Abstract
OBJECTIVE:
Ovarian mucinous metastases commonly present as the first sign of the disease and are capable of simulating primary tumors. Our aim was to investigate the role of intratumoral lymphatic vascular density together with other surgical-pathological features in distinguishing primary from secondary mucinous ovarian tumors.
METHODS:
A total of 124 cases of mucinous tumors in the ovary (63 primary and 61 metastatic) were compared according to their clinicopathological features and immunohistochemical profiles. The intratumoral lymphatic vascular density was quantified by counting the number of vessels stained by the D2-40 antibody.
RESULTS:
Metastases occurred in older patients and were associated with a higher proportion of tumors smaller than 10.0 cm; bilaterality; extensive necrosis; extraovarian extension; increased expression of cytokeratin 20, CDX2, CA19.9 and MUC2; and decreased expression of cytokeratin 7, CA125 and MUC5AC. The lymphatic vascular density was increased among primary tumors. However, after multivariate analysis, the best predictors of a secondary tumor were a size of 10.0 cm or less, bilaterality and cytokeratin 7 negativity. Lack of MUC2 expression was an important factor excluding metastasis.
CONCLUSIONS:
The higher intratumoral lymphatic vascular density in primary tumors when compared with secondary lesions suggests differences in the microenvironment. However, considering the differential diagnosis, the best discriminator of a secondary tumor is the combination of tumor size, laterality and the pattern of expression of cytokeratin 7 and MUC2.
Mucinous Ovarian Tumors; Ovarian Metastasis; Lymphatic Vascular Density; D2-40; Immunohistochemistry
INTRODUCTION
Malignant epithelial tumors account for 90% of all ovarian cancers and are the most
lethal gynecological neoplasia (11. D'Angelo E, Prat J. Classification of ovarian carcinomas
based on pathology and molecular genetics. Clin Transl Oncol. 2010;12(12):783-7,
http://dx.doi.org/10.1007/s12094-010-0599-0.
http://dx.doi.org/10.1007/s12094-010-059...
). Primary
mucinous tumors are not as frequent as serous tumors and account for 10-15% of all
ovarian neoplasms. Approximately 80% are benign (adenomas), 10-12% are borderline
and only 3-4% correspond to primary ovarian carcinomas (11. D'Angelo E, Prat J. Classification of ovarian carcinomas
based on pathology and molecular genetics. Clin Transl Oncol. 2010;12(12):783-7,
http://dx.doi.org/10.1007/s12094-010-0599-0.
http://dx.doi.org/10.1007/s12094-010-059...
). This last value was estimated after the recognition and
exclusion of metastatic carcinomas simulating primary tumors in the ovaries (22. Prat J. Ovarian carcinomas, including secondary tumors:
diagnostically challenging areas. Mod Pathol. 2005;18 Suppl 2:S99-111,
http://dx.doi.org/10.1038/modpathol.3800312.
http://dx.doi.org/10.1038/modpathol.3800...
,33. Young RH. From krukenberg to today: the ever present problems
posed by metastatic tumors in the ovary: part I. Historical perspective, general
principles, mucinous tumors including the krukenberg tumor. Adv Anat Pathol.
2006;13(5):205-27,
http://dx.doi.org/10.1097/01.pap.0000213038.85704.e4",-1,"xxx/85704.e4.
http://dx.doi.org/10.1097/01.pap.0000213...
).
Secondary mucinous carcinomas in the ovaries can mimic primary ovarian carcinomas
and even borderline tumors (44. McCluggage WG, Wilkinson N. Metastatic neoplasms involving the
ovary: a review with an emphasis on morphological and immunohistochemical
features. Histopathology. 2005;47(3):231-47,
http://dx.doi.org/10.1111/j.1365-2559.2005.02194.x.
http://dx.doi.org/10.1111/j.1365-2559.20...
). The most
common sources of secondary tumors are the colorectum, breast, stomach, endometrium,
appendix, endocervix, pancreas and bile ducts (55. Leen SL, Singh N. Pathology of primary and metastatic mucinous
ovarian neoplasms. J Clin Pathol. 2012;65(7):591-5,
http://dx.doi.org/10.1136/jclinpath-2011-200162.
http://dx.doi.org/10.1136/jclinpath-2011...
). Primary mucinous ovarian carcinomas are therefore rare, generally
unilateral and larger than 13 cm (44. McCluggage WG, Wilkinson N. Metastatic neoplasms involving the
ovary: a review with an emphasis on morphological and immunohistochemical
features. Histopathology. 2005;47(3):231-47,
http://dx.doi.org/10.1111/j.1365-2559.2005.02194.x.
http://dx.doi.org/10.1111/j.1365-2559.20...
,66. Yemelyanova AV, Vang R, Judson K, Wu LS, Ronnett BM. Distinction
of primary and metastatic mucinous tumors involving the ovary: analysis of size
and laterality data by primary site with reevaluation of an algorithm for tumor
classification. Am J Surg Pathol. 2008;32(1):128-38.). Despite the refined diagnostic criteria and
current ancillary techniques, particularly the coordinated expression of
cytokeratins 7 and 20 (77. Vang R, Gown AM, Barry TS, Wheeler DT, Yemelyanova A, Seidman JD,
et al. Cytokeratins 7 and 20 in primary and secondary mucinous tumors of the
ovary: analysis of coordinate immunohistochemical expression profiles and
staining distribution in 179 cases. Am J Surg Pathol.
2006;30(9):1130-9.), the problem of
distinguishing primary from metastatic carcinomas persists in at least 15% of
mucinous ovarian tumors.
Epithelial ovarian tumors present a variable stromal component that is particularly remarkable among those of the mucinous subtype. The most striking example is the Krukenberg tumor, which exhibits a unique cellular stroma. During cancer development, the stroma is remodeled to support cancer cell proliferation, migration, invasion, or metastasis. Lymphatic vessels are an important component of intratumoral stroma and are also responsible for creating conduits for tumor metastasis.
To the best of our knowledge, no studies have compared the intratumoral lymphatic vascular density (LVD) between primary and secondary mucinous ovarian tumors as a means of distinguishing between these tumors. Therefore, we proposed to investigate a potential role for LVD in the differential diagnosis of borderline and malignant mucinous ovarian tumors via the quantification of lymphatic vessels identified by podoplanin expression.
MATERIALS AND METHODS
Selection of cases
Cases of mucinous tumors in the ovary were identified from the surgical pathology files of the Division of Pathology of Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (São Paulo/SP) and from Consultoria em Patologia (Botucatu/SP), which is a private reference pathology laboratory. We included cases with borderline and malignant mucinous histologies for which the following were available: information about the primary site, paraffin blocks and at least one representative histologic section taken from each centimeter of the tumor. A total of 124 cases from 1996 to 2005 (Universidade de São Paulo) and from 2004 to 2011 (Consultoria em Patologia) met the inclusion criteria. The distribution of these cases according to their diagnosis and the primary site is shown in Table 1. The age of this cohort ranged from 16 to 81 years (50.2±15.8 years). From both the pathology report and the surgery description, we obtained information about laterality, tumor size and extraovarian extension, including the presence of pseudomyxoma. Slides from all cases were reviewed by two pathologists (BGLA and CRF). Doubtful cases were analyzed under a dual-head microscope by a third pathologist (FMC). The tumors were classified according to the presence and type of stromal invasion (infiltrative/destructive, multinodular and expansive/confluent) (Figure 1), cellular type (Mullerian, intestinal, pyloric, gastrointestinal, mixed Mullerian/intestinal and indeterminate) (Figure 2), histologic grade according to the Silverberg System (88. Silverberg SG. Histopathologic grading of ovarian carcinoma: a review and proposal. Int J Gynecol Pathol. 2000;19(1):7-15.), necrosis extension (focal, less than 50% or more than 50%) and peritumoral vascular involvement.
Patterns of invasion in two mucinous adenocarcinomas: infiltrative/destructive (A) and confluent with nodular configuration (B).
Mucinous carcinomas with intestinal (A), Mullerian (B) and gastric (C) phenotypes. Focal cytokeratin 7 expression in a metastatic mucinous carcinoma is shown.
The cases were grouped as primary (Group 1) and secondary (Group 2) tumors. Primary tumors were borderline tumors without associated pseudomyxoma and adenocarcinomas without clinical or surgical suspicions of other neoplasia. Among the secondary tumors, we included borderline tumors associated with pseudomyxoma peritonei and adenocarcinomas with a known primary mucinous carcinoma at another site with a morphology similar to that of the ovarian tumor. Sixty-three tumors were classified as primary ovarian tumors and 61 tumors were classified as secondary ovarian tumors. We selected a representative area of the tumor for tissue microarray (TMA) construction and immunohistochemical study.
Tissue microarray construction
TMA construction was conducted at the Consultoria em Patologia (Botucatu, SP). Representative areas were identified on slides stained with hematoxylin and eosin and marked on paraffin blocks. Cylindrical tissues with a diameter of 2.0 mm were punched from the areas of interest of the donor paraffin block and mounted into the recipient block with 1.0-mm intervals between the cores using a precision microarray instrument (Beecher Instruments, Silver Spring, MD) positioned on a fixed sideboard. The cores were organized in lines and columns using the hepatic tissue for orientation in Position 1A. After a final configuration of the recipient blocks, they were heated at 60°C for 10 minutes and sealed with the Paraffin Tape-Transfer System (Instrumedics, St. Louis, MO) for sectioning using the appropriate slides (Starfrost¯ slides) and a microtome at 3-μm intervals (Leica Instruments, Wetzlar, Germany). The first histological sections were stained with hematoxylin-eosin to identify losses for eventual study in whole sections.
Immunohistochemical analysis
Immunohistochemical detection of cytokeratin 7 (CK7), cytokeratin 20 (CK20), CA125, CDX-2, CA19.9, MUC2, MUC5AC and podoplanin was performed using slides from TMA blocks. The sources and dilutions of the antibodies as well as the epitope retrieval methods used are listed in Table 2. Bound antibodies were detected using Novolink¯ (Leica, Bannockburn, IL, USA). For all the markers, with the exception of podoplanin, any percentage of unequivocally positive neoplastic cells was scored as positive for the markers, although all the positive cases showed more than 10% stained cells. Identification of lymphatic vessels was established based on the presence of cells that were positive for podoplanin and that had a morphology consistent with vessel structure (Figure 3). In tumor sections that were negative for podoplanin staining, adjacent lymphatic endothelial cells that appeared normal served as positive internal controls.
Mucinous ovarian tumor showing ten lymphatic vessels identified by podoplanin staining using the D2-40 antibody (original magnification 200X).
Quantification of lymphatic vascular density
The quantification of LVD was performed as previously described by our group
(99. Zaganelli FL, Carvalho FM, Almeida BG, Bacchi CE, Goes JC, Calil
MA, et al. Intratumoral lymphatic vessel density and clinicopathologic features
of patients with early-stage cervical cancer after radical hysterectomy.
Int J Gynecol Cancer. 2010;20(7):1225-31.
10. Goes RS, Carvalho JP, Almeida BG, Bacchi CE, Goes JC, Calil MA,
et al. Intratumoral lymphatic vessel density in vulvar squamous cell carcinomas:
a possible association with favorable prognosis. Int J Gynecol Pathol.
2012;31(1):8-14.-1111. Kawamura L, Carvalho FM, Alves BG, Bacchi CE, Goes JC, Calil MA,
et al. Association between intratumoral lymphatic microvessel density (LMVD) and
clinicopathologic features in endometrial cancer: a retrospective cohort study.
World J Surg Oncol. 2010;8:89.). Briefly, stained TMA histologic sections were analyzed using
standard light microscopy (Nikon, Eclipse 200). Under low magnification, the
most vascularized intratumoral areas were identified. We counted the number of
immunostained lymphatic vessels found in 10 “hot spot” areas at
400X magnification. The LVD for each case was expressed by the mean value (total
number of vessels in 10 hot spot microscopic fields/10). The median of all the
mean LVD values was the cutoff used to divide tumors into high or low LVD, as
suggested by Hall et al. (1212. Hall FT, Freeman JL, Asa SL, Jackson DG, Beasley NJ.
Intratumoral lymphatics and lymph node metastases in papillary thyroid
carcinoma. Arch Otolaryngol Head Neck Surg. 2003;129(7):716-9,
http://dx.doi.org/10.1001/archotol.129.7.716.
http://dx.doi.org/10.1001/archotol.129.7...
).
Statistical analysis
A t-test was used to compare the ages of patients in Group 1 (primary tumors) and Group 2 (secondary tumors) after confirmation of a normal distribution by the Kolmogorov-Smirnov test. The Chi-square test was used to evaluate the association of the categorical variables within the two groups. The odds ratio with a 95% confidence interval was calculated for these variables. LVD was analyzed either as a dichotomous variable or as a continuous variable. The median (0.8) value was the cut-off used to determine low or high LVD. Continuous LVD values were compared between primary and secondary tumors using the Mann-Whitney U test. The correlation between continuous LVD and tumor size was tested using Spearman's rank correlation. For multivariate analysis, the selected variables were analyzed with logistic regression using the stepwise method. Statistical analyses were performed using MedCalc for Windows (version 11.5.0.0; MedCalc Software, Mariakerke, Belgium), and p-values less than 0.05 were considered significant.
Ethics statement
This study was approved by the Scientific Committee of the Department of Pathology of the Faculdade de Medicina da Universidade de São Paulo and by the Ethics Committee for Research Projects of the Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (Comissão de Ética para Análise de Pesquisa - CAPPesq) (process number 1312/09).
RESULTS
Patients with primary tumors were younger than those with secondary tumors, with mean values of 46.3 years and 54.0 years, respectively (p = 0.007). Sixty-seven (54.03%) of the cases exhibited an intestinal phenotype and only 7 (5.6%) presented pure Mullerian differentiation. Other tumors presented the following morphological phenotypes: 10 (8.06%) pyloric, 19 (15.32%) pyloric and intestinal, 7 (5.64%) mixed Mullerian and intestinal and 14 (11.29%) indeterminate. All tumors with diffuse or partial Mullerian differentiation were primary. Among the 93 cases with a diffuse or partial intestinal pattern, 42 (45.1%) were primary and 51 (54.8%) were secondary. Peritumoral vascular invasion was observed in only three cases, all of which were secondary tumors. The LVD values ranged from 0 to 10.1 (1.6±2.0). There was no correlation between tumor size and LVD (rho = 0.88; p = 0.89) or between age and LVD (rho = 0.04). The LVD was lower in secondary tumors (median 0.4 vs. 1.5; p = 0.02). The surgical-pathological characteristics of Groups 1 and 2 are presented in Table 3. Smaller and bilateral tumors, extensive tumoral necrosis and a surgical finding of extraovarian disease were associated with a higher probability of secondary ovarian involvement. High-grade invasive adenocarcinomas with multinodular patterns of ovarian parenchyma invasion had a higher probability of being metastatic. The comparative immunohistochemical study between primary and secondary tumors is shown in Table 3. Secondary tumors were mainly associated with the expression of CK20, CDX-2 and MUC2 and were negatively associated with a high LVD and the expression of CK7, CA125 and MUC5AC.
We constructed a logistic regression model including the patients' age, tumor size and laterality as predictors of a secondary tumor. The age of the patient was excluded from the model. Next, we tested a model with tumor size, laterality and all the immunohistochemical markers (CK7, CK20, CDX-2, CA125, CA19.9, MUC2 and MUC5AC). The variables that remained in the model were tumor size, laterality, CK7 and MUC2. Finally, we tested the LVD with these variables in a new model; however, LVD was excluded. The final model identified a tumor size of 10.0 cm or less (OR 9.4; 95% CI 1.2-69.2), bilaterality (OR 51.5; 95% CI 7.1-370.2) and CK7 negativity (OR 64.8; 95% CI 9.4-447) as predictors of a secondary deposit. The probability of a secondary tumor in this model is reduced if MUC2 is negative (OR 0.1; 95% CI 0.01-0.6). This model allows 90.0% of all cases to be classified correctly, including 92.2% of primary tumors and 86.2% of metastases.
DISCUSSION
Ovarian metastases commonly present as the first sign of many adenocarcinomas,
including (but not limited to) gastrointestinal adenocarcinomas, with the primary
tumor remaining undiagnosed (1313. Vang R, Ronnett BM. Distinction of primary ovarian mucinous
tumors and mucinous tumors metastatic to the ovary. A practical approach
with guidelines for prediction of primary site for metastases of uncertain
origen (Review). Pathology Case Reviews. 2006;11:18-30,
http://dx.doi.org/10.1097/01.pcr.0000196570.96459.9e.
http://dx.doi.org/10.1097/01.pcr.0000196...
). When
compounded by the fact that some metastatic carcinomas can stimulate primary tumors,
this presentation can lead even experienced pathologists to incorrectly diagnose a
secondary deposit as a primary neoplasm, causing delays and the implementation of
incorrect therapeutic approaches, with serious consequences for the patient. In such
situations, the use of morphological criteria can often be helpful; however, none of
these criteria are pathognomonic of metastasis (44. McCluggage WG, Wilkinson N. Metastatic neoplasms involving the
ovary: a review with an emphasis on morphological and immunohistochemical
features. Histopathology. 2005;47(3):231-47,
http://dx.doi.org/10.1111/j.1365-2559.2005.02194.x.
http://dx.doi.org/10.1111/j.1365-2559.20...
,66. Yemelyanova AV, Vang R, Judson K, Wu LS, Ronnett BM. Distinction
of primary and metastatic mucinous tumors involving the ovary: analysis of size
and laterality data by primary site with reevaluation of an algorithm for tumor
classification. Am J Surg Pathol. 2008;32(1):128-38.,1313. Vang R, Ronnett BM. Distinction of primary ovarian mucinous
tumors and mucinous tumors metastatic to the ovary. A practical approach
with guidelines for prediction of primary site for metastases of uncertain
origen (Review). Pathology Case Reviews. 2006;11:18-30,
http://dx.doi.org/10.1097/01.pcr.0000196570.96459.9e.
http://dx.doi.org/10.1097/01.pcr.0000196...
,1414. Lee KR, Young RH. The distinction between primary and metastatic
mucinous carcinomas of the ovary: gross and histologic findings in 50 cases.
Am J Surg Pathol. 2003;27(3):281-92.). The main
characteristics indicating that a deposit is secondary are a small tumor size;
bilaterality; multiple nodules on the cut surface; a microscopic pattern of stromal
invasion with a nodular, heterogeneous and infiltrative/destructive phenotype;
surface implants; lymphatic or blood vessel invasion, especially if conspicuous; and
the presence of signet-ring cells and neoplastic cells floating in mucin pools
(1414. Lee KR, Young RH. The distinction between primary and metastatic
mucinous carcinomas of the ovary: gross and histologic findings in 50 cases.
Am J Surg Pathol. 2003;27(3):281-92.,1515. Seidman JD, Kurman RJ, Ronnett BM. Primary and metastatic
mucinous adenocarcinomas in the ovaries: incidence in routine practice with a
new approach to improve intraoperative diagnosis. Am J Surg Pathol.
2003;27(7):985-93.). The pattern of ovarian parenchyma involvement can suggest a
secondary neoplasm. In our cases, we observed that all secondary tumors had a
multinodular pattern of invasion. In a retrospective study of 104 cases comparing
expansive versus infiltrative invasion, the authors found a worse
prognosis and a higher probability of lymph node metastasis among individuals with
the infiltrative pattern (1616. Muyldermans K, Moerman P, Amant F, Leunen K, Neven P, Vergote I.
Primary invasive mucinous ovarian carcinoma of the intestinal type: importance
of the expansile versus infiltrative type in predicting recurrence and lymph
node metastases. Eur J Cancer. 2013;49(7):1600-8.). A simple
algorithm based on tumor size and laterality has been previously determined and can
correctly classify 84-90% of the cases (66. Yemelyanova AV, Vang R, Judson K, Wu LS, Ronnett BM. Distinction
of primary and metastatic mucinous tumors involving the ovary: analysis of size
and laterality data by primary site with reevaluation of an algorithm for tumor
classification. Am J Surg Pathol. 2008;32(1):128-38.,1515. Seidman JD, Kurman RJ, Ronnett BM. Primary and metastatic
mucinous adenocarcinomas in the ovaries: incidence in routine practice with a
new approach to improve intraoperative diagnosis. Am J Surg Pathol.
2003;27(7):985-93.). In addition,
immunohistochemistry may help to identify the profile determined by coordinated CK7
and CK20 expression. For example, a CK7-/CK20+ immunoprofile suggests a
colorectal origin, whereas a CK7+/CK20- profile favors the ovary as the primary
site. However, this ancillary technique has limitations in this setting because
primary mucinous ovarian tumors may express CK20 focally or, at times, diffusely
(1717. Ji H, Isacson C, Seidman JD, Kurman RJ, Ronnett BM. Cytokeratins
7 and 20, Dpc4, and MUC5AC in the distinction of metastatic mucinous carcinomas
in the ovary from primary ovarian mucinous tumors: Dpc4 assists in identifying
metastatic pancreatic carcinomas. Int J Gynecol Pathol.
2002;21(4):391-400.). Similarly, large bowel
adenocarcinomas can show focal or multifocal staining for CK7, which happens more
frequently in poorly differentiated tumors and in those localized in the right colon
and rectum (1818. Lee MJ, Lee HS, Kim WH, Choi Y, Yang M. Expression of mucins and
cytokeratins in primary carcinomas of the digestive system. Mod Pathol.
2003;16(5):403-10,
http://dx.doi.org/10.1097/01.MP.0000067683.84284.66.
http://dx.doi.org/10.1097/01.MP.00000676...
). Additionally, the
CK7+/CK20- immunophenotype is also observed in adenocarcinomas originating in
the pancreas, breast, stomach, lung, bile ducts and female genital tract (1919. Chu P, Wu E, Weiss LM. Cytokeratin 7 and cytokeratin 20
expression in epithelial neoplasms: a survey of 435 cases. Mod Pathol.
2000;13(9):962-72, http://dx.doi.org/10.1038/modpathol.3880175.
http://dx.doi.org/10.1038/modpathol.3880...
). Due to this overlap, it is not advisable
to use immunohistochemistry alone when investigating whether a mucinous ovary tumor
is primary or secondary; rather, this approach should always be utilized in
conjunction with clinical and morphologic data. In the last few years, new
immunohistochemical markers have been used in combination with the cytokeratins (CK7
and CK20) to increase the accuracy of the test. Immunohistochemical markers, such as
Cdx-2, β-catenin, p504, Dpc4, MUC1, MUC2, MUC5AC and Hep Par, can be useful.
However, despite all the available approaches, there will be cases in which doubt
will remain. In this study, we included the most common predictors of metastatic
nature: surgical findings (such as tumor size, laterality and extraovarian spread)
and immunohistochemical markers. Although our study was limited by the use of TMA
for immunohistochemical reactions, our results agreed with the published data.
Interestingly, when multivariate analysis was performed only on tumors smaller than
10.0 cm, bilaterality and negative CK7 remained as predictors of metastasis. Our
model accurately predicted 86.2% of metastasis cases; thus, a correct diagnosis
could not be obtained for least 15% of cases.
Therefore, the search for a new tool that may help to accurately determine whether a mucinous tumor is primary or metastatic continues.
The lymphatic vasculature is one important route of neoplastic dissemination for most
carcinomas. Additionally, conspicuous lymphovascular invasion is one of the
characteristics indicative of metastases of ovarian tumors (1414. Lee KR, Young RH. The distinction between primary and metastatic
mucinous carcinomas of the ovary: gross and histologic findings in 50 cases.
Am J Surg Pathol. 2003;27(3):281-92.,1515. Seidman JD, Kurman RJ, Ronnett BM. Primary and metastatic
mucinous adenocarcinomas in the ovaries: incidence in routine practice with a
new approach to improve intraoperative diagnosis. Am J Surg Pathol.
2003;27(7):985-93.). On the other
hand, the stromal component, which includes the lymphovascular spaces, is an
important component of epithelial ovarian tumors (2020. Stacker SA, Achen MG, Jussila L, Baldwin ME, Alitalo K.
Lymphangiogenesis and cancer metastasis. Nat Rev Cancer. 2002;2(8):573-83,
http://dx.doi.org/10.1038/nrc863.
http://dx.doi.org/10.1038/nrc863...
,2121. Musrap N, Diamandis EP. Revisiting the complexity of the ovarian
cancer microenvironment-clinical implications for treatment strategies. Mol
Cancer Res. 2012;10(10):1254-64,
http://dx.doi.org/10.1158/1541-7786.MCR-12-0353.
http://dx.doi.org/10.1158/1541-7786.MCR-...
). Therefore, we decided to
investigate the potential role of the intratumoral LVD in the characterization of a
mucinous tumor as primary or secondary. Published studies examining LVD in patients
with ovarian tumors were generally designed to evaluate the behavior of primary
carcinomas but not to help identify secondary tumors. For example, intratumoral and
peritumoral LVD have been studied in borderline ovarian serous tumors in an attempt
to determine their role in nodal metastasis (2222. Fadare O, Orejudos MP, Jain R, Mariappan MR, Hecht JL, Renshaw
IL, et al. A comparative analysis of lymphatic vessel density in ovarian serous
tumors of low malignant potential (borderline tumors) with and without lymph
node involvement. Int J Gynecol Pathol.
2008;27(4):483-90.). No association between LVD and nodal metastasis could be
demonstrated, perhaps because the nodal tumor deposits observed in borderline tumors
do not occur via tumoral lymphatics (2222. Fadare O, Orejudos MP, Jain R, Mariappan MR, Hecht JL, Renshaw
IL, et al. A comparative analysis of lymphatic vessel density in ovarian serous
tumors of low malignant potential (borderline tumors) with and without lymph
node involvement. Int J Gynecol Pathol.
2008;27(4):483-90.).
Lymphangiogenesis was also investigated by Sundar et al. in 108 ovarian tumors,
including 12 mucinous type tumors. In that study, lymphatic vessel density was
statistically significant in a multivariate analysis of overall survival and
progression-free survival. However, lymphatic counts did not impact the survival
curves. The authors suggested that lymphatic spread might act in conjunction with
other biological factors to cause metastasis (2323. Sundar SS, Zhang H, Brown P, Manek S, Han C, Kaur K, et al. Role
of lymphangiogenesis in epithelial ovarian cancer. Br J Cancer.
2006;94(11):1650-7.).
In our previous experience with cancers of the vulva, cervix and endometrium, we
found an inverse correlation between intratumoral LVD and lymph node metastasis and
prognosis (99. Zaganelli FL, Carvalho FM, Almeida BG, Bacchi CE, Goes JC, Calil
MA, et al. Intratumoral lymphatic vessel density and clinicopathologic features
of patients with early-stage cervical cancer after radical hysterectomy.
Int J Gynecol Cancer. 2010;20(7):1225-31.
10. Goes RS, Carvalho JP, Almeida BG, Bacchi CE, Goes JC, Calil MA,
et al. Intratumoral lymphatic vessel density in vulvar squamous cell carcinomas:
a possible association with favorable prognosis. Int J Gynecol Pathol.
2012;31(1):8-14.-1111. Kawamura L, Carvalho FM, Alves BG, Bacchi CE, Goes JC, Calil MA,
et al. Association between intratumoral lymphatic microvessel density (LMVD) and
clinicopathologic features in endometrial cancer: a retrospective cohort study.
World J Surg Oncol. 2010;8:89.). To explain our previous results, we hypothesized that the
intratumoral lymphatic vessels were non-functional and therefore had the potential
to disturb local drainage, including the transport of neoplastic cells outside the
tumor. Another hypothesis to be considered is that the intratumoral lymphatics are
important in the early steps of neoplastic progression, just prior to the transport
of cells outside of the tumor. Once the dissemination has begun, intratumoral
lymphangiogenesis is no longer necessary. In this study, we aimed to determine a
possible role for LVD in the definition of primary or secondary origin. Although
primary tumors showed higher LVDs, this difference did not offer any advantage over
the classical features (tumor size, laterality and CK7 expression) with respect to
the diagnosis. In routine surgical pathology, 90% of the cases can be reliably
categorized using these predictors (size ≤ 10.0 cm, bilaterality and lack of
CK7 expression). Our deceptive results with the LVD did not exclude the possibility
of other differences between the stroma of primary and secondary tumors, which may
or may not involve the lymphatic vasculature. On the other hand, recent studies have
advocated a change in the paradigm with regard to what concerns an
“extraovarian origin” of epithelial ovarian cancer (either from tubal
fimbria or from endometriosis) (2424. Kurman RJ, Shih IeM. Molecular pathogenesis and extraovarian
origin of epithelial ovarian cancer—shifting the paradigm. Hum Pathol.
2011;42(7):918-31,
http://dx.doi.org/10.1016/j.humpath.2011.03.003.
http://dx.doi.org/10.1016/j.humpath.2011...
,2525. Diniz PM, Carvalho JP, Baracat EC, Carvalho FM. Fallopian tube
origin of supposed ovarian high-grade serous carcinomas. Clinics.
2011;66(1):73-6,
http://dx.doi.org/10.1590/S1807-59322011000100013.
http://dx.doi.org/10.1590/S1807-59322011...
). Because all epithelial ovarian tumors
might be secondary, this could explain why no great differences were detected in LVD
between our two study groups.
ACKNOWLEDGMENTS
This study was supported by FAPESP - São Paulo Research Foundation (process number 2012/11833-0).
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No potential conflict of interest was reported.
Publication Dates
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Publication in this collection
Oct 2014
History
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Received
1 Apr 2014 -
Reviewed
19 May 2014 -
Accepted
11 June 2014