Introduction

Epithelial neoplasms of the ovary are common, accounting for a significant proportion of ovarian tumours, of which approximately 40% are benign. The most frequent benign epithelial neoplasms are cystadenomas, which originate from the ovarian surface epithelium. These tumours typically present as unilocular or multilocular cysts with smooth inner and outer surfaces. They are easily diagnosed and treated, and carry an excellent prognosis, contributing to about 15% of all ovarian tumours.[1–3]

Among epithelial tumours, mucinous cystadenomas constitute a distinct subtype. These tumours arise from the surface epithelium, although in rare instances, they may have a germ cell origin. At molecular level, KRAS mutations have been identified in up to 58% of cases.[3] Mucinous tumours of the ovary are a heterogeneous group, and the term "mucinous epithelial neoplasm" broadly includes a spectrum of lesions ranging from benign mucinous cystadenomas to malignant mucinous carcinomas—either primary or metastatic in origin.

Accurate classification of mucinous ovarian tumours is often difficult due to overlapping clinical, radiological, morphological, and immunohistochemical features. The diagnostic challenge is further compounded by the striking resemblance that some metastatic mucinous tumours bear to primary benign lesions, both grossly and microscopically. Metastatic tumours can deceptively mimic benign mucinous cystadenomas, thereby obscuring the true nature of the disease.[4]

The most common primary sites for metastatic mucinous tumours to the ovary include the gastrointestinal tract, pancreas, and biliary tree. In particular, metastases from pancreatobiliary and gastrointestinal malignancies frequently simulate primary ovarian tumours.[4] appendicular mucinous neoplasm (LAMN) is increasingly recognized as a distinct and clinically significant entity.[4,5]

Given this complex and often confusing diagnostic landscape, a multidisciplinary approach is essential. Clinico radiological pathological correlation, supplemented with immunohistochemistry (IHC), is strongly recommended for accurate diagnosis and management of mucinous ovarian tumours.

The present case illustrates a rare and challenging scenario—a metastatic mucinous ovarian tumour originating from a low-grade appendiceal mucinous neoplasm, which closely mimicked a benign mucinous cystadenoma on morphology. This case underscores the critical importance of integrated diagnostic strategies to ensure appropriate classification and treatment planning.

Case Description:

A 50 year-old female patient, presented at outpatient department of Obstetrics and Gynaecology with massive abdominal distention and discomfort. Clinical examination showed lower abdominal distension from hypogastric to bilateral iliac fossa, which was soft and measuring 10 x 8 cm. Computed Tomography abdomen and pelvis revealed cystic lesions in both the ovaries, likely neoplastic along with ascites. Cervix, pancreas and rest gastrointestinal tract was unremarkable and appendix was reported as not visualized on Magnetic Resonance Imaging.

Ethical Considerations- Written informed consent was obtained from the patient for publication and waver was obtained for ethical committee clearance from institutional ethical committee as per institutional guidelines.

Diagnostic ascitic fluid tapping was done under aseptic precaution and the sample was sent for cytological examination. On gross examination, the fluid was thick and jelly like. (Figure 1 A) The fluid was smeared and stained with haematoxylin and eosin (H & E), May-Grunewald Giemsa (MGG), Papanicolaou (Pap) and Ziehl Nelson (ZN) for cytopathology analysis. Cytology smears revealed myxoid fibrovascular stromal fragments with atypical cells embedded within it as well as lying dispersed in the background. (Figure 1 B and C) Cell block from the fluid also revealed similar findings and hence the final diagnosis of pseudomyxoma peritonei on ascitic fluid was made at cytology. Patient underwent staging laparotomy and bilateral ovaries were sent for histopathological examination.

Figure 1: A-Ascitic fluid gross apprearance - the fluid was thick and jelly like.B and C- Cytology smears revealed myxoid fibrovascular stromal fragments with atypical cells embedded within it as well as lying dispersed in the background. (Haematoxylin and Eosin, x 200)	Figure 2: A-Gross: Both ovaries showing a smooth external surface with congested blood vessels. B- Cut surface shows cysts filled with thick viscous mucoid material. C- Section shows cyst wall lined by a single layer of columnar epithelium with intracytoplasmic mucin and a basally located benign appearing normochromatic nuclei. (Haematoxylin and Eosin, x 100)

The specimen consisted of bilateral cystic ovarian masses with attached fallopian tubes. The larger ovary measured 15×11×7.5 cm with a 6 cm fallopian tube, while the smaller ovary measured 9× 8.5×5.5 cm with a 4 cm long fallopian tube. Both ovaries had a smooth external surface with congested blood vessels. The cut surfaces revealed multiloculated cysts filled with viscous mucoid material, with no solid areas or necrosis. (Figure 2 A and B) The fallopian tube attached to the larger ovary was unremarkable. The contralateral fallopian tube, attached to the smaller ovary, showed multiple small serosal vesicles (0.2–0.4 cm), with the cut surface revealing a lumen and a mucin-containing wall.

At microscopy, sections from both the ovarian masses showed similar morphology. The cyst wall was made up of fibrocollagenous tissue which was lined by a single layer of columnar epithelium with intracytoplasmic mucin and a basally located benign appearing normochromatic nuclei. (Figure 2 C) There was no evidence of stratification, atypia or necrosis in any of the sections studied. Gross and microscopic features revealed a diagnosis of bilateral benign mucinous cystadenoma. However, at immunohistochemistry, mucinous epithelium was positive for CK20, SATB2 and negative for CK7, PAX8, and p16 suggesting metastasis from lower gastrointestinal tract lesion. Further surgical exploration was done, which confirmed appendiceal low grade mucinous neoplasm at histopathology as the primary tumour.

Discussion:

Both primary (benign/malignant) and metastatic mucinous ovarian neoplasms can present with variable clinical symptoms, such as abdominal and pelvic pain. Similarly, overlap in their morphologic, immunohistochemical, and molecular characteristics complicate the diagnostic process making it challenging to identify the primary nature of the lesion, impacting therapeutic outcome.

Approximately 80% of mucinous ovarian cysts are benign, occurring predominantly between the third and sixth decades of life, though they can also be found in younger women.[6] They are unilateral in 95% of cases.

With the advent of molecular diagnostics, it is now increasingly recognized that metastatic mucinous tumours are more common in ovary than primary mucinous neoplasm. [4,7]. Several studies suggest using algorithms that combine tumour size, laterality, and immunohistochemistry (IHC) results to distinguish between primary and metastatic ovarian mucinous tumours. However, these algorithms are not fool proof and can vary in their sensitivity and specificity.[8]

Several distinct morphologic criteria have been laid out which help to distinguish these two entities. Unilaterality, smooth external surface, tumour size more than 10 cm, benign or borderline areas and expansive growth pattern of invasion at microscopy all favour a primary ovarian neoplasm. In contrast, bilateralism, ovarian surface involvement, small size, an infiltrative growth pattern and aggressive morphology at microscopy all suggest a metastatic ovarian neoplasm. In the present case, both the lesions were large, had smooth surface, there was no capsular breach, any solid area or necrosis on cut surface as well and on extensive sampling did not reveal any nuclear stratification, atypical cells, invasion or necrosis, hence a morphologic diagnosis of bilateral primary mucinous cystadenoma was made.

Few reports mention that metastatic tumours to the ovary can be larger than their corresponding primary tumours, which can contribute to misdiagnosis, as was seen in the present case study.

Pseudomyxoma peritoni (PMP) is a rare condition characterized by mucinous ascites and typically arises from appendix (80-90%). [9] PMP can originate from the ovary (10 to 15%).[10] Ovarian causes of PMP include mucinous ovarian cancer, colon cancer with ovarian metastasis, rarely benign mucinous cystadenoma and malignant transformation of a mature cystic teratoma. In the present case the ascitic fluid was reported as pseudmyxoma peritoni. Though rare, there are very few case reports of PMP occurring due to benign mucinous cystadenoma of ovarian origin. [11] Rarely PMP has been reported to occur alongside synchronous independent primary mucinous neoplasms of both ovary and appendix.[12] The treatment of PMP typically includes cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). A multidisciplinary approach is often necessary for optimal diagnosis and management of these complex cases.

Serum tumour markers play a crucial role and serves as an adjunct tool in accurate diagnosis of mucinous neoplasms of ovary, especially CA 125 and CA 19.9.CA-125 is a marker associated with ovarian cancer, but can also be elevated in other conditions. Elevated levels of CA 19-9 and alkaline phosphatase may suggest a pancreaticobiliary origin. In the present case, CA 125 and CA19.9 were both elevated which added to the diagnostic dilemma.

IHC plays a crucial role in definitive diagnosis of mucinous ovarian neoplasms. Primary mucinous ovarian tumours are more likely to be CK7-positive and CK20-negative, while colorectal and appendicular metastases are often CK7-negative and CK20-positive. However, there can be overlap, with some metastatic tumours also expressing CK7. CDX2 is a marker for intestinal differentiation and is usually expressed in metastatic tumours from the lower gastrointestinal tract. Similarly, SATB2 is commonly expressed in colorectal and appendicular tumours and is rarely seen in primary ovarian mucinous tumours. PAX8 is expressed in a proportion of primary ovarian mucinous tumours, but is typically negative in tumours from the gastrointestinal tract. Metastatic pancreaticobiliary tumours often stain for MUC1 and CK17. Loss of DPC4 (SMAD4) expression is more common in pancreatic tumours and can help distinguish them from primary ovarian mucinous tumours. Using combinations of markers like CK7/CK20 can be more effective than using single markers alone. [7-9]

Growing evidence emphasized the crucial need to distinguish primary versus metastatic ovarian neoplasms, as this profoundly impacts therapeutic strategies and clinical outcome. Cytoreduction therapy is common to both the categories of mucinous ovarian neoplasms. However, metastatic category requires resection of primary tumours and specialized chemotherapy protocols similar to those used for primary sites. Recently, targeted therapies, directed towards KRAS and HER2/Neu is being actively explored with encouraging results, demanding further research to improve outcomes in this challenging disease.

Differentiating primary and metastatic mucinous ovarian tumours remains a diagnostic challenge due to overlapping clinical and pathological features. A combination of macroscopic, microscopic, and immunohistochemical features, along with clinical correlation, is essential for accurate diagnosis. The use of algorithmic approaches may improve diagnostic accuracy but is not a substitute for careful evaluation of all available data. Awareness of the different origins of ovarian metastases, including those from the gastrointestinal tract, pancreas, and biliary tree, as well as the various ovarian causes of PMP, is crucial for optimal patient care.

The present case report emphasizes the diagnostic challenges posed by mucinous ovarian neoplasm and the critical role of comprehensive diagnostic evaluation to avoid misdiagnosis and ensure accurate treatment.

Ethical considerations:

The procedures were carried out in accordance with relevant laws and institutional guidelines. The case presented here has received waiver from institution ethical committee for publication as per institutional guidelines.

Informed consent:

No patient data are included in the article, and if any are present, they do not violate patient privacy and confidentiality, nor do they allow for identification. The samples stored in the Pathology Departments were collected for diagnostic purposes to promote and safeguard patient health, not for experimental procedures.

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