennifer O, Tracey H, Bo W, Stephanie O. Clear cell basal cell carcinoma. Pathol Res Int 2011; 10:1–4.
Kulpa J, Wójcik E, Reinfuss M, Kołodziejski L. Carcinoembryonic antigen, squamous cell carcinoma antigen, CYFRA 21-1, and neuron-specific enolase in squamous cell lung cancer patients. Clin Chem 2002; 48:1931–1937.
Nisman B, Lafair J, Heching N, Lyass O, Baras M, Peretz T, Barak V. Evaluation of tissue polypeptide specific antigen, CYFRA 21-1, and carcinoembryonic antigen in nonsmall cell lung carcinoma: does the combined use of cytokeratin markers give any additional information?. Cancer 1998; 82:1850–1859.
Shinkai T, Saijo N, Tominaga K, Eguchi K, Shimizu E, Sasaki Y, et al
. Serial plasma carcinoembryonic antigen measurement for monitoring patients with advanced lung cancer during chemotherapy. Cancer 1986; 57:1318–1323.
Buccheri GF, Ferrigno D, Sartoris AM, Violante B, Vola F, Curcio A. Tumor markers in bronchogenic carcinoma. Superiority of tissue polypeptide antigen to carcinoembryonic antigen and carbohydrate antigenic determinant 19-9. Cancer 1987; 60:42–50.
Wang J, Ma Y, Zhu ZH, Situ DR, Hu Y, Rong TH. Expression and prognostic relevance of tumor carcinoembryonic antigen in stage IB non-small cell lung cancer. J Thorac Dis 2012; 4:490–496.
Anupam S, Rajjyoti D, Sharma J, Kataki A. Spindle cell carcinoma of the head and neck. A clinicopathological and immunohistochemical study of 40 cases. J Can Ther 2012; 3:1055–1059.
Heikinheimo K, Hormia M, Stenman G, Virtanen I, Happonen RP. Patterns of expression of intermediate filaments in ameloblastoma and human fetal tooth germ. J Oral Pathol Med 1989; 18:264–273.
Li TJ, Kitano M, Chen XM, Itoh T, Kawashima K, Sugihara K, et al
. Orthokeratinized odontogenic cyst: a clinicopathological and immunocytochemical study of 15 cases. Histopathology 1998; 32:242–251.
Kasper M, Karsten U, Stosiek P, Moll R. Distribution of intermediate-filament proteins in the human enamel organ: unusually complex pattern of coexpression of cytokeratin polypeptides and vimentin. Differentiation 1989; 40:207–214.
Pelissier A, Ouhayoun JP, Sawaf MH, Forest N. Evolution of cytokeratin expression in developing human tooth germ. J Biol Buccale 1990; 18:99–108.
Muramatsu T, Hashimoto S, Inoue T, Shimono M, Noma H, Shigematsu T. Clear cell odontogenic carcinoma in the mandible: histochemical and immunohistochemical observations with a review of the literature. J Oral Pathol Med 1996; 25:516–521.
Li TJ, Yu SF, Gao Y, Wang EB. Clear cell odontogenic carcinoma: a clinicopathologic and immunocytochemical study of 5 cases. Arch Pathol Lab Med 2001; 125:1566–1571.
Pal D, Chowdhury M. Renal type clear cell carcinoma of prostate. Indian J Surg 2007; 69:81.
Patne SC, Johri N, Katiyar R, Trivedi S, Dwivedi US. Renal-type clear cell carcinoma of the prostate: a diagnostic challenge. Diagn Pathol 2015; 10:193.
Singh H, Flores-Sandoval N, Abrams J. Renal-type clear cell carcinoma occurring in the prostate. Am J Surg Pathol 2003; 27:407–410.
Wang Q, Xue Y. Renal-type clear cell carcinoma of the prostate: a case report. Oncol Lett 2015; 9:2149–2152.
Catherine A, Jean P, Monique S, Olivier P, Eric B, Gregoire M, et al.
Full-length cytokeratin19 is released by human tumor cells: a potential role in metastatic progression of breast cancer. Breast Cancer Res 2009; 11:1–10.
Ali Y, Arshad H, Mohamed S, Aqel A, Salah M, Hussain G. Expressional analysis of p16 and cytokeratin19 protein in the genesis of oral squamous cell carcinoma patients. Int J Clin Exp Med 2014; 7:1524–1530.
De Matos PS, Ferreira AP, de Oliveira Facuri F, Assumpção LV, Metze K, Ward LS. Usefulness of HBME-1, cytokeratin 19 and galectin-3 immunostaining in the diagnosis of thyroid malignancy. Histopathology 2005; 47:391–401.
Cheung C, Ezzat S, Freeman J, Rosen I, Asa S. Immunohistochemical diagnosis of papillary thyroid carcinoma. Mod Pathol 2001; 14:338–342.
Debdas B, Ram N, Uttara C, Banerjee B. Cytokeratin 19 immunoreactivity in the diagnosis of papillary thyroid carcinoma. Indian J Med Paediatric Oncol 2012; 33:107–111.
Nasr M, Mukhopadhyay S, Zhang S, Katzenstein A. Immunohistochemical markers in diagnosis of papillary thyroid carcinoma: utility of HBME1 combined with CK19 immunostaining. Mod Pathol 2006; 19:1631–1637.
Hanan A. Utility of immunohistochemical markers in differential diagnosis of follicular cell-derived thyroid lesions. J Microsc Ultrastruct 2014; 2:127–136.
Liberman E, Weidner N. Papillary and follicular neoplasms of the thyroid gland: differential immunohistochemical staining with high molecular weight keratin and involucrin. Appl Immunohistochem Mol Morphol 2000; 8:42–48.
Sunati S, Syed A, Juan R, Ronald A. Cytokeratin 19 immunoreactivity in the diagnosis of papillary thyroid carcinoma. Am J Clin Pathol 2001; 116:696–702.
Kragsterman B, Grimelius L, Walin G. Cytokeratin 19 expression in papillary thyroid carcinoma. Appl Immunohistochem Molecul Morphol 1999; 7:181–185.
Schmitt A, Anlauf M, Rousson V. WHO 2004 criteria and CK19 are reliable prognostic markers in pancreatic neuroendocrine tumors. Am J Surg Pathol 2007; 31:1677–1682.
Charitini S, Panagiotis K, Paschalis C. CK19 and CD10 expression in pancreatic neuroendocrine tumors diagnosed by endoscopic ultrasound-guided fine-needle aspiration cytology. Cancer 2009; 25:516–521.
Takeda T, Sugihara K, Hirayama Y. Immunohistological evaluation of Ki-67, p63, CK19 and p53 expression in oral epithelial dysplasias. J Oral Pathol Med 2006; 35:369–375.
Chen S, Takahara M, Kido M. Increased expression of an epidermal stem cell marker, cytokeratin 19, in cutaneous squamous cell carcinoma. Br J Dermatol 2008; 159:952–955.
Ossama A, Joanna E, Ron Y, Meera M. Stem cell markers (cytokeratin 15, cytokeratin 19 and p63) in in situ
and invasive cutaneous epithelial lesions. Mod Pathol 2011; 24:90–97.
Roques B, Noble F, Dauge V, Fournie-Zaluski M, Beaumont A. Neutral endopeptidase 24.11: structure, inhibition, and experimental and clinical pharmacology. Pharmacol Rev 1993; 45:87–146.
Turner A, Tanzawa K. Mammalian membrane metallopeptidases: NEP, ECE, KELL, and PEX. FASEB J 1997; 11:355–364.
Galy A, Morel F, Hill B, Chen BP. Hematopoietic progenitor cells of lymphocytes and dendritic cells. J Immunother 1998; 21:132–141.
Buhring H, Battula V, Treml S, Schewe B, Kanz L, Vogel W. Novel markers for the prospective isolation of human MSC. Ann N
Y Acad Sci 2007; 1106:262–271.
Sunday M, Hua J, Torday J, Reyes B, Shipp M. CD10/neutral endopeptidase 24.11 in developing human fetal lung. Patterns of expression and modulation of peptide-mediated proliferation. J Clin Invest 1992; 90:2517–2525.
Stingl J, Raouf A, Emerman J, Eaves C. Epithelial progenitors in the normal human mammary gland. J Mammary Gland Biol Neoplasia 2005; 10:49–59.
Maguer-Satta V, Besancon R, Bachelard-Cascales E. Concise review: neutral endopeptidase (CD10): a multifaceted environment actor in stem cells, physiological mechanisms, and cancer. Stem Cells 2011; 29:389–396.
Piattelli A, Fioroni M, Iezzi G, Perrotti V, Stellini E, Piattelli M. CD10 expression in stromal cells of oral cavity squamous cell carcinoma: a clinic and pathologic correlation. Oral Dis 2006; 12:301–304.
Ogawa H, Iwaya K, Izumi M, Kuroda M, Serizawa H, Koyanagi Y, et al.
Expression of CD10 by stromal cells during colorectal tumor development. Hum Pathol 2002; 33:806–811.
Makretzov N, Hayes M, Carter B, Dabiri S, Gilks C, Huntsman D. Stromal CD10 expression in invasive breast carcinoma correlates with poor prognosis, estrogen receptor negativity, and high grade. Mod Pathol 2007; 20:84–89.
Marc A, Lawrence D, Andrew F, Michael P, Tracy M, Alvin Y. Differential expression of CD10 in prostate cancer and its clinical implication. BMC Urol, 2007; 7:3–10.
Osman I, Yee H, Taneja S, Levinson B, Zeleniuch-Jacquotte A, Chang C, et al.
Neutral endopeptidase protein expression and prognosis in localized prostate cancer. Clin Cancer Res 2004; 10:4096–4100.
Andreadis D, Nomikos A, Barbatis C. Metastatic renal clear cell carcinoma in the parotid gland: a study of immunohistochemical profile and cell adhesion molecules (CAMs) expression in two cases. Pathol Oncol Res 2007; 13:161–165.
Sayed A, Rabee A, Alsayed T, Emad R. The role of Bcl-2, CD10 and CD34 expression in differentiation between basal cell carcinoma and trichoepithelioma. Open J Pathol 2014; 4:116–124.
Ogawa H, Iwaya K, Izumi M, Kuroda M, Serizawa H, Kayanagi Y. Expression of CD10 by stromal cells during a colorectal tumor development. Hum Pathol 2002; 33:806–811.
Saleh A, Nurishmah M, Firouzeh M, Goh B. Primary clear cell carcinoma of minor salivary gland of the soft palate. Med J Malaysia 2012; 67:335–336.
Fujimoto Y, Nakanishi Y, Sekine S, Yoshimura K, Akasu T, Moriya Y. CD10 expression in colorectal carcinoma correlates with liver metastasis. Dis Colon Rectum 2005; 48:1883–1889.
Yao T, Takata M, Tustsumi S, Nishiyama K, Taguchi K, Nagai E. Phenotypic expression of gastrointestinal differentiation makers in colorectal adenocarcinomas with liver metastasis. Pathology 2002; 34:556–560.
Ohji Y, Yao T, Eguchi T, Yamada T, Hirahashi M, Iida M. Evaluation of risk of liver metastasis in colorectal adenocarcinoma based on the combination of risk factors including CD10 expression: multivariate analysis of clinicopathological and immunohistochemical factors. Oncol Rep 2007; 17:525–530.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]