doi:10.1111/jog.12881

J. Obstet. Gynaecol. Res. Vol. 42, No. 2: 206–210, February 2016

Combined large-cell neuroendocrine carcinoma and endometrioid adenocarcinoma of the endometrium: A case report and survey of related literature Harunobu Matsumoto1, Kaei Nasu1,2, Kentaro Kai1, Masakazu Nishida1, Hisashi Narahara1 and Haruto Nishida3 Department1 of Obstetrics and Gynecology, 3Diagnostic Pathology, Faculty of Medicine, and 2Division of Obstetrics and Gynecology, Support System for Community Medicine, Oita University, Oita, Japan

Abstract Primary large-cell neuroendocrine carcinoma of the endometrium is extremely rare and has a poor prognosis. This report describes a case of combined large-cell neuroendocrine carcinoma and endometrioid adenocarcinoma of the endometrium diagnosed as stage IIIA. The patient underwent surgery and chemotherapy and has been well with no evidence of disease for 20 months. The optimal treatment for this rare tumor has not been established. Considering its rarity and variability, it is difficult to establish an evidence-based therapeutic regimen. Key words: endometrioid carcinoma, endometrium, large-cell neuroendocrine carcinoma, ovary, post-therapy carcinoma.

Introduction

Case Report

Neuroendocrine carcinoma occurs predominantly in the lung but it can be occasionally found in the gastrointestinal and genitourinary tract. Primary neuroendocrine tumor of the endometrium includes small-cell neuroendocrine carcinoma (SCNEC), large-cell neuroendocrine carcinoma (LCNEC), and carcinoid tumours.1 Primary LCNEC of the endometrium is extremely rare, and only 14 cases are reported currently (see Table 1).2–10 Eight out of 14 cases (57%) were in advanced stages and had poor prognoses. Standard treatments have not been established due to the rarity of the tumor. This report describes a case of LCNEC of the endometrium combined with endometrioid adenocarcinoma. This patient received abdominal radical hysterectomy, bilateral salpingo-oophorectomy, and pelvic and para-aortic lymphadenectomy, and subsequent chemotherapy after the patient was diagnosed as stage IIIA. The patient is currently healthy without evidence of disease for 20 months.

A 51-year-old woman (gravida 2, para 1) was admitted because of suspected uterine tumor at gynecological cancer screening. Transvaginal ultrasonography revealed endometrial thickening (30 mm). An endometrial specimen collected by curettage showed adenosquamous carcinoma with neuroendocrine differentiation. Magnetic resonance imaging (MRI) and contrast-enhanced computed tomography (CT) scan showed endometrial hypertrophy (30 mm), myometrial (>1/2) and cervical invasions. There were no findings that suggested lymph node metastasis or distal metastasis. The patient underwent abdominal radical total hysterectomy, bilateral salpingo-oophorectomy, pelvic and para-aortic lymphadenectomy and subtotal omentectomy. Polypoid tumor was found in the endometrium to the cervix. Both adnexa were of normal appearance. The histological examination of the surgical specimens showed LCNEC and endometrioid adenocarcinoma (grade 1) of the

Received: June 10 2015. Accepted: September 7 2015. Correspondence: Dr Harunobu Matsumoto, Department of Obstetrics and Gynecology, Faculty of Medicine, Oita University, Hasama-machi, Yufu-shi, Oita 8795593, Japan. Email: [email protected]

206

© 2016 Japan Society of Obstetrics and Gynecology

Large cell carcinoma of the endometrium

Table 1 Reported cases of large-cell neuroendocrine carcinoma of the endometrium Stage

Erhan et al. 20042 Mulvany et al. 20073

52

Ic†

None

Surgery, RT, CT (EP)

NSE, synaptophysin

DOD 3

50

IIIc†

None

Surgery, RT, CT (EP)

NSE, synaptophysin

AWD 12

80

Ic†

Surgery

NSE, chromogranin A

DOD 5

77

IIb†

Endometrioid adenocarcinoma Endometrioid adenocarcinoma

Surgery, RT

DOD 23

79

IIIa†

Surgery, RT

88

IIIc†

AlboresSaavedra et al. 20084 Posligua et al. 20085 Terada et al. 20106 Deodhar et al. 20117

42

Ic†

Endometrioid adenocarcinoma Endometrioid adenocarcinoma, small-cell carcinoma None

NSE, Synaptophysin, chromogranin A, CD56 NSE, chromogranin A, CD56 NSE, chromogranin A, CD56

70

Shahibi et al. 20118 Makihara et al. 20129

Nguyen et al. 201310 Present case

IIIB

Treatment

Outcome (months)

Age

59

Associated neoplasm

Immunoprofile positivity

Reference

Surgery, RT

Surgery, CT (EP)

Serous adenocarcinoma Sarcomatoid tumor

Surgery, RT, CT (unknown) Surgery

IB

None

Surgery, CT (EP)

59

IIIC2

None

Surgery, RT, CT (TC, PLD, EP + Oct)

73

IVB

None

None

73

IIIC1

None

Surgery, CT (IP)

71

IVB

None

Surgery, CT (EP + Oct)

51

IIIA

Endometrioid adenocarcinoma

Surgery, CT (IP)

40

Ib†

Synaptophysin, chromogranin A, CD56 NSE, Synaptophysin, CD56 Synaptophysin, CD56 Synaptophysin, chromogranin A, CD56 NSE, synaptophysin, chromogranin A, CD56 NSE, Synaptophysin, chromogranin A Synaptophysin, chromogranin A, CD56 Synaptophysin, chromogranin A, CD56 Synaptophysin, chromogranin A, CD56

AWD 2 AWD 1

NED 9

NED 5 NED 26 NED 6

DOD 12

DOD 1 AWD 13

DOD 1

NED 18

†1998 FIGO staging. AWD, alive with disease; CT, chemotherapy; DOD, dead of disease; EP, etoposide/cisplatin; IP, irinotecan/cisplatin; NED, no evidence of disease; NSE, neuron-specific enolase; Oct, octreotide; PLD, pegylated doxorubicin; RT, radiotherapy; TC, paclitaxel/carboplatin.

endometrium. The tumor metastasized to the right ovary. There was no metastasis to lymph node and no dissemination of omentum. The patient was diagnosed as having FIGO (2008) stage IIIA disease and received monthly irinotecan/cisplatin therapy (irinotecan 60 mg/m2 day 1, 8, 15 cisplatin 60 mg/m2 day 1) for six cycles. The patient has been well without evidence of disease for 20 months.

Histologic findings Most of the endometrial tumor showed a polypoid lesion. The tumor cells were characterized by a dense

© 2016 Japan Society of Obstetrics and Gynecology

sheet-like growth pattern. Individual cells had plumping nuclei with severe atypia, one to two prominent nucleoli and high nuclear/cytoplasmic ratio. The peak of the tumor nuclear diameter/small lymphocyte size ratio was between 3 and 4. The average tumor cell size was about 15–20 μm (Fig. 1). The mitoses were >20 per 10 high-power fields. There were many vascular and lymphatic invasions. The tumor metastasized to the uterine cervix and right ovary, and invaded within the inner half of the uterine myometrium. The tumor did not metastasize to the pelvic and para-aortic lymph nodes. Immunohistochemically, the tumor cells

207

H. Matsumoto et al.

Figure 1 Histologic field of view of the large-cell neuroendocrine carcinoma of the endometrium. The overall aspect characteristically shows a dense layering pattern in which the individual tumor cells have a large nuclear : cytoplasmic ratio with severe atypia and prominent nucleoli. The peak tumor nuclear diameter/small lymphocyte size ratio is between 3 and 4.

were positive for synaptophysin, chromogranin A, CD56, and Ki-67 labeling index was >20% (Fig. 2). The tumor was diagnosed as LCNEC. Partially, endometrioid adenocarcinoma, grade 1, was found in the polypoid lesion.

Discussion According to the World Health Organization (WHO) classification of tumors of the uterine corpus, primary neuroendocrine tumor of the endometrium includes SCNEC, LCNEC, and carcinoid tumours.1 Most neuroendocrine carcinomas of the endometrium are SCNEC and approximately 90 cases have been reported in the published work. Primary LCNEC of the endometrium is extremely rare and only 14 cases have been reported.2–10 The diagnostic criteria for SCNEC of the endometrium have been proposed;11 however, there are no diagnostic criteria for LCNEC of the endometrium. According to the WHO classification of tumors of the lung, LCNEC is defined as large-cell carcinoma (generally, the tumor nuclear diameter/small lymphocyte size ratio is >3) that shows histological features of neuroendocrine morphology (including rosettes and peripheral palisading) and expresses of immunohistochemical neuroendocrine markers, such as chromogranin, synaptophysin, or CD56. One positive reaction is enough to make a

208

diagnosis of LCNEC if the staining is clear-cut.12 According to the WHO classification of tumors of the digestive system, neuroendocrine carcinoma should meet the mitotic count of >20 per 10 high-power fields and/or >20% Ki67 index.13 The current case meets the diagnostic criteria of LCNEC. The clinical characteristics, including the staging, treatment, and prognosis, are available in all 14 reported cases. Ten of the 15 patients (including the present case) were stage III or IV. Six patients were reported to have long-term (≥12 months) survival, and four of the six cases were stage III (Table 1). In primary SCNEC of the endometrium, the key factor that determines the prognosis is the stage.14 But the relation of stage and prognosis is unclear in primary LCNEC of the endometrium due to the limited number of cases. Primary SCNEC of the endometrium are often associated with endometrial atypical hyperplasia, endometrioid adenocarcinoma or adenosquamous carcinoma, and are rarely associated with mesodermal mixed tumors or papillary serous carcinoma. Primary LCNEC of the endometrium is also associated with endometrioid adenocarcinoma, serous adenocarcinoma or sarcomatoid tumor (Table 1). In this case, the LCNEC was thought to be originated from the endometrioid adenocarcinoma, which dedifferentiated and showed more malignant potential. The relation of the prognosis and the type of associated tumor is unclear due to the limited number of cases.

© 2016 Japan Society of Obstetrics and Gynecology

Large cell carcinoma of the endometrium

Figure 2 Immunohistochemical staining. The tumor cells are positive for (a) synaptophysin, (b) chromogranin A, (c) CD56, and (d) Ki-67 labeling index is >20%.

The mean age of patients with primary LCNEC of the endometrium has been 70 years, older than that of endometrial adenocarcinoma patients, and also older than SCNEC patients, who have a mean age of 60 years. However, the clinical presentations are similar to those of endometrial adenocarcinoma or SCNEC. These include postmenopausal or perimenopausal atypical genital bleeding, lower abdominal pain or distention, and, rarely, abnormal vaginal cytology. The current patient was younger than the reported mean age, and had no typical clinical presentation. No standard regimen of therapy for neuroendocrine carcinoma, including LCNEC or SCNEC of the endometrium, has been established. In view of the limited number of cases and their variability, it is difficult to establish an evidence-based therapeutic regimen. At this point, the standard modality of treatment is similar to that of endometrial adenocarcinoma: namely, surgical resection, radiotherapy, and chemotherapy. In most reported cases, regimens of chemotherapy designed for lung neuroendocrine carcinoma were selected. Irinotecan/cisplatin and etoposide/cisplatin have been established as standard regimens for lung neuroendocrine carcinoma.15 Therefore, the current patient received monthly irinotecan/cisplatin therapy. At any recurrence of this rare tumor, in view of the survey of related literature, it would likely be important to individualize the treatment as none of the current treatments have a significant impact on survival.

© 2016 Japan Society of Obstetrics and Gynecology

In conclusion, LCNEC of the endometrium is extremely rare and has a poor prognosis. In view of the limited number of cases in the literature, it is difficult to establish an evidence-based therapeutic regimen of LCNEC of the endometrium. Therefore we have reported here an additional case of LCNEC of the endometrium to establish an appropriate treatment for these cases in the future.

Disclosure All authors have declared no conflicts of interest.

References 1. Kurman RJ, Carcangiu ML, Herrington CS et al. (eds) WHO Classification of Tumours of Female Reproductive Organs, 4th edn. Lyon: IARC, 2014; 122. 2. Erhan Y, Dikmen Y, Yucebilgin MS et al. Large cell neuroendocrine carcinoma of the uterine corpus metastatic to brain and lung: Case report and review of the literature. Eur J Gynaecol Oncol 2004; 25: 109–112. 3. Mulvany NJ, Allen DG. Combined large cell neuroendocrine and endometrioid carcinoma of the endometrium. Int J Gynecol Pathol 2008; 27: 49–57. 4. Albores-Saavedra J, Martinez-Benitez B, Leuvano E. Small cell carcinomas and large cell neuroendocrine carcinomas of the endometrium and cervix: Polypoid tumours and those arising in polyps may have a favorable prognosis. Int J Gynecol Pathol 2008; 27: 333–339.

209

H. Matsumoto et al.

5. Posligua L, Malpica A, Liu J et al. Combined large cell neuroendocrine carcinoma and papillary serous carcinoma of the endometrium with pagetoid spread. Arch Pathol Lab Med 2008; 132: 1821–1824. 6. Terada T. Large cell neuroendocrine carcinoma with sarcomatous changes of the endometrium: A case report with immunohistochemical studies and molecular genetic study of KIT and PDGFRA. Pathol Res Pract 2010; 206: 420–425. 7. Deodhar KK, Kerkar RA, Suryawanshi P et al. Large cell neuroendocrine carcinoma of the endometrium: An extremely uncommon diagnosis, but worth the efforts. J Cancer Res Ther 2011; 7: 211–213. 8. Shahabi S, Pellicciotta I, Hou J et al. Clinical utility of chromogranin A and octreotide in large cell neuroendocrine carcinoma of the uterine corpus. Rare Tumours 2011; 3: e41. 9. Makihara N, Maeda T, Nishimura M et al. Large cell neuroendocrine carcinoma originating from the uterine endometrium: A report on magnetic resonance features of 2 cases with very rare and aggressive tumour. Rare Tumors 2012; 4: e37.

210

10. Nguyen ML, Han L, Minors AM et al. Rare large cell neuroendocrine tumour of the endometrium: A case report and review of the literature. Int J Surg Case Rep 2013; 4: 651–655. 11. van Hoeven KH, Hudock JA, Woodruff JM, Suhrland MJ. Small cell neuroendocrine carcinoma of the endometrium. Int J Gynecol Pathol 1995; 14: 21–29. 12. Brambilla E, Beasley MB, Chirieac LR et al. Large cell neuroendocrine carcinoma. In: Travis WD, Brambilla E, Burke AP et al. (eds). WHO Classification of Tumours of Lung, Pleura, Thymus and Heart, 4th edn. Lyon: IARC, 2015; 69–72. 13. Rindi G, Arnold R, Bosman FT et al. Nomenclature and classification of neuroendocrine neoplasma of the digestive system. In: Bosman FT, Carneiro F, Hruban RH et al. (eds). WHO Classification of Tumours of the Digestive System, 4th edn. Lyon: IARC, 2010; 13–14. 14. Bahig H, Portelance L, Legler C, Gilbert L, Souhami L. Small cell carcinoma of the endometrium: Report of a case and review of the literature. Minerva Ginecol 2009; 61: 365–369. 15. Noda K, Nishiwaki Y, Kawahara M et al. Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med 2002; 346: 85–91.

© 2016 Japan Society of Obstetrics and Gynecology

Combined large-cell neuroendocrine carcinoma and endometrioid adenocarcinoma of the endometrium: A case report and survey of related literature.

Primary large-cell neuroendocrine carcinoma of the endometrium is extremely rare and has a poor prognosis. This report describes a case of combined la...
565B Sizes 0 Downloads 9 Views