Rectal carcinoma presenting as vulvar metastasis: A case report

Highlights

• •Metastatic cancer to the vulva is exceptionally rare.
• •Low threshold for periodic examination, biopsy and PET of patients with vulvar complaints and history of colorectal cancer.
• •IHC useful to diagnose tumor origin, with focus on PAX8, CK7, CK20, CDX2, and CEA to confirm colorectal vs vulvar primary.
• •Treatment for vulvar metastasis of colorectal carcinoma requires an interdisciplinary approach.

Abstract

Introduction

Metastatic adenocarcinoma to the vulva is a rare phenomenon, with few cases reported in the literature. Here we discuss a 64-year-old woman with a history of colorectal adenocarcinoma presenting with a vulvar metastasis.

Methods

Clinical information was gathered via review of the electronic medical record.

Results

IHC is useful in diagnosis of unusual metastases. In this case, staining for CDx2, CK20, PAX8, and CK7 was helpful in distinguishing a gynecologic versus gastrointestinal primary.

Conclusion

Our case highlights the importance of an accurate and timely diagnosis of gynecologic metastases in patients with a history of colorectal cancer. Examiners should have a low threshold for biopsy and imaging when patients present with skin changes or vulvovaginal complaints. Appropriate treatment requires a multidisciplinary approach.

1. Introduction

Primary cancers of the vulva are rare, accounting for 3–5 % of cancers of the female genital tract.(Simcock, 2008) Specific risk factors for vulvar cancer include lichen sclerosis, age, HPV infection, smoking, radiation exposure and immunosuppression.(Simcock, 2008) The majority of gynecologic cancers of the vulva are squamous cell carcinomas, while the rest are melanomas and much less frequently adenocarcinomas, basal cell carcinomas and sarcomas. Metastatic cancer specifically to the vulva occurs, but is even more rare, accounting for 5–8 % of vulvar cancers.(Rocconi et al., 2004) These primary cancers range from other genital tract neoplasms to gastrointestinal cancers.(Neto et al., 2003) Significantly, Mazur et al. showed that 10 of the 22 metastases that originated elsewhere in the genital tract were located in the vulva.(Mazur et al., 1984) Vulvar disease originating in the gastrointestinal tract is vastly understudied. The presentation, treatment and long-term management of patients with vulvar disease of gastrointestinal origin varies on a patient-to-patient basis. We present a case of a patient with a complex history of colorectal adenocarcinoma presenting with vulvar adenocarcinoma of gastrointestinal origin that recurs, progresses and varies in presentation on examination. We discuss the unique management of this patient.

2. Case

A 64-year-old woman was referred to Gynecologic Oncology by her Medical Oncologist for potential gynecologic recurrence of her colorectal carcinoma. At age 49 she underwent a right hemicolectomy and creation of an ileostomy which revealed a stage I (pT2pN0) rectal adenocarcinoma. She did not require adjuvant therapy and her ileostomy was reversed several months later without incident. Germline genetic testing performed at that time revealed no deleterious MLH1, MSH2, or MSH6 mutation. She remained without evidence of disease until age 58, when she presented with right lower quadrant abdominal pain and imaging was suggestive of disease recurrence with carcinomatosis. She underwent neoadjuvant chemotherapy with FOLFOX (leucovorin calcium, fluorouracil, and oxaliplatin) and then underwent an exploratory laparotomy with tumor debulking, bilateral salpingo-oophorectomy, and HIPEC. Pathologic evaluation of the omental masses confirmed poorly-differentiated adenocarcinoma consistent with recurrence of her known rectal primary, and she then completed adjuvant chemotherapy. CEA at this time was 2.0. She remained asymptomatic and without evidence of disease until age 61, when she developed dyspareunia. Pap smear performed at that time favored adenocarcinoma of colorectal origin. Pelvic MRI at that time revealed an unremarkable uterus. CEA at this time was 3.0. PET-CT performed four months later demonstrated hypermetabolic left supraclavicular, retroperitoneal, retrocrural, and pelvic lymph nodes; CEA at this time was 3.3. She reinitiated chemotherapy with FOLFOX and then FOLFIRI (leucovorin calcium (folinic acid), fluorouracil, and irinotecan hydrochloride). Repeat PET-CT approximately one year later revealed no evidence of disease, and treatment was discontinued.

The patient was asymptomatic for approximately two months, and then developed vulvar pruritis and irritation. She underwent a pelvic exam and Pap smear with her general gynecologist with no abnormal findings. Repeat PET-CT approximately four months after the prior study revealed FDG-avid paraaortic, external iliac, and inguinal lymph nodes as well as FDG-avid foci in the right vagina and left labia. She then presented to gynecologic oncology. The patient’s review of systems was significant only for vaginal pruritis. She denied any vaginal bleeding or abnormal discharge. Her medical history was significant for colorectal adenocarcinoma as above, asthma without recent episodes, and esophageal reflux not currently treated with medication. In addition to her oncologic surgeries, her surgical history was notable for a Cesarean section. Her social history included occasional social use of alcohol, but no cigarette smoking. Her obstetric history was significant 2 prior full-term pregnancies with one vaginal delivery and one Cesarean section, with three living children. Age at menopause was 49 years. She had no history of sexually transmitted infections, HPV infections, or cervical dysplasia. The patient was adopted and had no knowledge of any family history of colorectal or gynecologic cancers. Exam at this time revealed thickened vulvar epithelium with fissuring in interlabial creases. Apical vaginal stenosis was noted, mucosa appeared smooth, and cervix was epithelialized. Bimanual exam was normal with no palpable adnexal masses, and rectovaginal exam revealed a smooth rectovaginal septum. There was some nonspecific soft fullness around the urethra in the anterior upper vagina. A biopsy was performed of the thickened, fissured area of the right vulva. Differential diagnosis included lichen simplex chronicus, lichen sclerosis, or malignancy. Microscopic analysis revealed poorly-differentiated adenocarcinoma within the dermis and focally in the epidermis. The tumor cells were large with increased N:C ratio and increased mitotic activity. Immunohistochemical stains were positive for CDx2, CK20, and negative for PAX8 and CK7 (Fig. 1). Biopsy findings were consistent with metastatic adenocarcinoma of colorectal origin. Pap smear at this time also demonstrated adenocarcinoma.

Fig. 1.

Histopathologic examination of tumor. (a) On microscopic examination after H&E stain the skin shows poorly differentiated adenocarcinoma within the dermis and focally within the epidermis. The tumor cells are large with increased N:C ratio and increased mitotic activity. Immunohistochemical stains showed the tumor cells are positive for CDX2 (b), CK20 (c), and negative for CK7 (d) and PAX8, confirming metastasis from colorectal primary.

Genomic analysis of circulating tumor DNA at the time of the patient’s recurrent disease revealed a high blood tumor mutational burden of 11 muts/mb; no evidence of microsatellite instability; and a MET amplification, APC mutation, FLCN mutation, FLT3 amplification, and TP53 mutation. There was no KRAS mutation. These findings were concordant with blood and tumor tissue genomic analysis at the time of initial diagnosis.

After diagnosis of the vulvar recurrence of her rectal adenocarcinoma, patient underwent systemic therapy with six cycles of FOLFIRI, and an interval PET demonstrated resolution of the hypermetabolic nodes. Repeat PET at completion of six cycles of FOLFIRI revealed increased FDG-avidity in the right labia and the inferoposterior vagina (Fig. 2), and gynecologic exam revealed progression of vulvar disease. Diffuse pink papules were noted over the mons and bilateral labia majora, as well as a friable sub-centimeter tumor at the right anterior introitus. Bimanual and rectovaginal exam at that time were otherwise unremarkable. She was referred to radiation oncology for radiation/local disease control.

Fig. 2.

Representative images from PET-CT study. Axial images from PET-CT at time of disease recurrence reveal (a) FDG-avid focus along the left labia as well as (b) FDG-avid right inguinal lymph nodes.

The patient underwent radiation therapy using a “Quad Shot” approach (i.e., four fractions in two days). She continued on alternating FOLFOX/FOLFIRI. She ultimately received RT to the pelvis for a total dose of 1440 cGy in 4 fractions, BID, in both March and April of this year. Re-evaluation revealed partial response with resolution of the friable tumor previously noted at the introitus. She continued to apply Aquaphor ointment and Silvadene cream to the vulva for relief of itching and irritation.

She then had a repeat PET-CT which demonstrated a focus of increased uptake in the uterus, mild soft tissue thickening adjacent to the uterus, and cutaneous nodule anterior to the right hip. MRI showed a thickened endometrium of 1.1 cm; a 7 mm intermediate-signal lesion within the distended endometrium with questionable enhancement. No adenopathy was noted. Endometrium sampling was precluded by significant post-radiation cervical stenosis. Suspicion for endometrial primary is low given known previous endocervical involvement of the rectal adenocarcinoma. The gynecologic, medical, and radiation oncology teams agreed to repeat a scan in 4–5 weeks to determine the need for additional RT.

3. Discussion

The incidence of cutaneous metastasis of rectal cancer is approximately 3–4 %, and metastasis to the vulva is exceedingly rare. When such cases are diagnosed, it is often a reflection of advanced disease and portends a poor prognosis. Primary vulvar or vaginal adenocarcinomas are also very rare, and typically occur in the setting of DES exposure or Bartholin’s carcinoma, and thus metastasis of another primary cancer should be considered whenever adenocarcinoma is noted in a vulvar lesion.

Rectal cancer can metastasize through lymphatic invasion, hematogenous spread, or direct extension. The most frequent sites of metastasis of rectal cancer are the liver and lungs. When the gynecologic organs are sites of colorectal metastasis it is thought to be secondary to hematogenous or lymphatic spread, and disease manifests more often in the ovaries or uterus than in the vulva. It is theorized that vulvar spread may be secondary to retroperitoneal lymphatic congestion and retrograde lymphatic diffusion.(Ren et al., 2015 Jan 1) Vulvar metastases cancers can present similarly to primary vulvar cancers or vulvar dermatoses, with pain or discomfort in the vulva or vagina, skin changes, ulcerations, masses or lesions, or groin lymphadenopathy.

Diagnosis typically involves a comprehensive physical exam, imaging with an MRI, CT, or PET-CT, and biopsy. Pathologic diagnosis may be strengthened with IHC testing to confirm colorectal versus vulvar pattern of staining, particularly with positive staining for CK7+/CK20+/CDX2+/CEA + confirming gastro-intestinal primary.

Treatment options may depend upon the prior treatment received and the extent of disease spread, but may involve surgery, chemotherapy, and radiation therapy, in accordance with treatment guidelines for the primary tumor.

Here we describe a case of a patient with known recurrent rectal carcinoma that presented with a vulvar metastasis fifteen years after her initial diagnosis. A thorough gynecologic exam by a gynecologist and a biopsy was ultimately crucial in making the diagnosis and referring the patient to the necessary therapy for local disease control. Examiners should have a low threshold for biopsy when patients present with skin changes or vulvar or vaginal complaints, even if the physical exam does not reveal findings that are obviously malignant. Repeated PET imaging was also crucial in this case in revealing areas of hypermetabolic activity suspicious for recurrence that were not readily apparent on physical exam.

There are no discrete guidelines to management of colorectal metastasis to the vulva, however one can extrapolate recommendations for metastatic colorectal cancer including systemic therapy with FOLFOX/FOLFIRI, radiation therapy, and/or consideration of surgery in the setting of oligometastatic disease. In this case, recognition of the vulvar spread of disease prompted the addition of radiation therapy.

Vulvar metastasis of colorectal cancer has been described infrequently in the literature.(Ren et al., 2015 Jan 1, Akpak et al., 2014 Jun, Matak et al., 2022, Papathanasiou et al., 2003, Pabuccu et al., 2012) Similar cases have also been described of rectal carcinoma metastasis to the clitoris and vagina.(Kobayashi, 1999, Chagpar and Kanthan, 2001 Feb, Marchal et al., 2006) In these cases, patients presented similarly to ours, with development of vaginal or vulvar pain, swelling, pruritis, or a vulvar mass or skin lesion. Diagnosis was confirmed by pathologic evaluation which relied upon IHC staining and in some cases KRAS gene mutation analysis. Evaluation of serum tumor markers such as CEA may also be helpful in diagnosis. Treatment in these cases consisted of surgery with wide local excision of the vulva, combination chemotherapy with a 5-FU based regimen, or radiation therapy.

Our case highlights the importance of accurate and timely diagnosis of potential gynecologic metastasis and may require examination by a gynecologic oncologist. Close attention should be paid to any patients who present with vulvar or vaginal symptoms including dyspareunia, pruritis, burning, or skin changes, to properly assess for metastatic disease versus treatment-related changes versus primary vulvar cancer or vulvar dermatoses or infections. Most importantly, a multidisciplinary approach to diagnosis and treatment is necessary.

Informed consent statement

Written informed consent was obtained from the patient for publication of this case report (and accompanying images). A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

CRediT authorship contribution statement

Megan Gorman: Writing – review & editing, Writing – original draft, Visualization, Resources, Investigation, Conceptualization. Vanessa Ross: Writing – original draft, Investigation. Lisa dos Santos: Writing – review & editing, Resources. Shaza Al-Atassi: Writing – original draft, Resources. Marina Frimer: Writing – review & editing, Supervision.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.