Aggressive anaplastic ovarian carcinoma in a young nulliparous patient

Abstract

Ovarian tumours harbouring foci of anaplastic carcinoma are extremely rare. With just a handful of cases reported in the literature, understanding of the disease and optimal management remains limited. A 38-year-old woman was referred to the gynaeoncologists with a multiloculated complex ovarian mass. High-grade mucinous ovarian carcinoma with mural nodules of anaplastic carcinoma was found on biopsy. Furthermore, an umbilical Sister Mary Joseph nodule signalled advanced metastatic disease. The patient underwent primary debulking surgery and was referred for adjuvant chemotherapy. High-quality radiological and surgical images are included to illustrate the approach taken to preoperative diagnosis and described surgical technique. Our case demonstrates the aggressive and rapidly progressive nature of mucinous ovarian carcinoma bearing anaplastic components. Sharing experience of such cases generates awareness and highlights the need for early detection and thorough investigations to guide subsequent management.

Background

Anaplastic ovarian carcinoma is an infrequently encountered component of mucinous ovarian tumours. First described in 1982, a paucity of cases published in the literature means the prognostic significance of anaplastic foci on disease behaviour and outcome remains poorly characterised. The case described here is of a 38-year-old woman who presented with abdominal discomfort and raised tumour markers. Not unusually with ovarian malignancy, subsequent investigations found advanced disease at diagnosis. However, what is unusual about this case is its extremely aggressive phenotype with rapid disease progression and recurrence, which ultimately proved fatal at just 8 weeks after initial presentation to primary care. In contrast to literature which indicate that anaplastic foci within ovarian tumours may be indolent and have little effect on outcome, this case adds evidence that they can have an extremely poor prognosis.

This case also demonstrates the need for high vigilance to pick up subtle clinical signs on abdominal and pelvic examination when a gynaecological malignancy is suspected. An umbilical Sister Mary Joseph nodule (SMJN) is an easily overlooked but important sign of advanced abdominal or pelvic malignancy. As described in this case report, it served as an ominous indicator with regard to prognosis.

Under current guidelines, optimal surgical effort with the aim of R0 cytoreduction is the mainstay of treatment for most ovarian cancers. This was particularly relevant to the present case, as the patient’s underlying mucinous ovarian carcinoma (mOC) is known to show poor chemosensitivity. Given the relatively younger age group that this tumour type tends to affect, this case also emphasises the importance of sensitively counselling the patient and her partner about the consequences of pelvic clearance on fertility, especially if they have yet to complete their family.

Case presentation

A 38-year-old nulliparous woman presented to her general practitioner in July 2020 with a 3-week history of painless abdominal distension. She was notably cachectic. Abdominal examination revealed a fixed pelvic mass extending above the umbilicus, with the clinical impression of ascites. There was no significant medical or surgical history and she was fit and well prior to the onset of her symptoms. Her only regular medication was hormonal contraception which she had stopped 1 month ago. A never smoker with no alcohol intake, the patient lived with her husband. There was no known family history of ovarian cancer or other malignancies. A urinary pregnancy test was negative.

A tumour marker panel including germ cell markers revealed a significantly raised cancer antigen 125 (Ca-125) (419 IU/mL, normal parameters 0–35 IU/mL) as well as raised cancer antigen 19-9 (Ca-19-9) and lactate dehydrogenase (table 1). Carcinoembryonic antigen, α-fetoprotein (AFP) and human chorionic gonadotrophin (hCG) were normal. An ultrasound scan (USS) was arranged to further evaluate the pelvic mass, which reported an 18 cm, part-solid part-cystic complex mass with significant ascites (figure 1). Combined with the Ca-125, the USS findings equated to a risk of malignancy index score of >250, hence a red flag referral was made to gynaeoncology. In the interim, however, the patient presented to the emergency department with significant deterioration in her clinical condition, experiencing worsening abdominal distension, pain, dyspnoea and persistent nausea. She reported that the mass had doubled in size in the past week.

Table 1.

The patient’s blood results on admission with tumour markers

Haemoglobin (Hb)	111	g/L
White cell count (WCC)	14.7	×109/L
Albumin	20	g/L
Cancer antigen 199 (Ca-19-9)	1266	U/mL
Cancer antigen 125 (Ca-125)	419	IU/mL
Carcinoembryonic antigen (CEA)	2.0	μg/L
α-fetoprotein (AFP)	<1.7	IU/L
C reactive protein (CRP)	244	mg/L
Lactate dehydrogenase (LDH)	365	IU/L
Human chorionic gonadotrophin (hCG)	<1	IU/L

Values that exceed the normal range are in red; those below the normal range are in blue.

Figure 1.

Transabdominal ultrasound sonography. A left adnexal mass with solid and cystic components is shown, measuring 18.3×12.2×15.9 cm.

On examination, the patient was tachycardic (106 bpm) with low-grade fever (37.8°C). The abdomen was grossly distended with a large palpable mass. The abdomen was tender but not diffusely peritonitic; bowel sounds were normal. Of note, a firm 2.5 cm smooth nodule was palpable on the umbilicus, suspicious for an SMJN. The patient was admitted under the care of the gynaecology team for further inpatient investigations and management.

Investigations

A septic screen was performed, which identified raised inflammatory markers: white cell count 14.7×10⁹/L, C reactive protein 244 mg/L (table 1). Biochemistry revealed significant hypoalbuminaemia (20 g/L, reference range 35–50 g/L), with normal liver function results and normal renal function, calcium, magnesium and phosphate.

An urgent CT chest abdomen pelvis was undertaken to further investigate the clinical findings per abdomen (figure 2). This demonstrated a complex cystic solid mass arising from the left ovary (130×130×145 mm), together with associated abdominopelvic lymphadenopathy and ascites. There was no evidence of acute bowel obstruction. Initial supportive management was instigated with intravenous fluids, intravenous antibiotics and analgesia. An ascitic drain was inserted for symptomatic relief, draining 7 L of ascites and a sample of this was sent for cytology.

Figure 2.

(A) Coronal CT image of the chest, abdomen and pelvis with intravenous contrast. A complex left ovarian mass measuring approximately 130×130×145 mm is visible. (B) Sagittal and (C) axial images show a hyperdense umbilical nodule measuring 2.5 cm in diameter.

In the interim, the case was discussed urgently by the Gynae-Oncology Multidisciplinary Team (MDT). CT imaging was reviewed and felt to be radiologically in keeping with a Federation of Gynaecology and Obstetrics (FIGO) stage IIIA primary ovarian cancer. The recommendation was made to proceed to image-guided biopsy. This was subsequently undertaken, and histopathology of mucinous adenocarcinoma with malignant mural nodule was confirmed. Further MDT discussion recommended proceeding to urgent primary debulking surgery (PDS).

Treatment

Prior to surgery, the patient was counselled by gynaeoncology as an inpatient with cancer nurse specialist (CNS) support, explaining the diagnosis and surgical risks. Specific time was dedicated to explaining to the patient and her husband the impact of pelvic clearance on fertility. Further preoperative input was sought from the dieticians to optimise the patient’s nutritional status in advance of surgery, as well as further counselling from the stoma team in preparation for potential bowel resection as a component of cytoreductive surgery. The patient was also seen preoperatively by the anaesthetist and informed about the possibility of postoperative admission to Intensive Therapy Unit (ITU).

Surgery was undertaken 14 days after initial admission to hospital. Exploratory laparoscopy undertaken to assess the extent of disease dissemination found a large, complex mass arising from the left hemipelvis with a mucinous appearance. Disseminated fibrin deposits were noted on the small bowel serosa suggestive of recent infection, perhaps spontaneous bacterial peritonitis secondary to ascitic drain insertion. No evidence of metastatic disease was seen on the omentum or in the upper abdomen, but peritoneal deposits were noted within the pelvis. Laparoscopic assessment deemed the disease to be resectable, and hence the surgery proceeded to midline laparotomy, total abdominal hysterectomy, bilateral salpingo-oophorectomy, total omentectomy, appendicectomy, pelvic and bladder peritonectomy, and dissection of bulky pelvic and para-aortic lymph nodes. Biopsies were taken from several sites throughout the abdomen and pelvis, including the small bowel surface. Due to disease compounded by recent infection, extensive dissection was required; however, bowel resection was avoided. R0 was achieved intraoperatively with an estimated blood loss of 1500 mL and transfusion of 2 units packed red cells. The patient remained stable throughout surgery.

Due to the complexity of surgery, the patient was admitted to ITU postoperatively and made a good recovery with no immediate complications. Input continued from the pain team and the dieticians, and the patient was discharged home 12 days postoperatively, with ongoing CNS support and plans for outpatient follow-up 4 weeks later.

Outcome and follow-up

The final histopathology was confirmed as high-grade primary ovarian mucinous adenocarcinoma with extensive elements of anaplastic carcinoma. Due to positive lymph nodes, final staging was confirmed as FIGO stage IIIA2 disease. The patient was informed of the diagnosis and counselled for adjuvant chemotherapy. Prior to commencing treatment, however, the patient was readmitted 30 days following debulking surgery with multiorgan failure. Urgent CT revealed rapid and aggressive disease progression with an 18 cm retroperitoneal lymph node bundle, causing bilateral ureteric obstruction and secondary hydronephrosis. New pulmonary and hepatic metastatic disease deposits were also identified. The patient was admitted to Intensive Care for supportive care including haemodialysis. Following MDT discussion and liaison with the patient’s family, palliative care input was sought and the patient was transferred to hospice facilities. The patient unfortunately died a few days later from advanced ovarian carcinoma, 5 weeks following her primary surgery.

Discussion

In this report, we describe a case of mucinous ovarian carcinoma with foci of anaplastic carcinoma in a young nulliparous patient, which followed an aggressive, rapid and ultimately fatal course. First described in 1982, anaplastic carcinoma arising in ovarian tumours are rare with few reported cases and sparse follow-up data.^{1 2} Like most ovarian cancers, the relatively asymptomatic nature of the disease means many women present late with advanced disease and bulky metastatic disease deposits.³ The rapidly growing pelvic tumour can cause symptoms including abdominal distension, progressive dyspnoea, nausea, early satiety and weight loss,⁴ all of which were present in our patient.

Ovarian anaplastic carcinoma is almost exclusively associated with an underlying mucinous ovarian tumour,⁵ where it classically takes the form of malignant mural nodules within the cyst wall. The mechanism by which anaplastic foci arise has remained unclear, whether these represent a collision phenomenon between tumours of separate origin or through clonal evolution of dedifferentiated cells from the underlying mucinous tumour.⁶ Recent molecular analyses have added evidence favouring the latter theory, as paired sequencing analysis of anaplastic foci and their associated mucinous tumours from seven different patients uncovered identical KRAS mutations in both tumours in six out of seven cases.⁷ Since somatic KRAS mutation is the most frequent molecular alteration in mucinous ovarian neoplasms,⁸ these findings would be consistent with a model of divergent evolution from an original mucinous tumour.

Owing to a highly invasive phenotype, ovarian tumours harbouring components of anaplastic carcinoma are often not confined to the ovary, frequently associated with infiltration of the surrounding pelvic and abdominal organs and distant metastases.⁹ An important clinical sign on examination that can provide a valuable clue about the extent of disease is the Sister Mary Joseph Nodule (SMJN). In our patient, this was palpable as a smooth, painless, firm nodule on the umbilicus. The term was originally coined by Hamilton Bailey¹⁰ in honour of Sister Joseph, a surgical assistant at the Mayo Clinic in the 19th century who observed the association between the presence of a cutaneous umbilical nodule and subsequent intraoperative discovery of underlying abdominal or pelvic malignancy. When present, SMJN is an ominous sign of advanced disease with a poor prognosis.¹¹ The umbilicus is an uncommon site of metastasis, and presentation can range from asymptomatic nodules to indurating painful ulcers. While differentials of primary umbilical pathology such as a tumour or hernia should be excluded, an umbilical nodule should not be dismissed as it can sometimes be the first sign of abdominal or pelvic malignancy. In men, SMJN is frequently associated with gastrointestinal cancers, but in women, the most common primary is a gynaecological cancer, particularly those of ovarian origin.^{12 13}

Anaplastic carcinoma occurring in any organ is generally associated with a dismal prognosis due to an unusually rapid clinical course and poor response despite aggressive management. Presence of anaplastic foci within ovarian tumours has also been thought to signify an invariably poor outcome, with early case reports indicating >60% mortality, usually within 1 year.^{1 14} However, more recent literature suggest that this may be an oversimplification. A case series of 34 patients with ovarian tumours containing anaplastic carcinoma found that 10 out of 15 women with FIGO stage Ia tumours (confined to the ovary) were alive with no disease recurrence at 5 years.¹⁵ This and similar studies have concluded that in early-stage tumours the presence of anaplastic foci has little influence on outcome, and that the most important predictive factor for prognosis is the FIGO stage of the underlying mucinous ovarian tumour. Given the favourable prognosis of early-stage disease, the importance of detecting disease prior to infiltration beyond the ovarian capsule and metastasis is abundantly clear. With a current lack of effective screening strategies, a high vigilance for suspecting ovarian malignancy is paramount for early detection.

The British Gynaecological Cancer Society (BGCS) guidelines¹⁶ recommend sequential testing with Ca-125 and pelvic ultrasound in women who present to primary care with suspicious symptoms such as abdominal distension and early satiety. If both tests are abnormal, or if a woman presents with an abdominal mass, urgent referral to secondary care is indicated. AFP and hCG levels should also be measured in women younger than 40 years to identify non-epithelial ovarian tumours. Once an ovarian tumour is presumed, radiological staging with CT abdomen chest pelvis is used to define the extent of disease and plan for any surgery. All patients with suspected or confirmed ovarian carcinoma should be discussed by the MDT. Involvement of the MDT was particularly relevant in our case with elements of anaplastic carcinoma, as there is no consensus on a standardised management approach for this rare tumour type. Management decisions were guided by a careful review of imaging and histopathology results, taking into account the patient’s fitness for surgery, as well as patient values and expectations.

PDS followed by platinum/taxane-based adjuvant chemotherapy has been established as the standard of care for newly diagnosed advanced ovarian cancer since the 1980s.¹⁷ The aim is ‘optimum’ cytoreduction to no residual disease (R0), based on evidence from large-scale studies including a retrospective meta-analysis of over 6800 cases which demonstrated a 5.5% longer median survival for each 10% increase in maximum cytoreduction.^{18 19} In our patient’s case, the underlying mucinous ovarian carcinoma is known to show poor sensitivity to standard chemotherapy,^{20 21} therefore the decision was made to proceed with PDS. However, the more radical the surgical approach, the greater the risks of complications: pelvic clearance, bowel resection and upper abdominal surgery may be required to attain R0, and thus PDS may not be suitable for patients with extensive metastatic disease. Neoadjuvant chemotherapy (NACT) followed by delayed interval debulking surgery (IDS) is an alternative treatment paradigm, where patients undergo three cycles of chemotherapy prior to IDS, followed by three further cycles of chemotherapy. European Organisation for Research and Treatment of Cancer (EORTC) 55971 and Medical Research Council Chemotherapy Or Upfront Surgery (CHORUS) were two large, prospective studies that investigated outcomes in patients with advanced ovarian cancer who were randomised to PDS or NACT-IDS.^{22 23} Both studies found no difference in progression-free survival or overall survival, with a reduced perioperative morbidity in the NACT arm. However, both studies were limited by inter-centre variability in complete resection rates, reporting lower-than-expected R0 rates and reduced survival rates overall compared with earlier studies,¹⁹ which has led to controversy over the validity of their findings. Trial of Radical Upfront Surgical Therapy (TRUST) is an ongoing randomised study that aims to address these concerns by recruiting specialist centres with high R0 rates to evaluate the outcomes of optimum cytoreduction achieved by either PDS or NACT-IDS.²⁴ The trial results are awaited in 2024.

In the case reported here, despite achieving R0 at primary surgery, the disease took a rapidly progressive course. In retrospect, the question remains whether our patient would have benefitted from NACT as first-line management. According to results from the EORTC 55971 study, patients with stage IIIC disease had better overall survival with PDS, whereas NACT was only associated with better survival in those with stage IV disease, and the authors concluded that PDS should remain the standard of care for women with earlier stage ovarian cancers.²² At present, the available evidence do not show a difference in outcomes between the two treatment approaches, and the single most important prognostic factor remains the extent of cytoreduction achieved during surgery.²⁵ Thus, decisions regarding choosing either PDS or NACT should be considered individually, taking into account the patient’s tumour stage, comorbidities, age and WHO performance score.

Learning points.

• The majority of women with ovarian malignancy present with advanced disease. This tendency for late presentation is mostly attributed to the vague nature of the associated symptoms—highlighting the diagnostic challenge that ovarian cancer presents.

• Clinical examination in ovarian cancer requires vigilance for subtle signs to detect a pelvic mass or abdominal ascites. An umbilical ‘Sister Mary Joseph’ nodule may be easily overlooked, but provides a valuable clue to the diagnosis and is an ominous sign regarding prognosis.

• Mucinous ovarian carcinoma (mOC) is a less common histological subtype of ovarian cancer, more prevalent among younger women—contrasting with epithelial carcinomas, seen mostly among the postmenopausal population.

• Our case report highlights the importance of optimal surgical effort to achieve R0 cytoreduction in cases of mOC due to the low chemosensitivity of this tumour type.

• This case demonstrates the poor prognosis associated with anaplastic tumour components, which typically exhibit aggressive behaviour—with rapid disease progression and relapse.