Journal Pre-proof

Retrospective diagnosis of malignant struma ovarii after discovery of pulmonary

metastasis

Maham Qureshi, MD, Lielt Derebew, MD, Laura Boucai, MD, Preeti Kishore, MD

PII: S2376-0605(21)00050-X
DOI: https://doi.org/10.1016/j.aace.2021.03.010
Reference: ACCR 94

To appear in: AACE Clinical Case Reports

Received Date: 27 January 2021

Revised Date: 23 March 2021
Accepted Date: 29 March 2021

Please cite this article as: Qureshi M, Derebew L, Boucai L, Kishore P, Retrospective diagnosis of
malignant struma ovarii after discovery of pulmonary metastasis AACE Clinical Case Reports (2021),
doi: https://doi.org/10.1016/j.aace.2021.03.010.

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1 Case Report

2 Retrospective diagnosis of malignant struma ovarii after discovery of

3 pulmonary metastasis
4

5 Maham Qureshi MD1, Lielt Derebew MD2,4, Laura Boucai MD3, Preeti Kishore, MD2,4

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6 Division of Endocrinology, Montefiore Medical Center, Bronx, NY, USA

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7 Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA

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Department of Medicine, Division of Endocrinology, Memorial Sloan Kettering Cancer Center,
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9 NY, USA
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10 Department of Medicine, Division of Endocrinology, Jacobi Medical Center, Bronx, NY, USA
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12 Corresponding author:
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13 Preeti Kishore, MD

14 Chief of Endocrinology, Health+Hospitals/Jacobi

15 Division of Endocrinology, Albert Einstein College of Medicine

16 1400 Pelham Pkwy S, The Bronx, NY 10461

17

18 718-918-5220, 914-329-8626
19

20 Email:[email protected]
21 Running title: Malignant struma ovarii with pulmonary metastasis

22 Key words: Malignant struma ovarii, Pulmonary Metastasis, Thyroglobulin

23 Disclosures: This case report did not receive any specific grant from funding agencies in the

24 public, commercial, or not-for-profit sectors.

25

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26 Abstract

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27 Objective: The diagnosis of malignant struma ovarii can be challenging due to its benign

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histologic appearance and rarity. We present a case of struma ovarii determined to be

malignant after pulmonary metastases were discovered incidentally.

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29

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31 Case Report: 29-year-old female with history of benign struma ovarii presented to the ER with
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32 right lower abdominal pain. CT- abdomen, pelvis reported multiple bilateral pulmonary
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33 nodules. Biopsy of these nodules demonstrated well differentiated thyroid tissue. Re-review of
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34 prior ovarian pathology showed features of highly differentiated thyroid carcinoma. Laboratory

35 studies showed negative thyroglobulin antibodies, thyroid stimulating hormone=0.713 mIU,

36 thyroglobulin=169ng/ml. Patient underwent total thyroidectomy and pathology demonstrated

37 0.3 cm follicular variant papillary thyroid microcarcinoma without lymphovascular invasion. I-

38 123 whole body scan revealed metastases in bilateral thigh muscles. Post-therapy scan after

39 receiving I-131 therapy demonstrated uptake in the lungs, thyroid bed and bilateral thighs. CT

40 scan done 5 months later revealed a decrease in the size of pulmonary nodules.

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42 Discussion: Distinguishing metastatic struma ovarii from benign disease is challenging. It

43 requires a high index of suspicion and close histologic examination to look for malignant

44 features mainly the presence of cytologically overlapping ‘‘ground glass’’ nuclei and mitotic

45 activity or vascular invasion. Additionally, thorough review of imaging is needed to identify any

46 abnormal findings suggestive of metastases.

47

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48 Conclusion: Careful histologic examination is key in making early diagnosis of malignant struma

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49 ovarii. Our case demonstrates this diagnosis maybe made retrospectively after the discovery of

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metastases and that patients can have excellent response to I-131 therapy despite a relatively
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51 low TG level.
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52
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53 Introduction
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54 Struma ovarii is a rare ovarian germ cell tumor that contains greater than 50% thyroid tissue
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55 [1]. The majority (90-95%) of struma ovarii are benign [2]. Although rare, malignant struma

56 ovarii is an important diagnosis to consider as subtle metastasis can occur at a later time.

57 Malignancy is more common in larger tumors, as almost 75% of malignancies occur in tumors

58 larger than 16 cm, and more rarely in tumors less than 5 cm [3]. Malignant struma ovarii shares

59 histologic features of differentiated thyroid cancer and can be classified as papillary or follicular

60 subtypes [4]. Because of its benign histological appearance, malignant struma ovarii,

61 particularly of follicular subtype, poses a diagnostic challenge and sometimes is not diagnosed

62 until the neoplasm spreads beyond the ovary [5]. While metastases are uncommon, the
63 predominant site of metastatic spread is within the adjacent pelvis. Distant metastases to lungs,

64 bones, liver, skin and brain are exceedingly rare [6]. We report a case of malignant struma

65 ovarii with distant metastasis that was retrospectively diagnosed after incidental discovery of

66 pulmonary metastases on an imaging study.

67 Case Report

68 A 29-year-old woman presented to the emergency room with right lower abdominal pain. A

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69 diagnosis of right ovarian torsion was made, and she underwent right salpingo-oophorectomy,

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70 with removal of 12.7x9.5x10.5cm multiloculated cystic ovarian mass. Pathology reported “small

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focus of mature cystic teratoma of ovary with struma ovari. The majority of the multi-cystic
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72 mass consists of mature thyroid tissue with colloid admixed with areas of fetal-type follicular
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73 tissue. No atypia is observed. No immature component is present.” No additional study for

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74 tumor markers or immunohistochemical staining was done. Two years later, she was
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75 incidentally noted to have bilateral pulmonary nodules that had increased in size and number
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76 compared to cross-sectional imaging done during her prior admission. The patient underwent

77 video assisted thoracoscopic surgery for biopsy of the lung nodules. Pathology report stated

78 “lung tissue with multiple thyroid nodules consistent with metastases from right ovarian

79 mature cystic teratoma with struma ovarii. No carcinoma or significant atypia is present in

80 metastatic thyroid tissue.” A non-blinded re-review of the right ovarian pathology was done at

81 two outside institutions. First examiner suggested “the ovarian tumor in isolation does not

82 show overt features of malignancy. However, in the context of an extra-ovarian similar-

83 appearing lesion in the lung, it has been proposed that this scenario would be consistent with

84 ovarian highly differentiated follicular carcinoma. It has also been suggested in the literature
 85 that the latter can only be diagnosed retrospectively after the detection of a metastasis.” The

86 second examiner reported that “the follicular cells show predominantly solid growth with rare

87 papillary structure and characteristic nuclear features of papillary thyroid carcinoma including

88 enlarged and overlapping nuclei, clear and open chromatin, scattered nuclear grooves and rare

89 mitotic figures.” [Image A], [Image B], [Image C], [Image D]

90 The patient underwent a total thyroidectomy and pathology demonstrated a 0.3x0.3cm

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91 follicular variant papillary thyroid microcarcinoma, without lymphovascular invasion.

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92 Preoperatively patient had negative thyroglobulin antibodies, Thyroid stimulating hormone

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(TSH)=0.713 mIU (0.5-5mIU) and Thyroglobulin (TG) level=169ng/ml (3-40mIU). Post operatively
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94 patient was started on levothyroxine with subsequent TSH suppression (TSH=0.058mIU) and TG
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95 levels decreased to 80ng/ml, fluctuating between 56-252 ng/ml thereafter.

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96 The patient completed an I-123 whole body scan that revealed uptake in the thyroid bed,
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97 bilateral pulmonary nodules and bilateral thigh muscles. Ultrasound of the lower extremities
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98 was negative for metastatic findings. After dosimetric studies, 200mCi of I-131 were

99 administered and a post-therapy scan showed uptake in the thyroid bed, bilateral lung nodules

100 and thigh. A CT of the chest five months later demonstrated a decrease in size of the lung

101 nodules -- the largest of which decreased from 0.5 to 0.3cm. One year post radioactive iodine

102 therapy, thyroglobulin level is undetectable (TSH and TG antibody negative), and the patient

103 remains clinically stable.

104

105 Discussion
106 We have described an interesting case of a young woman who initially presented with an

107 ovarian torsion due to a presumed benign struma ovarii and subsequently found to have

108 thyroid tissue within lung nodules suggestive of metastatic disease. As is recommended, the

109 patient underwent staging, followed by thyroidectomy revealing a 3 mm follicular variant of

110 papillary carcinoma. She was treated with levothyroxine to suppress TSH, underwent dosimetry

111 and was treated with 200 mCi of I-131. Her post treatment scan showed metastatic lesions in

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112 the lungs, thyroid bed and bilateral thighs. Interestingly her TG levels remained under 252ng/ml

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113 at all times despite high burden of metastatic disease, but still showed an excellent response to

114 I-131 therapy. -p

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115 Metastatic struma ovarii is rare and occurs in about 5-15% of all malignant struma ovarii cases
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116 [6]. The median age at presentation is usually 40-60 years, although it has been reported in
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117 patients as young as 10 years old [7]. The most common presenting clinical symptoms are

118 abdominal or pelvic pain, palpable mass and ascites, particularly when pelvic metastases are
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119 present. While uncommon, hyperthyroidism may occur in 5-8% of cases where an autonomic
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120 nodule within the teratoma exists or patient has a coexisting Graves’ disease [2,8].

121 The distinction between benign and malignant struma ovarii is a challenge to date to most

122 experienced pathologists. A combination of nuclear features which include the typical

123 characteristics of well-differentiated thyroid carcinoma (nuclear grooves, overlapping ground

124 glass nuclei), mitoses, necrosis, vascular invasion, or extension of the tumor outside of the

125 ovarian capsule with immunohistochemical stains and cross-sectional imaging studies

126 documenting metastatic disease aid in the differentiation between benign and malignant

127 struma [9].

128 However, sometimes these features are absent or very subtle and clinical features of

129 metastases e.g. lung with normal appearing thyroid tissue (as in our case) become critically

130 important to complement the diagnosis.

131 Given the rarity of malignant struma ovarii, very limited data is available to describe the value

132 of performing special stains or tumor markers on these tissues. Cancer antigen 125 is a

133 common tumor marker for malignant struma ovarii but yields very low diagnostic value due to

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134 its non-specificity [10]. A wide panel of immunohistochemical stains including Paired-box gene

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135 8 (PAX8), Thyroid transcription factor 1 (TTF-1) and thyroglobulin can be helpful to differentiate

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malignant struma ovarii from other ovarian malignancies, but it hasn’t been described if they
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137 can help differentiate benign Vs malignant struma ovarii [11]. It remains to be seen if markers
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138 found to be useful in thyroid malignancies such as, HBME-1, specific cytokeratins (CK) such as
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139 CK19, and ret might be helpful in the diagnosis of malignant struma ovarii [12]. The field of the

140 genetic profiling of thyroid tumors is relatively new and needs further data to evaluate if these
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141 tools may be helpful in differentiating benign VS malignant struma.

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142

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144 There are no consistent guidelines for the management of malignant struma ovarii after initial

145 surgical diagnosis [4]. Most recommendations are based upon review of available case reports

146 and case series [13]. The often-suggested treatment strategy includes debulking surgery (i.e.,

147 unilateral or bilateral salpingo-oophorectomy with or without hysterectomy) followed by

148 adjunctive therapies based on the presence of metastasis and the risk of recurrence. Patients
149 with gross extraovarian extension, larger lesions (>4cm) and presence of BRAF mutations have

150 higher risk of recurrence [14]. The practice for patients with high-risk features is to perform a

151 total thyroidectomy followed by radioactive I-131 therapy [13,14]. These patients also require

152 thyroxine supplementation for TSH suppression after ablation [13]. Following initial treatment,

153 patients with malignant struma ovarii require long term follow-up with regular monitoring of

154 serum thyroglobulin levels with or without whole body I-131 scintigraphy.

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155 A low thyroglobulin level in thyroid cancer is often seen with tumors that may have de-

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156 differentiated. Not much information is available regarding de-differentiation of metastatic

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struma ovarii. In our case, the histopathological findings of metastatic tissue very close in
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158 appearance to normal thyroid tissue and I-131 uptake within these lesions argues that the
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159 tumor remained differentiated maintaining its capacity to concentrate I-131 [10,15]. The
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160 presence of thyroid microcarcinoma also raises the possibility of metastasis from primary

161 thyroid malignancy, however the thyroid carcinoma was 3 mm in size, had clear margins with
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162 no evidence of lympovascular invasion making metastasis from primary thyroid cancer less
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163 likely. Moreover 2 of 3 pathologists agreed that the lung lesions were consistent with

164 metastatic follicular carcinoma in the context of the diagnosis of struma ovarii, with follicular

165 lesions similar in appearance to the lung. In the future, it’s possible that the genomic signature

166 of the tumor could be helpful in these diagnostically challenging cases.

167

168 Conclusion
169 Careful histologic examination of struma ovarii is key in making early diagnosis of malignant

170 cases as benign appearing histology or subtle histologic changes pose a diagnostic challenge.

171 Thyroglobulin levels usually give guidance on disease burden and treatment response;

172 however, in this case, thyroglobulin levels were lower than reported in previous cases despite a

173 well-differentiated appearance on pathology. Nonetheless, the patient had an excellent

174 response to radioactive iodine at all metastatic sites, indicating well-differentiated disease and

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175 favorable prognosis. Thus, thyroglobulin levels may not predict response to I-131 therapy in

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176 such cases.

177
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230

231 Image A: Ovary (low power): Ovarian stroma with thick-walled blood vessels and corpora

232 albicantia (top). Nodules of thyroid type tissue composed of variable sized follicles filled with

233 colloid and lined by low cuboidal to columnar follicular epithelial cells (bottom).

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234 Image B: Ovary (high-power): There is a hypercellular focus within the thyroid tissue showing

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follicular and trabecular pattern of growth and decreased colloid. Note that the follicular cells

are larger and have crowded oval to irregular nuclei with pale chromatin.
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236
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237 Image C: Ovary (high-power): Cells with pale to vesicular nuclear chromatin, elongated nuclei

238 and longitudinal nuclear grooves. A nuclear pseudo inclusion is visible (arrow). The cells have
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239 moderate amounts of eosinophilic cytoplasm

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240 Image D: Ovary (high-power): Follicular growth of intermediate sized low cuboidal cells with
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241 moderate amount of dense eosinophilic cytoplasm. The nuclei show crowding and overlapping.

242 Note the pale nuclear chromatin and scant dense colloid.

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Highlights

-Metastatic struma ovarii is very rare and only occurs in 5-15% of all malignant struma ovarii

cases.

-When struma ovarii is diagnosed, close attention should be paid to any abnormal imaging

findings that could signify the presence of metastasis.

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-Careful histologic examination of struma ovarii is key in making early diagnosis of malignant

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cases as benign appearing histology or subtle histologic changes pose a diagnostic challenge.

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-Thyroglobulin levels usually give guidance on disease burden and treatment response;
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however, in this case despite high disease burden and well differentiated appearance on
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pathology patient had lower than expected thyroglobulin levels but still responded very well to

radioactive iodine therapy.

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Clinical Relevance
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Contrary to previously published case reports our patient had relatively low thyroglobulin levels

despite high disease burden and well differentiated disease. Given the rare histologic and

biochemical findings discussed in our case, we strongly believe this paper can add to existing

literature and stimulate further research in the area.

Declaration of interests

☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.

☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests:

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