
==== Front
Oncol Lett
Oncol Lett
OL
Oncology Letters
1792-1074
1792-1082
D.A. Spandidos

10.3892/ol.2024.14633
OL-28-5-14633
Case Report
Diagnostic difficulties in the differentiation between an ovarian metastatic low‑grade appendiceal mucinous neoplasm and primary ovarian mucinous cancer: A case report and literature review
Kawecka Weronika 1
Adamiak-Godlewska Aneta 1
Lewkowicz Dorota 2
Urbańska Karolina 3
Semczuk Andrzej 1
1 The Second Department of Gynecological Surgery and Gynecological Oncology, University Clinical Hospital no. 4, Lublin Medical University, PL-20090 Lublin, Poland
2 Department of Clinical Pathomorphology, Lublin Medical University, PL-20090 Lublin, Poland
3 Students' Research Group at The Second Department of Gynecological Surgery and Gynecological Oncology, Lublin Medical University, PL-20090 Lublin, Poland
Correspondence to: Professor Andrzej Semczuk, The Second Department of Gynecological Surgery and Gynecological Oncology, University Clinical Hospital no. 4, Lublin Medical University, 8 Jaczewski Street, PL-20090 Lublin, Poland, E-mail: andrzej.semczuk@umlub.pl
11 2024
16 8 2024
16 8 2024
28 5 50027 2 2024
03 7 2024
Copyright: © 2024 Kawecka et al.
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Low-grade appendiceal mucinous neoplasm (LAMN) is a tumor that primarily originates from the appendix and belongs to the family of appendiceal mucinous neoplasms (AMNs). In 50% of female patients, AMNs (particularly LAMNs) have a tendency to metastasize to organs in the genital tract, where the neoplasm can mimic the features of primary ovarian mucinous cancer (POMC). The present case report reviewed the difficulties in differentiating between these two types of tumors. In the present case report, a 61-year-old female patient was admitted to the Second Department of Gynecological Surgery and Gynecological Oncology, University Clinical Hospital no. 4 at Lublin Medical University (Lublin, Poland) with the diagnosis of a right ovarian mass. After performing ultrasound and computed tomography (CT) scans and laboratory analysis, the patient underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, appendectomy and resection of the Douglas peritoneum. Notably, the postoperative pathological assessment revealed LAMN with metastases to the right ovary and omentum. Immunohistochemically, cytokeratin 20 and caudal type homeobox 2 both stained positively, whereas paired box gene 8 stained negatively. After surgery, the patient received the recommended hyperthermic intraperitoneal chemotherapy at the Department of Surgical Oncology at Lublin Medical University. After 1 year, a CT scan was performed, which indicated no evidence of recurrent disease. In conclusion, observations from the present case report suggest that gynecologists should be conscious of the possibility of malignancies of gastrointestinal origin in cases of ovarian tumors instead of making direct assumptions of POMC. If the mucinous mass involves the base of the appendix or if there is a suspicion of positive margins, then cytoreductive surgery and right-sided hemicolectomy must be performed. In addition, identifying the origin of mucinous tumors in the right ovary and/or the appendix requires the histopathological examination of a panel of markers using immunohistochemistry.

LAMN
metastasis
PMP
mucinous neoplasm
appendiceal tumor
immunohistochemistry
Lublin Medical University, Lublin, PolandDz. St. 326/24 The study was supported by a grant from Lublin Medical University, Lublin, Poland (grant no. Dz. St. 326/24).
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pmcIntroduction

Low-grade appendiceal mucinous neoplasm (LAMN) is an epithelial, non-invasive tumor with any of the following features: loss of muscularis mucosae, fibrosis of submucosa and/or ‘pushing invasion’ (expansile or diverticulum-like growth) (1–3). LAMN is detected in 0.7–1.7% of all appendectomies. In particular, the ‘pushing invasion’ feature of LAMNs may increase the possibility of ovarian involvement. Ovarian metastases are found in ~50% of female patients with appendiceal tumors (4). Symptoms of this disease are non-specific, although abdominal pain in the right lower quadrant is the most common complaint (3). If ovarian metastasis occurs, a pelvic mass may become palpable during gynecological examination (2). The most common clinical manifestation of LAMN is an acute appendicitis combined with a perforation of the appendiceal wall (3).

Although preoperative diagnosis can be made by computed tomography (CT) examination (5–7), LAMN is mostly frequently identified intraoperatively or even postoperatively incidentally. This issue particularly concerns female patients, since metastatic ovarian mucinous neoplasms also share similar atypical clinical manifestations and imaging findings (4). The most effective differential diagnostic technique known for LAMN is immunohistochemical examination. The most common immunohistochemistry (IHC) markers applied for diagnostic purposes include cytokeratin (CK)7, CK20, caudal type homeobox 2 (CDX2), paired box gene 8 (PAX8) and special AT-rich sequence-binding protein 2 (SATB2) (8–10).

The treatment method for LAMN typically depends on the tumor stage, whether perforation of the appendiceal wall has occurred, presence of metastases and the existence of peritoneal mucin spread. For localized LAMN, appendectomy is generally sufficient. In cases of metastases to the abdominal organs or the pseudomyxoma peritonei (PMP), cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (HIPEC) is highly recommended (1,3,11–13). In particular, the most dangerous complication among the aforementioned is PMP, when the mucin from the appendix spreads to the peritoneum (1,14,15). The risk of developing PMP increases significantly when spontaneous perforation of the appendiceal wall has occurred (16).

There are only a few articles concerning this topic worldwide, and they generally focus on different aspects of this tumor from the surgical point of view. The lack of articles from the perspective of gynecologists indicates that further exploration of this topic is required. Therefore, the present report documents the case of the 61-year-old female patient who was diagnosed postoperatively with LAMN metastasizing to the right ovary and omentum. Diagnostic difficulties during the clinical course of this patient were summarized before differentiation between metastatic LAMN in the ovary and primary ovarian mucinous cancer (POMC).

Case report

A 61-year-old female patient was admitted to the Second Department of Gynecological Surgery and Gynecological Oncology, University Clinical Hospital no. 4, Lublin Medical University (Lublin, Poland) with the primary diagnosis of a right ovarian tumor in May, 2021. The condition manifested as chronic pelvic pain and pain after defecation lasting several weeks. The patient denied having other symptoms, illnesses or medicaments. According to the medical history of the patient, the last menstruation occurred 10 years ago, and the patient underwent two vaginal deliveries. The last cervical cytological examination was performed 3 years ago and was normal. The patient also suffered from hepatitis B at the age of 15 years old and chronic varices in both legs for >10 years.

On gynecological examination, the external genitalia, vagina and uterine cervix all revealed normal results. However, a palpable pathological mass in the lower-right abdomen was detected. The body of the uterus had an uneven surface and was painful on palpation. The left ovary was not palpable. Biochemical examination revealed cancer antigen 125 levels of 20.2 U/ml [reference range (RR) <35 U/ml], carcinoembryonic antigen levels of 7.7 ng/ml (RR <2.5 ng/ml in non-smoking patients) and a Risk of Ovarian Malignancy Algorithm index of 12.4% (RR <29.9% in postmenopausal women). On transvaginal ultrasound examination, a 16-cm-wide tumor in the right ovary with heterogenous echogenicity was observed (Fig. 1). Between the tumor and circumfluent lesions, a noticeable border was confirmed. The uterus and the left ovary were normal, where the endometrium thickness was 4 mm. A small quantity of ascites fluid was detected in the Douglas pouch, but distant metastases or pathological regional lymph nodes could not be identified.

Abdominal CT scans revealed a large polycystic, pathological mass in the lesser pelvis. The size of the tumor was 17.4×11.7×9.9 cm. No other abnormalities were found in the pelvis minor. The patient was then recommended for explorative laparotomy. In the abdominal cavity, a wide litho-cystic tumor (10×17 cm) originating from the right adnexa was found. The mass in the right ovary was in continuity with the appendiceal neoplasm, the appendiceal walls were thickened and the lesion was swollen. The size of the uterus was normal. Numerous lesions were found to be localized on the left ovary, Douglas peritoneum, greater omentum and both diaphragmatic of the domes. The patient underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy, total omentectomy, appendectomy and resection of the Douglas peritoneum. The postoperative period was uneventful, and 5 days after the surgery the patient was discharged from the hospital in good condition.

Postoperative histopathological examination revealed a LAMN with metastases to the right ovary and omentum. Mucinous tumors were found in the Douglas peritoneum and in the ‘free end’ of the appendix (0.7 cm; Fig. 2). Wall perforation and neoplastic infiltration of the appendiceal mucosa were also observed (Fig. 3). For postoperative histopathological examination, the tissues were fixed with 10% formalin and embedded into paraffin blocks for 24–48 h at room temperature. Then, 5-µm sections were deparaffinized and rehydrated using routine techniques. Antigen retrieval by microwave and blocking of endogenous peroxidase activity (by 1% hydrogen peroxide in distillated water for 10 min at room temperature) was conducted before incubation with the following primary antibodies: CK20 (monoclonal mouse anti-human antibody; ready-to-use; cat. no. GA777; DAKO; Agilent Technologies, Inc.), CDX2 (monoclonal mouse anti-human antibody; ready-to-use; cat. no. GA080; DAKO; Agilent Technologies, Inc.) and PAX8 (monoclonal mouse anti-human antibody; ready-to-use; cat. no. 760-4618; Roche Diagnostics) at 4°C overnight. The primary antibodies were then removed, and the slides were incubated for 30 min at room temperature with a biotin-free horseradish peroxidase enzyme-labelled polymer of the DAKO RealTM EnVisionTM/HRP detection system (DAKO; Agilent Technologies, Inc.). Next, following reaction with 3,3′-diaminobenzidine, the sections were counterstained with hematoxylin for 2 h at room temperature, dehydrated and cover-slipped. Appropriate positive and negative controls were also applied. Stained slides were carefully examined by two investigators by light microscopy. The results indicated CK20 (Fig. 4A) and CDX2 (Fig. 4B) positive staining in the right ovary and appendix, whereas PAX8 (Fig. 4C) staining was negative.The patient was then referred to the Department of Surgical Oncology, Lublin Medical University, where the patient underwent a one-time HIPEC procedure with 30 mg mitomycin C for 1 h at 43°C. After HIPEC, the patient was discharged in good condition. The recurrence of LAMN was not reported during the 1-year follow-up. After 1 year, a CT scan was performed, which revealed no evidence of recurrent disease. The patient remains in the follow-up program devised by the gynecological oncology specialists and remains asymptomatic.

Discussion

One of the main difficulties with mucinous ovarian neoplasms is differentiating them from other types of metastatic tumor, particularly those originating from the gastrointestinal tract. POMCs represent 3% of all primary ovarian tumors, whereas metastatic ovarian tumors account for 5–30% of all ovarian malignancies. The majority of metastases to the ovaries arise from organs in the gastrointestinal tract, where those of appendiceal origin pertain to 13% of such cases (17–19).By gross morphology, ovarian metastases are generally smaller compared with those of primary neoplasms, with sizes typically ≤10 cm in diameter (Table I) (2,13,16,19,20). Histologically, the growth pattern in secondary mucinous tumors is mostly infiltrative and may present as a nodular growth with or without single-cell invasion. In addition, metastases frequently show signs of lymphovascular space invasion, surface and hilar involvements, whilst primary tumors are generally characterized by the presence of microscopic cystic glands and expansive invasion patterns (2,18,19). Differentiating between POMC and ovarian metastases of gastrointestinal tract tumors involves the immunohistochemical assessment of several valuable markers, including SATB2, CDX2, CK7, CK20 and PAX8 (Table II) (17,19). POMC was found to express CK7, CK20 and PAX8 in 90, 65–70 and 35% of all cases assessed, respectively. In addition, the concomitant expression of CK7 and CK20 is present in ~67% of all cases (9,17,20). By contrast, CDX2 expression is found in <50% of all cases of POMC, whereas expression in metastases of lower gastrointestinal tract origin is markedly more common, occurring in 90% of all tumors (17,20). SATB2 is a recently described marker that has been demonstrated to be a novel tool for the diagnosis of the gastrointestinal neoplasms. SATB2 positivity has been reported in 85–90% of all appendiceal tumors, where its expression is stronger and more specific compared with CDX2 (9,17,20–22). Generally, for POMC, CK7 is considered to be the most sensitive marker, whereas PAX8 is the most specific. Furthermore, CDX2 is considered to be the most sensitive marker for ovarian metastases of lower gastrointestinal tract origin, whilst SATB2 would appear to be the most specific (17,23). Although the aforementioned markers are invaluable diagnostic tools, they cannot be interpreted separately since tumors typically exhibit concomitant expression patterns of each of the individual markers. We recommended the analysis of expression of at least two independent immunohistochemical markers (Table III) (8,9,19,21–28).

The molecular mechanism underlying the growth of POMC and AMNs remains unresolved, since experimental data on these particular malignancies are still limited. KRAS and TP53 genetic alterations are the most frequent in POMCs, with their incidence accounting for 33–46 and 26–55% of cases, respectively (26–27,29).

The treatment strategy for LAMN depends on the clinical stage, histological grade, tumor invasion, the presence of metastases and the careful surgical management (3,28,30). There is an association between the expression profile of the IHC markers and histopathological parameters of the tumor. CDX2 expression has been found to be associated with histological grade and depth of tumor invasion, whilst loss of CK20 positivity has been reported to be associated with a higher histological grade of colorectal carcinoma (23). An appendectomy is typically sufficient for treating localized LAMN, whereas right-sided hemicolectomy should be considered if the positive margins persist after appendectomy (31). Metastases or PMP are generally treated with cytoreductive surgery and HIPEC, including oxaliplatin and mitomycin C. During cytoreductive operations, any suspicious lesions should be removed. However, if the tumor extends to the base of the appendix, then there would be a necessity to perform a caecal wedge resection. Peritoneal surfaces that must be inspected include the right iliac fossa, right paracolic gutter, right diaphragmatic surface, greater omentum and pelvic peritoneum (15). Ovarian metastases of appendiceal origin are reported in ~50% of patients, where they are generally metachronous. Both ovaries should be carefully investigated, in cases where malignancies are discovered, bilateral salpingo-oophorectomy is highly recommended, even in pre-menopausal patients (32–34).

In terms of the prognosis of patients with LAMN, namely overall and disease-free survival, it remains uncertain and depends on the clinical stage, presence of metastases, age and general health condition. However, the 5-year survival rate has been estimated to be 80%. Localized LAMN or PMP appear to have favorable clinical outcomes after complete resection of the primary tumor during early-stage disease, but caution must be taken due to data scarcity (35,36). By contrast, the prognosis for POMC depends on tumor staging and the subtype of cancer. Early-stage POMC has a 90% 5-year overall survival rate, though patients with metastatic mucinous ovarian cancer generally will not survive beyond 30 months (28). An abbreviated comparison between LAMN and POMC is shown in Table IV (4,15,28,31,35,36).

In conclusion, observations from the present case suggest that clinical specialists of gynecological oncology should remain conscious of the possibility of ovarian tumors of gastrointestinal origin in addition to POMC. If the mucinous mass involves the base of the appendix or if there is a suspicion of positive margins, detailed cytoreductive surgery combined with right-sided hemicolectomy is highly recommended. Differentiation of the origin of mucinous tumor in the area of the right ovary and/or the appendix requires histopathological and immunohistochemical examination using a panel of protein markers. In addition, molecular studies into LAMN and POMC are warranted to facilitate the development of novel diagnostic procedures in the future.

Acknowledgements

Not applicable.

Availability of data and materials

The data generated in the present study may be requested from the corresponding author.

Authors' contributions

WK made substantial contributions to conception and design, searched the articles and wrote the manuscript; AAG performed the surgery, collected medical records and wrote the manuscript; DL, as a pathologist, diagnosed the case and prepared the histopathological images; KU analyzed and interpreted the data and searched the articles; AS made substantial contribution to conception and design and edited the manuscript. All authors participated in the drafting of the manuscript. DL and AS confirm the authenticity of all the raw data. All authors read and approved the final version of the manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Written informed consent was obtained from the patient for the publication of anonymized data and all accompanying images.

Competing interests

The authors declare that they have no competing interests.

Abbreviations

AMN appendiceal mucinous neoplasm

LAMN low-grade appendiceal mucinous neoplasm

CT computed tomography

IHC immunohistochemistry

PMP pseudomyxoma peritonei

HIPEC hyperthermic intraperitoneal chemotherapy

POMC primary ovarian mucinous cancer

Figure 1. Abdominal ultrasound scan showing an irregular 16-cm-wide mass with heterogenous echogenicity. The mass was preliminarily diagnosed as an right ovarian mucinous tumor.

Figure 2. (A) Wall of the dilated appendix with neoplastic mucinous epithelial lining and extra-appendiceal mucus with serosal reaction, without infiltrative growth or desmoplastic reactions. H&E staining; magnification, ×100. (B) Neoplastic cells of the dilated appendix containing abundant apical mucin and elongated nuclei with low grade nuclear atypia. H&E staining; magnification, ×100.

Figure 3. (A-C) Ovary with metastatic low-grade appendiceal mucinous neoplasm. Focally preserved ovarian stroma are visible around the cystic spaces, lined with mucinous epithelium. H&E staining; magnification, ×100.

Figure 4. Right ovary with metastatic low-grade appendiceal mucinous neoplasm. Immunohistochemical staining for (A) caudal type homeobox 2, (B) cytokeratin 20 and (C) paired box gene 8. Magnification, ×100.

Table I. A comparison between primary ovarian mucinous tumors and mucinous ovarian metastases.

Feature	Primary tumor	Metastatic tumor	
Laterality	Unilateral	Bilateral	
Size, cm	>10	<10	
Age of patients, years	<50	>50	
Presence of signet ring cells	Absent	Present	
Type of invasion	Expansile	Infiltrative, vascular	

Table II. Expression patterns of the most common immunohistochemistry markers depending on the origin of the tumor.

Marker	POMN, %	APE, %	
CK7	90	26	
CK20	65-70	92	
PAX8	35	<5	
CDX2	<50	97	
SATB2	8	85-90	
POMN, primary ovarian mucinous neoplasm origin; APE, appendiceal origin; CK, cytokeratin; PAX8, paired box gene 8; CDX2, caudal type homeobox 2; SATB2, special AT-rich sequence-binding protein 2.

Table III. Expression patterns of concomitant IHC markers in POMN and APE.

IHC markers	POMN, %	APE, %	
CK7/CK20			
  (+)/(+)	67	22	
  (−)/(+)	7	78	
  (+)/(−)	26	-	
SATB2/CK20			
  (+)/(+)	-	80	
  (+)/(−) or (−)/(+)	-	20	
CDX2/CK20			
  (+)/(+)	-	90	
  (+)/(−) or (−)/(+)	-	10	
IHC, immunohistochemistry; POMN, primary ovarian mucinous neoplasm origin; APE, appendiceal origin; CK, cytokeratin; CDX2, caudal type homeobox 2; SATB2, special AT-rich sequence-binding protein 2.

Table IV. Comparison between POMC and LAMN.

Feature	POMC	LAMN	
Prevalence	3-12% of ovarian malignancies	1% of all appendectomies	
Treatment	Staging surgery/cytoreductive surgery, appendectomy, consider HIPEC with cisplatin.	Appendectomy in localized LAMN, cytoreductive surgery and HIPEC with oxaliplatin and mitomycin C. In advanced stage, consider right-sided hemicolectomy.	
Survival rate	90% in early-stage disease, 12–30 months in advance-stage.	80% in early-stage disease.	
POMC, primary ovarian mucinous cancer; LAMN, low-grade appendiceal mucinous neoplasm; PMP, pseudomyxoma peritonei; HIPEC, hyperthermal intraperitoneal chemotherapy.
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