Low Grade Appendiceal Mucinous Neoplasm with Concomitant

Saudi Journal of Internal Medicine Vol. 7 No. 2 - 2017 41

Low Grade Appendiceal Mucinous Neoplasm with Concomitant Ovarian Mucinous Tumor...M.A. Murad and S.T. Mufti

Low Grade Appendiceal Mucinous Neoplasm with Concomitant Ovarian Mucinous

Tumor, Mature Cystic Teratoma andPseudomyxoma Peritonei

Maradi A. Murad, mbbs and Shaguft a T. Muft i, mbbs, md, miap Department of Anatomic Pathology, Faculty of Medicine,

King Abdulaziz University, Jeddah, Saudi Arabia

ABSTRACT

Low grade appendiceal mucinous neoplasms are a challenging entity not just due to their innocent appearance and aggressive extension but also due to their origin dilemmas. We present one such interesting case in a 35-year-old Saudi female who presented to King Abdulaziz University Hospital with acute abdominal pain. Th e patient presented with the main bulk of the mucinous tumor in the left ovary with extensive pseudomyxoma peritonei. Incidentally there was also a mature cystic teratoma in the same ovary. Appendiceal origin was confi rmed on histology and immunohistochemistry. In conclusion our case scenario of low grade appendiceal mucinous neoplasms with concomitant ovarian mucinous tumor, mature cystic teratoma and pseudomyxoma peritonei suggests appendiceal origin both on morphology and immunohistochemistry. As such routine excision of appendix in these case scenarios remains a valid consideration.

Keywords

Ovarian; Mucinous; Appendicial; Teratoma.

CASE REPORT SJIMVOLUME 7 NO. 2

1439 H - 2017 G

Citation:Murad MA and Muft i ST. Low grade appendiceal mucinous neoplasm with concomitant ovarian mucinous tumor, mature cystic teratoma and pseudomyxoma peritonei. Saudi J Intern Med 2017; 7(2): 41-47.

Submission: 02 Sept. 2017 - Accepted: 08 Nov. 2017

Address for Correspondence:

Dr. Maradi A. MuradFaculty of Medicine, King Abdulaziz University

P.O. Box 80215Jeddah, 21589 Saudi Arabia

e-M: [email protected]

42 Saudi Journal of Internal Medicine Vol. 7 No. 2 - 2017


INTRODUCTION

Appendiceal mucinous neoplasms are a spectrum of tumors that keep challenging our knowledge of their existing defi nitions and classifi cation. One particularly interesting tumor in this group is the low grade appendiceal mucinous neoplasm (LAMN). Th ese tumors attract much interest for the fact that though they have an innocent gross and microscopic appearance they tend to penetrate through the appendiceal wall and disseminate into the peritoneum causing a distinctive syndrome called pseudomyxoma peritonei (PP). Oft en the pathologist fi nds him/her self in a diagnostic dilemma when faced with the bland cytological features closely resembling reactive epithelial atypia versus the aggressive behavior when they have disseminated to the peritoneum. Th is dilemma leads to a series of controversies that surround these tumors such as the classifi cation of LAMN itself, the nature and clinical signifi cance of PP in this scenario, whether the presence of grossly intact and microscopically bland appendix favors or disregards the appendiceal origin and most importantly whether the presence of a concomitant ovarian mucinous tumor (OMT) should be considered a separate primary or a metastasis from the appendix.

CASE REPORT

We present an interesting case of a LAMN arising from an intact appendix with disseminated PP associated with concomitant OMT and mature cystic teratoma (MCT) in a 35year old Saudi female at the time of diagnosis. To the best of our knowledge this is the fi rst such case reported from Saudi Arabia and among the very few reported globally[1-3]. Th e histopathology slides, report and relevant information were retrieved from the archives of Anatomic Pathology Department at King Abdulaziz University Hospital, Jeddah Saudi Arabia. Th e clinical history and operative notes were collected from the clinical team in person and from the patient’s hospital fi le. On history, the patient had four pregnancies all of which were spontaneous live vaginal deliveries. Her last delivery was six years back and had been on oral contraceptives for a period of three years following her last delivery. Th ere was no history of diabetes, hypertension, or any chronic disease.

Th e patient presented with acute left abdominal pain, distention, which was increasing gradually over two-weeks associated with fever and amenorrhea. Laboratory investigations revealed high titer of serum tumor markers such as CA-125 as 35.47 IU/mL (0-35) and CEA 42.47ng/mL (0-3.4). Serum beta HCG was negative. Ultrasound of the pelvis showed a complex left ovarian cystic mass measuring 27x21x12 cm. Th e right ovary, fallopian tube and uterus were unremarkable. Th e radiological diagnosis rendered was that of a “left ovarian neoplasm of undetermined signifi cance”. Based on the clinical, laboratory and radiological presence of a mass, a clinical diagnosis of malignant left ovarian mass was made by the gynecologist and the patient was scheduled for left oophorectomy. Over the course of the next few days the

patient complained of a severe increase in abdominal pain following which she was rushed for surgical intervention. Intraoperatively the gynecologist found a huge ruptured left ovarian mass. Th e abdomen was fi lled with gelatinous mucoid material. Intraoperative frozen section was performed from the ovarian mass which revealed a mature cystic teratoma associated with large mucinous neoplasm. In view of a suspicious OMT and its known association with appendiceal primary, intraoperative staging was performed and the ovarian mass, left and right pelvic nodes, appendix and related omentum was resected and submitted to histopathology for examination and confi rmation of frozen diagnosis. Th e right ovary and tube were found to be uninvolved and were not resected.

Grossly the left ovarian mass measured 27 x 20 x 9 cm. Th e outer surface showed focal rupture and was cystic, smooth and shiny oozing mucoid material. Th e tumor weighed 2 kg and a small fi rm hilar ovarian area was identifi ed along with a stump of left fallopian tube. Cut section through the mass showed a multi loculated cyst fi lled with mature hair shaft ; pultaceous material, bony tissue, intermingled with lakes of viscid mucoid material (Fig. 1a, 1b). Th ere were no solid areas or

FIGURE 1A.Gross appearance shows a cystic mass with smooth sequence and existing mucoid material.

FIGURE 1B.Gross showing multi loculated cyst fi lled with mature hair shaft intermingled with lakes of viscid mucoid material.

1b



necrosis. Representative sections were submitted one per cm of the tumor for microscopic examination. Th e appendix measured 4x2cm and was grossly intact and unremarkable. Cut section through the appendix revealed only fecolith with preserved lumen. Appendix was totally submitted in six cassettes. Th e omentum measured 10 x 8 x 5 cms and showed multiple suspicious fi rm areas which were submitted for histological examination. Four left and eleven right pelvic lymph nodes were identifi ed. Each was bisected, submitted separately and fully embedded.

On histopathological examination; the left ovarian mass revealed benign ectodermal elements including keratinizing squamous epithelium, mature hair shaft s, mature brain, sebaceous and apocrine glands (Fig. 2a). Mesodermal element such as calcifi ed bone, cartilage, adipose tissue with giant cell reaction were also present (Fig. 2b). Multiple variable cysts lined by tall intestinal type of epithelium with goblet cells were seen involving most of the ovary surrounded by a large amount of cellular and extra-cellular mucin dissecting the ovarian stroma (Fig. 3a). Th e glands were elongated exhibiting scalloped lumina and sub epithelial cleft s (Fig. 3b, 3c). Th e epithelium lining the glands showed stratifi cation, mild nuclear atypia with focal micropapillary formation. Psammoma bodies

FIGURE 2A.Ovary: Showing hair shafts intermingling with mucin fi lled cysts at 20x.

FIGURE 2B.Showing mature teratomatous elements like cartilage, and sebaceous glands at 20x.

FIGURE 3A.Ovary: Showing multiple cysts lined by intestinal type dysplastic epithelium and fi lled by mucin at 20x.

FIGURE 3B.Showing dysplastic, irregular, stratifi ed and elongated glands exhibiting scalloped Lumina at 20x.

FIGURE 3C.Showing linear sub epithelial clefts. Both detached epithelium and stroma retain parallel orientation at 40x.

were frequent. Th ere was no mitosis, necrosis, mucin granulomas or ovarian type cellular stroma. Th e left fallopian tube was uninvolved by the tumor. Th e appendix revealed intact wall with mucosa lined by adenomatous mucinous columnar epithelium (Fig. 4a) similar to that present within the mucinous areas of left ovary. Th e epithelium showed crowded pseudostratifi ed villiform

2 b

3 b



columnar cells with low grade dysplastic features. Th e nuclei were basal elongated hyperchromatic with large amount of apical mucin. Muscularis mucosa was thinned out. Th e submucosa showed marked histocytic response. Mucin lakes were seen focally within the wall of the appendix and focal direct invasion of the muscle wall by jagged neoplastic glands was present (Fig. 4b). Th e serosal surface showed lakes of mucin (Fig. 4c). Section from the

proximal margin of the appendix was also involved by the dysplastic epithelial lining. Th e omentum showed pools of extracellular mucin, low grade adenomatous mucinous epithelium (Fig. 5a, b) and psammoma bodies with focal mesothelial hyperplasia and giant cell reaction. Th e lymph nodes showed reactive cellular changes with no metastatic epithelial deposits and negative mucicarmine stain. A panel of immunohistochemical (IHC) markers was performed in an attempt to determine the origin of the mucinous tumor. Immunohistochemical markers were performed separately for section from left ovary, omentum and appendix. Th e markers included CK7, CK20, CEA, MUC-2, CDX2, CA-125. Th e epithelium of the mucinous tumor at all three sites was diff usely (more than 50% of the tumor) and strongly (high intensity) positive for CK20, CEA, CDX2, MUC-2 and negative for CK7 and CA125.

In the histopathological diagnostic conclusion, the fact that all the three involved sites showed similar morphological pattern of mucinous tumor and expressed IHC markers supporting appendiceal origin, the fi nal diagnosis was “LAMN with concomitant OMT, mature cystic teratoma and pesudomyxoma peritonei”. At one-year follow-up currently the patient is disease free.

FIGURE 4A.Appendix: Showing dysplastic lining intestinal epithelium at 20x.

FIGURE 4B.Showing dysplastic lining epithelium invading the wall at 40x.

FIGURE 4C.Showing mucin covering the appendiceal serosa at 20x, arrow showing the mucin on serosa.

FIGURE 5A.Omental fat: Showing pools of mucin with fl oating low grade dysplastic mucinous glands at 20x.

FIGURE 5B.Showing high power of dysplastic mucinous glands at 40x.

4 a

4 b

4 c

5 a

5 b



DISCUSSION

Our case supports the currently established concept that OMT with PP almost always results from the spread of primary gastrointestinal tract tumor usually of appendiceal origin[1].Th e ovarian tumors in such cases are large in size mimicking a primary while on the other hand the primary appendiceal tumors may arise in a grossly unremarkable and intact appendix[1] and frequently lack classic infi ltrative invasion of the appendiceal wall yet managing to seed the peritoneum causing PP[2], as in our case. Although clinicopathological, IHC, molecular and genetic studies have established the concomitant OMT with PP as being of metastatic nature from an occult appendiceal primary[1] yet an element of reasonable doubt of it being vice versa remains in the minds of many pathologists to date. Th e reason for this being the presence of diversity among such case reports in literature that convincingly seem to support the opposite origins. To add to the confusion is the fact that isolated cases of histologically benign, borderline, or malignant OMT may as well be associated with MCT and PP[1]. Our detailed knowledge regarding these tumors and their biological behavior however remains limited since much of it is derived only from individual case reports or case series. Ronnett and Seidman[3] reported a subset of OMT arising in a background of MCT associated with PP and exhibiting an IHC expression more supportive of gastrointestinal origin rather than ovarian. Stewart et al.[1]

reported two cases of primary OMT arising in MCT with PP and compared it with four cases of OMT secondary to primary LAMN by using IHC markers. Interestingly both categories of primary origin tumors expressed the same set of IHC markers such as CK 20, CEA, CDX2 and MUC2. Th us IHC markers are reasonably helpful to diff erentiate the origin in such complicated case scenarios. A study by McKenney et al.[4] targeting 42 patients with OMT arising in MCT and associated with 24% PP showed no signifi cant risk for intra-abdominal recurrence. In their case series Stewart et al.[1] reported that primary OMT arising in MCT and associated with PP were similar in morphology and IHC expression to those arising secondary to LAMN. Th e fact that primary OMT rarely gives rise to PP leaves an unresolved dilemma as to whether or not among OMT arising in MCT, presence of PP is simply an extension from an occult appendiceal primary which would necessitate the routine resection of appendix in all such cases. Recently, however a case of intestinal type borderline mucinous tumor (IBMT) ovary arising in a MCT and associated with PP without appendiceal involvement was reported by Chiruvella et al.[5]. Th is raises the possibilities that IBMT arising in MCT may or may not result from LAMN and that they may be associated with PP in either case. A morphological study by Stewart et al.[6] compared 16 cases of ovarian involvement by LAMN associated with PP with 18 cases of primary ovarian IBMT devoid of PP and 6 ovarian IBMT arising within MCT associated with PP. Th ey concluded that the presence of scalloped glands with sub epithelial cleft s were more frequent in LAMN than ovarian IBMTs. On the other hand, ovarian IBMT

more frequently showed cellular ovarian type stroma with formation of mucin granulomas. In our case, although we found scalloped glands with sub epithelial cleft s in the ovarian involvement by LAMN, the interpretation of applying these microscopic features as solely reliable criteria to consistently diff erentiate the origin would require validation by large case studies.

Th e plethora of confl icting evidence in literature[7-17]

and the reconciliation with the fact that both tumors appear similar in morphology and IHC expression regardless of origin raises important research questions. First; if these tumors are so mysteriously similar in morphology and IHC expression, do they have a similar biological behavior? Second; does their origin, similarity or diff erence impact clinical outcome and management? Th ird; should appendiceal resection be routinely considered in all such cases? Fourth; what prognostic impact does LAMN with concomitant OMT, MCT and PP have? With the best of our eff orts we found no convincing answers to our questions worth scientifi c documentation.

CONCLUSION

In conclusion all these questions could be reasonably answered by more comprehensive studies involving large number of cases targeting the detailed clinicopathological, immunophenotypical and prognostic comparison of the two categories LAMN with concomitant OMT, MCT, PP and LAMN without concomitant OMT, MCT, PP. Our case scenario of LAMN with concomitant OMT, MCT and PP suggests appendiceal origin both on morphology and IHC. As such routine excision of appendix in these scenarios is clinically warranted.

Confl ict of Interest

Th e authors have no confl ict of interest.

Disclosure

None of the authors received any type of commercial support either in forms of compensation or fi nancial for this study. Th ey have no fi nancial interest in any of the products or devices, or drugs mentioned in this article.

Ethical Approval

Obtained.

REFERENCES

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ورم الزائدة الدودية من الدرجة المنخفضة مصاحبا لورم مخاطي بالمبيض بالإضافة إلى ورم مسخي ناضج وورم مخاطي صفاقي كاذب

شقفته طاهر مفتيومرادي عبدالقادر مراد، قسم علم الأمراض، كلية الطب، جامعة الملك عبد العزيز

المملكة العربية السعودية -جدة

المستخلص.

الحميدة التشريحية صفاتها حيث من التشخيصية الإشكاليات إحدى تعد المنخفضة الدرجة من المخاطية الدودية الزائدة أورام ٣٥ العمر من تبلغ لسيدة نادرة حالة لكم نعرض هنا ومن ومصدرها، الخبيث وانتشارها إلى أدخلت الجنسية، سعودية عاما

الورم معظم وكان البطن، في شديدة آلام من ةشاكي العزيز عبد الملك جامعة مستشفى إلى إضافة الأيسر، المبيض في منصبا والأنسجة الخلايا بفحص إثباته تم الذي الورم مصدر ويعود الأيسر، المبيض نفس في ناضج مسخي ورم وجود استكشاف الدودية. الزائدة إلى المناعية الهيستولوجية الكيمياء صبغات إلى بالإضافة وورم المبيض، في مخاطي ورم إلى بالإضافة المنخفضة الدرجة من الدودية الزائدة ورم في المتمثلة الحالة هذه من نستخلص

وصبغات والأنسجة الخلايا شكل إلى استنادا الدودية الزائدة هي الورم مصدر بأن كاذب، صفاقي مخاطي وورم ناضج، مسخي هذه مثل في بها المعترف الإجراءات من يعتبر يزال لا الدودية الزائدة استصال فإن ولهذا ،المناعية الهيستولوجية الكيمياء

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Low Grade Appendiceal Mucinous Neoplasm with Concomitant