Journal of Pathology and Translational Medicine

Original Articles

CD44s and CD44v6 Are Predominantly Expressed in the Non-germinal Center B-Cell-like Type of Diffuse Large B-Cell Lymphomas.: Kyueng Whan Min, Young Ha Oh, Chan Kum Park, So Dug Lim, Wan Seop Kim; Korean J Pathol. 2011;45(6):589-595.; DOI: https://doi.org/10.4132/KoreanJPathol.2011.45.6.589

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Abstract PDF: BACKGROUND
CD44 protein is known as a homing cellular adhesion molecule that is linked to diverse cellular functions such as adhesion, migration and invasion, which are all important in cancer progression and metastasis. The expression of CD44 standard and variant isoforms (CD44 standard isoform [CD44s] and CD44 splice variants containing exon v6 [CD44v6], respectively) is associated with an unfavorable clinical outcome in various neoplasms.
METHODS
Forty patients who were diagnosed with diffuse large B-cell lymphoma (DLBCL) through biopsy at Hanyang University Hospital between 1996 and 2003 were included in this study. CD44 proteins expression was analyzed by immunohistochemical staining on a tissue microarray and the correlation of CD44 with the types of DLBCL and clinical parameters, including the factors defined by the International Prognostic Index, was evaluated.
RESULTS
A high CD44s and intermediate to strong CD44v6 expression, including cytoplasmic membranous staining patterns, was present in 35% (14/40) and 25% (10/40) of DLBCL patients, respectively. High CD44s expression was correlated significantly with non-germinal center B-cell-like types (non-GCB, p=0.004) and patients with old age (p=0.041).
CONCLUSIONS
High CD44s expression may be significantly associated with the non-GCB type compared to the GCB type and may be essential to the prediction of disease outcome in tumor stage III in DLBCL patients.

Clinicopathological Significance of Invasive Ductal Carcinoma with High Prevalence of CD44(+)/CD24(-/low) Tumor Cells in Breast Cancer.: Ji Youn Sung, Gou Young Kim, Yong Koo Park, Juhie Lee, Youn Wha Kim, Sung Jig Lim; Korean J Pathol. 2010;44(4):390-396.; DOI: https://doi.org/10.4132/KoreanJPathol.2010.44.4.390

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BACKGROUND
Epithelial tumor cells with a CD44(+)/CD24(-/low) immunoprofile may have the ability to cause breast cancer. We studied these cells and their clinicopathological significance.
METHODS
The clinicopathologic findings of 100 invasive ductal carcinoma (IDC) cases and 45 ductal carcinoma in situ (DCIS) cases were reviewed. CD44(+)/CD24(-/low) tumor cells were identified by immunohistochemistry, and their clinicopathological implications in IDC and DCIS were analyzed.
RESULTS
IDC with a high prevalence of CD44(+)/CD24(-/low) tumor cells was significantly associated with larger mass, higher grade, estrogen receptor (ER) negativity, and tumor cells with a higher frequency of metastasis. The proportion of CD44(+)/CD24(-/low) tumor cells in IDC, and its DCIS components was not significantly different, whereas the proportion of CD44(+)/CD24(-/low) tumor cells was higher in DCIS than in the DCIS component of IDC (p < 0.001).
CONCLUSIONS
IDC with a high prevalence of CD44(+)/CD24(-/low) tumor cells might correlate with aggressive features, such as ER and higher grades. Moreover, the proportion of CD44(+)/CD24(-/low) tumor cells in the DCIS components of IDC and DCIS might harbor different biology, which may lead to differences in cancer progression and early carcinogenesis.

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Clinicopathologic Characteristics of Breast Cancer Stem Cells Identified on the Basis of Aldehyde Dehydrogenase 1 Expression
Yoon Seok Kim, Min Jung Jung, Dong Won Ryu, Chung Han Lee
Journal of Breast Cancer.2014; 17(2): 121. CrossRef
CD44/CD24 as potential prognostic markers in node-positive invasive ductal breast cancer patients treated with adjuvant chemotherapy
Agnieszka Adamczyk, Joanna A. Niemiec, Aleksandra Ambicka, Anna Mucha-Małecka, Jerzy Mituś, Janusz Ryś
Journal of Molecular Histology.2014; 45(1): 35. CrossRef

CD44 and MMP14 Expression Associated with WHO Grade of the Astrocytoma and the Prognostic Implications.: Jaekyung Myung, Bogun Jang, Heae Surng Park, Woongjae Yon, Hyun Ju Lee, Sung Hye Park; Korean J Pathol. 2010;44(1):35-41.; DOI: https://doi.org/10.4132/KoreanJPathol.2010.44.1.35

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Abstract PDF: BACKGROUND
CD44 is a cell surface receptor that has been implicated in tumor cell invasion and metastasis in a range of tumors of various organs, including breast, ovary, colon, lung, and brain. CD44 stimulates the invasive ability by interacting with matrix metalloproteinase 14 (MMP14). The expression of MMP14 on the cell surface is thought to trigger multiple proteinase cascades and to stimulate cell migration.
METHODS
A total 54 astrocytoma patients were eligible for this study. We performed a retrospective clinicopathological review and CD44 and MMP14 immunohistochemistry.
RESULTS
The expressions of CD44 and MMP14 were significantly correlated with the World Health Organization (WHO) grade. On univariate analysis, the WHO grade and the expression of CD44 were the significant prognostic factors affecting overall survival (OS) and disease progression free survival (DPFS). On the multivariate analysis by the Cox regression model, the only WHO grade was shown to be a significant independent prognostic factor for predicting the DPFS and OS.
CONCLUSIONS
In this study, the CD44 and MMP14 expressions were related to the WHO grade of astrocytoma. The CD44 expression status was a prognostic factor for DPFS and OS on univariate analysis, but it was not an independent prognostic factor on the multivariate analysis.

Expression Pattern of Tumor Progression and Metastasis-related Gene Proteins - CD44H, CD44v6, erbB-2, and p53 -in Gastric Carcinoma.: Sung Woo Joo, Young Jhoon Chin, Dae Cheol Kim, Gi Yeoung Huh, Sook Hee Hong; Korean J Pathol. 1996;30(9):751-763.

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Abstract PDF: Immunohistochemical studies of the molecules associated with gastric tumor progression and metastasis were done to evaluate their relationship with known prognostic factors and their usefulness in assessment of the progression of gastric carcinoma in 127 gastric carcinoma tissues. The 4 antibodies used in this study were CD44H, CD44v6, erbB-2, and p53. The CD44H expression was detected in 76 (59.8%), CD44v6 in 63 (49.6%), erbB-2 in 18 (14.2%), and mutant p53 in 98 (77.2%) out of 127 cases of gastric carcinomas. There was no significant correlation between the expression rates of each four proteins. The expression rates of all 4 proteins were not significantly correlated with age and sex of the patients and lymph node metastasis, but the correlation between CD44v6 expression and the depth of tumor invasion and tumor stage was significant (p<0.05). These results suggest that CD44v6 is closely associated with tumor invasion, and high levels of CD44H, erbB-2 and p53 are associated with tumorigenesis of the stomach as they are highly expressed in early as well as in advanced gastric carcinomas. The findings also support the conclusion that the loss of control of alternative CD44 mRNA splicing resulted in production of CD44v6 splicing variant in tumor cell facilitates tissue invasion by increased adherence of the tumor cell to an extracellular matrix or by tumor cell migration. It can be expected that CD44v6 overexpression in tumor cells appears to be an important prognostic indicator for gastric tumor progression.

The Significance of the Expression of p53, E-cadherin, nm23, CD44, and Tumor Angiogenesis in Colorectal Adenocarcinoma.: Sung Suk Paeng, Hee Jin Chang, Jung Il Suh; Korean J Pathol. 1997;31(4):314-325.

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Abstract PDF: Many oncogenes and tumor supressor genes have been identified and studied in colorectal carcinoma. Among them, p53 is a tumor supressor gene and its mutation is frequently noted in human tumors. E-cadherin is a cell adhesion molecule and associated with tumor differentiation. CD44 is a cell surface glycoprotein that plays a role in cell migration and metastasis. nm23 is a gene known to lower metastatic potential of tumors and has been proposed to be a metastasis supressor gene. Tumor angiogenesis is required for the expansion of the primary tumor and metastasis and its degree is related to the potential of malignancy. We studied the expression of p53, E-cadherin, nm23, CD44 and tumor angiogenesis in 36 cases of colorectal adenocarcinomas. They were compared with previously known prognostic factors such as the stage, tumor size, depth of invasion, differentiation, presence of lymphatic or venous invasion, the lymph node and distant metastasis. The results were as follows. 1) The expression of p53 was not significantly associated with any prognostic factors. 2) The expression of E-cadherin was significantly associated with tumor differentiation. In the well differentiated adenocarcinomas, its expression was higher than in the poorly differentiated adenocarcinoma. 3) The expression of nm23 was also significantly associated with tumor differentiation. In carcinoma with lymph node metastasis, the expression of nm23 was reduced, but statistically it was not significant. 4) The expression of CD44 was higher in tumors with lymph node metastasis than in tumors without lymph node metastasis, but it was not statistically significant. 5) The degree of microvessel density was significantly associated with lymphatic invasion. According to the above results, the expression of E-cadherin and nm23 are related to the differentiation of the tumor and tumor angiogenesis is related to the lymphatic invasion of the colorectal adenocarcinoma.

The Expression of CD44H and CD44v6 in Gastric Adenocarcinoma.: Myoung Jin Ju, Hae Kyung Lee, Kwang Min Lee, Dong Kyu Chung, Choo Hong Park; Korean J Pathol. 1997;31(4):326-331.

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Abstract PDF: CD44, also known as the Hermes antigen, H-CAM, pgp-1 antigen, and extracellular matrix receptor ECM-III, is a widely distributed integral membrane protein that exists in a variety of forms with different molecular sizes ranging from 85kd to 160kd. A number of evidence implicates CD44 as a cell adhesion molecule with a possible role in tumor progression. To evaluate the possible roles of CD44 in the metastatic process of gastric carcinoma to the regional lymph nodes, we applicated immunohistochemical stains with the CD44H and CD44v6 primary antibodies onto the 2 groups of gastric adenocarcinomas. Each group was comprised of 22 primary tumors extending to the subserosa, and one group showed nodal metastasis, while the other group did not. Seventeen primary tumors (77%) out of the 22 cases with the nodal metastasis demonstrated positivity to the CD44v6, while only 9 primary tumors (41%) out of the 22 cases without nodal metastasis did. However CD44H immunoreactivity was demonstrated in tumor cells of all cases (100%) of both groups as well as in the normal cell components. These results suggest that CD44H form is not related to the metastasis to the regional lymph nodes of gastric carcinoma. However, the expression of CD44v6 seems to play a certain role in the metastatic process of the gastric carcinoma.

Expression of CD44 Splice Variants(v4/5 and v6), alpha-Smooth Muscle Actin, and nm23 Proteins in IB-IIB Uterine Cervical Cancer.: Hee Kyung Chang, Man Ha Huh, Dong Hee Kim, Un Dong Park; Korean J Pathol. 1997;31(6):546-556.

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Abstract PDF: We examined the expressions of CD44 splice variants (v4/5, v6), alpha-smooth muscle actin, nm23 to evaluate their roles as prognostic factors in 70 cases of uterine cervical carcinoma (stage IB to IIB) who were surgically treated from January 1989 to June 1990 with a clinical follow-up of a minimum of 5 years. The expression was examined by an immunohistochemical method using archival formalin fixed paraffin embedded tissue. In the 70 cases, 61 cases were squamous cell carcinoma and 9 cases were adenocarcinoma. CD44v4/5, CD44v6, alpha-smooth muscle actin, and nm23 were detected in 41.4%, 70%, 100%, and 74.3% of tumor samples, respectively. CD44 splice variants and nm23 showed membrane and cytoplasmic staining of tumor cells, respectively. The expression of alpha-smooth muscle actin showed cytoplasmic staining confined to stromal cells and was classified into three grades by the extent in stromal cells: with less than 10% of stromal cells; 32.9%, 10-50% of stromal cells; 40.0%, more than 50%; 27.1%. These expressions were not correlated with histologic types, lymph node involvement, recurrence, and grades of tumor infiltrating lymphocyte (TIL). But CD44v4/5 had significantly inverse correlation with TIL (p=0.049). The expression of CD44v4/5 was significantly correlated with that of CD44v6 (p=0.05), and that of alpha-smooth muscle actin was inversely correlated with that of nm23 (p=0.049). In conclusion, in FIGO IB-IIB uterine cervical carcinoma CD44 variants, nm23, and SMA show high prevalence, however, with little prognostic significance assessed by recurrence and lymph node metastasis.

Prognostic Value of CD44v6 Isoform in Infiltrating Ductal Carcinoma of Breast.: Seung Cheol Lee, Yoon Kyung Sohn, Jung Sik Kwak, Woon Bok Jhung, Jung Wan Kim; Korean J Pathol. 1997;31(7):635-643.

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Abstract PDF: CD44 is a family of transmembrane glycoproteins involved in cell-cell and cell-matrix interactions. Expression of CD44 isofonns (splice variants) has been shown to be associated with poor prognosis in several human cancers. We evaluated the expression patterns of the CD44 isofortn (CD 44 splice variant v6) in infiltrating ductal carcinoma of the breast by immunohistochemical and RT-PCR method. Paraffin embedded blocks from seventy-five cases of mastectomized samples were analyzed immunohistochemically using monoclonoal antibody against CD44v6. CD44v6 was detected in fifty-seven cases (76%) of the tumor samples. Adjacent normal myoepithelial cells and ductal epithelial cells revealed focal positive reaction to CD44v6. Thirtytwo cases (80.0%) with lymph nodal metastasis revealed overexpression of CD44v6 monoclonal antibody, but twenty-five cases (71.4%) without nodal metastasis also showed positive reaction to CD44v6 monoclonal antibody, and there is no statistically significant value. Other prognostic factors of infiltrating ductal carcinoma, such as tumor size, histologic grade and hormonal receptors did not show any significant correlation with CD44v6 expression. The RT-PCR studies for 9 cases of infiltrating ductal carcinoma showed the same band patterns both in the normal and tumor tissues. From the above results, it is concluded that the expression of CD44v6 is not a valuable prognostic marker of infiltrating ductal carcinoma of breast.

A Study of the Correlation between Prognostic Factors of Human Gastric Carcinomas and the Expression of CD44.: Ho Lee, Hyung Chul Kim, Woo Sung Moon, Myoung Jae Kang; Korean J Pathol. 1997;31(9):873-883.

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Abstract PDF: This study was performed to investigate the relationship between CD44 expression and depth of, tumor invasion histopathologic differentiation, tumor size, lymph node metastasis, and proliferating capacity of tumor cells in the gastric carcinoma. In 20 cases of early gastric carcinoma (EGC) and 40 cases of advanced gastric carcinoma (AGC), the immunohistochemical staining for CD44v3, CD44v5, and PCNA gave the following results. 1) In all 60 cases, the positive rates for CD44v3 and CD44v5 were 18.3% and 71.7%, respectively. 2) CD44v5 was expressed in 45% of EGC and 85% of AGC. 3) Larger tumors exhibited higher positive rates for CD44v5. 4) There were 28 cases of lymph node metastases out of 43 cases of CD44v5- positive primary gastric carcinomas (65.1%), and there were 4 cases of lymph node metastases out of 17 CD44v5-negative cases (23.5%). 5) There was no relationship between CD44v5 expression and PCNA index. Because the tumors that exhibit deep invasion, and large in size and have lymph node metastses tend to have more frequent expression of CD44v5, CD44v5 may be one of the useful prognostic markers for gastric carcinoma.

Expression of CD44 in Epithelial Ovarian Tumors.: Kye Weon Kwon, Hee Jeong Ahn, Yoon Jeong Choi, Hee Jae Joo, Nam Hoon Cho; Korean J Pathol. 1998;32(8):596-602.

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Abstract: CD44 is a hyaluronic acid receptor that exists as a standard 90-kd form (CD44H) as well as several CD44 variants isoforms are produced through alternative splicing. Alternatively spliced variants of the CD44 molecule have been found to be associated with invasive and metastatic potential of cancer cells and poor prognosis in several types of carcinoma. The purpose of the present study is to define the expression of CD44H and CD44v6 in ovarian tumors and to investigate whether the expression of these molecules is associated with adverse prognosis. We evaluated the expression of CD44 isoforms in 58 ovarian tumors by means of immunohistochemistry, and correlated between CD44 expression and the histologic types, tumor grade, peritoneal implants, pseudomyxoma peritonei and FIGO stage. While the CD44H was commonly expressed in ovarian tumors, the CD44v6 was expressed in a minor proportion of serous tumors in comparison with frequent expression of v6 isoform in mucinous tumors. The CD44H expression was significantly higher in stage I/II than in stage III. However, there was no correlation between the expression of CD44 and the presence of peritoneal implants or pseudomyxoma peritonei. These results suggest that CD44H could play an important role in the adhesive function in the lower stage of the ovarian tumor and reduced expression in the higher stage might be related to the metastasis and widespread invasion of ovarian carcinoma cells.

Expression of Cell Adhesion Molecules -CD44H and CD44v6- in Colorectal Carcinoma.: Dae Cheol Kim, Seo Hee Rha, Jin Sook Jeong, Sook Hee Hong; Korean J Pathol. 1998;32(9):655-662.

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Abstract: During tumor progression, a subset of cells acquires metastatic properties, presumably through a series of genetic alterations. As the result, cells detach from the primary tumor, penetrate the basement membrane and invade the adjacent structures including lymph and blood vessels. Loss of adhesive functions and gain of new adhesive functions are thought to play a crucial role in this metastatic cascade. Since tumor metastasis is the principle cause of death for cancer patients including colon cancer, there is a consensus that a search for tools that allow effective assessment of the metastatic potential of tumors is a prime goal for cancer research. An immunohistochemical study of cell adhesion molecules, CD44H and its variant CD44v6, was done to evaluate their relationship with known prognostic factors related to the progression and metastasis of colorectal carcinoma in 94 cases of colorectal carcinoma tissues. The results were as follows. The CD44H expression was detected in 90 (95.7%) and CD44v6 in 53 (56.4%) out of 94 cases of colorectal carcinoma, and the CD44H was overexpressed in tumor tissue more than in normal mucosa in 62% of the cases. The expression rates of both protein were not significantly correlated with age and sex of the patients, invasion depth, lymph node metastasis, tumor differentiation, and tumor site. The coexpression of CD44H and CD44v6 in tumor was significant (p<0.05). The above results suggest that overexpression of CD44H and loss of function to control the alternative splicing of CD44 mRNA resulting in CD44v6 expression and alteration of adhesive function are closely associated with tumorigenesis of the colorectum.

Expression of CD44 Splicing Variants v4/5 and v6 in Gastric Adenocarcinoma and Its Relationship with Prognostic Factors.: Lee So Maeng, Hae Kyung Lee, Byung Kee Kim, Eun Jung Lee; Korean J Pathol. 2000;34(2):119-124.

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Abstract PDF: CD44, an integral membrane glycoprotein expressed by many cell types, serves as the principal transmembrane hyaluronate receptor and may be a determinant of metastatic and invasive behavior in carcinomas. This study was performed to investigate the relationship between CD44 splicing variants v4/5 and v6 expression and histopathologic prognostic factors (depth of tumor invasion, histologic classification, vascular and lymphatic invasion, and lymph node metastasis) in 107 gastric adenocarcinomas. In 107 cases of gastric carcinoma, the immunohistochemical stainining for CD44 v4/5 and CD44 v6 gave the following results. CD44 v4/5 was expressed in 40.2% and CD44 v6 in 67.3% of gastric carcinomas. The expression of CD44 v4/5 was correlated with histologic classification by Lauren (p<0.05), lymphatic invasion (p<0.05), and lymph node metastasis (p<0.004). In contrast, expression of CD44 v6 had no impact on prognostic markers. This study suggests the role of CD44 v4/5 in invasion, metastasis, and its prognostic significance in gastric adenocarcinoma.

Expression of CD44v6 Protein in the Progression of Colorectal Carcinomas.: Eunhee Lee, Kyoung Mee Kim, Anhi Lee, Byung Kee Kim; Korean J Pathol. 2000;34(9):636-641.

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Abstract PDF: During tumor progression, a subset of cells acquires metastatic properties, presumably through a series of genetic alterations. CD44 variant glycoproteins containing sequences encoded by exon v6 are related to tumor progression of human colorectal cancer. But their expression in normal colonic epithelium is controversial and studies of CD44 on each step of colorectal carcinogenesis are scanty. We studied CD44v6 expression in the normal colonic mucosa, adenoma, carcinoma in situ, and invasive colorectal carcinomas of different Astler-Coller stages. Endoscopically or surgically resected 36 normal colonic mucosa, 19 adenomas, 8 cases of carcinoma in situ, and 25 cases of carcinoma were selected. After immunohistochemical stain with CD44v6 antibody, positivity was graded as 0 to 4 based on the estimated percentage of positively stained tumor cells. The intensity of positive staining cells was also graded as 0 to 3. In all but one cases (97.2%), normal colorectal mucosa was negative for CD44v6. Positive rates in adenoma, carcinoma in situ, Astler-Coller stage A/B and C/D carcinoma were 73.6%, 88.9% and 87.5%, respectively. There was no statistically significant difference in the positivity between these groups. The staining intensity was significantly higher in the cases of stage C/D carcinoma group than those of adenomas (p<0.05). The percentage of positivity for CD44v6 was higher in stage C/D carcinoma group than adenoma, carcinoma in situ, and stage A/B carcinoma group (p<0.05). Expression of CD44v6 in the normal colonic mucosa was extremely rare and the positivity was increased according to the progression of colorectal tumors. Furthermore, it is more important to interpret the CD44v6 positivity according to the estimated percentage of positively stained tumor cells.

Preferential Expression of CD44 in Thyroid Papillary Carcinoma.: jung Yeon Kim, Jinye Yoo, Hyejae Cho; Korean J Pathol. 2001;35(4):314-318.

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Abstract PDF: BACKGROUND
Papillary carcinoma is one of the most common malignant thyroid tumors and an important prognostic factor is the lymph node status. CD44 is a cell adhesion molecule and is associated with metastasis. The purpose of this study was to discover whether CD44 is valuable in the diagnosis of the papillary carcinoma, and whether Ki-67 and p53 are correlated with CD44 in the papillary carcinoma.
METHODS
We studied CD44, Ki-67 and p53 expressions in 34 cases of formalin-fixed paraffin embedded papillary thyroid carcinomas, and 20 cases of the follicular neoplasm using mouse anti-CD44 (H-CAM), Ki-67 and p53 monoclonal antibodies. RESULTS: Most of the papillary carcinomas expressed diffuse and intense membrane staining of CD44 (32/34 cases, 94.1%). Focal scattered immunoreactivity was observed in the follicular neoplasm (8/20 cases, 40.0%). The staining patterns of CD44 were similar in both follicular adenoma and carcinoma. Both groups with or without lymph node metastasis showed similar expression patterns for CD44. There were no differences in Ki-67 and p53 staining between papillary carcinomas and follicular neoplasms.
CONCLUSIONS
The result shows that papillary carcinomas preferentially display the CD44 antigen, and it is a useful diagnostic tool in the equivocal cases. There is no correlation among CD44, Ki-67 and p53 expressions in the papillary carcinoma.

Expressions of CD44s Is Associated with the Expression of Cyclooxygenase-2 in Non-Small Cell Lung Cancers.: Sung Jig Lim, Hyun Jung Kim, Jung Yeon Kim, Kyeongmee Park; Korean J Pathol. 2006;40(1):17-23.

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Abstract PDF: BACKGROUND
The overexpression of Cox-2 in tumors is important for tumor invasion, angiogenesis, resistance to apoptosis and the suppression of host immunity. Moreover, a tumor's CD44 expression plays an important role in tumor invasion and metastasis. We examined the expression of COX-2 and also CD44 and its variants as well as the biological implications and relationship between Cox-2 and the CD44 variants in non-small cell lung carcinoma.
METHODS
The expressions of Cox-2 and also CD44s and its variants (CD44v3 and CD44v6) were examined by performing immunohistochemistry on 98 surgical specimens.
RESULTS
The expressions of CD44s, CD44v3 and CD44v6 were significantly more frequent in squamous cell carcinoma specimens than in the adenocarcinoma (CD44s, p=0.033; CD44v3, p=0.007; CD44v6, p=0.022). The loss of CD44s and CD44v3 were significantly correlated with poor tumor differentiation (CD44s, p=0.03; CD44v3, p=0.011). Patients with Cox-2 positive-adenocarcinoma tumors had a significantly worse cumulative survival than did those adenocarcinoma patients without the Cox-2 (p=0.048). The expression of Cox-2 was significantly associated with the CD44s expression in non-small cell lung cancer, and especially in squamous cell carcinoma.
CONCLUSIONS
These findings suggest that expression of CD44s is associated with the expression of Cox-2 in NSCLC, and especially squamous cell carcinoma.

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