Dyspnoea and the ovaries: a rare presentation of Krukenberg tumour

Abstract

Krukenberg tumour is a metastatic signet-ring adenocarcinoma of the ovary, usually with a gastrointestinal primary detected metachronously or synchronously. We present here a case of a 48 year-old woman who presented with a prolonged history of dyspnoea on exertion. Workup had revealed a pelvic mass. Thoracocentesis of her pleural effusion, with cytology, and pathology reports from her total abdominal hysterectomy with bilateral salpingo-oophorectomy revealed a carcinoma with signet-ring cells. Immunostains were positive for CDX2, CK7 and CK20, which was highly suggestive of a gastric primary. Colonoscopy was negative, and an oesophagogastroduodenoscopy revealed a few small crater ulcers, the biopsy of which was negative for cancer. A right-sided pleurodesis was performed for the unremitting malignant effusion, and a PleurX catheter was placed in her left pleural space. She was discharged home with a very poor prognosis.

Background

Krukenberg tumours are not a common disease entity, forming 1–2% of all ovarian tumours.¹

The most common symptoms are related to the ovaries, and the patients usually present with abdominal pain and distention, largely due to bilateral ovarian involvement.¹

Here we present a case, with an uncommon manifestation of Krukenberg tumour, which presented with dyspnoea as the chief complaint. This unusual presentation warrants the fact that the physicians should have a broad perspective in mind when dealing with patients who present with symptoms that might be pointing towards a certain pathological process.

Case presentation

A 48-year-old Caucasian woman was referred to the University Hospital after she was found to have bilateral pleural effusion and a pelvic mass on a CT scan performed at the referring healthcare facility. The patient's initial symptom of dyspnoea started when she was diagnosed with, and treated for, bronchitis 7 months ago. The patient's symptoms did not resolve and she continued to have dyspnoea on exertion. Imaging of the lungs at that time showed bilateral pleural effusion for which the patient underwent bilateral thoracocentesis. Her dyspnoea temporarily resolved, but started again later, progressing to a level at which she needed assistance, even for her activities of daily living. The patient was again found to have bilateral pleural effusion and underwent second bilateral thoracocentesis. During the workup, she was also found to have a pelvic mass that appeared to be arising from her right ovary. The patient was then referred to the University Hospital for further workup and management.

Upon further enquiry, the patient revealed that she had had unintentional weight loss of about 25 pounds over the course of the last 7 months. The patient also reported that her dyspnoea had got subjectively worse for about 2 weeks before she presented to the referring healthcare facility.

The patient was a gravida 2, para 2. Her menstrual history had been unremarkable and she did not have any significant gynaecological issues in the past. A non-smoker, she denied any alcohol use and her family history was insignificant for any malignancies.

General physical examination and vital signs were within normal limits. Her respiratory exam revealed diminished breath sounds over the left lung base and no breath sounds over the right lung base—there were no added sounds. Abdominal examination did not have any positive findings. No supraclavicular lymphadenopathy was present.

Investigations

Complete blood count and liver function tests were normal. Tumour marker values, done at the referring healthcare facility, showed CA-125 of 484 U/ml.

A CT scan of the abdomen and pelvis performed at the referring healthcare facility showed a 12.8×8.6 cm large, lobulated, inhomogeneous pelvic mass anterior to the uterus with mild free fluid (figures 1 and 2). It also revealed large right and left pleural effusions (figure 3). The patient also underwent transvaginal ultrasound that confirmed a 12 cm lobulated, inhomogeneous pelvic mass, anterior and superior to the uterus, that appeared to be arising from the right ovary (figures 4 and 5).

Figure 1.

‘CT abdomen—scout view’: lobulated, inhomogeneous pelvic mass.

Figure 2.

‘CT abdomen—Transverse View’ lobulated, inhomogeneous pelvic mass anterior to the uterus.

Figure 3.

‘CT chest—transverse view’: large left and right-sided pleural effusions.

Figure 4.

‘Transvaginal ultrasound—long axis’: lobulated, inhomogeneous pelvic mass, anterior and superior to the uterus.

Figure 5.

‘Transvaginal ultrasound—transverse axis’: lobulated, inhomogeneous pelvic mass, anterior and superior to the uterus.

An endometrial biopsy performed at the University Hospital was essentially negative. The patient underwent thoracocentesis for right-sided pleural effusion and the pleural fluid cytology revealed poorly differentiated carcinoma with signet-ring cells, indicative of malignancy.

Treatment

A total abdominal hysterectomy with bilateral salpingo-oophorectomy with omentectomy was performed. Pathological reports on the surgical specimen showed bilateral involvement of ovarian parenchyma with a signet-ring cell carcinoma (figures 6–8) and extensive lymphatic space invasion of the cervix, myometrium and fallopian tubes. The omentum also revealed two tumour nodules with poorly differentiated adenocarcinoma with signet-ring cell features. Immunostains revealed that the tumour cells were positive for CDX2, CK7 and CK20, which was suggestive of a gastrointestinal primary, with a gastric primary being highly favourable.

Figure 6.

‘Left ovary ×200’ H&E stain shows complete effacement of the ovarian parenchyma with a population of tumour cells with signet-ring configuration.

Figure 7.

‘Left ovary ×100’ H&E stain shows the left ovary with extensive invasion of the signet-ring cells into the lymphovascular spaces. There is some residual normal ovary in the very top right corner.

Figure 8.

‘Right ovary ×200’ H&E stain shows effacement of the ovarian parenchyma with a population of tumour cells with signet-ring configuration.

For her unremitting pleural effusion, she underwent right-sided pleurodesis. Pleural biopsy (figure 9) obtained during the procedure revealed signet-ring cell adenocarcinoma with characteristically similar cytopathological features as seen during pathological reports of right and left-sided salpingo-oopherectomies.

Figure 9.

‘Pleural biopsy’ H&E stain shows a population of signet-ring cells invading and dissecting through the fibrovascular tissue of the pleura.

Colonoscopy with random biopsies was normal. Oesophagogastroduodenoscopy grossly revealed a few crater ulcers ranging in size from 5 to 7 mm in the gastric body and incisura. Cold forcep biopsies were obtained that were negative for inflammation and cancer.

A PleurX catheter was placed in her left pleural space, and she was discharged home.

Discussion

Krukenberg tumour is a metastatic signet-ring adenocarcinoma of the ovary with variants of the gastrointestinal primary being detected either synchronously or metachronously. These tumours form 1–2% of all the ovarian tumours.¹ They are usually bilateral (>80%)^{1 2} characterised by mucin-laden signet-ring cells. The most common primary is gastric.^{3 4} The next most common primary sites are the colon, appendix and breast (mainly invasive lobular carcinoma). Rare cases of tumour originating from carcinomas of the gallbladder, biliary tract, pancreas, small intestine, ampulla of Vater, cervix and urinary bladder/urachus have been reported.² The average age of presentation is 40–50 years^{2 3} being more common in premenopausal and pregnant women, as opposed to postmenopausal women.^{5 6}

The common presenting symptoms are usually related to ovarian involvement, the most common of which are abdominal pain and distension.² Woodruff and Novak⁷ reported ascites in 22 of their 48 patients at the time of diagnosis.

There have been a few case reports of pseudo-Meig's syndrome (benign hydrothorax and ascites in a setting of malignant ovarian tumour) reported in patients with ovarian cancer from a gastrointestinal primary.^8–16 The uniqueness of our case is in its initial presentation with shortness of breath. Workup was later found in the pleural effusion to have malignant cells, indicative of widespread metastasis. Our literature review revealed only a few cases that have a presentation like ours.^{12 17}

Median survival of patients diagnosed with Krukenberg tumour is 7–14 months.^{1 5 6 18} In a review article analysing 34 patients with this tumour, median survival periods according to the extent of metastasis were 10.9 months for patients with disease confined to the ovaries, 13.1 months for patients with disease confined to the pelvis, 7.5 months for patients with intra-abdominal disease and 3.6 months for patients with disease spread outside the abdomen and pelvis. In contrast, patient age, size of ovarian tumour and initial stage of gastric adenocarcinoma were not prognostic indicators.¹⁸ In another study involving 54 cases, the median survival among patients with Krukenberg tumours of gastric origin, colon and rectum origin, as well as of other origins, was 13, 29.6 and 48.2 months, respectively.¹⁹

Pathways of spread to ovaries include lymphatic, vascular and peritoneal. It is now evident that retrograde lymphatic spread is the most likely route of metastasis.²

Krukenberg tumour should be suspecte when one sees solid ovarian tumours containing well-demarcated intratumoral cystic lesions, especially if the walls of those cysts demonstrate apparently strong contrast enhancement.²⁰ Grossly, the capsular surface of the ovaries with Krukenberg tumours is typically smooth and free of adhesions or peritoneal deposits.²

The cells stain with Mayer mucicarmine, periodic acid Schiff with diastase digestion and Alcian blue stains. Immunohistochemically, the tumour cells are immunoreactive to epithelial markers, such as cytokeratins (AE1/AE3), and epithelial membrane antigen, and they do not show immunoreactivity to vimentin and inhibin.^{2 21} In a comparison of 3 primary signet-ring stromal tumours to 10 cases of Krukenberg tumours, the signet-ring stromal tumours were devoid of epithelial differentiation (glands, nests, cords), whereas all of the Krukenberg tumours contained these epithelial structures at least focally.²² Primary ovarian carcinomas are almost always immunoreactive to CK7 (90–100%) but generally are not immunoreactive to CK20. By contrast, metastatic gastric carcinoma tends to be less frequently positive for CK7 (55%) but is positive for CK20 in approximately 70% of cases.² Park  et al²³ found that 71% (207 of 289) of the gastric carcinomas stained positively for CK7, whereas only 9% (21 of 225) of the colorectal carcinomas proved to be CK7 positive, and 41% (117 of 289) of the gastric carcinomas and 73% (165 of 225) of the colorectal carcinomas were CK20 positive. Our patient's tumour stained positively for both CK7 and CK20, indicative of a gastric source. Primary carcinomas, particularly those arising in the breast and stomach, may remain silent for many years, and may be very small, requiring exhaustive sectioning to detect them,² which is probably why the stomach biopsy in our case was negative.

Carcinoembryonic antigen (CEA) is a useful marker to distinguish non-gynaecological from primary ovarian carcinoma, while CA125, which will usually be elevated, can also serve as a significant prognostic marker for non-gynecological ovarian carcinoma.²⁴ The levels of both these markers were above the normal reference range in our patient.

A lower rate of respectability when the primary tumour metastasises to other sites (in addition to the ovaries) and overall dismal prognosis are the  two major factors that usually dissuade resection of Krukenberg tumours. Surgery with debulking operation can have a beneficial effect on the survival of some patients. Ayhan  et al²⁵ found this to be true, especially for patients with colorectal cancer metastatic to the ovary.

Chemotherapy or radiotherapy has no significant effect on the prognosis of patients with Krukenberg tumours.² Conversely, Taylor et al suggest that chemotherapy may be useful in patients with ovarian metastasis (regardless of whether Krukenberg or non-Krukenberg) with a gastrointestinal primary. When stratifying the response according to the site, they found a partial response in only 14% of the patients in the ovaries versus 31% in those with extraovarian metastasis.²⁶

Learning points.

• An uncommon pathological process can be missed if it presents with uncommon manifestations.

• A thorough workup of the patient is essential when the presenting symptoms cannot be explained by routine workup.

• Krukenberg tumour can present with symptoms of metastasis, yet discerning the primary source can be a diagnostic challenge and cannot be always determined.

• Although an uncommon ovarian neoplasm, Krukenberg tumour needs to be in the list of differential diagnoses when the patient or relevant age group presents to the healthcare facility, especially when the presenting symptoms are uncommon.