A Signet-Ring Cell Stromal Tumor of the Ovary Diagnosed After Treatment of Hodgkin's Lymphoma: The First Case and Review of the Literature

Abstract

Background:

Signet-ring cell tumor of the ovary is a rare condition in gynecology. All of the English literature was checked for the terms signet-ring cell tumor ovary and signet ring cell stromal tumor ovary. All cases that were published until this writing are included in this report, which describes a case of signet-ring cell tumor of the ovary.

Case:

A 33-year-old woman, who had been diagnosed with Hodgkin's lymphoma, appeared to have a solid-cystic mass of 59 × 49 × 37 mm in the right adnexial region after receiving treatment for her Hodgkin's lymphoma. She was operated on, and her condition was diagnosed as a signet-ring cell stromal tumor of the ovary. This diagnosis was histologically confirmed.

Results:

There was no recurrence of the patient's disease ∼14 months later at follow-up.

Conclusions:

Signet-ring cell stromal tumor of the ovary is an extremely rare kind of ovarian tumor. In the English literature, fewer than 20 cases have been reported. In addition, the current patient is the first case of signet-ring cell tumor of the ovary diagnosed after treatment of Hodgkin's lymphoma. There have been 17 established cases of this type of tumor in the English literature as of this writing. (J GYNECOL SURG 34:154)

Introduction

Ramzy reported, in 1976, the first signet-ring cell stromal tumor of the ovary case. This condition is now considered to fall within the spectrum of the thecoma-fibroma group of sex cord–stromal tumors, including thecomas, fibromas, and sclerosing stromal tumors.¹ This tumor is benign and occurs in females over a wide age range. In the English literature, the youngest case was a 4-year-old girl.² Because the tumor is not associated with the hormonal symptoms patients commonly reveal, this kind of tumor is discovered incidentally or is found when a patient present with nonspecific abdominal pain.³ During a pathologic examination, the tumor is characterized by extensive cytoplasmic vacuolation of tumor cells, resulting in a “signet-ring” appearance.¹ The hallmark of this tumor is a variable component of signet-ring cells in a background of spindle cells, which are less spindled. The tumor is also associated with less collagen production and includes vacuoles of various sizes.^3,4 Abdominal ultrasonography, computed tomography (CT), or magnetic resonance imaging (MRI) can show this lesion in the adnexa.⁵ The tumor is treated with surgery, but there is no standard treatment, such as total abdominal histerectomy+bilateral salpingo-oophorectomy, bilateral salpingo-oophorectomy, or unilateral oophorectomy.⁶

Hodgkin's lymphoma is a rare B-cell malignant neoplasm affecting ∼9000 new patients yearly. Staging of this disease is essential in order to choose optimal therapy. Prognostic models to identify patients at high or low risks for recurrence have been developed, and these models, along with positron emission tomography, are used to provide optimal therapy.⁷ At the beginning, treatment for patients with this disease is based on the histologic characteristics of the disease, the stage at presentation, and the presence or absence of prognostic factors associated with a poor outcome. Radiotherapy and chemotherapy are used alone or combined. Patients with early stage Hodgkin's lymphoma generally received combined-modality therapies that include chemotherapy followed by involved-field radiation treatment.⁸ In contrast, patients with advanced-stage Hodgkin's lymphoma commonly receive a more-prolonged course of combination chemotherapy, with radiation therapy used only in selected cases.⁷

The association of Hodgkin's lymphoma with signet-ring cell stromal tumor of the ovary has not been reported before in the English literature. The current authors checked all the English literature, using the terms signet-ring cell tumor ovary and signet ring cell stromal tumor ovary. All cases that have been published as of this writing are included in this current report.

Informed consent was obtained from the patient to publish this case report.

Case

A 33-year-old gravida 1, para 1, woman had received chemotherapy and radiotherapy 11 years prior and autologous bone-marrow stem-cells transplanted 10 years prior as treatments for Hodgkin's lymphoma. She was now diagnosed with a solid-cystic mass of 59 × 49 × 37 mm in the right adnexial region. The mass was noticed during a routine follow-up.

Her menarche had begun at age 11 and her menses had been normal until she reached age 23. Her menses had stopped for 2 years after she had the autologous bone marrow transplantation. Yet, after the treatment, she had a healthy baby spontaneously. After her pregnancy she had regular menses with a 29-day cycle and a flow lasting for 4 days. Then, her menses stopped again in January of 2017. Her ß-human chorionic gonadotropin was negative, her follicle stimulating hormone value was 111 mIu/mL, and her luteinizing hormone was 54 mIu/mL.

Her past medical history included no diseases, except for Hodgkin's lymphoma. She received radiotherapy, 6 cycles of adriablastine+bleomycin+vinblastine+dacarbazine combination chemotherapy, 2 cycles carmustine+etoposide+cytarabine+melphalan combination chemotherapy, and then autologous bone marrow was transplanted. Her family history was unremarkable.

Her physical examination was unremarkable. She had an essentially healthy appearance and normal vital signs. Vaginal speculum examination revealed a normal vagina and cervix. Bimanual pelvic examination revealed an anteflexed normal-sized uterus and a mobile right adnexal mass. The left adnexa could not be palpated.

A Doppler ultrasound was performed. An ∼60-mm mass was noticed on the lateral side of the right ovary. MRI showed a solid-cystic lesion that was hypointense on T-1–weighted images and heterogeneous hyperintense on T-2–weighted images (Fig. 1).

FIG. 1.

Signet-ring cell stromal tumor of the ovary appearance on magnetic resonance imaging. (A) On the sagittal plane, fat-saturated contrast enhanced T-1–weighted image. (B) On the axial plane, fat-saturated contrast enhanced T-1–weighted image. (C) On the sagittal plane, T-2–weighted image. (D) On the axial plane, fat-saturated T-2–weighted image.

Her laboratory tests showed that her CA-125 was 52 international units(IU)/mL; her CA-1-5-3 was 21 IU/mL, and her CA-19-9 was 1 IU/mL. The results of hematocrit, hemoglobin, liver function, and renal function tests were normal.

An abdominal CT had shown no pathology in the adnexial regions 6 years prior.

A laparoscopic unilateral salpingo-oophorectomy was performed. During the surgery, the mass, which originated from the right ovary, was noted. The left ovary and left fallopian tube were normal. The right fallopian tube and right ovary were excised and sent for pathologic examination for histologic confirmation.

Results

There was no recurrence of the disease ∼14 months later at a follow-up.

Macroscopically, the right ovary and the right fallopian tube measured 8 × 6 cm; the tumor was a well-demarcated mass, 6 × 5 × 4.5 cm, with a wall that measured between 0.6 and 0.8 cm. Sectioning disclosed that the tumor was irregular and contained cystic materials.

In the pathology report, the right tube was seen as normal. The right ovary contained a sex-cord stromal ovary tumor. Immunohistochemically, clear vacuoles of the signet-ring-like cells were negative for cytokeratin. The signet-ring cells showed diffusely positive immunoreactivity for calretinin and inhibine. Her Ki-67 proliferation index was under 1%. The diagnosis of a signet-ring stromal ovary tumor was made after histomorphologic and immunohistochemical examinations were completed (Fig. 2).

FIG. 2.

Signet-ring cell stromal tumor of the ovary. (A) Arrow indicates cells showing a signet-ring cell appearance (hematoxylin and eosin). (B) Negative for cytokeratin. (C) Diffuse positive for calretinin (D) Ki-67 proliferation index under 1%. (E) Diffuse positive for inhibine. (B–E are shown immunohistochemically.)

Discussion

The original case was reported by Ramzy in 1976 as a signet-ring stromal tumor,¹ and the term is still used currently. However, in the text, the tumor was referred to as a signet-ring cell stromal tumor just as Roth and Ramzy had reported in 2014.⁹ This report described a case of a signet-ring cell stromal tumor of the ovary that was associated with Hodgkin's lymphoma.

A signet ring–like appearance can be found associated with nonneoplastic processes and in a variety of nonadenocarcinomatous neoplasms, such as several varieties of malignant lymphomas,¹⁰ malignant melanomas,¹¹ meningiomas,¹² and gastrointestinal stromal tumors.¹³ However, the relationship between Hodgkin's lymphoma and a signet-ring cell stromal tumor of the ovary is unclear. Perhaps this tumor is related to the Hodgkin's lymphoma's therapy.

The main differential diagnostic disease is a Krukenberg tumor, which is commonly bilateral and nearly always has epithelial components other than signet-ring cells, being positive for different cytokeratins and epithelial membrane antigen, and containing mucin within the vacuoles.³ If periodic acid Schiff, mucin, and cytokeratins are negative in the signet-ring cell stromal tumor cells, that is strong evidence against a mass being a Krukenberg tumor.² The primary characteristic separating a signet-ring cell stromal tumor from the other ovarian sex-cord stromal tumors is the presence of nonmucin/nonlipid signet-ring cells. In addition, Su et al. showed in 2003 that the ultrastructure of the vacuole in the signet-ring–like cells consists of cytoplasmic pseudoinclusions of extracellular edematous matrix.¹⁴ General edema of the cytoplasmic matrix, dilatation of the mitochondria, and invagination of the cell membrane by the extracellular matrix are three possible mechanisms of vacuole formation that were described previously in signet-ring cell stromal tumors by Dickersin et al. in 1995.¹⁵

The difference between a Krukenberg tumor and a signet-ring cell stromal tumor is critical, as a Krukenberg tumor is malignant with an extremely bad prognosis and a signet-ring cell stromal tumor is benign.¹⁶ Krukenberg tumors are bilateral nearly 63% of the time and are often multinodular. On the contrary, all of the previously reported signet-ring cell stromal tumors have been unilateral and uninodular. These two findings have been the only significant distinguishing characteristics for differentiating these tumors, but Forde et al. reported a case multinodular and bilateral signet ring cell stromal tumor of the ovary in 2010.⁵ A microcystic stromal tumor of the ovary can include both a signet-ring cell stromal tumor and a Krukenberg tumor. The distinguishing microscopic features are small round–to–oval cystic spaces or a reticular pattern.¹⁷ Some neoplastic cells have intracytoplasmic eosinophilic globules positive with alpha-1-antitrypsin¹⁸ (Table 1).

Table 1.

Comparison of Krukenberg and Signet-Ring Cell Stromal Tumors ^a

Characteristic	Krukenberg tumor	Signet-ring cell stromal tumor
Laterality	Bilateral	Unilateral
Classification	Malignant	Benign
Mucin	Positive	Negative
PAS diastase	Positive	Negative
Nodules	Multinodular	Uninodular
Extraovarian disease	Yes	No
Epithelial structures	Present	Not present
Hyaline bodies	Not present	Present
CK-20	Positive	Negative
Pancytokeratin	Positive	Negative

Modified from Forde et al.⁵

PAS, periodic acid–Schiff; CK, cytokeratin.

A signet-ring cell stromal tumor of the ovary may be associated with a Brenner tumor¹⁹ and must be differentiated from other stromal tumors of the ovary, especially a techoma-fibroma. Stromal tumors of the ovary have shown positivity for vimentin, actin, inhibin, and calretinin immunohistochemically.²⁰ A sclerosing stromal tumor, a luteinized thecoma associated with sclerosing peritonitis, and a microcystic stromal tumor must be considered in the differential diagnosis of a signet-ring cell stromal tumor. All of these tumors are benign conditions of the ovarian stroma. Macroscopically distinguishing a signet-ring cell stromal tumor from the other tumors is very difficult due to their solid or solid and cystic nature and yellow–gray surfaces. Luteinized thecomas have scattered lutein cells and brisk mitotic activity associated with sclerosing peritonitis, both of which are not seen in Signet-ring cell stromal tumors. Signet-ring cell stromal tumors of the ovary have no documented association with sclerosing peritonitis, hormone production, or other syndromes. Signet-ring cell stromal tumors occur especially in adult women, but other sclerosing stromal tumors are identified in young women.⁵

There have been 17 cases in the English literature as of this writing until when these studies were examined, the following were found: The mean age was 46.94 ± 23.17 (minimum: 4; maximum: 83) The mean size of the tumors was 6.84 ± 3.03 cm (minimum: 2.5; maximum: 13.0). In studies with available data, the mean follow-up time was 40.2 months (minimum 1; maximum: 208). The majority of these patients presented with abdominal pain and their tumors were localized in the left adnexial region. Unilateral oophorectomy was the most-performed procedure but optimal treatment is not yet established (Table 2).

Table 2.

Summary of Findings in Signet-Ring Cell Tumor of the Ovary and Review of the Literature

Study (author, year, & reference	Age	Symptoms	Laterality	Size of tumor (cm)	Macroscopy	Treatment	Follow-up time
Ramzy, 1976¹	28	Abdominal pain	Right	8	Solid	TAH, right SO	NED,1.3 years
Suarez et al., 1993¹⁸	50	Abdominal pain	Left	9	Solid	Left oophorectomy	NED, 2.2 years
Dikersin et al., 1995¹⁵	21	NI	NI	5	Solid–hemorrhagic	NI	NED, 2 years
	78	NI	NI	8.5	Solid–cystic	NI	NED, 1.6 years
	83	NI	NI	8.9	Solid	NI	NED, 2 months
Cashell et al., 2000¹⁹	52	Weight loss	Left	2.5	Solid	TAH, BSO	NED, 2 years
Su et al., 2003¹⁴	76	Abdominal pain	Left	5	Solid	BSO	NED, 1.4 years
Vang et al., 2004^16,a	34	Pelvic mass	Left	13	NI	TAH, BSO	NED, 17.4 years
	35	Pelvic mass	Right	3.5	NI	Right oophorectomy	NED, 4.7 years
	41	Abdominal pain	Right	13	NI	TAH, BSO	NED, 1 month
Matsumoto et al., 2008⁴	76	Incidentally discovered	Left	6	Solid	TAH, BSO	NED, 9 months
Hardisson et al., 2008²⁰	54	Abdominal pain	Left	5.5	Solid	BSO	NED, 1.9 years
He et al., 2009²	4	Premature thelarche	Right	4.4	Cysticlike degeneration	Right oophorectomy	NED, 4 months
Sükür et al., 2011⁶	44	Polymenorrhea	Right	5	Semisolid	Right SO	NED, NI
Forde et al., 2010⁵	69	Abdominal pain	Bilateral	4	Solid	BSO, partial omentectomy	NED, NI
Roth et al, 2013⁹	28	Abdominal pain	Right	8^b	Solid	TAH, right SO,WRLO	NED, 10 years
	25	Incidentally discovered	Left	7^b	Solid–cystic	Left SO	NED, 5 years
Present case, 2017	33	Incidentally discovered	Right	6	Solid–cystic	Right SO	NED, 14 months

This case was previously reported by Dickersin et al.¹⁵

Size of ovary.

NI, no information; TAH, total abdominal hysterectomy; BSO, bilateral salpingo-oophorectomy; SO, salpingo-oophorectomy; WRLO, wedge resection of left ovary; NED, no evidence of disease.

Conclusions

The association of Hodgkin's lymphoma with signet-ring cell stromal tumor of the ovary was not established prior to the current case. This is the first case after Hodgkin's lymphoma was treated with chemotheraphy, radiotherapy and transplanted autologous bone-marrow stem cell. The current authors believe that signet-ring cell stromal tumor of the ovary might be associated with Hodgkin's lymphoma or chemotherapy, radiotherapy, or transplanted autologous bone-marrow stem cells.

Footnotes

Author Disclosure Statement

All authors declare that there are no conflicts of interest in connection with this article.

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