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Synchronous invasive squamous cell carcinoma and clear cell adenocarcinoma of the uterine cervix: A different human papillomavirus status
Gynecologic Oncology 97 (2005) 976 – 979 www.elsevier.com/locate/ygyno
Case Report
Synchronous invasive squamous cell carcinoma and clear cell adenocarcinoma of the uterine cervix: A different human papillomavirus status Kenji Goto*, Yuzuru Takeuchi, Akira Yakihara, Fumikazu Kotsuji Department of Obstetrics and Gynecology, University of Fukui, Matsuoka-Cho, Yoshida-Gun, Fukui 910-1193, Japan Received 7 January 2005
Abstract Background. A multiple primary invasive carcinoma of the cervix is a rare condition and is seldom composed of squamous cell carcinoma and clear cell adenocarcinoma. Case. A 47-year-old woman presented with contact bleeding. The anterior lip of the cervix revealed a 2.0-cm protruded mass. Preoperative pathological and imaging studies demonstrated the squamous cell carcinoma of the exocervix alone. Radical hysterectomy was performed on the diagnosis of stage 1B cervical cancer. Histological examination of the specimen manifested a coexisting invasive clear cell adenocarcinoma in the endocervix. Human papillomavirus (HPV) 18 was detected in the squamous cell carcinoma; however, no HPV was detected in the clear cell adenocarcinoma. Conclusion. This finding suggests that there was an obvious difference in association of HPV with the two neoplasms. D 2005 Elsevier Inc. All rights reserved. Keywords: Multiple primary carcinoma; Clear cell adenocarcinoma; Squamous cell carcinoma; Cervical cancer; Human papillomavirus
Introduction
Case report
Coexistence of varying degrees of cervical intraepithelial neoplasia and primary adenocarcinoma has been reported [1 –3]. However, reports of synchronous invasive squamous cell carcinoma and invasive adenocarcinoma of the uterine cervix are rare [3,4]. Especially, combination of squamous cell carcinoma and clear cell adenocarcinoma is very rare. We report on a case of synchronous invasive squamous cell carcinoma and clear cell adenocarcinoma, in which human papillomavirus (HPV) 18 was detected in the lesion of squamous cell carcinoma, but no HPV was found in the lesion of clear cell adenocarcinoma. This finding suggests different etiology between squamous cell carcinoma and clear cell adenocarcinoma.
A 47-year-old premenopausal woman, gravida 2, para 2, presented with contact bleeding in February 1999. She had no history of exposure to in utero exogenous steroid hormone. The gynecological examination revealed a 2.0-cm exophytic mass protruding from the anterior lip of the cervix. Papanicolaou smear taken from the exocervix surrounding the mass showed malignant epithelial cells compatible with squamous cell carcinoma, however, that from the endocervix revealed normal columnar cells. Biopsy specimen from the exophytic mass showed a poorly differentiated squamous cell carcinoma. Curettage specimens from the endocervix and endometrium revealed normal glandular histology. There was no evidence of tumor expansion neither to vagina, parametrium, nor to endometrium. No lymph node involvement of pelvic and para-aortic nodes was found. T2-weighted magnetic resonance imaging (MRI) and dynamic MRI clearly delineated only a solitary tumor of the anterior lip (Fig. 1). No
* Corresponding author. Fax: +81 776 61 8117. E-mail address: [email protected] (K. Goto). 0090-8258/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2005.03.027
K. Goto et al. / Gynecologic Oncology 97 (2005) 976 – 979
977
Fig. 1. T2-weighted MR image showing high signal intensity mass in the anterior lip of the cervix (left panel; white arrow). Dynamic MR image delineating the same hypointense lesion (right panel; black arrow).
metastatic lesion was observed. Serum squamous-cell carcinoma antigen (SCC), CEA, and CA 125 levels were all within normal limits. On the diagnosis of stage 1B cervical cancer, a radical hysterectomy with systemic pelvic lymphadenectomy was performed. Parametria and adnexa were free from tumor. Macroscopical examination of the specimen revealed the exophytic lesion and an unexpected distinct cancerous lesion, which was 1.5 cm in size and was located in the endocervical glandular region. Both carcinomas were apart from each other (Fig. 2). Histological study demonstrated an invasive squamous cell carcinoma (poorly differentiated, non-keratinizing type, Fig. 3) accompanied with an invasive clear cell adenocarcinoma of the endocervix (Fig. 4). Tumor involvement to pelvic lymph nodes was free. The postoperative diagnosis was a double primary carcinoma of stage 1B1 of the cervix. The adjuvant irradiation therapy was not done. Postoperative re-examination of MRI, Pap smear, and biopsy specimens showed negative findings for concomitant exis-
Fig. 2. Cross section showing an exophytic lesion of the exocervix (arrow; squamous cell carcinoma) and an endophytic lesion of the endocervix (arrow head; clear cell adenocarcinoma) (hematoxylin and eosin, 1.0, original magnification). C; normal cervical epithelial region used for control for HPV detection.
tence of clear cell adenocarcinoma. She has been followed for over 70 months, with no evidence of recurrent disease. Histological findings The exophytic lesion was composed of cells with hyperchromatic oval nuclei and scant indistinct cytoplasm with less squamous differentiation, suggesting poorly differentiated squamous carcinoma (Fig. 3).
Fig. 3. The exophytic lesion showing hyperchromatic oval nuclei with less squamous differentiation (upper panel, 5; lower panel, 200).
978
K. Goto et al. / Gynecologic Oncology 97 (2005) 976 – 979
lesion of clear cell adenocarcinoma. Control sample of normal cervical epithelium away from the two carcinomas was also negative for HPVs. These findings were confirmed by additional PCR analysis using E6 specific probes for HPV 16 and 18.
Discussion
Fig. 4. Endocervical tumor showing cells with clear cytoplasm and hyperchromatic, pleomorphic ‘‘hobnail cells’’ (upper panel, 5; lower panel, 200).
Tumor of the endocervix was composed of cells that have clear cytoplasm and form glandular or trabecular pattern covered by normal columnar epithelium. Cytoplasm showed PAS positive and diastase digestion. There are cells with hyperchromatic and pleomorphic nuclei that project into the lumen, suggesting hobnail cells of clear cell adenocarcinoma (Fig. 4). HPV detection Three 10-Am sections of formalin-fixed, paraffin-embedded tissue were placed on glass slides and were deparaffinized. As shown in Fig. 2, tumor tissues were microdissected from the lesion of squamous cell carcinoma and clear cell adenocarcinoma. Histologically benign cervical epithelium away from the two carcinomas was also microdissected as a negative control (Fig. 2, C). DNA was extracted by using a DNA isolation kit (QIAGEN K.K., Tokyo Japan). HPV detection and genotyping was performed using a commercially available HPVDNAChip (Biomedlab Co., Seoul, South Korea, MBC, Tokyo, Japan), a PCR-based DNA microarray system, as described elsewhere [5,6]. HPVDNAChip contains 22 type-specific probes, 15 high-risk HPVs (16/18/31/33/35/39/45/51/52/56/58/59/66/68/69) and 7 lowrisk HPVs (6/11/34/40/42/43/44). h-globin was amplified as an internal control. Sample from lesion of squamous cell carcinoma was positive for HPV 18. However, no HPV was found in the
This case presented an invasive double primary carcinoma of the uterine cervix composed of a squamous cell carcinoma and a clear cell adenocarcinoma. A double primary carcinoma of one organ is defined as a condition when the two carcinomas are histologically distinct and separated from each other by stroma or basal lamina. A collision tumor, on the other hand, is defined as two independently occurring neoplasms invading one another. Simultaneous occurrence of cervical intraepithelial neoplasia and primary adenocarcinoma has been reported [1– 3]; however, concomitant presence of invasive squamous cell carcinoma and invasive adenocarcinoma occurring independently in the cervix has been reported sporadically [3,4]. Furthermore, report of combination of squamous cell carcinoma and clear cell adenocarcinoma could not be found in the literature. Maiyer et al. [3] analyzed the coexistence of squamous cell neoplasm in 230 cases of primary adenocarcinoma of the cervix. They found that cervical intraepithelial neoplasia was present in 43% (99/230) cases, but only six cases (2%) exhibited concurrent invasive squamous cell carcinoma. Further, the coexistence of primary clear cell adenocarcinoma with invasive squamous cell adenocarcinoma was not found in their six cases. Similarly, Choo et al. [4] analyzed larger cases of 502 patients with adenocarcinoma and 2175 patients with squamous cell carcinoma and found that only eight cases were of synchronous invasive squamous cell carcinoma and invasive adenocarcinoma. In their report, however, the cell types of adenocarcinoma were not described. Recently, Anastasiadis et al. [7] reported a case of invasive cervical adenocarcinoma of mixed endocervical and clear cell type associated with a squamous cell carcinoma (collision tumor). In the present case, we failed to detect the veiled adenocarcinoma preoperatively. More than half of cervical adenocarcinomas grow endophytically, and this may result in later detection of the disease than the typically exophytic squamous cell carcinomas. It is reported that clear cell adenocarcinomas of the cervix showed predominantly endophytic growth (80%) and extended to the uterine corpus, creating a barrel-shaped cervix, significantly more often than squamous cell carcinoma and non-clear cell adenocarcinoma [8]. Kaminski et al. [9] reported that two of 22 patients (9%) were grossly non-visible and that only three patients (13%) revealed cytology suspicious before treatment. Recent study of Hanselaar et al. [10] showed that 35% of cases of cervical or vagina clear cell adenocarcinomas were cytologically false-negative. This low sensitivity was attributed to the fact
K. Goto et al. / Gynecologic Oncology 97 (2005) 976 – 979
that the development of clear cell adenocarcinoma may be confined to the submucosal space for a long time. The etiology of synchronous occurrence of squamous cell carcinoma and adenocarcinoma of the cervix is not clear. To date, approximately 50 types of HPV are known to infect the female genital tract and a subset of high-risk HPVs is known to have oncogenic potential. HPV DNA is detected in >90% of squamous cell carcinomas of the cervix and approximately one half of squamous cell carcinomas are attributed to HPV 16 [11]; however, the prevalence of HPV DNA in adenocarcinomas of the cervix is about 70% and approximately one half of adenocarcinomas are attributed to HPV 18 [12 –14]. In this case, HPV 18 infection was observed in the lesion of squamous cell carcinoma; however, no HPV infection was observed in the lesion of clear cell adenocarcinoma. This finding suggests that there was an obvious difference in association of HPV with the two neoplasms. Recently, Pirog et al. [15] studied the prevalence of HPV DNA in different histological subtypes of cervical adenocarcinomas. They found that HPV DNA was detected in 91% (82 of 90) of mucinous adenocarcinomas, including endocervical, intestinal, and endometrioid histological subtypes, and that in contrast to mucinous adenocarcinomas, no HPV DNA was detected in any nonmucinous adenocarcinomas (0/6), including clear cell, serous, and mesonephric adenocarcinomas. The lack of association of HPVs with clear cell adenocarcinoma demonstrated in their report is consistent with our finding. In summary, a rare case of multiple primary invasive carcinoma of the cervix, composed of squamous cell carcinoma and clear cell adenocarcinoma, was presented. The specific tumor growth patterns, predominantly exophytic growth of squamous cell carcinoma and endophytic growth of clear cell adenocarcinoma, were demonstrated. Despite recent advanced diagnostic techniques, it is still difficult to detect another carcinoma. Therefore, we should keep in mind the possibility of a multiple primary carcinoma of the cervix. Because of its rarity of coexistence of invasive squamous cell carcinoma and invasive adenocarcinoma of the cervix, there is no report of analysis of HPV status in such double primary carcinoma. This report may be the first to show the HPV status in the invasive double primary carcinoma of the uterine cervix. Further accumulation and analysis of HPV status in such carcinoma may be helpful for understanding the etiology of this unique entity.
979
References [1] Qizilbash AH. In-situ and microinvasive adenocarcinoma of the uterine cervix. A clinical, cytological and histological study of 14 cases. Am J Clin Pathol 1975;64:155 – 70. [2] Dougherty CM, Cotten N. Mixed squamous-cell and adenocarcinoma of the cervix. Cancer 1964;17:1132 – 43. [3] Maier RC, Norris HJ. Coexistence of cervical intraepithelial neoplasia with primary adenocarcinoma of the endocervix. Obstet Gynecol 1980;56:361 – 4. [4] Choo YC, Naylor B. Coexistent squamous cell carcinoma and adenocarcinoma of the uterine cervix. Gynecol Oncol 1984;17: 168 – 74. [5] An HJ, Cho NH, Lee SY, Kim IH, Lee C, Kim SJ, et al. Correlation of cervical carcinoma and precancerous lesions with human papillomavirus (HPV) genotypes detected with the HPV DNA chip microarray method. Cancer 2003;97:1672 – 80. [6] Kim CJ, Jeong JK, Park M, Park TS, Park TC, Namkoong SE, et al. HPV oligonucleotide microarray-based detection of HPV genotypes in cervical neoplastic lesions. Gynecol Oncol 2003;89:210 – 7. [7] Anastasiadis P, Koutlaki N, Tamiolakis D, Liberis V, Galazios G, Sivridis E. Invasive adenocarcinoma of mixed endocervical and clear cell type, associated with invasive squamous cell carcinoma of the cervix uteri. A case report. Eur J Gynaecol Oncol 2000;21: 173 – 6. [8] Reich O, Tamussino K, Lahousen M, Pickel H, Haas J, Winter R. Clear cell carcinoma of the uterine cervix: pathology and prognosis in surgically treated stage 1B – 2B disease in women not exposed in utero to diethylstilbestrol. Gynecol Oncol 2000;76:331 – 5. [9] Kaminski PF, Maier RC. Clear cell adenocarcinoma of the cervix unrelated to diethylstilbestrol exposure. Obstet Gynecol 1983;62: 720 – 7. [10] Hanselaar A, Loosbroek van M, Schuurbiers O, Helmerhorst T, Bulten J, Bernheim J. Clear cell adenocarcinoma of the vagina and cervix. An update of the central Netherlands registry showing twin age incidence peaks. Cancer 1997;79:2229 – 36. [11] Bosch FX, Lorincz A, Munoz N, Meijer CJLM, Shah KV. The causal relation between human papillomavirus and cervical cancer. J Clin Pathol 2002;55:244 – 65. [12] Andersson S, Rylander E, Larsson B, Strand A, Silfversva¨rd C, Wilander E. The role of human papillomavirus in cervical adenocarcinoma carcinogenesis. Eur J Cancer 2001;37:246 – 50. [13] Iwasawa A, Nieminen P, Lehtinen M, Paavonen J. Human papillomavirus DNA in uterine cervix squamous cell carcinoma and adenocarcinoma detected by polymerase chain reaction. Cancer 1996;77: 2275 – 9. [14] Duggan MA, McGregor SE, Benoit JL, Inoue M, Nation JG, Stuart GC. The human papillomavirus status of invasive cervical adenocarcinoma: a clinicopathological and outcome analysis. Hum Pathol 1995;26:319 – 25. [15] Pirog EC, Kleter B, Olgac S, Bobkiewicz P, Lindeman J, Quint WG, et al. Prevalence of human papillomavirus DNA in different histological subtypes of cervical adenocarcinoma. Am J Pathol 2000;157:1055 – 62.
Case Report
Synchronous invasive squamous cell carcinoma and clear cell adenocarcinoma of the uterine cervix: A different human papillomavirus status Kenji Goto*, Yuzuru Takeuchi, Akira Yakihara, Fumikazu Kotsuji Department of Obstetrics and Gynecology, University of Fukui, Matsuoka-Cho, Yoshida-Gun, Fukui 910-1193, Japan Received 7 January 2005
Abstract Background. A multiple primary invasive carcinoma of the cervix is a rare condition and is seldom composed of squamous cell carcinoma and clear cell adenocarcinoma. Case. A 47-year-old woman presented with contact bleeding. The anterior lip of the cervix revealed a 2.0-cm protruded mass. Preoperative pathological and imaging studies demonstrated the squamous cell carcinoma of the exocervix alone. Radical hysterectomy was performed on the diagnosis of stage 1B cervical cancer. Histological examination of the specimen manifested a coexisting invasive clear cell adenocarcinoma in the endocervix. Human papillomavirus (HPV) 18 was detected in the squamous cell carcinoma; however, no HPV was detected in the clear cell adenocarcinoma. Conclusion. This finding suggests that there was an obvious difference in association of HPV with the two neoplasms. D 2005 Elsevier Inc. All rights reserved. Keywords: Multiple primary carcinoma; Clear cell adenocarcinoma; Squamous cell carcinoma; Cervical cancer; Human papillomavirus
Introduction
Case report
Coexistence of varying degrees of cervical intraepithelial neoplasia and primary adenocarcinoma has been reported [1 –3]. However, reports of synchronous invasive squamous cell carcinoma and invasive adenocarcinoma of the uterine cervix are rare [3,4]. Especially, combination of squamous cell carcinoma and clear cell adenocarcinoma is very rare. We report on a case of synchronous invasive squamous cell carcinoma and clear cell adenocarcinoma, in which human papillomavirus (HPV) 18 was detected in the lesion of squamous cell carcinoma, but no HPV was found in the lesion of clear cell adenocarcinoma. This finding suggests different etiology between squamous cell carcinoma and clear cell adenocarcinoma.
A 47-year-old premenopausal woman, gravida 2, para 2, presented with contact bleeding in February 1999. She had no history of exposure to in utero exogenous steroid hormone. The gynecological examination revealed a 2.0-cm exophytic mass protruding from the anterior lip of the cervix. Papanicolaou smear taken from the exocervix surrounding the mass showed malignant epithelial cells compatible with squamous cell carcinoma, however, that from the endocervix revealed normal columnar cells. Biopsy specimen from the exophytic mass showed a poorly differentiated squamous cell carcinoma. Curettage specimens from the endocervix and endometrium revealed normal glandular histology. There was no evidence of tumor expansion neither to vagina, parametrium, nor to endometrium. No lymph node involvement of pelvic and para-aortic nodes was found. T2-weighted magnetic resonance imaging (MRI) and dynamic MRI clearly delineated only a solitary tumor of the anterior lip (Fig. 1). No
* Corresponding author. Fax: +81 776 61 8117. E-mail address: [email protected] (K. Goto). 0090-8258/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2005.03.027
K. Goto et al. / Gynecologic Oncology 97 (2005) 976 – 979
977
Fig. 1. T2-weighted MR image showing high signal intensity mass in the anterior lip of the cervix (left panel; white arrow). Dynamic MR image delineating the same hypointense lesion (right panel; black arrow).
metastatic lesion was observed. Serum squamous-cell carcinoma antigen (SCC), CEA, and CA 125 levels were all within normal limits. On the diagnosis of stage 1B cervical cancer, a radical hysterectomy with systemic pelvic lymphadenectomy was performed. Parametria and adnexa were free from tumor. Macroscopical examination of the specimen revealed the exophytic lesion and an unexpected distinct cancerous lesion, which was 1.5 cm in size and was located in the endocervical glandular region. Both carcinomas were apart from each other (Fig. 2). Histological study demonstrated an invasive squamous cell carcinoma (poorly differentiated, non-keratinizing type, Fig. 3) accompanied with an invasive clear cell adenocarcinoma of the endocervix (Fig. 4). Tumor involvement to pelvic lymph nodes was free. The postoperative diagnosis was a double primary carcinoma of stage 1B1 of the cervix. The adjuvant irradiation therapy was not done. Postoperative re-examination of MRI, Pap smear, and biopsy specimens showed negative findings for concomitant exis-
Fig. 2. Cross section showing an exophytic lesion of the exocervix (arrow; squamous cell carcinoma) and an endophytic lesion of the endocervix (arrow head; clear cell adenocarcinoma) (hematoxylin and eosin, 1.0, original magnification). C; normal cervical epithelial region used for control for HPV detection.
tence of clear cell adenocarcinoma. She has been followed for over 70 months, with no evidence of recurrent disease. Histological findings The exophytic lesion was composed of cells with hyperchromatic oval nuclei and scant indistinct cytoplasm with less squamous differentiation, suggesting poorly differentiated squamous carcinoma (Fig. 3).
Fig. 3. The exophytic lesion showing hyperchromatic oval nuclei with less squamous differentiation (upper panel, 5; lower panel, 200).
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K. Goto et al. / Gynecologic Oncology 97 (2005) 976 – 979
lesion of clear cell adenocarcinoma. Control sample of normal cervical epithelium away from the two carcinomas was also negative for HPVs. These findings were confirmed by additional PCR analysis using E6 specific probes for HPV 16 and 18.
Discussion
Fig. 4. Endocervical tumor showing cells with clear cytoplasm and hyperchromatic, pleomorphic ‘‘hobnail cells’’ (upper panel, 5; lower panel, 200).
Tumor of the endocervix was composed of cells that have clear cytoplasm and form glandular or trabecular pattern covered by normal columnar epithelium. Cytoplasm showed PAS positive and diastase digestion. There are cells with hyperchromatic and pleomorphic nuclei that project into the lumen, suggesting hobnail cells of clear cell adenocarcinoma (Fig. 4). HPV detection Three 10-Am sections of formalin-fixed, paraffin-embedded tissue were placed on glass slides and were deparaffinized. As shown in Fig. 2, tumor tissues were microdissected from the lesion of squamous cell carcinoma and clear cell adenocarcinoma. Histologically benign cervical epithelium away from the two carcinomas was also microdissected as a negative control (Fig. 2, C). DNA was extracted by using a DNA isolation kit (QIAGEN K.K., Tokyo Japan). HPV detection and genotyping was performed using a commercially available HPVDNAChip (Biomedlab Co., Seoul, South Korea, MBC, Tokyo, Japan), a PCR-based DNA microarray system, as described elsewhere [5,6]. HPVDNAChip contains 22 type-specific probes, 15 high-risk HPVs (16/18/31/33/35/39/45/51/52/56/58/59/66/68/69) and 7 lowrisk HPVs (6/11/34/40/42/43/44). h-globin was amplified as an internal control. Sample from lesion of squamous cell carcinoma was positive for HPV 18. However, no HPV was found in the
This case presented an invasive double primary carcinoma of the uterine cervix composed of a squamous cell carcinoma and a clear cell adenocarcinoma. A double primary carcinoma of one organ is defined as a condition when the two carcinomas are histologically distinct and separated from each other by stroma or basal lamina. A collision tumor, on the other hand, is defined as two independently occurring neoplasms invading one another. Simultaneous occurrence of cervical intraepithelial neoplasia and primary adenocarcinoma has been reported [1– 3]; however, concomitant presence of invasive squamous cell carcinoma and invasive adenocarcinoma occurring independently in the cervix has been reported sporadically [3,4]. Furthermore, report of combination of squamous cell carcinoma and clear cell adenocarcinoma could not be found in the literature. Maiyer et al. [3] analyzed the coexistence of squamous cell neoplasm in 230 cases of primary adenocarcinoma of the cervix. They found that cervical intraepithelial neoplasia was present in 43% (99/230) cases, but only six cases (2%) exhibited concurrent invasive squamous cell carcinoma. Further, the coexistence of primary clear cell adenocarcinoma with invasive squamous cell adenocarcinoma was not found in their six cases. Similarly, Choo et al. [4] analyzed larger cases of 502 patients with adenocarcinoma and 2175 patients with squamous cell carcinoma and found that only eight cases were of synchronous invasive squamous cell carcinoma and invasive adenocarcinoma. In their report, however, the cell types of adenocarcinoma were not described. Recently, Anastasiadis et al. [7] reported a case of invasive cervical adenocarcinoma of mixed endocervical and clear cell type associated with a squamous cell carcinoma (collision tumor). In the present case, we failed to detect the veiled adenocarcinoma preoperatively. More than half of cervical adenocarcinomas grow endophytically, and this may result in later detection of the disease than the typically exophytic squamous cell carcinomas. It is reported that clear cell adenocarcinomas of the cervix showed predominantly endophytic growth (80%) and extended to the uterine corpus, creating a barrel-shaped cervix, significantly more often than squamous cell carcinoma and non-clear cell adenocarcinoma [8]. Kaminski et al. [9] reported that two of 22 patients (9%) were grossly non-visible and that only three patients (13%) revealed cytology suspicious before treatment. Recent study of Hanselaar et al. [10] showed that 35% of cases of cervical or vagina clear cell adenocarcinomas were cytologically false-negative. This low sensitivity was attributed to the fact
K. Goto et al. / Gynecologic Oncology 97 (2005) 976 – 979
that the development of clear cell adenocarcinoma may be confined to the submucosal space for a long time. The etiology of synchronous occurrence of squamous cell carcinoma and adenocarcinoma of the cervix is not clear. To date, approximately 50 types of HPV are known to infect the female genital tract and a subset of high-risk HPVs is known to have oncogenic potential. HPV DNA is detected in >90% of squamous cell carcinomas of the cervix and approximately one half of squamous cell carcinomas are attributed to HPV 16 [11]; however, the prevalence of HPV DNA in adenocarcinomas of the cervix is about 70% and approximately one half of adenocarcinomas are attributed to HPV 18 [12 –14]. In this case, HPV 18 infection was observed in the lesion of squamous cell carcinoma; however, no HPV infection was observed in the lesion of clear cell adenocarcinoma. This finding suggests that there was an obvious difference in association of HPV with the two neoplasms. Recently, Pirog et al. [15] studied the prevalence of HPV DNA in different histological subtypes of cervical adenocarcinomas. They found that HPV DNA was detected in 91% (82 of 90) of mucinous adenocarcinomas, including endocervical, intestinal, and endometrioid histological subtypes, and that in contrast to mucinous adenocarcinomas, no HPV DNA was detected in any nonmucinous adenocarcinomas (0/6), including clear cell, serous, and mesonephric adenocarcinomas. The lack of association of HPVs with clear cell adenocarcinoma demonstrated in their report is consistent with our finding. In summary, a rare case of multiple primary invasive carcinoma of the cervix, composed of squamous cell carcinoma and clear cell adenocarcinoma, was presented. The specific tumor growth patterns, predominantly exophytic growth of squamous cell carcinoma and endophytic growth of clear cell adenocarcinoma, were demonstrated. Despite recent advanced diagnostic techniques, it is still difficult to detect another carcinoma. Therefore, we should keep in mind the possibility of a multiple primary carcinoma of the cervix. Because of its rarity of coexistence of invasive squamous cell carcinoma and invasive adenocarcinoma of the cervix, there is no report of analysis of HPV status in such double primary carcinoma. This report may be the first to show the HPV status in the invasive double primary carcinoma of the uterine cervix. Further accumulation and analysis of HPV status in such carcinoma may be helpful for understanding the etiology of this unique entity.
979
References [1] Qizilbash AH. In-situ and microinvasive adenocarcinoma of the uterine cervix. A clinical, cytological and histological study of 14 cases. Am J Clin Pathol 1975;64:155 – 70. [2] Dougherty CM, Cotten N. Mixed squamous-cell and adenocarcinoma of the cervix. Cancer 1964;17:1132 – 43. [3] Maier RC, Norris HJ. Coexistence of cervical intraepithelial neoplasia with primary adenocarcinoma of the endocervix. Obstet Gynecol 1980;56:361 – 4. [4] Choo YC, Naylor B. Coexistent squamous cell carcinoma and adenocarcinoma of the uterine cervix. Gynecol Oncol 1984;17: 168 – 74. [5] An HJ, Cho NH, Lee SY, Kim IH, Lee C, Kim SJ, et al. Correlation of cervical carcinoma and precancerous lesions with human papillomavirus (HPV) genotypes detected with the HPV DNA chip microarray method. Cancer 2003;97:1672 – 80. [6] Kim CJ, Jeong JK, Park M, Park TS, Park TC, Namkoong SE, et al. HPV oligonucleotide microarray-based detection of HPV genotypes in cervical neoplastic lesions. Gynecol Oncol 2003;89:210 – 7. [7] Anastasiadis P, Koutlaki N, Tamiolakis D, Liberis V, Galazios G, Sivridis E. Invasive adenocarcinoma of mixed endocervical and clear cell type, associated with invasive squamous cell carcinoma of the cervix uteri. A case report. Eur J Gynaecol Oncol 2000;21: 173 – 6. [8] Reich O, Tamussino K, Lahousen M, Pickel H, Haas J, Winter R. Clear cell carcinoma of the uterine cervix: pathology and prognosis in surgically treated stage 1B – 2B disease in women not exposed in utero to diethylstilbestrol. Gynecol Oncol 2000;76:331 – 5. [9] Kaminski PF, Maier RC. Clear cell adenocarcinoma of the cervix unrelated to diethylstilbestrol exposure. Obstet Gynecol 1983;62: 720 – 7. [10] Hanselaar A, Loosbroek van M, Schuurbiers O, Helmerhorst T, Bulten J, Bernheim J. Clear cell adenocarcinoma of the vagina and cervix. An update of the central Netherlands registry showing twin age incidence peaks. Cancer 1997;79:2229 – 36. [11] Bosch FX, Lorincz A, Munoz N, Meijer CJLM, Shah KV. The causal relation between human papillomavirus and cervical cancer. J Clin Pathol 2002;55:244 – 65. [12] Andersson S, Rylander E, Larsson B, Strand A, Silfversva¨rd C, Wilander E. The role of human papillomavirus in cervical adenocarcinoma carcinogenesis. Eur J Cancer 2001;37:246 – 50. [13] Iwasawa A, Nieminen P, Lehtinen M, Paavonen J. Human papillomavirus DNA in uterine cervix squamous cell carcinoma and adenocarcinoma detected by polymerase chain reaction. Cancer 1996;77: 2275 – 9. [14] Duggan MA, McGregor SE, Benoit JL, Inoue M, Nation JG, Stuart GC. The human papillomavirus status of invasive cervical adenocarcinoma: a clinicopathological and outcome analysis. Hum Pathol 1995;26:319 – 25. [15] Pirog EC, Kleter B, Olgac S, Bobkiewicz P, Lindeman J, Quint WG, et al. Prevalence of human papillomavirus DNA in different histological subtypes of cervical adenocarcinoma. Am J Pathol 2000;157:1055 – 62.