Accepted Manuscript Vulvar Metastasis of an Early-Stage Well-Differentiated Endometrial Cancer after Minimally Invasive Surgery Amer Abdullah, MD Brandon-Luke L. Seagle, MD Erleine Bautista, MD Barinder S. Hansra, BS Robert Samuelson, MD Shohreh Shahabi, MD PII:
S1553-4650(14)00056-9
DOI:
10.1016/j.jmig.2014.01.026
Reference:
JMIG 2248
To appear in:
The Journal of Minimally Invasive Gynecology
Received Date: 6 January 2014 Revised Date:
31 January 2014
Accepted Date: 31 January 2014
Please cite this article as: Abdullah A, Seagle BLL, Bautista E, Hansra BS, Samuelson R, Shahabi S, Vulvar Metastasis of an Early-Stage Well-Differentiated Endometrial Cancer after Minimally Invasive Surgery, The Journal of Minimally Invasive Gynecology (2014), doi: 10.1016/j.jmig.2014.01.026. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1 Abdullah
ACCEPTED MANUSCRIPT Case Report Vulvar Metastasis of an Early-Stage Well-Differentiated Endometrial Cancer after Minimally Invasive Surgery
Hansra, BS, Robert Samuelson, MD, and Shohreh Shahabi, MD
RI PT
Amer Abdullah, MD, Brandon-Luke L Seagle, MD, Erleine Bautista, MD, Barinder S
SC
Department of Obstetrics, Gynecology and Reproductive Biology, Division of Gynecologic Oncology, Western Connecticut Health Network, Danbury Hospital, 24 Hospital Ave,
M AN U
Danbury, CT 06810
Corresponding Author: Shohreh Shahabi, MD, Department of Obstetrics, Gynecology and Reproductive Biology, Danbury Hospital, 24 Hospital Ave, Danbury, CT 06810
TE D
Tel: 203-739-7466; Fax: 203-739-1522; E-mail: [email protected]
Funding: None
EP
Conflicts of Interest and Disclosures: None
AC C
Prior presentation footer: A poster describing this case was presented at the 1st Annual State of Connecticut OB/GYN Residents’ Research Day, September 19th, 2013, Danbury Hospital, Danbury, CT.
2 Abdullah
ACCEPTED MANUSCRIPT Precis A case report of vulvar metastasis of an early-stage, well-differentiated endometrial endometrioid adenocarcinoma 8 months after minimally invasive surgical staging with uterus
RI PT
removal through the vagina.
ABSTRACT
Endometrial cancer is the most common gynecologic malignancy, often presenting as early-
SC
stage well-differentiated endometrioid adenocarcinoma associated with a high likelihood of long-term recurrence-free survival. Minimally invasive surgery (MIS) for surgical staging of
M AN U
endometrial cancers is now routinely practiced, with laparoscopy being the preferred surgical approach at many cancer centers. Recurrence or metastasis of early-stage well-differentiated endometrial endometrioid adenocarcinoma is uncommon, and may occur due to iatrogenic microscopic seeding of malignant cells during surgery as suggested by previous reports of
TE D
cancer metastasis to port sites after MIS, laparotomy incisions after open surgery, or intraperitoneal spread after hysteroscopy or uterine manipulation. Here we report the only described case of an isolated vulvar metastasis of an early-stage (International Federation of
EP
Gynecology and Obstetrics (FIGO) stage IB), well-differentiated (histologic grade 1) endometrial endometrioid adenocarcinoma after MIS for surgical staging. The patient
AC C
presented with recurrent endometrioid adenocarcinoma metastasis at the vulva 8 months after robotically-assisted total laparoscopic hysterectomy and surgical staging with specimen removal through the vagina. In selected cases, we suggest that using a specimen bag during removal of the uterus through the vagina may limit seeding of malignant cells during MIS for cancer.
3 Abdullah
ACCEPTED MANUSCRIPT Keywords: Endometrial cancer; Minimally invasive surgery; Metastasis; Vulva; Surgical
AC C
EP
TE D
M AN U
SC
RI PT
staging
4 Abdullah
ACCEPTED MANUSCRIPT
Endometrial cancer is the most common gynecologic malignancy in the United States, with approximately 50,000 new cases annually (1). The uterus is the fourth most common primary site of cancer in women, accounting for 6% of all cancers in women (2).
RI PT
Postmenopausal women are at greater risk (3). Endometrial cancer initially invades the
endometrial stroma and myometrium. Lymphatic and vascular spread of disease is more common with deeper myometrial invasion, as well as with aggressive or poorly-differentiated
SC
histological types (4). Approximately 70% of endometrial cancer recurrences are detected within the first 3 years after primary surgery (5). Grade 1 endometrial endometrioid
M AN U
adenocarcinoma treated at FIGO stage I-II infrequently recurs, with a 5-year recurrence-free survival (RFS) of 95%, disease-specific survival (DSS) of 99%, and overall survival of 89% (6). In the same series, lymphovascular space involvement and histologic grade were independent predictors of RFS and DSS (6).
TE D
We present the first case of an isolated recurrence at the vulva of an early-stage, welldifferentiated endometrial endometrioid adenocarcinoma, and a brief review of the literature
AC C
Case Report
EP
regarding recurrence of endometrial cancer at the vulva.
An 87-year-old gravida 2, para gravida 1-0-1-1 postmenopausal Caucasian woman with obesity (BMI 31.8), hypertension, hyperlipidemia, and a remote history of smoking 10pack-years presented for evaluation of a nontender vulvar mass located at the posterior fourchette 8 months after having undergone an uncomplicated robotically-assisted total laparoscopic hysterectomy, bilateral salpingo-oophorectomy, pelvic and para-aortic lymphadenectomy, and cystoscopy, during which the uterus was retrieved vaginally.
5 Abdullah
ACCEPTED MANUSCRIPT She originally presented to Gynecologic Oncology for postmenopausal bleeding. Menarche occurred at age 12 years, childbirth occurred vaginally at age 41 years, and menopause at age 50. She had a history of one spontaneous abortion. The patient never breastfed, used contraception, or hormone replacement therapy. Pelvic ultrasound revealed a
RI PT
10 cm x 5 cm x 5.1 cm multi-fibroid uterus, without report of endometrial thickness.
Endometrial biopsy demonstrated complex atypical hyperplasia with focal changes consistent with low-grade adenocarcinoma. She was therefore consented for surgical staging, which was
SC
performed robotically without complications by a board-certified Gynecology Oncologist. A V-Care uterine manipulator was used during the procedure. Intraoperative cytology was
M AN U
negative. The intact uterus with attached fallopian tubes and ovaries was removed transvaginally. Final pathology revealed a FIGO stage IB, histologic grade 1, nuclear grade 2 endometrial endometrioid adenocarcinoma with myometrial invasion to 59% of total myometrial depth, with a total uterine mass of 185 grams. The lower uterine segment was
TE D
involved. Tumor nests were found within the intralumenal lymphatic spaces of the uterus. All pelvic (4/4) and para-aortic (2/2) lymph nodes were negative for malignancy. Soon after surgical staging, the patient underwent a long-distance move of her
EP
primary residence and transferred care. Upon transfer of care, the findings of final pathology
AC C
were confirmed by an independent pathology review of available slides. The patient declined adjuvant pelvic external beam radiation, and chose to undergo three treatments of vaginal cuff brachytherapy, which were well-tolerated. On routine follow-up 8 months after surgical staging, physical exam revealed a nontender, 1.5 cm x 1 cm, well-circumscribed, exophytic mass at the posterior fourchette (Figure 1) and no palpable inguinal lymphadenopathy. The rest of her physical exam was normal, and without evidence of vaginal involvement. The vulvar lesion was biopsied and revealed endometrioid adenocarcinoma consistent with recurrence of her primary endometrial cancer. Pap smear of the vaginal cuff was negative.
6 Abdullah
ACCEPTED MANUSCRIPT Computed tomography of the chest, abdomen, and pelvis with contrast was without evidence of local recurrence or distant metastasis. Positron emission tomography revealed a focal area of activity at the site of the vulvar metastasis. To define the extent of rectovaginal involvement, magnetic resonance imaging of the pelvis with and without contrast was
RI PT
performed, demonstrating a 1.9 cm x 0.6 cm x 1.2 cm lesion between the rectum and
posterior margin of the external genitalia in the region of the perineal body. Given no
evidence of other metastatic disease, management options including radiation therapy and/or
SC
surgical resection with or without additional radiation were discussed at a multidisciplinary tumor board and with the patient. She elected to undergo modified partial vulvectomy, and
M AN U
the vulvar metastasis was excised to a 1.5 cm margin. The patient recovered and healed well postoperatively. Final pathology confirmed recurrent well-differentiated endometrioid adenocarcinoma with negative surgical margins and biopsies. The patient declined further treatment. She subsequently has no evidence of disease with follow-up to 28 months after her
TE D
initial staging procedure.
Discussion
EP
Metastases to the vulva are uncommon, accounting only for 5-8% of all vulvar
AC C
cancers (7). Metastatic lesions at the vulva may originate from gynecologic primary cancers. A systematic English-language literature search (PubMed and MEDLINE) between 19662012 using the terms “well differentiated,” “endometrial carcinoma,” “laparoscopic,” “robotic,” “vulva,” “metastasis,” or “spread” found 18 reported cases involving endometrial cancer metastasis to the vulva (8-14). There were no reported cases of an isolated vulvar metastasis of an endometrial endometrioid adenocarcinoma. Based on existing case reports, most often metastasis of endometrial cancer to the vulva is associated with the presence of metastases to additional sites and/or more aggressive histologic types of endometrial cancer.
7 Abdullah
ACCEPTED MANUSCRIPT Describing possible mechanisms to explain an isolated metastasis of a low grade, stage I endometrial cancer to the vulva is speculative. Direct local extension from a pelvic recurrence can be ruled out because of a lack of vaginal involvement of metastatic disease, as can intraperitoneal spread since the vulva is an extraperitoneal organ. Lymphatic drainage
RI PT
from the uterus is mostly to the pelvic and paraaortic lymph nodes. Lymphatic drainage from the vulva is mostly to the superficial inguinal nodes. Since most lymphatic drainage from the uterus and vulva are to different lymphatic chains, a finding of inguinal lymphadenopathy
SC
being positive for malignancy at the time of staging for endometrial cancer indicates distant metastasis and therefore stage IVB disease. It has been speculated that after disruption of the
M AN U
pelvic lymphatic system by radical pelvic surgery or radiation, lymphostasis and retrograde lymphatic flow may occur (13). Although endometrial cancer typically spreads in an orderly fashion by local extension and/or via the pelvic then para-aortic lymphatic chains, there are lymphatic vessels that anastomose the pelvic and superficial inguinal lymphatic tributaries
TE D
and therefore provide a potential pathway for lymphatic drainage from the uterus to reach the vulva. In the setting of pelvic lymphostasis secondary to iatrogenic disruption of the pelvic nodal chains, uterine lymphatic drainage through these anastomoses and toward the
EP
superficial inguinal chains and then retrograde toward other organs may be possible.
AC C
Additionally, the impact of pneumoperitoneum on cancer cell spread has been studied, primarily in animal models (15). Many reports suggest that pneumoperitoneum may alter peritoneal surfaces such that cancer cell adherence or spread is increased (15). However, due to limited data and some conflicting reports, the potential effect of pneumoperitoneum on lymphatic spread of cancer cells remains speculative (15). Hematologic spread of disease to a vulvar location may be a reasonable speculation given that vulvar metastases have often been described in the presence of or just preceding the discovery of additional distant metastases (8-13). Also, a case of tumor-to-tumor spread
8 Abdullah
ACCEPTED MANUSCRIPT of an endometrial endometrioid adenocarcinoma found to be contained entirely within a distinct second, primary squamous cell cancer of the vulva may suggest hematologic spread (14). Another mechanism of metastasis of an endometrial cancer to the vulva is
RI PT
theoretically from seeding of cancer cells to the vulva during surgery. The incidence of
iatrogenic cancer cell seeding during surgery is unknown, as is the malignant potential of seeded cancer cells to adhere and multiply at the vulva or other sites if seeding does occur.
SC
Since minimally invasive surgical staging of endometrial cancer with transvaginal specimen removal is now commonly practiced, but cases of vulvar metastasis are rare, clinically
M AN U
significant iatrogenic seeding of cancer cells to the vulva during transvaginal specimen removal must also be (at most) very rare. Nonetheless, the possibility of iatrogenic cancer cell spread leading to the vulvar metastasis observed in this case report cannot be ruled out. Additionally, many surgeons use a uterine manipulator commonly during MIS for
TE D
endometrial cancer, but concern has been reported that uterine manipulators, such as was used in this case, may spread cancer cells of early-stage endometrial cancer retrograde through the fallopian tubes into the intraperitoneal cavity, or spread cancer cells into the
EP
lymphovascular spaces of the uterus. The first randomized controlled trial testing these
AC C
hypotheses failed to demonstrate an association between uterine manipulation and increased positive postoperative peritoneal cytology or lymphovascular involvement on final pathology (16). Vaginal and/or vulvar trauma likely occurred during specimen removal in this case. Most likely this trauma would have been an abrasion of stretched, atrophic tissue under tension and exposed to friction with forceful specimen removal, creating a more receptive surface for seeded cancer cells to grow. Pulling and pushing the specimen through the vagina could have aided transcervical or retrograde flow of endometrial cancer cells onto this receptive surface, explaining a possible mechanism for surgical seeding of cancer cells to the
9 Abdullah
ACCEPTED MANUSCRIPT metastatic site at the posterior fourchette even in the absence of cancer involvement on the surface of the specimen. One simple and widely available method that can reasonably be expected to decrease the likelihood of cancer cell seeding during minimally invasive surgical staging procedures would be the use of a specimen bag during transvaginal specimen
RI PT
removal. Given the rarity of vulvar metastases of endometrial cancer, even if using a
specimen bag were assumed to be a 100% effective method to prevent iatrogenic cancer cell spread to the vulva, using a specimen bag product as a general practice during transvaginal
SC
specimen removal may not be cost effective. However, in patients with an inelastic, atrophic vagina, during transvaginal specimen removal of large specimens the posterior fourchette
M AN U
may be fragile and easily traumatized, allowing adherence of cancer cells if seeding occurs with specimen removal. Therefore, in selected cases, use of a specimen bag during transvaginal specimen removal may be considered.
TE D
Acknowledgements
References
EP
None
30.
AC C
1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11-
2. Parazzini F, Franceschi S, La Vecchia C, Chatenoud L, Di Cintio E. The epidemiology of female genital tract cancer. Int J Gynecol Cancer. 1997;7:169-181. 3. Anderson MC, Robboy SJ. Etiology and histopathology of endometrial hyperplasia and carcinoma. Curr Obstet Gyneacol. 1997;7:2-7. 4. Abeler VN, Kjorstad KE. Endometrial adenocarcinoma in Norway, a study of a total population. Cancer. 1991;12:3093-3103.
10 Abdullah
ACCEPTED MANUSCRIPT 5. Ben Arie A, Lavie O, Gdalevich M, Voldarsky M, Barak F, Schneider D, Levy T, Anteby E, Gemer O. Temporal pattern of recurrence of stage I endometrial cancer in relation to histological risk factors. Eur J Surg Oncol. 2012;38:166-169. 6. Gayar OH, Patel S, Schultz D, Mahan M, Rasool N, Elshaikh MA. The impact of tumor
RI PT
grade on survival end points and patterns of recurrence of 949 patients with early-stage endometrial carcinoma: a single institution study. Int J Gynecol Cancer. 2014;24:97-101. 7. Lerner LB, Andrews SJ, Gonzalez JL, Heaney JA, Currie JL. Vulvar metastases
SC
secondary to transitional cell carcinoma of the bladder: a case report. J Reprod Med. 1999;44:729-732.
57.
M AN U
8. Dehner LP. Metastatic and secondary tumors of the vulva. Obstet Gynecol. 1973;42:47-
9. Muzer MT, Hsueh S, Gersell DJ. Metastases to the female genital tract: analysis of 325 cases. Cancer. 1984;53:1978-1984.
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10. Neto AG, Deavers MT, Silva EG, Malpica A. Metastatic tumors of the vulva: a clinicopathologic study of 66 cases. Am J Surg Pathol. 2003;27:799-804. 11. Giordano G, Gnetti L, Melpiqnano M. Endometrial carcinoma metastatic to the vulva: a
EP
case report and review of the literature. Pathol Res Pract. 2005;201:751-756.
AC C
12. Temkin SM, Hellman M, Lee YC, Abulafia O. Surgical resection of vulvar metastases of endometrial cancer: a presentation of two cases. J Low Genit Tract Dis. 2007;11:118-121. 13. Fakor F, Falah HH, Jahromi SK. Endometrial carcinoma metastatic to the clitoris: a case report and review of the literature. Acta Medica Iranica. 2013;51:652-654. 14. Wimmer JL, Coffey DM, Kaplan AL, Ayala AG, Ro JY. Tumor-to-tumor metastasis with endometrial carcinoma metastatic to squamous cell carcinoma of vulva: the first reported case. Arch Pathol Lab Med. 2013;137:1825-1828.
11 Abdullah
ACCEPTED MANUSCRIPT 15. Goldfarb M, Brower S, Schwaitzberg SD. Minimally invasive surgery and cancer: controversies part 1. Surg Endosc. 2010;24:304-334. 16. Lee M, Kim YT, Kim SW, Kim S, Kim JH, Nam EJ. Effects of uterine manipulation on surgical outcomes in laparoscopic management of endometrial cancer: a prospective
RI PT
randomized controlled trial. Int J Gynecol Cancer. 2013;23:372-379.
Figure Legends
SC
Figure 1: Vulvar metastasis of a well-differentiated endometrial endometrioid
AC C
EP
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M AN U
adenocarcinoma.
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
ACCEPTED MANUSCRIPT
Precis A case report of vulvar metastasis of an early-stage, well-differentiated endometrial endometrioid adenocarcinoma 8 months after minimally invasive surgical staging with uterus
AC C
EP
TE D
M AN U
SC
RI PT
removal through the vagina.
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
S1553-4650(14)00056-9
DOI:
10.1016/j.jmig.2014.01.026
Reference:
JMIG 2248
To appear in:
The Journal of Minimally Invasive Gynecology
Received Date: 6 January 2014 Revised Date:
31 January 2014
Accepted Date: 31 January 2014
Please cite this article as: Abdullah A, Seagle BLL, Bautista E, Hansra BS, Samuelson R, Shahabi S, Vulvar Metastasis of an Early-Stage Well-Differentiated Endometrial Cancer after Minimally Invasive Surgery, The Journal of Minimally Invasive Gynecology (2014), doi: 10.1016/j.jmig.2014.01.026. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1 Abdullah
ACCEPTED MANUSCRIPT Case Report Vulvar Metastasis of an Early-Stage Well-Differentiated Endometrial Cancer after Minimally Invasive Surgery
Hansra, BS, Robert Samuelson, MD, and Shohreh Shahabi, MD
RI PT
Amer Abdullah, MD, Brandon-Luke L Seagle, MD, Erleine Bautista, MD, Barinder S
SC
Department of Obstetrics, Gynecology and Reproductive Biology, Division of Gynecologic Oncology, Western Connecticut Health Network, Danbury Hospital, 24 Hospital Ave,
M AN U
Danbury, CT 06810
Corresponding Author: Shohreh Shahabi, MD, Department of Obstetrics, Gynecology and Reproductive Biology, Danbury Hospital, 24 Hospital Ave, Danbury, CT 06810
TE D
Tel: 203-739-7466; Fax: 203-739-1522; E-mail: [email protected]
Funding: None
EP
Conflicts of Interest and Disclosures: None
AC C
Prior presentation footer: A poster describing this case was presented at the 1st Annual State of Connecticut OB/GYN Residents’ Research Day, September 19th, 2013, Danbury Hospital, Danbury, CT.
2 Abdullah
ACCEPTED MANUSCRIPT Precis A case report of vulvar metastasis of an early-stage, well-differentiated endometrial endometrioid adenocarcinoma 8 months after minimally invasive surgical staging with uterus
RI PT
removal through the vagina.
ABSTRACT
Endometrial cancer is the most common gynecologic malignancy, often presenting as early-
SC
stage well-differentiated endometrioid adenocarcinoma associated with a high likelihood of long-term recurrence-free survival. Minimally invasive surgery (MIS) for surgical staging of
M AN U
endometrial cancers is now routinely practiced, with laparoscopy being the preferred surgical approach at many cancer centers. Recurrence or metastasis of early-stage well-differentiated endometrial endometrioid adenocarcinoma is uncommon, and may occur due to iatrogenic microscopic seeding of malignant cells during surgery as suggested by previous reports of
TE D
cancer metastasis to port sites after MIS, laparotomy incisions after open surgery, or intraperitoneal spread after hysteroscopy or uterine manipulation. Here we report the only described case of an isolated vulvar metastasis of an early-stage (International Federation of
EP
Gynecology and Obstetrics (FIGO) stage IB), well-differentiated (histologic grade 1) endometrial endometrioid adenocarcinoma after MIS for surgical staging. The patient
AC C
presented with recurrent endometrioid adenocarcinoma metastasis at the vulva 8 months after robotically-assisted total laparoscopic hysterectomy and surgical staging with specimen removal through the vagina. In selected cases, we suggest that using a specimen bag during removal of the uterus through the vagina may limit seeding of malignant cells during MIS for cancer.
3 Abdullah
ACCEPTED MANUSCRIPT Keywords: Endometrial cancer; Minimally invasive surgery; Metastasis; Vulva; Surgical
AC C
EP
TE D
M AN U
SC
RI PT
staging
4 Abdullah
ACCEPTED MANUSCRIPT
Endometrial cancer is the most common gynecologic malignancy in the United States, with approximately 50,000 new cases annually (1). The uterus is the fourth most common primary site of cancer in women, accounting for 6% of all cancers in women (2).
RI PT
Postmenopausal women are at greater risk (3). Endometrial cancer initially invades the
endometrial stroma and myometrium. Lymphatic and vascular spread of disease is more common with deeper myometrial invasion, as well as with aggressive or poorly-differentiated
SC
histological types (4). Approximately 70% of endometrial cancer recurrences are detected within the first 3 years after primary surgery (5). Grade 1 endometrial endometrioid
M AN U
adenocarcinoma treated at FIGO stage I-II infrequently recurs, with a 5-year recurrence-free survival (RFS) of 95%, disease-specific survival (DSS) of 99%, and overall survival of 89% (6). In the same series, lymphovascular space involvement and histologic grade were independent predictors of RFS and DSS (6).
TE D
We present the first case of an isolated recurrence at the vulva of an early-stage, welldifferentiated endometrial endometrioid adenocarcinoma, and a brief review of the literature
AC C
Case Report
EP
regarding recurrence of endometrial cancer at the vulva.
An 87-year-old gravida 2, para gravida 1-0-1-1 postmenopausal Caucasian woman with obesity (BMI 31.8), hypertension, hyperlipidemia, and a remote history of smoking 10pack-years presented for evaluation of a nontender vulvar mass located at the posterior fourchette 8 months after having undergone an uncomplicated robotically-assisted total laparoscopic hysterectomy, bilateral salpingo-oophorectomy, pelvic and para-aortic lymphadenectomy, and cystoscopy, during which the uterus was retrieved vaginally.
5 Abdullah
ACCEPTED MANUSCRIPT She originally presented to Gynecologic Oncology for postmenopausal bleeding. Menarche occurred at age 12 years, childbirth occurred vaginally at age 41 years, and menopause at age 50. She had a history of one spontaneous abortion. The patient never breastfed, used contraception, or hormone replacement therapy. Pelvic ultrasound revealed a
RI PT
10 cm x 5 cm x 5.1 cm multi-fibroid uterus, without report of endometrial thickness.
Endometrial biopsy demonstrated complex atypical hyperplasia with focal changes consistent with low-grade adenocarcinoma. She was therefore consented for surgical staging, which was
SC
performed robotically without complications by a board-certified Gynecology Oncologist. A V-Care uterine manipulator was used during the procedure. Intraoperative cytology was
M AN U
negative. The intact uterus with attached fallopian tubes and ovaries was removed transvaginally. Final pathology revealed a FIGO stage IB, histologic grade 1, nuclear grade 2 endometrial endometrioid adenocarcinoma with myometrial invasion to 59% of total myometrial depth, with a total uterine mass of 185 grams. The lower uterine segment was
TE D
involved. Tumor nests were found within the intralumenal lymphatic spaces of the uterus. All pelvic (4/4) and para-aortic (2/2) lymph nodes were negative for malignancy. Soon after surgical staging, the patient underwent a long-distance move of her
EP
primary residence and transferred care. Upon transfer of care, the findings of final pathology
AC C
were confirmed by an independent pathology review of available slides. The patient declined adjuvant pelvic external beam radiation, and chose to undergo three treatments of vaginal cuff brachytherapy, which were well-tolerated. On routine follow-up 8 months after surgical staging, physical exam revealed a nontender, 1.5 cm x 1 cm, well-circumscribed, exophytic mass at the posterior fourchette (Figure 1) and no palpable inguinal lymphadenopathy. The rest of her physical exam was normal, and without evidence of vaginal involvement. The vulvar lesion was biopsied and revealed endometrioid adenocarcinoma consistent with recurrence of her primary endometrial cancer. Pap smear of the vaginal cuff was negative.
6 Abdullah
ACCEPTED MANUSCRIPT Computed tomography of the chest, abdomen, and pelvis with contrast was without evidence of local recurrence or distant metastasis. Positron emission tomography revealed a focal area of activity at the site of the vulvar metastasis. To define the extent of rectovaginal involvement, magnetic resonance imaging of the pelvis with and without contrast was
RI PT
performed, demonstrating a 1.9 cm x 0.6 cm x 1.2 cm lesion between the rectum and
posterior margin of the external genitalia in the region of the perineal body. Given no
evidence of other metastatic disease, management options including radiation therapy and/or
SC
surgical resection with or without additional radiation were discussed at a multidisciplinary tumor board and with the patient. She elected to undergo modified partial vulvectomy, and
M AN U
the vulvar metastasis was excised to a 1.5 cm margin. The patient recovered and healed well postoperatively. Final pathology confirmed recurrent well-differentiated endometrioid adenocarcinoma with negative surgical margins and biopsies. The patient declined further treatment. She subsequently has no evidence of disease with follow-up to 28 months after her
TE D
initial staging procedure.
Discussion
EP
Metastases to the vulva are uncommon, accounting only for 5-8% of all vulvar
AC C
cancers (7). Metastatic lesions at the vulva may originate from gynecologic primary cancers. A systematic English-language literature search (PubMed and MEDLINE) between 19662012 using the terms “well differentiated,” “endometrial carcinoma,” “laparoscopic,” “robotic,” “vulva,” “metastasis,” or “spread” found 18 reported cases involving endometrial cancer metastasis to the vulva (8-14). There were no reported cases of an isolated vulvar metastasis of an endometrial endometrioid adenocarcinoma. Based on existing case reports, most often metastasis of endometrial cancer to the vulva is associated with the presence of metastases to additional sites and/or more aggressive histologic types of endometrial cancer.
7 Abdullah
ACCEPTED MANUSCRIPT Describing possible mechanisms to explain an isolated metastasis of a low grade, stage I endometrial cancer to the vulva is speculative. Direct local extension from a pelvic recurrence can be ruled out because of a lack of vaginal involvement of metastatic disease, as can intraperitoneal spread since the vulva is an extraperitoneal organ. Lymphatic drainage
RI PT
from the uterus is mostly to the pelvic and paraaortic lymph nodes. Lymphatic drainage from the vulva is mostly to the superficial inguinal nodes. Since most lymphatic drainage from the uterus and vulva are to different lymphatic chains, a finding of inguinal lymphadenopathy
SC
being positive for malignancy at the time of staging for endometrial cancer indicates distant metastasis and therefore stage IVB disease. It has been speculated that after disruption of the
M AN U
pelvic lymphatic system by radical pelvic surgery or radiation, lymphostasis and retrograde lymphatic flow may occur (13). Although endometrial cancer typically spreads in an orderly fashion by local extension and/or via the pelvic then para-aortic lymphatic chains, there are lymphatic vessels that anastomose the pelvic and superficial inguinal lymphatic tributaries
TE D
and therefore provide a potential pathway for lymphatic drainage from the uterus to reach the vulva. In the setting of pelvic lymphostasis secondary to iatrogenic disruption of the pelvic nodal chains, uterine lymphatic drainage through these anastomoses and toward the
EP
superficial inguinal chains and then retrograde toward other organs may be possible.
AC C
Additionally, the impact of pneumoperitoneum on cancer cell spread has been studied, primarily in animal models (15). Many reports suggest that pneumoperitoneum may alter peritoneal surfaces such that cancer cell adherence or spread is increased (15). However, due to limited data and some conflicting reports, the potential effect of pneumoperitoneum on lymphatic spread of cancer cells remains speculative (15). Hematologic spread of disease to a vulvar location may be a reasonable speculation given that vulvar metastases have often been described in the presence of or just preceding the discovery of additional distant metastases (8-13). Also, a case of tumor-to-tumor spread
8 Abdullah
ACCEPTED MANUSCRIPT of an endometrial endometrioid adenocarcinoma found to be contained entirely within a distinct second, primary squamous cell cancer of the vulva may suggest hematologic spread (14). Another mechanism of metastasis of an endometrial cancer to the vulva is
RI PT
theoretically from seeding of cancer cells to the vulva during surgery. The incidence of
iatrogenic cancer cell seeding during surgery is unknown, as is the malignant potential of seeded cancer cells to adhere and multiply at the vulva or other sites if seeding does occur.
SC
Since minimally invasive surgical staging of endometrial cancer with transvaginal specimen removal is now commonly practiced, but cases of vulvar metastasis are rare, clinically
M AN U
significant iatrogenic seeding of cancer cells to the vulva during transvaginal specimen removal must also be (at most) very rare. Nonetheless, the possibility of iatrogenic cancer cell spread leading to the vulvar metastasis observed in this case report cannot be ruled out. Additionally, many surgeons use a uterine manipulator commonly during MIS for
TE D
endometrial cancer, but concern has been reported that uterine manipulators, such as was used in this case, may spread cancer cells of early-stage endometrial cancer retrograde through the fallopian tubes into the intraperitoneal cavity, or spread cancer cells into the
EP
lymphovascular spaces of the uterus. The first randomized controlled trial testing these
AC C
hypotheses failed to demonstrate an association between uterine manipulation and increased positive postoperative peritoneal cytology or lymphovascular involvement on final pathology (16). Vaginal and/or vulvar trauma likely occurred during specimen removal in this case. Most likely this trauma would have been an abrasion of stretched, atrophic tissue under tension and exposed to friction with forceful specimen removal, creating a more receptive surface for seeded cancer cells to grow. Pulling and pushing the specimen through the vagina could have aided transcervical or retrograde flow of endometrial cancer cells onto this receptive surface, explaining a possible mechanism for surgical seeding of cancer cells to the
9 Abdullah
ACCEPTED MANUSCRIPT metastatic site at the posterior fourchette even in the absence of cancer involvement on the surface of the specimen. One simple and widely available method that can reasonably be expected to decrease the likelihood of cancer cell seeding during minimally invasive surgical staging procedures would be the use of a specimen bag during transvaginal specimen
RI PT
removal. Given the rarity of vulvar metastases of endometrial cancer, even if using a
specimen bag were assumed to be a 100% effective method to prevent iatrogenic cancer cell spread to the vulva, using a specimen bag product as a general practice during transvaginal
SC
specimen removal may not be cost effective. However, in patients with an inelastic, atrophic vagina, during transvaginal specimen removal of large specimens the posterior fourchette
M AN U
may be fragile and easily traumatized, allowing adherence of cancer cells if seeding occurs with specimen removal. Therefore, in selected cases, use of a specimen bag during transvaginal specimen removal may be considered.
TE D
Acknowledgements
References
EP
None
30.
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1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11-
2. Parazzini F, Franceschi S, La Vecchia C, Chatenoud L, Di Cintio E. The epidemiology of female genital tract cancer. Int J Gynecol Cancer. 1997;7:169-181. 3. Anderson MC, Robboy SJ. Etiology and histopathology of endometrial hyperplasia and carcinoma. Curr Obstet Gyneacol. 1997;7:2-7. 4. Abeler VN, Kjorstad KE. Endometrial adenocarcinoma in Norway, a study of a total population. Cancer. 1991;12:3093-3103.
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ACCEPTED MANUSCRIPT 5. Ben Arie A, Lavie O, Gdalevich M, Voldarsky M, Barak F, Schneider D, Levy T, Anteby E, Gemer O. Temporal pattern of recurrence of stage I endometrial cancer in relation to histological risk factors. Eur J Surg Oncol. 2012;38:166-169. 6. Gayar OH, Patel S, Schultz D, Mahan M, Rasool N, Elshaikh MA. The impact of tumor
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grade on survival end points and patterns of recurrence of 949 patients with early-stage endometrial carcinoma: a single institution study. Int J Gynecol Cancer. 2014;24:97-101. 7. Lerner LB, Andrews SJ, Gonzalez JL, Heaney JA, Currie JL. Vulvar metastases
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secondary to transitional cell carcinoma of the bladder: a case report. J Reprod Med. 1999;44:729-732.
57.
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8. Dehner LP. Metastatic and secondary tumors of the vulva. Obstet Gynecol. 1973;42:47-
9. Muzer MT, Hsueh S, Gersell DJ. Metastases to the female genital tract: analysis of 325 cases. Cancer. 1984;53:1978-1984.
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10. Neto AG, Deavers MT, Silva EG, Malpica A. Metastatic tumors of the vulva: a clinicopathologic study of 66 cases. Am J Surg Pathol. 2003;27:799-804. 11. Giordano G, Gnetti L, Melpiqnano M. Endometrial carcinoma metastatic to the vulva: a
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case report and review of the literature. Pathol Res Pract. 2005;201:751-756.
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12. Temkin SM, Hellman M, Lee YC, Abulafia O. Surgical resection of vulvar metastases of endometrial cancer: a presentation of two cases. J Low Genit Tract Dis. 2007;11:118-121. 13. Fakor F, Falah HH, Jahromi SK. Endometrial carcinoma metastatic to the clitoris: a case report and review of the literature. Acta Medica Iranica. 2013;51:652-654. 14. Wimmer JL, Coffey DM, Kaplan AL, Ayala AG, Ro JY. Tumor-to-tumor metastasis with endometrial carcinoma metastatic to squamous cell carcinoma of vulva: the first reported case. Arch Pathol Lab Med. 2013;137:1825-1828.
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ACCEPTED MANUSCRIPT 15. Goldfarb M, Brower S, Schwaitzberg SD. Minimally invasive surgery and cancer: controversies part 1. Surg Endosc. 2010;24:304-334. 16. Lee M, Kim YT, Kim SW, Kim S, Kim JH, Nam EJ. Effects of uterine manipulation on surgical outcomes in laparoscopic management of endometrial cancer: a prospective
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randomized controlled trial. Int J Gynecol Cancer. 2013;23:372-379.
Figure Legends
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Figure 1: Vulvar metastasis of a well-differentiated endometrial endometrioid
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Precis A case report of vulvar metastasis of an early-stage, well-differentiated endometrial endometrioid adenocarcinoma 8 months after minimally invasive surgical staging with uterus
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removal through the vagina.
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