Metastatic Papillary Adenocarcinoma in a 22-Year-Old: Is Her History of Mayer-Rokitansky-Küster-Hauser Syndrome Causative or Incidental?

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A 22-year-old college student with primary amenorrhea due to Müllerian agenesis presented with a headache, dysarthria, nausea, vomiting, and left upper extremity weakness. MRI of the brain showed numerous intracranial lesions.

The Case

A 22-year-old college student with primary amenorrhea due to Müllerian agenesis presented with a headache, dysarthria, nausea, vomiting, and left upper extremity weakness. MRI of the brain showed numerous intracranial lesions, with mild edema associated with some of the lesions. CT of the abdomen and pelvis showed widespread osseous metastatic disease, widespread hepatic metastatic disease, and abnormal appearance of the gallbladder. CT of the chest revealed left-sided pleural effusion and a large mass-like consolidation in the left upper lobe of the lung. Neurosurgical consultation was obtained, and a craniotomy and biopsy were performed.

Histopathologic examination of the biopsy specimen demonstrated moderately differentiated metastatic adenocarcinoma, with intracellular mucin in a focal micropapillary pattern. The findings were suggestive of gallbladder adenocarcinoma. Also considered in the differential diagnosis was an ovarian mucinous carcinoma; this was thought to be a possibility because of the patient’s history of maldevelopment of the Müllerian tract, also known as Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, diagnosed at age 16 years. Medical history also revealed that she had been conceived within 9 months of her mother’s completing chemotherapy for non-Hodgkin lymphoma and was born with anosmia.

Following the biopsy, the patient developed left-sided hemiparesis as a result of bleeding into the biopsy site, and she declined rapidly. She received urgent palliative radiation therapy to the whole brain and was transferred to the neurosurgical intensive care unit (ICU) for further management. She had minimal improvement and was discharged home to complete whole-brain radiation therapy and pursue hospice care.

She improved significantly over 6 weeks: she was able to hold a conversation, sit up on her own, walk without assistance, and drink from a cup without difficulty. She participated in commencement exercises and received her college degree. Once she had demonstrated improvement from whole-brain radiotherapy, she wanted to attempt systemic therapy. Using molecular profiling, agents with potential benefit were identified; these included liposomal doxorubicin. Testing limitations did not permit analysis of the benefit of adding platinum-based therapy to the treatment plan. However, given that a few cases of ovarian neoplasms have been associated with MRKH syndrome, treatment with both carboplatin and liposomal doxorubicin was initiated. After 3 cycles of chemotherapy (given every 21 days), she had an overwhelming response, as shown in the Figure. She completed 6 cycles, was working as a dog walker, and resumed jogging.

Are the following statements true or false?

1. There is an association between MRKH syndrome and cancer.
2. This patient’s malignancy may have been caused by DNA damage sustained in utero as a result of chemotherapy her mother received months before egg fertilization.


1. MRKH syndrome occurs in 1 in 4,000 to 1 in 5,000 live female births and is the second most common cause of primary amenorrhea.[1] Our patient had type 1 MRKH: Fallopian tubes were present but her uterus was hypoplastic; she had normal kidneys and a normal female karyotype (46,XX). Type II MRKH syndrome includes other non-Müllerian anomalies, such as urinary tract and cervicothoracic disorders, and hearing defects.[2] In addition to primary amenorrhea, our patient was born with anosmia, but it was unclear whether this was associated with her MRKH syndrome.

MRKH syndrome accompanied by malignancy is rare. There is a report of a 4-year-old with the syndrome who had an immature teratoma.[3] Bae and colleagues reported on a case of cancer of a supernumerary ovary, which is extremely rare.[4] There is a case report of a 16-year-old found to have MRKH syndrome and renal cell carcinoma.[5] A case of a pelvic-abdominal mass in a 40-year-old with MRKH syndrome and urologic abnormalities has also been described; the patient was found to have a leiomyoma of the rudimentary uterus.[6] With at least two other cases of ovarian cancer in patients with MRKH syndrome,[7,8] we had to consider it in our differential diagnosis and treatment planning, even though there is insufficient evidence to support a causal relationship between the two entities.

A current area of clinical focus in patients with MRKH syndrome-especially those with vaginal hypoplasia-is restoration of sexual function. While there does not appear to be an association between the syndrome and cancer, future research should focus on cancer prevention and the development of screening tools for these patients, given the impossibility of performing a bimanual exam.

2. What happens when a woman conceives less than 6 to 12 months after completing cancer treatment? Our patient’s mother was treated for non-Hodgkin lymphoma and completed chemotherapy less than 9 months prior to conception. Animal studies have shown an increase in abortions and fetal malformations in pregnancies resulting from oocytes exposed to cyclophosphamide at different stages of oocyte maturation.[9] Vinca alkaloids are known to induce aneuploidy in oocytes, resulting in malformed fetuses.[10,11] Adriamycin has been shown to induce dominant lethal mutations in maturing/preovulatory oocytes in female mice.[12] Our patient’s mother received all of these drugs and yet was still able to conceive. We don’t know whether there was DNA damage to the fertilized egg from previous chemotherapy exposure, or whether such damage was the specific cause of MRKH syndrome in our patient, but the history suggests this possibility. The presentation of this cancer diagnosis is rare, especially in a young, otherwise healthy, individual.

Much of our research into the effects of cancer treatment has focused on preserving fertility in younger patients and establishing recommendations for when to conceive after aggressive chemotherapy and radiotherapy. Another focus of such research needs to be on delaying conception with effective contraception until it is reasonably certain that the risk of therapy-related damage to a patient’s oocytes is past. As we increase the emphasis on survivorship in our cancer patients, we need to include their offspring and develop cancer screening guidelines for them as well.

Outcome of This Case

Unfortunately, our patient succumbed to her disease 10 months after diagnosis. However, it was a remarkable period of time, as we had not expected her to live more than a few weeks following her admission to the neurosurgical ICU. She had specific goals in mind and was able to accomplish them. We had other treatment options planned when she showed progression, but she declined. She died at home with hospice care, surrounded by family, including her four younger siblings.

In her initial work-up, the patient had genetic testing. This included chromosome analysis, chromosomal microarray, and CancerNext (a panel containing 22 cancer susceptibility genes). Results of the chromosome analysis and microarray were normal. The CancerNext panel did find a variant of uncertain significance in the MSH6 (Lynch syndrome) gene, but the patient’s family history did not demonstrate a typical inheritance pattern for Lynch syndrome. Thus, the underlying cause of her cancer remains unclear.

Financial Disclosure:The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

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11. Meirow D, Epstein M, Lewis H, et al. Administration of cyclophosphamide at different stages of follicular maturation in mice: effects on reproductive performance and fetal malformations. Hum Reprod. 2001;16:632-7.

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