Carcinoid ovary with synchronous carcinoid tumour of the appendix: report of a rare occurrence with review of literature

Abstract

Carcinoid tumours are present in a wide range of organs but most frequently involve the gastrointestinal tract and rarely reported in gynaecological organs. Literature reports that the prevalence of ovarian carcinoid is 0.3%–1% of ovarian neoplasms and accounts for only 5% of ovarian teratomas. The pathogenesis of neuroendocrine tumours associated with synchronous primaries is undetermined and many theories have been proposed, such as existence of a common carcinogenic effect or a common stem cell undergoing similar genetic mutation. Paracrine or autocrine growth loop effect by the secretory peptides of the neuroendocrine cell tumours is also suggested. Since carcinoids are variably positive in neuroendocrine and organ-specific markers, there are no immunohistochemistry markers to delineate the definite primary site of origin versus metastasis. We report a rare case of carcinoid ovary with synchronous carcinoid tumour of the appendix. In our case, the presence of contralateral teratomatous elements may hint primary struma carcinoid instead of being metastatic from the appendix. A strumal carcinoid component was also highlighted by PAX8 positivity. This led us to conclude the case as concurrent appendix carcinoid with struma carcinoid as two independent primaries with uncertain pathogenesis. Histologically, as both tumours are well differentiated with Ki-67 of less than 3%, the decision of the joint tumour board was to keep the patient on surveillance, with no adjuvant treatment needed. The patient is currently on surveillance and the follow-up period of 24 months to date has been uneventful.

Background

Carcinoid tumours have been reported in a wide range of organs but most frequently involve the gastrointestinal tract (GIT) and rarely reported in gynaecological organs. Previous literature reported that the prevalence of ovarian carcinoid was only 0.1% of ovarian neoplasms and 0.8%–5%¹ of carcinoid tumours. Many of these carcinoid tumours are associated with metachronous and synchronous lesions of another histological type. Primary carcinoid tumours of different organs in the same patient are rare. The most common neuroendocrine neoplasms in the GIT are located in the colon and rectum (69%), followed by the small intestine (36%), stomach (10%) and appendix (5%), as described by Parra-Medina et al² and with similar findings made by Habal et al.³ The pathogenesis of neuroendocrine tumours associated with synchronous primaries is undetermined and many theories have been proposed, such as existence of a common carcinogenic effect or a common stem cell undergoing similar genetic mutations. Paracrine or autocrine growth loop effect by the secretory peptides of the neuroendocrine cell tumours^{3 4} has also been suggested.

Case presentation

A P5L5 perimenopausal woman was evaluated for complaints of undue bloating and abdominal distention. The patient was referred to our centre with an outside ultrasound report suggestive of complex adnexal mass of about 10×15 cm with ascites. She is a non-alcoholic, non-smoker and has no history of any substance abuse. She has never undergone screening for cervical cancer and has no family history of any malignancy.

On clinical examination, the patient had a body mass index of 25 kg/m² and her ECOG performance score was 1. Overall general and systemic examinations were within normal limits. Per examination of the abdomen, she had moderate ascites, with a well-defined, 10×15 cm cystic mobile mass. Per speculum, a pap smear was taken and visual inspection with acetic acid was done, demonstrating normal cervix and vagina. Bimanual examination revealed a uterus of normal size, with the cystic mass felt separately through the right fornix.

Ascitic fluid tapping was done and was sent for cytology and cell block. At our institute, a CECT of the abdomen and pelvis was done and depicted moderate ascites and complex cystic abdominopelvic mass of about 11×10 cm, with multiple internal septations and solid mural nodules. Another bilocular cystic lesion of 7.2×4.8 cm in size, with fat density component and tiny calcific focus within the wall of the lesion, suggestive of a dermoid cyst was seen in the left adnexa.

Investigations and treatment

The patient’s preoperative tumour markers showed the following: CA-125: 944 IU; CEA: 1.02 ng/dL; CA: 19.9 944 ng/dL. Ascitic fluid cytology and cell block were negative for malignancy. She was planned for exploratory laparotomy and frozen section.

On thorough inspection, the appendix was indurated at the base. Appendicectomy was done and sent for frozen section. The findings on frozen section showed carcinoid tumour of the appendix, left ovarian dermoid cyst and right ovarian struma ovarii. After the frozen section report hysterectomy was completed. A comprehensive retroperitoneal lymphadenectomy was not done as the frozen section of the ovary did not suggest any malignant change.

As the appendiceal carcinoid involved the base of the appendix, right hemicolectomy was performed followed by side-to-side ileocolic anastomosis. On gross appearance, the right-sided tumour showed solid heterogeneous neoplasm of grey-white to tan-yellow colour. Nearly the entire left ovary, about 70–80 mm in size, was composed of firm yellowish tissue in nodular configuration containing gelatinous areas and some calcifications. Further structures resembling dermoid cysts (grease, hair, etc) were also present. The tubes and uterus were of normal appearance (figures 1 and 2).

Figure 1.

Specimen from ileocolic resection with the base of the appendix.

Figure 2.

Intraoperative image of struma carcinoid of the right ovary.

The tumour, which was about 1.5 cm in size, involved the base of the appendix, which was indurated.

Microscopic examination of the right ovary showed features of struma ovarii with a thyroid follicle-like structure containing colloid and intricately admixed neuroendocrine cell component with a trabecular and acinar arrangement, which were highlighted by positive immunohistochemistry (IHC) markers for synaptophysin and CD56 suggestive of stromal carcinoid. We know that strumal carcinoid is a mixture of monodermal teratoma and somatic malignancy, but we have found a mature cystic teratoma component in the other ovary only (figures 3–5).

Figure 3.

Ovarian stroma displaying features of struma ovary on H&E ×200.

Figure 4.

Appendix with obliterated lumen and infiltrated by carcinoid in insular pattern on H&E ×200.

Figure 5.

Struma ovary intricately admixed with clusters and an acinar pattern of cells displaying salt-and-pepper chromatin on H&E ×400.

On the other hand, microscopic examination of the appendix showed obliterated lumen by a tumour displaying features of carcinoids of insular variant. The tumour infiltrated all the layers of the appendix wall, infiltrating into the mesoappendix. The positivity of IHC markers (synaptophysin and CD56) supports the neuroendocrine nature of the tumour (figure 6). The omentum was free of any tumour deposits.

Figure 6.

CD56 highlighting the struma carcinoid on immunohistochemistry (×200).

Since carcinoids are variably positive in neuroendocrine and organ-specific markers, there are no IHC markers to delineate the definite primary site of origin versus metastasis.

In our case, the presence of contralateral teratomatous elements may hint primary struma carcinoid instead of being metastatic from the appendix. The strumal carcinoid component was also highlighted by PAX8 positivity. This led us to conclude the case as concurrent appendix carcinoid with struma carcinoid as two independent primaries with uncertain pathogenesis.

Histologically, as both tumours were well differentiated with Ki-67 of less than 3%, the decision of the joint tumour board was to keep the patient on surveillance, with no adjuvant treatment needed. In accordance with review of literature, the patient is being followed up with clinical examination 3 monthly and a CT scan 6 monthly.

Differential diagnosis

In our case, the coexistence of strumal carcinoid of the ovary with appendiceal carcinoid posed a diagnostic dilemma as ovarian carcinoid tumours may also be metastatic from the GIT. As metastatic tumours tend to be aggressive and have poor outcome, the distinction between ovarian primary and metastatic carcinoids has clinical and prognostic implications.

Outcome and follow-up

The patient is currently on surveillance and the follow-up period of 24 months to date has been uneventful.

Discussion and review of literature

Carcinoid tumours are present in a wide range of organs but most frequently involve the GIT and rarely reported in gynaecological organs. Literature reports that the prevalence of ovarian carcinoid is 0.3%–1%⁵ of ovarian neoplasms and account for only 5% of ovarian teratomas. Ovarian teratomas can form a wide variety of tissues and even recapitulate the development of few organs imperfectly. Strumal carcinoid is the rare coexistence of both struma ovarii (thyroid tissue) and carcinoid. It is seen in 25% of primary ovarian carcinoids and is mostly unilateral, up to 20 cm in size,⁶ and can be nearly pure or part of a cystic teratoma. Primary ovarian strumal carcinoid is classified under borderline malignant tumour,⁷ and management with total abdominal hysterectomy or simple salpingo-oophorectomy is adequate. It was first described by Stewart et al⁸ in 1939. Most of these tumours are commonly found in perimenopausal or postmenopausal women and usually present with heterogeneous adnexal mass or as an incidental finding. Our patient was 52 years of age, which falls within the age range reported for this tumour (21–77 years). Majority (three-fifths) of strumal carcinoids arise in dermoid cysts or mature, solid teratomas and are associated with another type of neoplasm,⁹ usually a dermoid cyst in the contralateral ovary in 10% of patients, similar to our case. Functioning ovarian carcinoids cause typical carcinoid syndrome, with facial flushing being the most common symptom and with two-thirds of patients having diarrhoea. However, strumal carcinoids are usually asymptomatic and 41%¹⁰ are associated with abdominal discomfort due to tumour size or constipation. Our patient also presented with distension of the abdomen due to ascites and abdominopelvic mass and had no other complaints.

Appendiceal carcinoid tumours are rare neuroendocrine neoplasms¹¹ that usually behave as benign tumours. However, certain lesions have the potential for malignancy and metastasis. The probability of metastasis is low and represents 4.7%¹² of all appendiceal carcinoid tumours. Lymphatic dissemination is the primary metastatic route,¹³ while hepatic metastases are rare. They comprise more than 50% of all appendiceal neoplasms¹⁴ and therefore are the most common neoplasm of the appendix. The clinical presentation of these lesions is mostly similar to that of acute appendicitis; however, patients may be asymptomatic. The presence of neuroendocrine symptoms,¹⁵ including flushing, diarrhoea and cardiac disease, is rarely reported. They are commonly found incidentally on histopathological examination of the resected appendix following appendectomy or other abdominal procedures. Appendiceal carcinoids usually behave as benign tumours, and in most cases appendicectomy alone is sufficient, while for larger lesions right colectomy is performed. During assessment, tumour size is the most reliable indicator of the malignant potential of the lesions. In most patients with appendiceal carcinoids, the tumour diameter is less than 1 cm and treatment with appendectomy alone is sufficient. However, tumours measuring more than 2 cm in diameter may have the potential for metastasis,¹⁶ and patients with tumours of this size require right hemicolectomy. Other candidates for right hemicolectomy include lesions where there is evidence of mesoappendiceal extension, involvement of the base of the appendix or caecum, and high-grade malignant carcinoids. In our patient, carcinoid tumour of the appendix was diagnosed incidentally on frozen section during inspection of the abdomen. As the base of the appendix was involved, right hemicolectomy was undertaken.

Although not frequent, the coexistence of neuroendocrine tumours of the GIT with other secondary primary malignancies (SPM) is not uncommon. Such association was initially reported in 1949 by Pearson and Fitzgerald,¹⁷ who found in their series 9 of 29 (31%) carcinoid tumours to be associated with a malignant tumour of different histological types. Six of the nine non-carcinoid malignant tumours were in the intestinal tract. Over the years, many such cases have been reported. On literature search, majority of the studies showed the most common site of additional malignancy was the GIT (table 1).

Table 1.

Reported rates of second primary malignancies in gastrointestinal carcinoids.

Study (year)	Author	Reported rates of second primary malignancies in gastrointestinal carcinoids
		SPM/NEN of GIT (n)	Most common SPM	Gynaecological
1974	Morgan et al35	35/135	Small intestinal 37%	Not specified
1975	Godwin36	334/2471	Small intestinal, appendiceal 32%	Not specified
1989	Saha et al37	29/112	Colorectal (n=11)	2 (cervical cancer)
1995	Gerstle et al38	33/69	Gastrointestinal	Not specified
1999	Shebani et al39	47/150	Colorectal (n=20)	9 (6 uterine, 1 cervical, 2 ovarian cancer)
1997	Burke et al40	23/167	Colorectal (n=6)	Not specified
2002	Tichansky et al41	299/2086	Colorectal (n=126)	10
2012	Kamp et al42	67/459	Breast (n=10)	3 uterine cancer
2012	Amin et al43	2424/8331	Prostate 24.3%, followed by breast 10.9%	Not specified
2015	Clift et al44	26/169	Colorectal (n=6)	1 uterine,1 ovarian

GIT, gastrointestinal tract; NEN, neuroendocrine neoplasm; SPM, secondary primary malignancy.

On literature review, Habal et al³ stated that among gastrointestinal carcinoids the rate of SPM ranges from 12% to 46%, with small bowel carcinoids having the highest rate. Meanwhile, Parra-Medina et al² found that 80% of cases of SPM were located in the GIT, 4.5% in the lung and 3.4% in the kidney. Only 1.1% were present in the ovary, lymph node, cervix, bone marrow, ureter, liver and prostate. Briefly, the average rate of SPM with carcinoid is 17%, which is significantly higher when compared with the rate for SPM in other cancers¹⁸ (2.3% of patients undergoing surgery and 8.1% of autopsied patients). Also, the presence of SPM in the ovary, either synchronous or metachronous, is extremely uncommon as derived from these studies.

In our case, the coexistence of strumal carcinoid of the ovary with appendiceal carcinoid posed a diagnostic dilemma as ovarian carcinoid tumours may also be metastatic from the GIT. As metastatic tumours tend to be aggressive and have poor outcome, the distinction between ovarian primary and metastatic carcinoids has clinical and prognostic implications. We did literature search for evidence supporting primary ovarian carcinoid versus metastatic carcinoid of the ovary and found that the earliest evidence published was in 1974 by Robboy et al.¹⁹ They studied 35 cases of carcinoid tumour metastatic to the ovary and found that 28 out of 35 patients¹⁹ had bilateral ovarian involvement, while in the rest of the patients bilaterality could not be assessed due to previous oophorectomy and lack of data. In contrast, another study on primary ovarian carcinoids (48 cases) by the same authors found that patients with primary ovarian carcinoids had unilateral ovarian involvement in majority of cases. In patients with bilateral ovarian enlargement,²⁰ they found the presence of dermoid cysts. Predominance of unilateral ovary in primary ovarian carcinoids was also found in a retrospective analysis by Devis²¹ of 17 cases of primary ovarian carcinoids. Other case reports mentioning primary ovarian carcinoids, strumal carcinoids and metastatic carcinoid have also shown predominance of unilaterality in primary ovarian carcinoids (table 2). In addition, primary ovarian carcinoids are frequently found to have teratomatous elements in the background, as reported in several case reports and series^21–31 (table 2). Histologically, there are four major variants of primary ovarian carcinoid: insular, trabecular, strumal, mucinous and mixed (insular and trabecular). The most common variant of primary ovarian carcinoid is the insular type, followed by the strumal and trabecular variant, whereas mucinous carcinoids are the least common. Metastatic carcinoids in the ovary are mostly of insular type and therefore differentiation with primary ovarian variety is difficult. Similar dilemmas may occasionally occur with trabecular or mucinous types. Soga et al²⁴ in 2000 analysed 329 cases of primary ovarian carcinoids and reported that 57% had teratoma in the background, whereas 47% occurred as pure form. They concluded that pure forms were larger in size (average 8.9 cm), had higher rates of metastases (22%) (table 2) and had higher incidence of carcinoid syndrome (22.9%). With advancement in IHC, distinction between primary, metastatic and synchronous tumours is now possible. Midgut carcinoids and their metastatic tumours express high levels of CDX2 compared with foregut and hindgut carcinoids. Other immunohistochemical markers such as transcription termination factor 1 (TTF-1), CK7 and CK20 have also been used to characterise^32–34 gastrointestinal and metastatic neuroendocrine carcinomas. In contrast, the study by Rabban et al²⁶ in 2009 did not find the expression of CDX2 as diagnostic of metastatic carcinoid as in their study there was also diffuse expression of CDX2 in primary ovarian carcinoids. In addition, expression of CK7, CK20 and TTF-1 was also not helpful in their series. They suggested that more weightage should be given on previously defined clinicopathological features, including laterality, multinodularity, stage and presence or absence of teratomatous elements. PAX8 was helpful in the differentiation in our case as it was positive in the ovarian carcinoid but negative in the appendiceal carcinoid, indicating a synchronous tumour rather than metastatic. Different histopathology on IHC, that is, strumal carcinoid in the right ovary and insular carcinoid in the appendix, helped in confirming dual/synchronous primaries in our case.

Table 2.

Reported cases of Ovarian Carcinoids

Serial number	Case report/case series	Patients (n)	Author (year)	Primary/metastatic	UL/BL	Presence of teratomatous elements in background	Evidence of distant metastasis	Predominant HPE	IHC
1	Case series	35	Robboy et al (1974)19	Metastatic	80% BL	0	92%	Not specified	Not done
2	Case series	48	Robboy et al (1975)20	Primary	81% UL	76%	0%	Insular	Not done
3	Case report	1	Finn et al (1991)21	Metastatic	BL	Absent	Present	Insular	Neuron-specific enolase, chromogranin, serotonin+
4	Case report	1	Ikeda et al (1991)22	Metastatic	BL	Absent	Present	Goblet cell carcinoid	Chromogranin A, serotonin+
5	Case series	17	Davis et al (1996)23	Primary	100% UL	63%	35%	Insular	Not done
6	Case series	329	Soga et al (2000)24	Primary	–	57%		Insular+trabecular	–
7	Case series	17	Strosber et al (2007)25	Metastatic	88% BL	Absent	76%	Insular	Not done
8	Case series	26	Rabban et al (2009)26	16 primary/10 metastatic	100% UL in primary 70% BL in metastatic	62% in primary Absent in metastatic	6% in primary 60% in metastatic	Insular in both primary and metastatic	CDX2+ in 37.2% in primary and 100% in metastatic
9	Case report	1	Chen et al (2010)27	Primary	UL	Present	Absent	Strumal carcinoid	Chromogranin, synaptophysin+, CK7, CK20−
10	Case report	1	Kanayama et al (2012)28	Primary	UL	Present	No	Insular	Grimelius+, chromogranin A+, synaptophysin+
11	Case report	1	Hinshaw et al (2012)29	Primary	UL	Present	Absent	Strumal carcinoid	Synaptophysin, TTF-1
12	Case series	56	Desouki et al (2013)30	46 primary/10 metastatic	Details not available	35% in primary Absent in metastatic	Details not available	Insular	CDX2+ in 90% metastatic carcinoid, <1

BL, bilateral; IHC, immunohistochemistry; TTF-1, transcription termination factor 1; UL, unilateral.

Conclusion

Strumal carcinoid represents a very rare ovarian tumour and the presence of synchronous appendiceal and ovarian tumour is even more rare. To our knowledge, this is the first ever report of concurrent primary ovarian strumal carcinoid with an appendiceal carcinoid tumour. It is necessary to publish this unique case report in order to note on other possible characteristics. It is also necessary to conduct long-term follow-up of patients in order to obtain more relevant information on their biological behaviour.

Patient’s perspective.

I was very apprehensive when I was diagnosed with the large ovarian tumor. I and my family were counselled regarding the possible malignant nature of the disease, its course and the appropriate management. Post surgery I was explained about the dual tumors I had and I am grateful to my oncosurgeons who helped me get rid of both the tumors. Also I understand the importance of follow up and shall comply with the same.

Learning points.

• Primary ovarian strumal carcinoid is classified under borderline malignant tumour, and management and thus staging laparotomy, including total abdominal hysterectomy and salpingo-oophorectomy, is adequate. Primary carcinoid tumours of different organs in the same patient are rare.

• The pathogenesis of neuroendocrine tumours, associated with synchronous primaries, is undetermined and many theories have been proposed, such as existence of a common carcinogenic effect or a common stem cell undergoing similar genetic mutations, with paracrine or autocrine growth loop effect by the secretory peptides of the neuroendocrine cell tumours also suggested.

• Histologically, there are four major variants of primary ovarian carcinoid: insular, trabecular, strumal, mucinous and mixed (insular and trabecular), with the most common variant being the insular type, followed by the strumal and trabecular variant, whereas mucinous carcinoids are the least common.

• Metastatic carcinoids in the ovary are mostly of insular type and therefore differentiation with the primary ovarian variety is difficult. Midgut carcinoids and their metastatic tumours express high levels of CDX2 compared tocompared with foregut and hindgut carcinoids.

• PAX8 was helpful in the differentiation in our case as it was positive in the ovarian carcinoid but negative in the appendiceal carcinoid, indicating a synchronous tumour rather than metastatic. Different histopathology on IHC, that is, strumal carcinoid in the right ovary and insular carcinoid in the appendix with IHC, helped us in confirming dual/synchronous primaries in our case.

Ethics statements

Patient consent for publication

Obtained.