Dear Editor,
A very important issue was assessed by Yang et al in their
outstanding study recently published by this journal1. As pointed out by
the authors, distant metastasis is the most preoccupant complication of
differentiated thyroid carcinoma (DTC) and a very anguishing therapeutic
challenge for the attending physician. A series of studies have been
trying to establish a molecular pattern able to predict more aggressive
follicular cell behavior. One of the most promissory markers integrating
this molecular pattern is the expression of neural cell adhesion molecules
(NCAM).
Yang et al studied a series of 365 surgical cases of thyroid disease
- 214 DTC and 151 benign lesions. Immunohistochemistry showed that most
benign lesions presented NCAM expression, whereas a significant proportion
of DTC lost completely or showed a reduced NCAM expression, which confirms
previous results suggesting that NCAM could be a diagnostic marker of DTC
2. We also studied NCAM expression in a series of 527 surgical cases of
thyroid tissues - 395 DTC (343 papillary thyroid carcinomas and 52
follicular carcinomas) and 132 nonmalignant thyroid tissues (18 normal
thyroids, 58 goiters and 56 adenomas). One hundred fifty-three of our
patients presented metastasis at diagnostic and 58 developed distant
metastasis during a follow-up of 12-298 months (43.50?33.29 months), Mo=21
months. NCAM expression was evaluated by immunohistochemistry and the same
technique used by Yang et al, but with anti-NCAM monoclonal 123C3 clone
antibody (DAKO- Carpenteria, CA, USA). We also considered NCAM positive
those cases with NCAM expression in more than 30% of tumor cells. Fisher's
exact test showed total loss or reduction of NCAM expression in 74.65% of
DTC cases, while a significant portion (52.73%) of benign lesions were
positive for NCAM (p< 0.0001). However, NCAM expression was not able to
predict malignancy due to low sensibility (25.35%) and low specificity
(47.27%), suggesting that NCAM alone is not a useful diagnostic marker.
In addition, Yang et al found that persistent NCAM expression in DTC
is associated with a higher rate of metastasis. In our cohort, NCAM
expression was not correlated with the presence of metastasis at diagnosis
(p=0.4506), neither to tumor size (p=0.3814) nor to extrathyroid invasion
(p=0.9855), multifocality (p=0.2747) or pTNM stage (p=0.6928). A log-rank
test failed to show NCAM expression as a prognostic marker of relapse-free
survival (p=0.8846). Nevertheless, NCAM positivity was more frequent in
encapsulated tumors (37.78%) than in nonencapsulated tumors (20.62%;
p=0.0399), suggesting that the peritumoral fibrotic reaction is associated
with NCAM expression. In fact, 51.11% of our NCAM positive cases presented
concurrent chronic lymphocytic thyroiditis (CLT), while only 25.89% of
NCAM negative cases presented concurrent CLT (p=0.0045). We also evaluated
the presence of tumor infiltrating lymphocytes (TIL) in DTC specimens by a
routine HE staining. We found that NCAM expression was associated with the
presence of TIL (p=0.0427). In order to distinguish TIL subsets, we
performed immunohistochemical analysis using classical immune cell
markers. We observed that NCAM expression was associated with the presence
of CD4+ lymphocytes (p=0.0477), CD8+ lymphocytes (p=0.0015), CD20+
lymphocytes (p=0.0284) and FoxP3+ lymphocytes (p=0.0024). Interestingly,
most NCAM negative cases (80.10%) were also negative for sodium/iodine
symporter (NIS) protein immunohistochemical expression, whereas 71.43% of
NCAM positive cases were positive for NIS as well (p< 0.0001),
suggesting that NCAM could boost immunogenicity in DTC. These results
suggest that NCAM expression is engaged in the antitumor immune response.
However, the outcome of patients is not modified by NCAM expression,
perhaps because an appropriate management of DTC patient is the most
important and modifiable prognostic factor, impeding the natural course of
malignancy.
The differences between Yang results and our data could be related to
different population backgrounds, which are thought to affect antitumor
immunity in DTC 3. Since the tumorigenic process is a complex biological
system in which multiple molecular interactions may occur, minimum genetic
differences in populations might affect dramatically the obtained results.
An antitumor effect of NCAM may be expected in cases presenting genetic
background that facilitates antitumor immune defense 3-4. We also cannot
exclude that the different antibody used may lead to different results. In
addition, it is worthy noting that NCAM may be engaged in pleiotropic
functions in tumor progression, making the interpretation of NCAM
expression a difficult task. More studies are warranted to understand the
functional biologic role of NCAM expression in DTC tumors.
Unfortunately, our data do not support the conclusion of Yang et al that
NCAM expression in well differentiated thyroid carcinoma is an indicator
for a higher risk of distant metastasis.
Sincerely,
Lucas Leite Cunha1, Elaine Cristina Morari2, Suely Nonogaki3,
Fernando Augusto Soares4, Jose Vassallo5, and Laura Sterian Ward1.
1Laboratory of Cancer Molecular Genetics, Faculty of Medical Sciences
- University of Campinas (Unicamp). 126 Tessalia Vieira de Camargo Street,
Campinas, SP, Brazil.
2Department of biological sciences and health- State University of
Roraima. 231, Sete de Setembro Street, Boa Vista, Roraima, Brazil.
3. Adolfo Lutz Institute. 355, Doutor Arnaldo Avenue, S?o Paulo,
Brazil.
4Department of Pathology, A. C. Camargo Cancer Hospital. 211 Antonio
Prudente Street, S?o Paulo, SP, Brazil.
5Laboratory of Investigative and Molecular Pathology (Ciped), Faculty
of Medical Sciences - University of Campinas (Unicamp). 126, Tessalia
Vieira de Camargo Street, Campinas, SP, Brazil.
REFERENCES
1. Yang AH, Chen JY, Lee CH. Expression of NCAM and OCIAD1 in well-
differentiated thyroid carcinoma: correlation with the risk of distant
metastasis. J Clin Pathol 2011;
2. El Demellawy D, Nasr AL, Babay S, Alowami S. Diagnostic utility of
CD56 immunohistochemistry in papillary carcinoma of the thyroid. Pathol
Res Pract 2009;205:303-9.
3. Cunha LL, Tincani AJ, Assumpcao LV, Soares FA, Vassallo J, Ward
LS. Interleukin-10 but not interleukin-18 may be associated with the
immune response against well-differentiated thyroid cancer. Clinics (Sao
Paulo) 2011;66:1203-8.
4. Scarpino S, Di Napoli A, Melotti F, Talerico C, Cancrini A, Ruco
L. Papillary carcinoma of the thyroid: low expression of NCAM (CD56) is
associated with downregulation of VEGF-D production by tumour cells. J
Pathol 2007;212:411-9.
Conflict of Interest:
None declared
Dear Editor,
A very important issue was assessed by Yang et al in their outstanding study recently published by this journal1. As pointed out by the authors, distant metastasis is the most preoccupant complication of differentiated thyroid carcinoma (DTC) and a very anguishing therapeutic challenge for the attending physician. A series of studies have been trying to establish a molecular pattern able to predict more aggressive follicular cell behavior. One of the most promissory markers integrating this molecular pattern is the expression of neural cell adhesion molecules (NCAM).
Yang et al studied a series of 365 surgical cases of thyroid disease - 214 DTC and 151 benign lesions. Immunohistochemistry showed that most benign lesions presented NCAM expression, whereas a significant proportion of DTC lost completely or showed a reduced NCAM expression, which confirms previous results suggesting that NCAM could be a diagnostic marker of DTC 2. We also studied NCAM expression in a series of 527 surgical cases of thyroid tissues - 395 DTC (343 papillary thyroid carcinomas and 52 follicular carcinomas) and 132 nonmalignant thyroid tissues (18 normal thyroids, 58 goiters and 56 adenomas). One hundred fifty-three of our patients presented metastasis at diagnostic and 58 developed distant metastasis during a follow-up of 12-298 months (43.50?33.29 months), Mo=21 months. NCAM expression was evaluated by immunohistochemistry and the same technique used by Yang et al, but with anti-NCAM monoclonal 123C3 clone antibody (DAKO- Carpenteria, CA, USA). We also considered NCAM positive those cases with NCAM expression in more than 30% of tumor cells. Fisher's exact test showed total loss or reduction of NCAM expression in 74.65% of DTC cases, while a significant portion (52.73%) of benign lesions were positive for NCAM (p< 0.0001). However, NCAM expression was not able to predict malignancy due to low sensibility (25.35%) and low specificity (47.27%), suggesting that NCAM alone is not a useful diagnostic marker.
In addition, Yang et al found that persistent NCAM expression in DTC is associated with a higher rate of metastasis. In our cohort, NCAM expression was not correlated with the presence of metastasis at diagnosis (p=0.4506), neither to tumor size (p=0.3814) nor to extrathyroid invasion (p=0.9855), multifocality (p=0.2747) or pTNM stage (p=0.6928). A log-rank test failed to show NCAM expression as a prognostic marker of relapse-free survival (p=0.8846). Nevertheless, NCAM positivity was more frequent in encapsulated tumors (37.78%) than in nonencapsulated tumors (20.62%; p=0.0399), suggesting that the peritumoral fibrotic reaction is associated with NCAM expression. In fact, 51.11% of our NCAM positive cases presented concurrent chronic lymphocytic thyroiditis (CLT), while only 25.89% of NCAM negative cases presented concurrent CLT (p=0.0045). We also evaluated the presence of tumor infiltrating lymphocytes (TIL) in DTC specimens by a routine HE staining. We found that NCAM expression was associated with the presence of TIL (p=0.0427). In order to distinguish TIL subsets, we performed immunohistochemical analysis using classical immune cell markers. We observed that NCAM expression was associated with the presence of CD4+ lymphocytes (p=0.0477), CD8+ lymphocytes (p=0.0015), CD20+ lymphocytes (p=0.0284) and FoxP3+ lymphocytes (p=0.0024). Interestingly, most NCAM negative cases (80.10%) were also negative for sodium/iodine symporter (NIS) protein immunohistochemical expression, whereas 71.43% of NCAM positive cases were positive for NIS as well (p< 0.0001), suggesting that NCAM could boost immunogenicity in DTC. These results suggest that NCAM expression is engaged in the antitumor immune response. However, the outcome of patients is not modified by NCAM expression, perhaps because an appropriate management of DTC patient is the most important and modifiable prognostic factor, impeding the natural course of malignancy.
The differences between Yang results and our data could be related to different population backgrounds, which are thought to affect antitumor immunity in DTC 3. Since the tumorigenic process is a complex biological system in which multiple molecular interactions may occur, minimum genetic differences in populations might affect dramatically the obtained results. An antitumor effect of NCAM may be expected in cases presenting genetic background that facilitates antitumor immune defense 3-4. We also cannot exclude that the different antibody used may lead to different results. In addition, it is worthy noting that NCAM may be engaged in pleiotropic functions in tumor progression, making the interpretation of NCAM expression a difficult task. More studies are warranted to understand the functional biologic role of NCAM expression in DTC tumors. Unfortunately, our data do not support the conclusion of Yang et al that NCAM expression in well differentiated thyroid carcinoma is an indicator for a higher risk of distant metastasis.
Sincerely,
Lucas Leite Cunha1, Elaine Cristina Morari2, Suely Nonogaki3, Fernando Augusto Soares4, Jose Vassallo5, and Laura Sterian Ward1.
1Laboratory of Cancer Molecular Genetics, Faculty of Medical Sciences - University of Campinas (Unicamp). 126 Tessalia Vieira de Camargo Street, Campinas, SP, Brazil.
2Department of biological sciences and health- State University of Roraima. 231, Sete de Setembro Street, Boa Vista, Roraima, Brazil.
3. Adolfo Lutz Institute. 355, Doutor Arnaldo Avenue, S?o Paulo, Brazil.
4Department of Pathology, A. C. Camargo Cancer Hospital. 211 Antonio Prudente Street, S?o Paulo, SP, Brazil.
5Laboratory of Investigative and Molecular Pathology (Ciped), Faculty of Medical Sciences - University of Campinas (Unicamp). 126, Tessalia Vieira de Camargo Street, Campinas, SP, Brazil.
REFERENCES
1. Yang AH, Chen JY, Lee CH. Expression of NCAM and OCIAD1 in well- differentiated thyroid carcinoma: correlation with the risk of distant metastasis. J Clin Pathol 2011;
2. El Demellawy D, Nasr AL, Babay S, Alowami S. Diagnostic utility of CD56 immunohistochemistry in papillary carcinoma of the thyroid. Pathol Res Pract 2009;205:303-9.
3. Cunha LL, Tincani AJ, Assumpcao LV, Soares FA, Vassallo J, Ward LS. Interleukin-10 but not interleukin-18 may be associated with the immune response against well-differentiated thyroid cancer. Clinics (Sao Paulo) 2011;66:1203-8.
4. Scarpino S, Di Napoli A, Melotti F, Talerico C, Cancrini A, Ruco L. Papillary carcinoma of the thyroid: low expression of NCAM (CD56) is associated with downregulation of VEGF-D production by tumour cells. J Pathol 2007;212:411-9.
Conflict of Interest:
None declared