Karavanas George

Cryotech, Larissa, Greece
Hellenic Association of Cord Blood Banks, Athens, Greece
 

Correspondence: Karavanas George, Cryotech, Larissa, Greece

 

 


 

 

 

Discussion around cord blood stem cells is not new in Greece. Sadly the discussion has been focused mainly in the model of storage that would be preferable (public banking vs family banking) and far less in the possible medical applications of cord blood itself. It's important to notice however, that the vast quantity of cord blood in today's Greece is neither stored publicly or in a family bank – rather it's discarded in the medical waste, depleting the country from a valuable and potentially life-saving resource. Behind this reality, lies the incomplete information of most obstetricians and gynecologists which in turn has resulted from the extreme claims provided by some family banks, in the one hand, and on the corporatist polemic developed by public banks, in the other hand. As a result, most obstetricians and gynecologists remain cautious, despite compelling data on the growing therapeutic use of cord blood, both in terms of treatable diseases and numbers of therapies1.

Historically the breaking point for any new therapeutic agent's acceptance by most doctors is the commencement of its widespread application. In the case of cord blood however, there is a catch. Although the number of cord blood transplantations internationally has exceeded 30,0002, they tend to concern mainly rare hematologic disease, whose frequency however increases with age. For every 100,000 United States citizens there are 0, 18 and 2 incidents of myeloma, leukemia and lymphoma respectively for ages 0 to 10 years old (these numbers raise to 0, 6 and 7 for ages 10 to 20 years old), whilst it skyrockets to 16, 26 and 58 for ages 50 to 60 years old (with further raise to 38, 60 and 116 for ages 60 to 70 and even further to 67, 111 and 197 for ages 70 to 80)3. A similar trend is shown for most cancers in which cord blood transplantation could be useful. It is thus obvious that the therapeutic value of cord blood units wasted today may reflect in a worst prognosis for newborns, if they happen to fall ill, 30 to 40 years from now (the average age of privately stored cord blood units is currently between 5 to 10 years, so the likelihood of these units being used to treat cancer is still low). Exceptions include related allogeneic transplantations (most commonly between siblings) for non malignant hematologic diseases (hereditary or acquired) like sickle-cell anemia and thalassemia (majority of cord blood transplantations with family stored units in some parts of the world).

It's though imperative to convince everyone involved in cord blood collection, that this harmless procedure with apparently no immediate consequence to the baby and its mother, may become a life saving measure for that child later on. cord blood collection should become one of the many precautionary procedures obstetricians and gynecologists prescribe, such as ultrasound and maternal hormonal testing among others. After all, the odds of a child needing therapy with cord blood, especially for situations associated with prematurity or brain damage during delivery, such as cerebral palsy or nervous damage due to hypoxia, is not that different from many conditions potentially detected during pregnancy. According to the most recent related scientific review, the lifetime probability of a family stored cord blood unit to be used is around 1/200, which is significantly above the possibility of most medical conditions and syndromes investigated prenatally, which none of course would dare to consider unnecessary or overly.

It is clear that the medical world will be increasingly accepting cord blood collection as a standard precautionary procedure, as will be provided with accurate, recent and quality scientific data. To this end, the far reaching promises and sensationalist statements of some few family banks are not at all helpful. On the other hand, scientists involved in the business of promoting cord blood collection need to be insisting on its value, almost adopting a missionary approach, faithful to the claim that the service they provide may cure an ever expanding list of serious disease, including some forms of cancer, and this is a great deal. This way only they will succeed to overcome the derogatory comments by some misinformed doctors, who may discredit what they do. The track to be covered by family banks is still long and will require dedication, seriousness and a long term commitment to providing quality scientific data to medical doctors.

 

Conflict of interest

The author declares no conflict of interest

 

 

References

1. http://www.clinicaltrials.gov/.

2. Ballen KK, Gluckman E, Broxmeyer H. Umbilical cord blood transplantation: the first 25 years and beyond. Blood 2013;122:491-8. PubMed

3. Nietfeld JJ, Pasquini MC, Logan BR, Verter F, Horowitz MM. Lifetime probabilities of hematopoietic stem cell transplantation in the U.S. Biol Blood Marrow Transplant 2008;14:316-22. PubMed

Kougioumtsidou Anna, Kougioumtsidou Niki, Athanasopoulou Maria, Pados George, Tarlatzis Vasileios

1st Department of Obstetrics and Gynecology, Aristotelian University of Thessaloniki, Papageorgiou hospital, Thessaloniki, Greece

Correspondence: Kougioumtsidou Anna, 1st Department of Obstetrics and Gynecology, Aristotelian University of Thessaloniki, Papageorgiou hospital, GR-54623, Thessaloniki, Greece. E-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.

 

 


 

 

Abstract

Ovarian goiter is a rare tumor of the ovary that is characterized by a presence of thyroid tissue in the ovary and occupies more than 50% of the total mass of the tumor. It is accompanied by ascites in the 1/3 of cases. Τhe combination of struma ovarii, ascites and increased levels of CA125 is extremely rare. We report a case of a 77 years old woman with ascites, a big mass on the left ovary and increased levels of CA125, which are signs and symptoms of malignant tumor of the ovary.The patient underwent surgical removal of tumor with rapid remission of the ascites and decrease of the levels of CA125. Struma ovarii can imitate a malignant tumor of the ovary, especially when it is accompanied by ascites and increased levels of CA125.

Key words: ovarian goiter, struma ovarii, ascites, thyroid tissue, CA125

 

 

Ovarian goiter is a rare type of tumor of the ovaries, that constitutes 0.3-1.2% of all the ovarian luteomas and 2.7% of the dermoid tumors of the ovary1. It is characterized by a presence of thyroid tissue in the ovary that occupies more than 50% of its total mass. Struma ovarii is usually benign, but in rare occasions (5%) we notice a malignant change2. Preoperative diagnosis is difficult, since there are no notable symptoms and points of the disease. Patients usually come in with asymptomatic ovarian mass, widespread abdominal pain, distension of the abdominal walls due to ascites and abnormal ovarian bleeding. While ascites appears in 1/3 of the cases3, there is rarely an additional increase of the CA125. Few cases of strumaovarii have been reported to be accompanied by a pseudo-Meigs syndrome. Thyrotoxicosis appears in 5% of the cases4.

A 77 years old woman is presented with ascites, ovarian mass, increased levels of CA125, without symptoms of hyperthyroidism. This case was treated at first as a malignant tumor of the ovary and was submitted to exploratory laparotomy surgery.

 

Case report

The case of a 77 years old woman is reported, in menopause (since 20 years) with a maternity medical history of 8 natural childbirths and 3 spontaneous abortions. From the personal history, the following are reported: appendectomy, coronary disease, heart failure under treatment and mild degree of obstructive pulmonary disease. The woman came in the outpatient clinic of the First Department of Obstetrics and Gynecology of the Aristotle University of Thessaloniki at Papageorgiou hospital, due to a two month's widespread abdominal pain and meteorism. During the physical examination it was detected that there was distension of the abdominal walls due to a palpable mass on the lower abdomen, on the anatomical position of the left adnexal region. The woman was admitted to our clinic for further examination. An abdominal ultrasound and a computed tomography of the upper and lower abdomen and the retroperitoneal space were conducted, where moderate degree of ascites and cystic mass to the space of distribution of the left ovary, with dimensions 7 x 5 x 4cm, were detected.

The uterus was of normal size while the right adnexum was not depicted. In the rest of the intra-abdominal organs (liver, spleen, kidneys and adrenal glands) no pathological findings were detected. During the examination, a computed tomography of the chest was done, which showed absence of pleural effusion and absence of swollen mediastrinal and portal lymph nodes. In the lab test, an increased rate of CA125 (264.0 U/ml) was observed, while CEA (1.0 U/ml), CA15-3 (15.6 U/ml), CA19-9 (19.25 U/ml), and AFP (4.83 U/ml) were within normal limits. The rest of the test had no pathological findings.

The patient underwent exploratory laparotomy. Approximately 500ml of a tinged yellow ascetic fluid was found and was sent for a cytology examination. A complete hysterectomy on both andexasides, a removal of a multiple space-occupying tumor on the left ovary (Figure 1) and a partial omentectomy were conducted. No traces of intraperitoneal spread of the disease were noticed.

The histopathological examination of the tumor presented struma ovarii (thyroid tissue of follicles of various diameter filled with colloid) (Image 2), without omental cakes and without malignant cells at the cytology examination of the ascetic fluid. The uterus, the right ovary, the right salpinx and the left salpinx were examined with no pathological findings.

The postoperative course was smooth and the check of the functioning of the thyroid gland two days later was normal. The patient was discharged the seventh postoperative day. The recheck two months later showed remission and improvement of the clinical presentation without evidences of ascites and the CA125 levels were within normal limits.

  

 

image11 low        image12 low

 

 Figure 1. Macroscopic view of the struma ovarii                                   Figure 2. Typical microscopic presentation  of struma ovarii

 

Discussion

Struma ovarii is characterized by a presence of thyroid tissue that occupies more than 50% of the tumor's total mass and it was first described in 18995. The tumor is usually benign, but in rare occasions (5%) we notice a malignant change. Despite the fact that the tumor mainly consists of thyroid tissue, thyrotoxicosis appears only in 5% of the cases. The typical age of appearance is the 5th and 6th decade. It rarely appears before adolescence5. The clinical presentation of struma ovarii is similar to the other cancers of the ovary, with no special characteristics. Abdominal pain, palpable abdominal mass, ascites, abnormal vaginal bleeding are the most common symptoms. In rare occasions it could be accompanied by pseudo-Meigs syndrome and clinical hyperthyroidism3. Differential diagnosis must be done from all the ovarian tumors (benign and malignant), ectopic pregnancy, hydrosalpinx, tubo-ovarian abscess. The treatment is surgical and varies according to the age of the patient and the wish to preserve the fertility.

The increase of CA125 combined with ascites can usually be found in cases of malignant epithelial tumors of the ovary and more rarely in cases of endometrial, colorectal, breast and lung cancer. Moreover, the increase of its levels might accompany situations such as menstruation, pregnancy, endometriosis and ovarian fibroma6. The precise mechanism of the increase of the levels of CA125 in the case of struma ovarii is unknown. The probable cause is the inflammation of the peritoneum, the stimulation of the mesothelial cells and, as a result, the increased production of CA125 from its surface7. Concerning ascites, there are various speculations, such as the obstruction of the peritoneal lymphatic vessels by the overian mass, the inflammatory response of the peritoneal and the increased permeability of the membranes at the surface of the tumor8. An ovarian mass combined with increased levels of CA125 and ascites to a woman in menopause usually points to malignant mass. During the review of the literature, eight reports of cases with the stated findings were discovered3. All cases were treated at first as malignant tumors (Table 1).

In our case, a patient with ovarian mass, ascites and increased levels of CA125 is depicted. She was treated surgically with removal of the tumor and total hysterectomy, with total remission of the ascites and a decrease of the CA125 to normal levels right after the operation that still remains two months later. In conclusion, even though few similar cases are reported in literature, ovarian goiter should be included to the differential diagnosis of adnexal masses that coexist with ascites and increased levels of CA125.

 

table-struma

 

 

Conflict of interest

All authors declare no conflict of interest

 

 

 

References

1.Roth LM, Talerman A. The enigma of struma ovarii. Pathology 2007;39:139-46. PubMed

2. Bal A, Mohan H, Singh SB, Seghal A. Malignant transformation in mature cystic teratoma of the ovary: report of five cases and review of the literature. Arch Gynecol Obstet 2007;275:179-82. PubMed

3. Mui MP, Tam KF, Tam FK, Ngan HY. Coexistence of struma ovarii with marked ascites and elevated CA-125 levels: case report and literature review. Arch Gynecol Obstet 2009;279:753-7. PubMed

4. Yoo SC, Chang KH, Lyu MO, Chang SJ, Ryu HS, Kim HS. Clinical characteristics of struma ovarii. J Gynecol Oncol 2008;19:135-8. PubMed

5. Yassa L, Sadow P, Marqusee E. Malignant struma ovarii. Nat Clin Pract Endocrinol Metab 2008;4:469-72. PubMed

6. Leung YC, Hammond IG. Limitations of CA 125 in preoperative evaluation of a pelvic mass: struma ovarii and ascites. Aust N Z J Obstet Gynecol 1993;33:216-7. PubMed

7. Lin JY, Angel C, Sickel JZ. Meigs syndrome with elevated serum CA125. Obstet Gynecol 1992;80:563-5. PubMed

8. Abad A, Cazorla E, Ruiz F et al. Meigs syndrome with elevated CA125: case report and review of the literature. Eur J Obstet Gynecol Reprod Biol 1999;82:97-9. PubMed

9. Jotkowitz MW, Gee DC. Unique case of massive ascites, extreme elevation of serum CA125 tumor marker. Aust N Z J Obstet Gynecol 1993;33:453-4. PubMed

10. Mancuso A, Triolo O, Leonardi I, De Vivo A. Struma ovarii: a rare benign pathology which may erroneously suggest malignancy. Acta Obstet Gynecol Scand 2001;80:1075-6. PubMed

11. Loizzi V, Capuccini F, Berma ML. An unusual presentation of struma ovarii mimicking a malignant process. Obstet Gynecol 2002;100:1111-2. PubMed

12. Bokhari A, Rosenfeld GS, Cracchiolo B, Heller DS. Cystic struma ovarii presenting with ascites and an elevated CA125 levels. J Reprod Med 2003;48:52-6. PubMed

13. Rim SY, Kim SM, Choi HS. Struma ovarii showing clinical characteristics of ovarian malignancy. Int J Gynecol Cancer 2005;15:1156-9. PubMed

14. Guida M, Mandato VD, Spiezio Sardo A. Coexistence of Graves' disease and benign Struma ovarian in a patient with marked ascites and elevated CA125 levels. J Endocrinol Invest 2005;28:827-30. PubMed

 

Nikolaou Marinos1, Papadimitriou Ifigenia2, Michail George2, Androutsopoulos George2, Adonakis George2, Relakis Konstantinos3, Decavalas George2

1Department of Obstetrics and Gynecology, Agios Nikolaos hospital, Agios Nikolaos, Crete, Greece
2Department of Obstetrics and Gynecology, University of Patras, Medical School, Patras, Greece
3Department of Obstetrics and Gynecology, University of Crete, Medical School, Herakleio, Crete, Greece
 
Correspondence:  Nikolaou Marinos, Department of Obstetrics and Gynecology, Agios Nikolaos hospital, Agios Nikolaos, GR-72100, Greece. 
Email: This email address is being protected from spambots. You need JavaScript enabled to view it.

 

 


 

Abstract

The incidence of cervical glandular lesions has significantly increased during the past two decades especially among young women. This rise in registered cases is predominantly attributed to this entity's rising prevalence as well as recent advances in cytology. Atypical glandular cells identified by secondary cervical screening (Papanicolaou) might actually harbor significant underlying pathology. The natural history and progression of cervical glandular lesions comparing to that of their squamous counterparts is less well understood. High-risk HPV's (HPV 16, 18 and 45) have been identified in glandular lesions with high frequency. Cytology and colposcopy illustrate poor sensitivity in the diagnosis of glandular lesions. Diagnostic excisional procedures are of paramount importance in the management of high-grade glandular lesions. Treatment options are conservative surgery, predominantly conization or definitive therapy (mainly hysterectomy). Cervical conization appears to give satisfactory results especially in young women with high grade glandular lesions who strongly wish to preserve their fertility potential. However, adequate counseling should be provided to patients before therapeutic decisions. Long-term follow-up is mandatory for women treated for glandular lesions to detect any possible residual disease and early signs of recurrence.

Key words: cervical glandular lesions, diagnostic investigations, treatment options

 

 

 

 

Cervical cancer (CxCa) is presented to be the 3rd most common type of cancer among women worldwide, with 500,000 new cases and 273,000 deaths annually1. CxCa originates predominantly from the squamous cervical epithelium (85-90%), the remainder emanating either purely from the columnar endocervical epithelium, or representing mixed types (10-15%). Despite the reduction in squamous CxCa over the last few decades in the western world, mainly with the implementation of Pap screening, cervical glandular adenocarcinoma is globally on the rise, especially among young women. In particular, while cases of glandular cervical cancer were making up only 5% to the summation of cervical cancers in the 50's, they have now risen up to 25% during the last decades2-3.

The new, revised Bethesda cytological classification system (TBS 2001), defines four different entities of glandular lesions of the cervix uteri (Table 1)4. In this way the older AGUS (atypical glandular cells of undetermined significance) terminology is abolished and is replaced with the term atypical glandular cells (AGC), to avoid confusion with the squamous counterpart (ASCUS). Furthermore, two distinct categories of atypical glandular cells are determined with the use of special morphological criteria, correlated with the risk of underlying malignancy (FN-favor neoplasia, and AIS-adenocarcinoma in situ), while cytologists and pathologists are encouraged to comment on the possible source of the atypical cells, as their origin differentiates their management (endocervical, endometrial, unspecified).

 

 table1-management

 

Epidemiology

Atypical glandular cells 

The rate of detection of AGC in the cervicovaginal smear (Pap test) is very low varying from 0.4% to 0.8%, depending on the study5. The presence of AGC significantly increases the probability of high grade squamous or glandular dysplasia (HSIL or AIS) in 9-38% of the cases, and the risk of invasive cervical or endometrial cancer in 3-17% of the cases6-9.

The origin of the atypical glandular cells and the related risk of malignancy, as defined with the implementation of special cytologic diagnostic criteria, represent major prognostic factors. Studies with large series of patients confirm that AGC-FN is linked to higher risk of malignancy than that of AGC-NOS (atypical glandular cells-not otherwise specified). The prevalence of precancer (dysplasia) or cancer lesions in women with AGC-NOS is 9-41%, while in AGC-FN it might reach 96%9.

Accordingly, a significant percentage of AGC (70%) corresponds to benign lesions10. Atypical glandular cells might be related with endometrial polyps, intrauterine contraceptive devices (ΙUD), or chronic endometritis – especially if the cells are described as of endometrial origin. Additionally, detection of atypical glandular cells in Pap smears has been described in some rare cases of cervical endometriosis as well as in cases of tuboendometrial metaplasia (ΤΕΜ) in women who have previously undergone conization.

ΤΕΜ was initially described in 1988 as a benign glandular cytological change that could potentially be misinterpreted as cGIN (cervical glandular intraepithelial neoplasia). It was identified as a distinct entity in 199111, as a reactive cellular change of the glandular cells of the regenerating endocervix post conization. ΤΕΜ should be considered as a likely diagnosis in cases of smears with atypical or metaplastic glandular cells in women post conization, so that a contemplated unnecessary re-operation on the cervix is avoided.

Other benign situations that present as glandular changes and should be distinguished from true glandular dysplasia are: HPV infection, endocervicitis, active glandular atypia related to irradiation or thermal effect, congenital squamocolumnar junction (CTZ – in this case the atypical cells exhibit acanthotic characteristics) as well as hormonal effects (tamoxifen, diethylstilbestrol). These changes could additionally be attributed to Arias-Stella reaction, appearing as atypical glandular cells in the course of pregnancy (decidual reaction).

Widespread use of combined oral contraceptive pills, genital herpes (HSV), poor hygiene, multiparity, early sexual debut in combination with increased number of sexual partners and obesity are additional documented risk factors predisposing towards the development of glandular cervical changes. On the contrary, some studies suggest a possible protective role for endometrial devices (IUD)12.

 

Adenocarcinoma in situ 

Adenocarcinoma in situ (AIS) originates from the glandular endothelium of the endocervix and is recognized as precursor lesion of infiltrating adenocarcinoma. The median age at presentation ranges between 35-39 years, and the time span needed for its development is between 5-13 years13. Factors impeding the diagnosis of AIS are the multifocal localization of the lesions, cytology's poor performance in terms of sensitivity and specificity (50% to 72-80% in coexistent lesions) as well as colposcopy's limitations in terms of diagnostic sensitivity and specificity14. AIS's relative frequency, compared with high-grade squamous counterparts (CIN 2/3) is quite low, while it frequently coexists with them (47.3%)15. However, during the last decades a significant rise of cases with AIS has been documented, especially among young women, predominantly in the Western World12. This trend is attributed mainly to modern pathologists' and cytologists' improved competence in the recognition of glandular lesions, to the abilities of liquid-based cytology (LBC), and to the increased exposure of young women to HR- HPVs (High-Risk HPVs) (HPV 16, 18 and 45), in 96% of cases12,16.

 

Microinvasive cervical adenocarcinoma

Microinvasive cervical adenocarcinoma still remains a controversial clinical entity. It is defined as invasion of the cervical stroma to a depth < 3 mm with overall length < 7mm (FIGO stage ΙΑ1)17. Simple hysterectomy rather than radical hysterectomy remains the practiced treatment of choice for women with micro-invasive cervical adenocarcinoma. Radical hysterectomy with simultaneous pelvic and para-aortic lymphadenectomy remains the practiced treatment of choice for women with microinvasive cervical adenocarcinoma. However, recent studies illustrate excellent survival rates equivalent to those of the squamous microinvasive counterpart with more conservative surgical approach (conization), mainly among women who desire to preserve their fertility18-20.

 

Cervical adecocarcinoma

As stated, cervical adecocarcinoma's prevalence is lower compared to its squamous infiltrative counterpart, 24.9% and 69.3% respectively21. However, increasing trends are documented globally among young women (<40 years), with significant geographical fluctuations3. This rise is attributed predominantly to two factors: a) the increased exposure to HR-HPV's, and b) the poor - in general - performance of cytology in correctly characterizing glandular lesions, in a manner that precursor lesions are not identified until the tumor develops to reach an infiltrative stage22.

An increased prevalence (as high as 85-90%16) of HR-HPVs (HPV 16, 18, 45) has been documented in cervical adecocarcinoma. Consequently, preventive anti-HPV vaccination is anticipated to induce a significant reduction in the prevalence of the disease in the future. Modified radical hysterectomy remains the treatment of choice for cervical adenocarcinoma. However, prognosis and survival of patients is poorer compared to the infiltrative squamous counterpart because of the increased probability of pelvic lymphatic metastases23.

 

HPV- related glandular cervical lesions

According to recent studies, HR-HPVs (18, 16, 31 and 45) have been identified approximately in 38% of the entirety cervical columnar lesions9,10. However, HPV positiveness in synchronous high-grade squamous and glandular lesions (adenocarcinoma) reaches 93%, while in AIS and in AGC it is 71% and 29% respectively9,10,24.

In cervical adenocarcinoma the rate of HPV detection varies around 60%, with HR genotypes isolated in 92% of positive cases25. In particular, HPV 16 is documented in 30-55% of cases, while HPV 18 is detected in 40-60% of women with glandular lesions, conferring an elevated risk for development of cervical adenocarcinoma9,10,12,13. HPV 45 and HPV 31 account for the remainder 7% up to 9% of cases13. In a global perspective, the detection of HR-HPV is associated with a 81-fold increased risk for cervical adenocarcinoma development. HPV genotypes' prevalence illustrates significant geographic fluctuation among regions; in Eastern Asia for example, HPV 18 is more frequent than HPV 1612.

 

Diagnosis

The role of cytology

The sensitivity of conventional cytology in the detection of glandular lesions varies, overall is rather low (45%-76%)22. Liquid-based cytology (LBC) provides smears of superior quality, yielding improved sensitivity, specificity, reproducibility and stronger correlation with the final histological diagnosis. In LBC, detection rate for glandular lesions ranges from 72% to 87%22,26. LBC however is not without limitations and drawbacks, being unable to detect inaccessible cellular abnormalities that lie deep in the endocervical canal. Furthermore, even if some lesions are indeed detected, difficulties might arise in their identification and classification, given that the morphologic criteria of atypical glandular cells are poorly defined.

In a recent study it was illustrated that the detection rate of pure glandular high-grade lesions (HcGIN, AIS) was higher compared to mixed type lesions with squamous counterpart (AIS and coexistent HSIL); 75.2% and 47.3%, respectively15.

Finally, a recent meta-analysis of 12 studies which included 1,374 women with endocervical adenocarcinoma corroborates that cervical mass screening predominantly decreased the risk of development of subsequent severe squamous SIL's rather than those of the columnar epithelium27.

 

Combination of cytology and HPV-DNA test (co-testing)

According to recent studies, the addition of HPV-DNA test in the cytological work-up (co-testing) for women aged >30, contributes to earlier and safer detection of cervical precancer16,28,29.

A substantial 63% of women with cervical adenocarcinomas diagnosed over a 5-year span though initially presented with negative (normal) cytology had a positive HPV-DNA test at enrollment30. Furthermore, among 72 glandular lesions (cGIN) that had been tested with HPV-DNA test, 70 (97.2%) proved HPV positive31.

The above points emphasize the importance of incorporating HPV-DNA test in the initial workup of atypical glandular cells. Especially in the management of women with AGC and negative colposcopy (without findings), an initial positive HPV-DNA test is an important tool in the discrimination of women in high risk of harboring insidious glandular lesions.

 

The role of colposcopy

Disappointingly, glandular cervical lesions do not posses straightforward, accurate, specific nor exclusive colposcopic criteria. Glandular lesions are often left unrecognized during meticulous colposcopy, since they can be hidden deep in the endocervical canal, or be located in the deeper part of a glandular crypt under the metaplastic epithelium, while in 60% of cases colposcopy is not diagnostic (unsatisfactory - inadequate because of type 2 or 3 ΤΖ). Therefore, colposcopy's sensitivity in the recognition of glandular lesions or invasive disease is extremely low; while in several cases insidious lesions resemble and mimic normal findings. Inexperience among colposcopists in the recognition of atypical glandular patterns is expected and justified, but accentuates further the issues.

However colposcopy's negative predictive value still remains relatively high (80%), rendering the procedure essential in the management of women with atypical glandular cells. The following colposcopic criteria are considered as the most characteristic or suggestive of glandular changes: 1) distinct acetowhite areas boasting large crypt openings following application of acetic acid in 85% of cases, 2) whitish or reddish macula's in smooth, flat areas of columnar epithelium with swelling, bulging and fusion of the cylindric villi, coexisting amidst squamous lesions, 3) raised papillary projections, within off-white areas, following application of acetic acid, and 4) atypical blood vessels, without mosaicism or punctuation patterns.

Unsurprisingly, given the absence of exclusive colposcopic criteria for the recognition of glandular endocervical lesions, the differential diagnosis is difficult (Table 2)32. Additionally, the common coexistence of squamous lesions (LSIL/HSIL) in more than 50% of women with glandular lesions is usually more pronounced and therefore drives the diagnostic work-up6-9,15. However, according to the standard procedures, each women with a smear exhibiting ACG should undergo colposcopy, in order to unearth a possible lesion, visualize the ectocervix and the squamous epithelium (possible coexistant squamous CIN in 50% of cases) and finally assess the current anatomic situation (vagina-cervix-corpus uterii) aiming to select the most purposeful excisional treatment modality.

 

table2-management

 

Topographical development of glandular lesions

Knowledge of the architectural pattern followed during the course of glandular lesions (cGIN/AIS) extension is an essential prerequisite for their optimal diagnosis and treatment. Thus, about 82% of all lesions are located within 1cm from the SCJ (squamous columnar junction), while 65% are located within the transformation zone (TZ). In contrast, only 18% of the changes are interspersed amidst the length of the endocervical canal (skip lesions). Therefore, glandular lesions exhibit a multifocal growth pattern along the canal (islets of abnormal glandular tissue) ranging from 5 to 25mm (median 12mm)33-35.

 

Management 

Cytology, punch cervical biopsies and endocervical sampling, solely or in combination may just raise the suspicion of a possible glandular cervical lesion, but are unable to give a definitive diagnosis. Keys to the concept of the necessary diagnostic work-up are the multifocal growth patterns of glandular disease and the age of patient, both reflecting on the frequency, type, and localization of the in-question lesions.

The Updated Consensus Guidelines for the management of women with abnormal cervical smears issued by the of American Society Colposcopy and Cervical Pathology (ASCCP, 2013)36,37 are indeed very informative and essentially differentiate the initial diagnostic approach of women with cytological AGC depending on the documentation or not of atypical endometrial cells. For smears harboring atypical endometrial cells, initial evaluation commences with endocervical and endometrial sampling, with colposcopy following only if no endometrial pathology is identified. Endometrial sampling is warranted in the initial management of women 35 years of age and older, as there exists a substantial risk (5%) for severe endometrial pathology (hyperplasia or adenocarcinoma)38.

In all the other subcategories, colposcopy with endocervical sampling (pipelle/curettage) is the mainstay of the initial evaluation. This is supplemented by endometrial sampling, for women younger than 35 but with clinical indications suggesting increased risk for endometrial neoplasia (unexplained vaginal bleeding, conditions suggesting chronic anovulation)36-37.

Due to the high prognostic value the cytological documentation of atypical glandular cervical cells confers for occult high grade glandular lesions (HG-cGIN/AIS) or cervical adenocarcinoma, further diagnostic evaluation is warranted. It should be emphasized that repeating the Pap smear has low sensitivity in detecting or verifying a possible high grade glandular lesion (cGIN/adenoCa), and is thus not encouraged.

Subsequent management of women with AGC-NOS cytology (atypical glandular cells not otherwise specified) among whom CIN 2+, AIS or CxCa is not identified, is the repetition of two consecutive co-testing's at 12 and 24 months. If both tests are negative, then a return for a repeat co-testing in 3 years time is recommended 36,37. Otherwise, if any test is abnormal, colposcopy is warranted.

For women with AGC-NOS and documented squamous CIN2+ but without glandular neoplasia identified histologically during the initial diagnostic evaluation of AGC, further management is advised as per the 2012 Consensus Guidelines depending on the type of the lesion found36, 37.

Correspondingly, subsequent work-up for women with initial cytological high grade glandular abnormalities (atypical glandular cells favor neoplasia/adenocarcinoma in situ - AGC-FN/AIS), among whom invasive disease was not identified during the initial colposcopic evaluation, a diagnostic excisional procedure is warranted. This should be in the form of a wide and deep cone biopsy which encompasses the totality of the transformation zone and the most part of the endocervical canal, aiming at one intact specimen with interpretable margins. Endocervical curettage is also performed at that time36, 37, 39.

 

Atypical glandular cells in pregnancy and the puerperium

Reporting of atypical glandular cells represents an uncommon cytological diagnosis in pregnancy and early puerperium (until 6 weeks post partum). Difficulties in the accurate cytological diagnosis are caused by decidual cells, trophoblastic cells, Arias-Stella reaction and other pregnancy-related changes. However, the diagnosis of AGCs has significant clinical impact because of the high frequency of co-existent severe cervical pathology (HG-CIN, AIS-adenocarcinoma in situ, invasive squamous CaCx, HPV infection, molar pregnancy). Colposcopy is therefore warranted in this patient group but biopsies are justified only to exclude invasive disease40. Obviously endocervical curettage and endometrial biopsy are omitted.

 

Women aged 21-24 years

Indeed this represents a very rare clinical scenario. Same management is suggested for the general population as per updated ASCCP (American Society for Colposcopy and Cervical Pathology) guidelines.

 

Benign glandular changes

For asymptomatic, premenopausal women with benign endometrial cells, endometrial stromal cells, or histiocytes, no further diagnostic evaluation is recommended. The literature illustrates an increased representation of atypical endometrial cells in liquid-based cytology samples, attributed perhaps to easier harvesting from deeper zones of the endocervical canal19. In those cases, the day of the menstrual cycle at sampling must be taken into account, as well as the use of hormones or oral contraceptive pills, intrauterine devices and clinical signs suggesting risk for endometrial pathology. However, in some instances, normal endometrial cells might be misinterpreted as atypical glandular cells by the cytologist.

For postmenopausal women with smears harboring benign endometrial cells, endometrial assessment is recommended. Conversely, in hysterectomised women with smears harboring benign glandular cells, no further diagnostic evaluation is recommended36,37.

 

Therapeutic approach for women with AGC

In the past, the only alternative therapeutic choice for high-grade glandular lesions (HGIN/AIS) was the performance of total hysterectomy27,28. Total hysterectomy still represents the treatment of choice for a) women who have completed childbearing, b) cases with involved conization margins, or positive for disease endocervical sampling obtained at the time of excision (in such cases, re-cone to exclude invasive disease is mandated), c) cases with recurrence of disease after conservative management, d) women who desire for definitive treatment, and e) women with practical difficulties in regular post-operative follow-up.

Conservative surgical management (conization) represents an acceptable treatment option for young women with AIS or microinvasive adenocarcinoma (FIGO stage ΙΑ1) who wish to preserve their fertility. According to the 2013 ASCCP guidelines36,37, when the cone excision margins are involved, or the endometrial sampling tissue obtained at the time of the excisional procedure is positive for disease (positive ECC-endocervical curettage), two alternative managements are acceptable: a) re-excision to obtain clear margins (preferred), and b) follow-up vigilance, which is an acceptable option, with reevaluation following in 6 months, using a combination of co-testing, colposcopy and endocervical sampling.

Otherwise, in clear excision margins, obtaining informed consent from the patients is essential, stressing on the necessity of long-term follow-up (>20 years) for timely detection of residual/recurrent disease36,37. Recent studies illustrate excellent survival rates for women with AIS and microinvasive adenocarcinoma, similar of those of microinvasive squamous18-20,41-46. However, compared to the microinvasive squamous counterpart, further randomized prospective studies are needed to reinforce the safety of conservative management46.

 

Factors that determine the choice of therapeutic approach

Age of women: glandular lesions appear one decade later from their squamous counterparts. Among women 36-40 years of age, an ectocervical localization of the disease is the usual growth pattern, with shallow depth of invasion and usually limited size of the affected area.

Desire for childbearing and concerns on fertility preservation.

Colposcopy findings

The status of conization margins.

 

Surgical techniques of cone excision/biopsy

The main purpose of cervical conization is the excision of the TZ and the lower part of endocervical canal ideally in one intact surgical specimen avoiding fragmentation. For nulliparous young women (30-35 years of age) with desire for fertility and satisfactory colposcopy, the surgeon aims for a cylindrical-shaped cone with a 10-15 mm length, including the entirety of the TZ with an additional 10 mm above the squamocolumnar junction (SCJ).

For women >35 years of age who have completed childbearing with non-satisfactory colposcopy, a cylindrical cone is also recommended with a 20-25mm length and a 5mm depth of excision from the border of the endocervical canal in order to exclude invasive or residual disease lurking deep in a crypt, even if the cone surgical margins are reassuring (negative for disease).

Cold knife conization remains the treatment method of choice (Table 3)47. Stumdorf sutures should be positioned with caution; in a manner they do not hamper easy identification of emerging VaIN (vaginal intraepithelial neoplasia) during postoperative follow-up. Alternative, laser conization is preferred over large loop excision of transformation zone (LLETZ) since margin status and interpretability are crucial for future treatment planning.

 

table3-management

 

Complications of conservative treatment

Documentation of incomplete excision-residual disease in the first follow-up visit, or recurrence in subsequent follow-up visits after conization, represents possibly the ultimate negative prognostic factor, indicating failure of the conservative surgical management48.

The main short term surgical complication is primary cervical hemorrhage (quite frequently observed due to increased depth of conization), while in the following 8-10 days the combination of sloughing of the eschar and post-operative infection of cervix might cause secondary cervical hemorrhage.

Among long-term post-operative complications: difficulties arise in colposcopic evaluation of TZ because of cervical stenosis (mainly after cold knife conization with >50% removal of endocervical cone) or due to intense use of electrocoagulation.

Adverse long-term obstetrical implications should be probably anticipated in all the aforementioned excisional treatment modalities which aim for a depth of excision over 10-15mm, namely: increased rates of neonatal prematurity and morbidity, birth of low birth-weight babies, preterm premature rupture of membranes, preterm birth and possible increased rates of cesarean sections48-50.

The main factors responsible for post-operative residual or persistence disease are analyzed in Table 4.

 

table4-management

Conization margins 

When the margins of the cone biopsy specimen are positive, residual disease is documented at rates varying from 13% to 75% (average 52.7%)47,48,51,52. In these cases, a further excisional procedure is required in order to obtain clear margins and thus exclude occult invasive disease.

When the margins are free of disease, occult residual disease ranges from 0% to 44% (average 19.3%)47,48,51-54. However, even in cases of negative margins, women remain at risk for residual or recurrent disease for a prolonged period. In a recent meta-analysis investigating the prognostic value of the surgical margins in conizations for AIS, 47.5% of women underwent a repeated excisional procedure in order to detect residual disease. 48. Hence, when a conservative method is contemplated, vigilant long term follow up using cytology, HPV DNA testing and colposcopy is mandatory (Table 5).

 

table5-management

 

Endocervical curettage during conization

According to a recent study, the performance of endocervical curettage at the time of conization has better positive predictive value (100% vs 47%, p<0,01), when compared to margin status, and improved negative predictive value (94% vs 57%, p=0.01) over margin status in detecting residual disease among women who opt for conservative treatment in AIS 54,55. However, previous studies have raised concerns regarding the predictive value and the safety of practicing endocervical curettage, as residual disease has been detected in 67%56.

In the USA, both historically and also according to the updated ASCCP algorithms endocervical sampling in the form of curettage is mandatory, as it is considered helpful in the work-up of glandular lesions, and it is thus never omitted; possibly for additional medico-legal issues. In contrast, some European authorities, for example BSCCP do not recommend endocervical curettage in any case57 given that the samples are often unsatisfactory and the lesion depth cannot be assessed precisely, relying for the diagnosis in the histological evaluation of a large, deep cylindrical cone.

 

Combination of prognostic factors in detecting invasive endocervical disease

A helpful prognostic index for residual disease is the consideration of “suspicion of invasion” in conization pathology specimens (PSI - Pathologic Suspicion of Invasion), as well as a positive ECC (Endo-cervical curettage).

In patients with invasive disease in hysterectomy specimens, positive PSI in combination with positive ECC was illustrated in 75% and 100% of cases respectively. In patients with positive PSI and positive ECC, positive predictive value for invasive disease is 33%. Moreover, the negative prognostic value of a negative PSI for invasive disease is 94%. Furthermore, negative predictive value for invasive disease, if both prognostic markers (PSI/ECC) are negative, reaches 100%58.

 

HPV-DNA test

Detection of high-risk HPV genotypes (HR-HPV DNA test) contributes significantly in the detection of residual/recurrent disease during post-operative follow-up59,60. A negative HR-HPV DNA test post-operative designates patients with low risk for residual or recurrent disease. In contrast, a positive HR-HPV DNA test possibly represents the most robust independent recurrence prognostic factor.

Debate is ongoing regarding the optimal test of cure (TOC), whether it should be HR-HPV genotyping as a stand-alone test or a combination of HR-HPV genotyping plus cytology (co-testing) in the pursuit of residual or recurrent disease. However, it is accepted that a small percentage of patients who had conservative surgical treatment (conization) will finally turn up with persistent, recurrent, or progressive disease (HG-cGIN or microinvasive adenocarcinoma) rather late in the course of post-operative follow up; prolonged vigilance is therefore warranted 59.

Excisional treatment modalities

In the typical CKC, surgical margins do not exhibit thermal injuries in contrast with other excisional modalities (predominantly LLETZ) which can possibly impair the diagnostic accuracy of the histological interpretation. Rates for recurrent or residual disease are statistically significantly lower, compared with other excisional treatments47,56, possibly because of the usually large volumes of the excised specimens. On the other hand, the latter might represent the reason that CKC exhibits the highest rates of complications when compared with other techniques, mainly primary and secondary post-operative bleeding, constriction of the ectocervical os (producing future inadequate smears), neonatal prematurity, and obstetric morbidity49,50.

Laser conization illustrates a favorable profile in the treatment of AIS, and is almost as effective as CKC53.

Loop conization (LLETZ/LEEP) should preferably by executed under constant colposcopic view. Unfortunately, without prior planning, sufficient accessibility and surgical field, and without selection of the appropriate electrode (loop), it produces shallow cones (±10-15mm), frequently with extensive thermal damage in the excision borders, rendering the evaluation of the surgical margins uncertain. The “top-hat” technique may well achieve tissue removal in sufficient depths; however there might again be uncertainty on the surgical margins. However, newer studies encourage the use of LLETZ with excellent effectiveness and prolonged follow up 56,62-64.

 

Postoperative follow-up

It has been repeatedly mentioned that regular and prolonged (at least 20-25 years) post operative follow up is mandatory for the timely detection of therapeutic failures (residual, recurrent or invasive disease)65. A judicious approach could be i) 6-months: cytology or co-testing, ii) 12 months: cytology or co-testing, iii) 18 months: cytology, and iv) 24 months: cytology or co-testing; co-testing to be repeated in a yearly-basis thereafter. Colposcopy is not mandatory but can be very helpful as indicated. Detection of HPV postoperatively has possibly higher sensitivity, specificity and prognostic value in the detection of recurrent disease, compared to cytology or conzation margin status66-68. Following completion of the individual's family, a definite solution is advised (hysterectomy), not only due to incomplete understanding of the biological course of the disease, but predominantly because of the incessant pending danger of developing AIS/endocervical adenocarcinoma65.

Recent literature has conclusively illustrated that preventive anti-HPV vaccination is effective in the long-term protection of women from high-grade cervical intraepithelial lesions attributed to HR-HPV genotypes (mainly 16, 18). Accordingly, in countries with organised vaccination systems which achieved high population coverage, a substantial reduction in the incidence of cervical adenocarcinoma is anticipated.16,68

 

Conclusions

Although atypical glandular cells represent a relatively rare finding in cytology smears, their management remains difficult and problematic, not only because of their occult origin, but also because of the stronger correlation with dysplastic or preinvasive lesions compared to the squamous counterparts. There is a genuine increase in their incidence, attributed to increased rates of HPV infection, their facilitated recognition with the aids of LBC, and the increased vigilance of cytologists both towards unmasking the entity and also signing a relevant report. Their clinical significance varies, given the wide range of underlying pathology which exists.

For younger patients, the appropriate management of glandular lesions is difficult to be standardised and it is often individualized, tailored to their fertility concerns. However, management of menopausal women with severe glandular cervical lesions should follow the relevant guidelines of the scientific societies and health authorities.

When conservative surgical approach is contemplated for young women, detailed advising is mandatory on the possible postoperative complications and the increased rates of recurrent or residual disease, while regular follow-up is mandatory. Given that the natural history and the evolution of glandular dysplasias to adenocarcinoma have been not yet fully elucidated, upon completion of the family, a definite treatment (hysterectomy) is advised.

 

 

Conflict of interest

All authors declare no conflict of interest

 

 

 

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Lazarou George1, Stournaras Stamatios2, Nousia Konstantina2, Zygouris Dimitrios3

1Department of Obstetrics and Gynecology, Stony Brook University, School of Medicine, Winthrop University hospital, Stony Brook, New York, USA

26th Department of Obstetrics and Gynecology, Elena Venizelou hospital, Athens, Greece

3Department of Gynecology, Agios Savvas hospital, Athens, Greece

Correspondence: Lazarou George. Email: This email address is being protected from spambots. You need JavaScript enabled to view it.

 

 


 

 

Abstract

Microscopic hematuria is a common finding in urinalysis during gynecological-obstetric control. We present the case of a 58 years old woman with recurrent hematuria in annual gynecological check. The literature review highlights a series of tests that must be carried out to investigate these cases. Medical history and physical examination are the first steps approach to identify potential causes and risk factors. The laboratory investigation includes intravenous urography, ultrasound, CT and MRI. Moreover cystoscopy contributes to the evaluation of the lower urinary tract and should be performed in all cases over 35 years. Finally, we must always have in mind that in 20% of cases it is not found any cause of the microscopic hematuria.

Key words: hematuria, microscopic hematuria, pregnancy

 

 

 

Whether it is an annual gynecologic visit in obstetrics or an office visit for evaluation of urinary symptoms, the obstetrician-gynecologist typically evaluates patients with one of the most commonly used diagnostic tests in modern medicine, the urinalysis. Since microscopic hematuria is frequently found on urine dipstick, it is important for the provider to have a good understanding of how to proceed with the finding of microscopic hematuria. This article will focus on the differential diagnosis and work-up for microscopic hematuria in the gynecologic and obstetric patient.

 

Case report

A 58 years old female presents with recurrent microscopic hematuria on urinalysis during her routine annual gynecologic evaluation. She only reports some mild dysuria and urinary incontinence when coughing or sneezing. She is post-menopausal and not taking hormone replacement. She smokes ½ pack of cigarettes for over 20 years. The patient is taking coumadin (therapeutic range) for a recent deep vein thrombosis of her lower extremity. What is the appropriate and current recommended evaluation for her microscopic hematuria?

The patient presented is at higher risk for a urologic malignancy due to her smoking history and age. She was evaluated with multiphasic CT urography with and without IV contrast and cystoscopy revealing a small polypoid tumor in the bladder. Cystoscopic transurethral resection revealed superficial low-grade transitional cell carcinoma.

 

Discussion

The American Urologic Society (AUA) has released new 2012 guidelines for diagnosis and evaluation of microscopic hematuria. According to the AUA microscopic hematuria is defined as 3 or more blood cells per high powered field in one centrifuged urinary sediment1. Obtaining a clean catch specimen is especially important in women to decrease contamination from the vagina2. It is unclear exactly how prevalent microscopic hematuria is, however studies have reported a broad range from 2.4% to 31.1% of patients depending on their age and sex1. In contrast to macroscopic hematuria where 25% of people have urologic cancers only 1-10% of patients with microscopic hematuria have urologic cancer . Blood in the urine can arise from any point in the urinary tract; the kidneys, the ureters, the bladder, or the urethral meatus. When microscopic hematuria is found on a urine dipstick the differential diagnosis must include all etiologies for all possible anatomic locations. There are several benign causes of microscopic hematuria in women which include menstrual contamination, excessive exercise, sexual intercourse, urinary tract infection, urolithiasis, idiopathic or recent urologic instrumentation. And some times in pregnancy is normal because the changes in the kidney function.

An algorithm of the work-up for microscopic hematuria in women is shown in Figure 1. As with any workup, the approach to microscopic hematuria starts with a complete history and physical examination. A history of trauma may suggest injury to the urinary tract. It is important during the history to determine if microscopic hematuria may be explained by one of the benign causes listed previously. After such benign causes have been ruled out the next step is to determine if there are any symptoms associated with the microscopic hematuria.  Most importantly, is the patient experiencing any pain? Pain can indicate inflammation or obstruction in the urinary tract. The specific locations of pain, that are of interest, are abdominal, flank, suprapubic or urethral. Unilateral flank pain which is episodic and radiating to the groin may indicate a high suspicion for a kidney stone. Symptoms such as fever and dysuria may suggest a urinary tract infection. An inflamed urethral caruncle in a postmenopausal woman may also be a source of microscopic hematuria.

Aspirin or anticoagulant use is not a cause of microscopic hematuria unless the patient is over-anticoagulated3. Certain medications such as quinidine, anti-inflammatory medications and some antibiotics can cause acute interstitial nephritis which could present as microscopic hematuria4. Past medical history of previous urinary pathology or past urologic procedures can indicate current pathology. Microscopic hematuria can be a manifestation of systemic diseases with renal involvement such as lupus erythematosus and the vasculitides. Some familial disorders to inquire about which may cause microscopic hematuria include polycystic kidney disease and hereditary nephritis. Noting any recent travel history is also important because infectious pathogens vary by region and continent.

After the history, a focused physical examination should be performed. Tenderness at the costovertebral angle may indicate renal calculus or pyelonephritis. Pain radiating to the groin from the kidney also may suggest a kidney stone. Suprapubic tenderness indicates the bladder may be involved and a possible cystitis. Finally, urethral tenderness is suspicious of urethritis. Additionally, in all female patients it is important to perform a speculum and bimanual pelvic examination to investigate for non-urinary bleeding from the vagina, cervix or uterus. Women with a history and physical suggestive for benign causes of hematuria should be re-tested after the likely etiology has stopped. Patients with symptomatic microscopic hematuria or those who are at high risk for urologic malignancies (Table 1) should be referred to a urologist for further evaluation.

The differential diagnosis for microscopic hematuria is illustrated in Table 2. It is divided into glomerular and nonglomerular causes. Glomerular causes of hematuria will show red cell casts on microscopy and traditionally present with dysmorphic red blood cells. The glomerular causes of microscopic hematuria can also be associated with proteinuria and renal insufficiency. Patients with these findings should be referred to a nephrologist for further evaluation3.

The four imaging modalities which are used to evaluate the upper urinary tract are intravenous urography (IVU), ultrasonography, computed tomography (CT) urography and magnetic resonance imaging (MRI) urography. IVU and ultrasonography have fallen out of favor because additional studies are usually needed. IVU is unable to distinguish between solid and cystic masses and ultrasonography is limited in its assessment of small renal masses (<3cm)1. Multi-phasic CT urography with and without intravenous (IV) contrast as well as delayed images (CT urogram) is considered the best diagnostic modality for evaluation of microscopic hematuria. The sensitivity for identifying renal pathology is reported as approximately 94% 5. MRI urography is useful for patients who cannot tolerate the contrast needed for the CT urography. Although the efficacy of MRI urography is equivalent to CT urography for imaging the renal parenchyma, the efficacy of the imaging of the collecting systems has not been studied sufficiently1. The AUA recommends multi-phasic CT urography as the preferred radiologic modality of choice for upper urinary tract imaging in patients with microscopic hematuria.

Cystoscopy and urine cytology are two commonly used diagnostic modalities for the evaluation of the lower urinary tract. Cystoscopy should be part of the initial workup for microscopic hematuria in patients over 35 years old1. If and when a cystoscopy is being performed, a regrograde pyelogram can be performed intraoperatively under fluoroscopy to evaluate the upper urinary tracts. This can be especially useful in those with contraindications for IV contrast. For patients less than 35 years of age the risk of having a urologic malignancy is very low that a cystoscopy is not typically necessary unless the history and physical examination is significant or additional risk factors exist1. Urine cytology has a sensitivity of approximately 90% for high grade carcinoma however only 50% for low grade lesions6. Therefore, the current AUA recommendations do not include routine urine cytology as part of the initial work up for microscopic hematuria however; urine cytology may be included in the evaluation for patients with a negative workup and persistent microscopic hematuria as well as patients with risk factors for urinary malignancies1. Those patients who are considered low-risk for urologic malignancy may be followed conservatively1.

In approximately 20% of female patients there is no definitive cause for microscopic hematuria after an appropriate workup. Approximately 3% of these patients will eventually be diagnosed with a urologic cancer. It is suggested that those who have persistent microscopic hematuria and have a negative initial work up should have another workup in 3 to 5 years in addition to yearly urinalysis. Those patients who fall into the low risk group can stop the yearly urinalysis after 2 years if the urinalysis is consistently negative1.

 

image8 low

 Figure 1. Urologic evaluation of microscopic hematuria in women

  table1-microscopic               table2-microscopic

 

Conflict of interest

All authors declare no conflict of interest

 

 

 

References

1. Davis R, Jones JS, Barocas DA, et al. Diagnosis, evaluation and follow-up of asymptomatic microhematuria (AMH) in adults: AUA guideline. J Urol 2012;188:2473-81. PubMed

2. Erekson, EA, McMahon MD, Moule BA, Rardin CR. Microscopic hematuria in women. Obstet Gynecol 2011;117:1429–34. PubMed

3. Rao PK, Jones JS. How to evaluate “dipstick hematuria”: what to do before you refer. Cleve Clin J Med 2008;75:227–33. PubMed

4. Sandhu KS, LaCombe JA, Fleischmann N, Greston WM, Lazarou G, Mikhail MS. Gross and microscopic hematuria: guidelines for obstetricians and gynecologists. Obstet Gynecol Surv 2009;64:39-49PubMed

5. Albani JM, Ciaschini MW, Streem SB, Herts BR, Angermeier KW. The role of computerized tomographic urography in the initial evaluation of hematuria. J Urol 2007;177:644-8. PubMed

6. Feifer AH, Steinberg J, Tanguay S, Aprikian AG, Brimo F, Kassouf W. Utility of urine cytology in the workup of asymptomatic microscopic hematuria in low-risk patients. Urology 2010;75:1278–82. PubMed

 Iliodromiti Zoe1, Grigoriadis Charalampos1, Stournaras Stamatis2, Daniilidis Angelos3, Dafopoulos Konstantinos4, Vrachnis Nikolaos1

1 2nd Department of Obstetrics and Gynecology, Aretaieio hospital, University of Athens, Medical School, Athens, Greece
2 6th Department of Obstetrics and Gynecology, Elena Venizelou hospital, Athens, Greece
3 2nd Department of Obstetrics and Gynecology, Hippokrateio hospital, University of Thessaloniki, Medical School, Thessaloniki, Greece
4 Department of Obstetrics and Gynecology, Larissa University hospital, University of Thessaly, Medical School, Larissa, Greece

 

Correspondence: Vrachnis Nikolaos, 2nd Department of Obstetrics and Gynecology, University of Athens, Medical School, Aretaieio hospital, 76 Vasilissis Sofias Avenue, GR-11528, Athens, Greece. Email: This email address is being protected from spambots. You need JavaScript enabled to view it.

 

 


 

Abstract

Eicosanoids, biologically active molecules possessing a wide range of functions, include prostaglandins, thromboxanes and leukotrienes. During pregnancy, eicosanoids are produced by the chorionic membranes and the decidua as well as by the placenta. The eicosanoids play an important role throughout pregnancy. During implantation, they enable the trophoblast to invade and colonize the maternal spiral blood vessels of the myometrium. Through the entire period of fetal growth and development, eicosanoids play a significant role as vasoregulators of fetal-uterine blood flow and circulation. Prostaglandins also have the ability to affect placental protein synthesis and the modulation of the production of certain other hormones. Finally, eicosanoids promote the initiation and progress of labor. The aim of this study was to review recent literature data on the spectrum of eicosanoids functions during pregnancy while seeking to identify their potential role in pathological conditions.

Key words: eicosanoids; prostaglandins; pregnancy; labor; placenta

 

 

 

Eicosanoids represent a wide category of hormones, among which are prostaglandins, thromboxanes and leukotrienes. Arachidonic acid, a multi-unsaturated fatty acid consisting of 20 carbon atoms, is the initial molecule in the process of their synthesis. Since eicosanoids cannot be stored after their production, their synthesis is dictated by the organism's needs. The primary molecule, arachidonic acid, is an enzyme released by membrane phospholipids under the action of phospholipase Α2. It is of note that the cells of several target tissues may respond to eicosanoids via specific receptors of their cellular membrane.

During pregnancy, eicosanoids are produced by the chorionic membranes and the decidua, while a number of leukotrienes are also produced by the placenta itself. Additionally, the placenta may convert arachidonic acid into thromboxanes, prostacyclin, prostaglandins PGE2, PGF2a and PGD21.

The role of eicosanoids is important throughout pregnancy. Eicosanoids favor the procedures of implantation as well as the initiation and progress of delivery, while they simultaneously support the maintenance of gestation and normal fetal growth. Oxytocin stimulates the decidual cells thereby increasing the rhythm of PGF2a synthesis2. Towards the end of gestation, the concentration of arachidonic acid becomes extremely elevated in the chorionic membranes3. Eicosanoids exert numerous functions all through pregnancy, which can be divided according to the stage of pregnancy.

The aim of this review study was to analyze current literature data concerning the wide range of functions of eicosanoids throughout gestation while concurrently seeking to pinpoint their potential role in pregnancy complications.

 

Implantation

The crucial role of eicosanoids at the stage of implantation was proven following the observation that indomethacin, a cyclooxygenase inhibitor, inhibits the procedure of implantation as well. In addition, research studies have clearly demonstrated that during implantation, the production of prostaglandins and thromboxanes and, most importantly, the synthesis of prostacyclin enable the trophoblast to invade and colonize the maternal spiral blood vessels of the myometrium. Prostacyclin is a vasodilating molecule which also inhibits platelet aggregation. The final outcome is the creation of an ideal milieu for implantation4-6.

 

Fetal growth

Eicosanoids participate in the complex procedures of fetal growth and development. Prostaglandins, thromboxanes and prostacyclin play a major role as vasoregulators of the fetal-placental-uterine blood flow and circulation that supplies all the necessary molecules and oxygen to the fetus, thus ensuring normal intrauterine growth7.

The PGE2 acts via vasodilation of the uterine vessels and vasoconstriction of umbilical circulation, while PGF2a exerts vasoconstrictive action on both uterine and umbilical circulation. In cases of arterial hypertension in pregnancy or preeclampsia, reduced levels of prostacyclin and an increased production of thromboxanes have been described8-10.

However, prostaglandins do not have only a vasoregulatory role. They are also capable of affecting placental protein synthesis and modulating the production of certain other hormones. Although PGF2a is a factor which down-regulates the production of human chorionic gonadotropin (hCG), there are however in parallel controversial data supporting the notion that PGF2a may also stimulate the secretion of hCG. Other in vitro research studies conclude that arachidonic acid—more robustly than its derivatives—is responsible for the down-regulation of hCG. Furthermore, both prostacyclin and PGE2 seem to increase the levels of cAMP.

 

Labor

Τhe eicosanoids play a major role not only in the initiation but also in the progress of labor. The prostaglandins are involved in the contraction of the uterine smooth muscle cells, while PGF2a enhances the uterine contractions after the administration of oxytocin, which results in the creation of gap ligaments among uterine smooth muscle cells2,11. Estradiol favors this procedure as well. The abovementioned gap ligaments enable the uterine smooth muscle cells to contract in a synchronized manner, one that closely resembles the contractions of the heart ventricles. Finally, prostaglandins act upon the cervix uteri leading to cervical ripening, via softening, and to elimination and dilatation of the cervix early in labor. This ripening resembles to the inflammatory response during which an invasion of polymorphonuclear leukocytes takes place. The above understanding of prostaglandin functions has resulted in recourse to high-dose prostaglandins administration in pregnant women prior to the 24th week of gestation to induce iatrogenic termination of pregnancy (pharmaceutical abortion) when a major indication for this decision is present.

At specific doses, prostaglandins are ideal for induction of labor. Depending on the mechanism of cervical ripening, prostaglandins are administered in women with a low Bishop score as a method for induction of labor in full-term pregnancies or when the maintenance of gestation increases the risk of perinatal morbidity and mortality (for example, in cases of maternal diabetes mellitus in combination with fetal macrosomia). In addition, their administration is helpful prior to such gynecological procedures as diagnostic or operative hysteroscopy, especially in women without a history of vaginal delivery.

Finally, arachidonic acid has been shown to act similarly when given intraamniotically, this being inversed in cases of prolonged aspirin administration, as aspirin is a cyclooxygenase inhibitor12-14.

 

Factors associated with increased eicosanoids production

The factors which are associated with increased eicosanoids production include corticotropin releasing hormone (CRH), several cytokines and growth factors.

Both CRH and cytokines actively participate in labor, with the increase of eicosanoids representing one of their main potential pathways of action. Additionally, glucocorticosteroids, progesterone and estrogens influence the production of eicosanoids, and especially that of prostaglandins. Furthermore, gonadotropin releasing hormone (GnRH) affects the production of prostaglandins by the placenta. However, the character and the degree of association between chorionic GnRH and placental prostaglandins depends on the age of gestation. Generally, in cases of elevated GnRH levels, the placental production of prostaglandins is higher. Of particular interest is fact that a GnRH antagonist may lead to the down-regulation of prostaglandins production.

Several growth factors, mainly endothelial growth factor (EGF) and platelet activating factor (PAF), favor prostaglandins production, this leading to increased secretion by the chorionic membranes. PAF plays a major role in regulating prostaglandins secretion during labor, this factor being found in the amniotic fluid during the process of labor but not prior to its initiation15-17.

 

Conclusions

It appears clear that eicosanoids crucially contribute to an uncomplicated start of pregnancy through their significant involvement in the process of trophoblast implantation, the maintenance and progress of gestation by means of their participation in the complex procedures of fetal growth and development, and the initiation and progress of labor via multiple actions in the myometrium and the cervix uteri.

 

Conflict of interest

All authors declare no conflict of interest

 

 

References

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