Hidden carcinoma of uterine cervix

The objectives were to evaluate the prevalence of Hidden Cervical Cancer (HCC), to analyze diagnostic and histopathological aspects, and clinical evolution of 677 patients with cervical cancer, attended from January 1995 through December 2013. The design was retrospective and observational. The diagnostic methods used were cytology, colposcopy and histopathological study of surgical specimens. The HCC was found in 68/677 patients (10,04%): 55,9% of which consulted for a medical checkup, 33,8% for metrorragia, 19,1% for sinusorragia, 2,9% for bleeding and 1,5% for inguinal node; whereas 62% of the patients with exocervical or exoendocervical cancer (EEC) consulted for bleeding, 23% for sinusorragia and vaginal discharge with odor, and 16% for a medical checkup (p< 0.0003). The cytology’s sensitivity for HCC was 47,1% (CI 95%, 35.2-59), 36,8% were false negatives; whereas for EEC it was 69,1% (CI 95%, 65.4-72.8) and 12,3% respectively (p< 0.001). The colposcopy’s sensitivity for HCC was 17,65% (CI 95%, 8.6-26.7); whereas for EEC it was 85,55% (CI 95%, 82.8-88.4; p< 0.0001). 30,9% of the cases of HCC were diagnosed by biopsies and 41,2% by surgical procedures; whereas 89,3% of the cases of EEC were detected in biopsies and 7,22% in surgical pieces (p< 0.0002). The torpid evolution of the disease, its rapid progression and death was significantly greater in patients with HCC than in patients with EEC (34,43% vs. 17,1%; P< 0.002), since HCC was diagnosed in more advanced stages and it had 19,12% adenocarcinoma and adenosquamous histology vs. 8,37% in EEC. Conclusions: patients with HCC had a worse evolution and poor outcome significantly greater than in patients with EEC. The use of virological tests in the screening would allow to detect HCC in early stages. Correspondence to: Dr. Delia B. Dalbert, Mayor P. Castelli 834, Villa Sarmiento, Haedo, Zip Code: 1706, Buenos Aires, Argentina, Tel: (54-11) 4654-7564; E-mail: dbdalbert@yahoo.com.ar


Introduction
Hidden cancer of uterine cervix is an endocervical and /or endoglandular carcinoma located deep or higher up in the miocervix, reason by which it constitutes a big diagnosis problem and a challenge for colposcopist and cytopathologist experts.
The revision of smears in patients with cervical carcinoma, demonstrated 4% of diagnostic doubts originated in reactive and inflammatory changes, and the presence of immature squamous metaplastic type cells (ISM) in 68,75% [1,2].
The squamous carcinomas originated in ISM that evolve deep in the endocervical canal and into de glandular crypt are very frequently, inaccessible to colposcopic and cito-histophatologic diagnosis, with delayed expression in advanced stages [3]. In 60% of ISM, HPV types 16 and 18 have been detected [4]. In the same way, the adenocarcinomas, specially the 'endometroide' variant, originated high up in the cervical canal evolves hidden or inaccessible to diagnostic methods. The latter is the most frequent type in the cervix [5].
Glandular or squamous lesions originated in glandular epithelium or ISM, into the cervical canal, 3 to 4 cm long, with cripts that reach up to 8-10 mm deep in the miocervix according to the authors, cause difficulties and delays in the diagnosis, since their evolution is hidden and thus are detected in more advanced stages. The chances of missing out the lesion are considerable [6,7]. Frequently, these are patients with negative smears and normal or low suspicion colposcopies, even in the last six to twelve months preceding a diagnosis of carcinoma [8,9].
The objectives were to evaluate the incidence of hidden cervical cancer (HCC), to analyze the diagnostic, histopathological aspects and clinical evolution.

Material and methods
In Gynecological Services of the National Hospital Prof. Dr. A. Posadas, between January 1995 and December 2013, 677 patients were diagnosed with cervical cancer.
Design: retrospective and observational study.
Unit of study: all women with cervical cancer who were attended during this period. A revision of their clinical cards and histories was made.
Selection criteria: patients with cervical cancer and a follow-up of more than twelve months. The tumor diagnosis and stage was assessed according to criteria of the Argentine Association of Gynecology and Oncology (AAGO), FIGO 2009 norms and staging and the histopathological criteria of the World Health Organization (WHO). Ectocervical and endocervical cytology with brush (brushing), and colposcopy of lower genital tract were performed. Histopathological study of all biopsies and surgical specimens was performed.
Patients received treatments according to the clinical staging of disease: total hysterectomy, radical hysterectomy with lymph node dissection, with removal of the fallopian tubes and ovaries (Wertheim-Meigs), or without removal fallopian tubes and ovaries, neoadyuvant chemotherapy, concurrent chemotherapy and radiotherapy, braquitherapy and telecobaltotherapy. A follow-up was held for more than twelve months.
Statistical analysis: Chi square, Fisher´s exact and probability test.
The probability values <0.05 was considered significant.
Definition: hidden cancer of the uterine cervix (HCC) refers to the cancer located deep or up in the endocervical canal and miocervix, whose detection is delayed, with negative cytology, colposcopy and biopsies 6 to 12 months before its clinical and / or cyto-colposcopical expression; distinguishing it from the cancer located in the exocervix or exo-endocervix (EEC).

Results
The mean age of the patients with HCC was 47.5 years old  and the age of those who presented EEC was 48.7 years old (21-90). The hidden cervical carcinoma was found in 68/677 patients representing 10,04%.

Follow-up
In 7/68:10,29% patients data was not registered because they were treated or their follow-up was carried out in other centers. Out of the 61 patients with HCC, 21 (34,43%) with advanced stages had a rapid progression of the disease and death: 9 (42,86%) of them in less than one year (2 patients with stage IIab, 4 with stage III and 3 with stage IV), 10 (47,62%) of them between one and two years (3 patients with stage IIab, 5 with stage III and 2 with stage IV) and 2 (9,52%) of them between two and three years (stages IIab and IV); whereas 104/ 609 (17.1%) patients with advanced stages of EEC had torpid evolution and death in less than three years (p<0.002).

Discussion
The HCC is originated deep in the endocervical canal, or into glandular crypts in the upper part of the canal, or in focal Immature Squamous Metaplasia (ISM). Its detection in advanced stages was most frequently observed by delays in the clinical expression [3,5].
The presence of small adenocarcinomas in absence of prior adenocarcinomas in situ, suggests the possibility of rapid progression [5]. Symonds P. et al. suggest that diagnosis in advanced stages is more dependent on the biological behavior of the tumor than on the delay in its clinical expression. However they observed, and it is noteworthy, that the diagnosis of asymptomatic invasive cervical cancer was made following a routine smears only in 5,7% 10 .
Most of the patients with HCC were asymptomatic (55,8%) and consulted for a medical checkup; whereas only 16% of the women with EEC were asymptomatic. These results match previous studies [9,10] (p<0.0003).
The sensitivity of cytology for HCC was less than for EEC, and the number of false negatives and subdiagnosis was greater in the HCC patients; the differences were significant and match findings in previous studies [11,12].
In this study we found ISM cells without atypia in patients with   In previous studies, we have observed by hibridation in situ, HPV types 16 and 18 in areas of mature and immature squamous metaplasia, near condilomas and Cervical Intraepithelial Neoplasia (CIN), associated with CIN II-III more frequently in the immature metaplasia than in mature metaplasia, where HPV types 6 and 11 predominated. Similar findings were observed by others autors [4,13,15].
The false-negatives cytologic smears, either because of inadequate sampling or because of diagnostic errors, are recognized causes of the delayed detection of the disease [16][17][18][19].
Therefore, it is necessary to consider the possible existence of a hidden carcinoma deep in the cervix and to optimize the diagnostic methodology, adding, as well, some of the virological tests that are already successfully being used in some developed countries [20][21][22][23][24]. Using exocervical cytology and endocervical brushing, the falsenegatives decrease only 3% [25,26].
Hatem and Wilbur in the Rochester University Medical Center, related false-negative smears with rapid progression and they published the presence of atypical immature squamous metaplasia cells in 68% [3].
Al-Nafussi et al. observed that the cellular changes associated with inflammation, atrophy or mature squamous metaplasia have minor cervical predictive value for neoplasia, than those associated with immature squamous metaplasia [27].
Most of the patients with HCC displayed negative colposcopy or low suspicion, with delayed clinical expression. The HCC was missed on cytology smears as well as on colposcopically directed biopsies and was detected only on abrasive brushing and/ or endocervical curettage, LLETZ, conisation and hysterectomy. The difference with EEC was significant. Similar data was observed by others authors [28][29][30].
Kodiathodi et al., found a significant proportion of women with negative colposcopy and nuclear borderline changes in endocervical cells, and the presence of H-SIL and carcinomas during the first year of follow-up. They propose to optimize the algorithm diagnosis to detect high grade histology and cancer in earlier stages [31].
As regards the evolution of the disease, its rapid progression and death was significantly greater in patients with HCC than in patients with EEC (34,43% vs. 17,1%; P<0.002), due to its presentation in advanced stages and its histologic type. These differences were related, not only to the stage of the tumor, advanced in most cases, but also to the histologic type (adenocarcinoma and adenosquamous: 19,12% in HCC and 8,37% in EEC) and its differentiation, since its biological behavior is more aggressive and with worse prognosis [10,33,34].
It is important to focus in early diagnosis of cervical cancer. Therefore, it is necessary to optimize the diagnostic methodology available, investigating risk factors for cervical cancer development and including virological tests that would allow to detect hidden endocervical lesions [20][21][22][23][24][35][36][37].
We consider of great importance to implement health policies that aim to prevention and early detection of cervical cancer. This will lead to improve prognosis of the disease, survival, quality of life and to significantly reduce therapeutic costs.

Conclusions
• The squamous and glandular lesions originated deep or in the crypts or in the upper part of the endocervical canal, evolve hidden, and are missed by the diagnostic methods. They are frequently asymptomatic and detected in advanced stages.
• Patients with HCC have a rapid progression and death significantly greater than in patients with EEC.
• To optimize the usual diagnostic methodology and to use virological tests in the screening, would allow to detect with greater success endocervical and endoglandular lesions, and the hidden carcinoma in earlier stages.