Clinica Chimica Acta 438 (2015) 181–185
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Case report
Discrepant serum and urine β-hCG results due to production of β-hCG by a cribriform-morular variant of thyroid papillary carcinoma Mir Alikhan a, Anoopa Koshy b, Elizabeth Hyjek a, Kerstin Stenson c, Ronald N. Cohen b,1, Kiang-Teck J. Yeo a,⁎,1 a b c
Department of Pathology, Biological Sciences Division, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, United States Section of Endocrinology, Department of Medicine, Biological Sciences Division, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, United States Department of Surgery, Biological Sciences Division, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, United States
a r t i c l e
i n f o
Article history: Received 11 July 2014 Received in revised form 21 August 2014 Accepted 22 August 2014 Available online 30 August 2014 Keywords: Human chorionic gonadotrophin Thyroid papillary cancer hCG immunoassays
a b s t r a c t Background: Although patients with medullary thyroid cancer are known to present with paraneoplastic hormone production, this is much less common with papillary thyroid cancer. Methods: We present a patient with the cribriform morular variant of papillary thyroid cancer in association with familial adenomatous polyposis who developed a positive pregnancy test in the absence of known pregnancy. The patient had developed vaginal bleeding, and her laboratory testing was characterized by elevated serum human chorionic gonadotropin (β-hCG) concentrations, but negative qualitative urine results. After a thorough gynecological evaluation to exclude unexpected normal, ectopic, or molar pregnancy, we pursued an evaluation for other sources of β-hCG production. Results: We showed that the elevated serum β-hCG concentrations were not the result of heterophile antibody interferences, and ultimately we proved that her recurrent tumor produced the ectopic β-hCG. This is the first report of β-hCG production by papillary thyroid cancer. Thus, the possibility of ectopic production of β-hCG by papillary thyroid cancer needs to be included in the differential diagnosis of elevated hCG concentration in the absence of pregnancy. Conclusions: This study of an unusual paraneoplastic syndrome highlights the importance of investigating discrepancies in the clinical laboratory. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Human chorionic gonadotropin (hCG) is a 37 kDa glycoprotein primarily secreted by the fetal placenta following conception and implantation [1]. It functions to stimulate progesterone secretion by the corpus luteum during the first weeks of pregnancy, which promotes the viability of the fetus largely through thickening and maintenance of the uterine lining, providing adequate nourishment for the developing conceptus. Thereafter, concentrations of hCG decline as the placenta begins production of progesterone and estrogen [2]. hCG is also thought to have an immunosuppressant function [3], reducing the likelihood of fetal rejection by the maternal immune system. The hCG molecule is composed of 244 amino acids and consists of a heterodimer with an α and β subunit. The alpha subunit is identical among the glycoprotein hormones, namely LH, FSH, and TSH. The β subunit, however, is unique to the hCG molecule. It is the targeting of antibodies against various epitopes of the β subunit that confers relative ⁎ Corresponding author at: 5841 S. Maryland Ave., MC 0004, TW-010, Chicago, IL 60637, United States. E-mail address: [email protected] (K.-T.J. Yeo). 1 Co-senior authors.
http://dx.doi.org/10.1016/j.cca.2014.08.026 0009-8981/© 2014 Elsevier B.V. All rights reserved.
specificity for laboratory hCG testing, and this methodology is employed by most modern clinical chemistry assays [4]. The main physiologic role of hCG is within the context of normal pregnancy. As a result, increased hCG concentrations are essentially diagnostic of pregnancy; hCG testing can quickly and effectively rule in or rule out pregnancy in the appropriate clinical context. Recent development of point-of-care (POC) devices for its measurement in urine has provided rapid, simple methods for the detection of pregnancy, with sensitivities approaching that of serum in conventional laboratory analyzers [5]. Elevated hCG concentrations are most often due to pregnancy, whether intra-uterine or ectopic. However, the specificity is not perfect due to the uncommon occurrence of elevated concentrations seen in disease states, both benign and malignant. Rarely, the pituitary gland may secrete hCG in perimenopausal women due to release of negative feedback on gonadotropin releasing hormone (GnRH) secretion [6]. Gestational trophoblastic diseases (GTDs) are rare and comprise a spectrum of both benign (hydatidiform moles) and malignant (invasive moles, choriocarcinomas, placental site trophoblastic tumor, and epithelioid trophoblastic tumor) disorders. Each is characterized by the production by the lesional trophoblast of abnormally high concentrations of β-hCG [7]. Rarely, a non-pregnant woman with a history of
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gestational trophoblastic disease may have persistent low concentrations of hCG following treatment, termed “quiescent GTD.” [8]. An exceptionally rare cause of elevated hCG in a non-pregnant female is due to paraneoplastic secretion of the hormone by extraplacental tissues. Such cases have been reported in various neoplasms [9–14]. Paraneoplastic syndromes associated with thyroid carcinoma are rare, and hCG secretion has never been reported in association with this neoplasm. The present patient with papillary thyroid carcinoma (PTC) and subsequent vaginal bleeding had elevated plasma β-hCG concentrations due to secretion by her thyroid neoplasm. 2. Patient The patient is a 31-y-old woman with a history of Gardner syndrome (familial adenomatous polyposis; FAP). Due to her family history of colon cancer, she underwent colonoscopy at age 20 y and on biopsy, had multiple colonic tubular adenomas. She underwent total colectomy at the age of 22 y. She also developed a retroperitoneal desmoid tumor requiring surgical excision and repeated placement of ureteral stents due to hydronephrosis. The patient first presented to the Endocrinology Clinic at the University of Chicago at the age of 25 y for goiter. Physical exam revealed bilateral thyroid nodules. She was clinically euthyroid, and a TSH was 0.9 mIU/l (reference range, 0.3–3.8 mIU/l) with free thyroxine index (FTI) of 8.1 (reference range, 6.0–10.5). A thyroid ultrasound confirmed multiple bilateral thyroid nodules. Fine needle aspiration of two of these nodules was consistent with papillary thyroid carcinoma. She underwent a total thyroidectomy, which revealed multifocal papillary thyroid carcinoma (cribriform-morular variant), that extended to the inked margins of the surgical specimen. No nodes with metastatic carcinoma were identified. After surgery, she was treated with 30 mCi 131I (TSH was 130 mIU/l, and a thyroglobulin concentration was 3.0 ng/ml with negative anti-thyroglobulin antibodies); a post-therapy scan showed uptake only in the thyroid bed. She was lost to follow-up for about a year. When she returned back to clinic, her TSH was 0.7 mIU/l with a thyroglobulin of 2.0 ng/ml. On physical exam, multiple abnormal masses in her neck were identified. Fine needle aspiration of these lesions was consistent with recurrent carcinoma. She underwent neck dissection, and the pathology showed metastatic cribriform-morular variant (C-MV) of papillary thyroid carcinoma was present in the lymph nodes and neck musculature. She was taken off levothyroxine after surgery and her TSH increased to 170 mIU/l with a thyroglobulin concentration of b1.0 ng/ml. A dose of 100 mCi 131 I was given, and a post-therapy scan was negative for metastatic disease. She developed persistent macroscopic disease on cross-sectional imaging that increased in size. She declined further surgery at that time, as well as consideration of external beam radiation therapy. Over the next few years, she tried various alternative treatment strategies, and took her levothyroxine dose only intermittently. She returned to the Endocrine Clinic at age 29 y with large, bulky neck masses, a left pleural effusion, and pleural-based masses. The pleural fluid was drained, and cytology was consistent with reactive mesothelial cells. The patient continued to refuse radiation or consider chemotherapy, and preferred to experiment with alternative therapies. Her neck masses continued to grow and eventually broke through the overlying skin. A surgical debulking procedure was planned. She was seen at another institution for a second opinion and was scheduled for an MRI of the neck. A serum pregnancy test at this institution was positive and the MRI was canceled. The patient also recalled a recent episode of abnormal vaginal bleeding. She was subsequently seen at the Ob-Gyn clinic at the University of Chicago for further evaluation. A urine pregnancy test was negative. The patient was then referred to a family planning center for IUD placement; a plasma pregnancy test there was again positive. She was then referred back to the University of Chicago for further evaluation.
The clinical chemistry laboratory was consulted to address the apparent discrepancy between the urine and plasma hCG tests, as the sensitivity of the POC device is comparable with that of laboratory analyzers. This was resolved by a series of studies. First, a linearity study was set up to assess parallelism with serial dilutions of the patient's samples. Frozen serum samples received two and six months previously for thyroglobulin testing from the same patient were retrieved and also tested for β-hCG concentration as part of this study. The results demonstrated excellent parallelism in all samples, indicating good recovery for β-hCG (data not shown). The possibility of a falsely positive plasma β-hCG was considered due to heterophile antibodies - endogenous human anti-animal antibodies that may interfere non-specifically with immunometric assays by cross-linking the signal and capture antibodies [15,16]. The detection of heterophile antibodies in the context of hCG testing may be undertaken using three different approaches. The first employs the concept that heterophile antibodies are too large to be excreted in urine. Thus, a urine test for hCG would help confirm if the plasma test was truly positive. In our case, this was considered a possibility, but further testing of this patient's plasma on the QuickVue hCG POC device used in urine testing showed a negative hCG reading even though the quantitative value was ~ 160 mIU/l by an alternate hCG method. (A male control plasma showed negative reading while a pregnant female patient of hCG of 166 mIU/l showed a positive reading with the POC device). Additionally, a mixing study was carried out, where control pregnant patient plasma at a predetermined concentration of 437 mIU/l was added as an equal parts mixture to this patient plasma, yielding a βhCG of 282 mIU/l. When both the undiluted control and the equal parts mixture were tested on the QuickVue POC device, they gave a positive result, while the patient's undiluted plasma was negative. This verified that no endogenous interfering substances were present in the patient's plasma that could be interfering with the assay. A second approach is to measure the plasma sample by different quantitative hCG assays, since it is unlikely that all of them will show the same false positive results due to interference by heterophile antibodies. In our case patient, an hCG of 139 mIU/ml was obtained with the Elecsys total hCG, while b0.5 mIU/ml was obtained using the Elecsys intact hCG assay. Thus the calculated “free β-hCG”, (defined as total hCG-intact hCG) constitutes the predominant form of hCG in our patient. Another total hCG assay (Beckman Access) showed a similar value of ~ 129 mIU/ml, while various other commercial hCG assays yielded values of 50–346 mIU/ml (Table 1). A third, more specific approach, however, is the use of heterophile antibodies blocking agents (Scantibodies Laboratory). These are nonimmune, animal immunoglobins that are able to block heterophile antibodies in patient serum, preventing them from binding reagents antibodies in the assay. In our case, the addition of the blocking agents, however, did not appreciably affect the hCG results suggesting that heterophile antibodies were unlikely present to interfere with the hCG assay. Taken together, these results strongly suggest that the positive plasma hCG detected in this patient represents true, circulating hCG in this patient. Within the next couple of weeks, the patient agreed to undergo a surgical debulking procedure as palliative therapy to reduce tumor burden in her neck. The resected specimen was received by surgical pathology (Fig. 1A) and showed a 16 cm mass with tumor erupting through the overlying skin. The otherwise white-tan skin showed foci of hemorrhage and discoloration overlying the tumor. Serial sectioning of the tumor demonstrated an infiltrative, solid, heterogeneous cut surface with gross infiltration into fat and skeletal muscle and involvement of surgical margins (Fig. 1B). Microscopy of the tumor showed histology similar to the patient's previous thyroidectomy and resection specimens. More specifically, the lesion was composed of sheets and nests of malignant cells (Fig. 1C) with increased nucleus to cytoplasm ratio, elongated, grooved nuclei, and prominent nucleoli, indicative of PTC. Areas of cribriform architecture were identified (Fig. 1D) as well as
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Table 1 Case patient hCG results. Sample
Roche Elecsys total β-hCG (mIU/ml)
Roche Elecsys intact hCG (mIU/ml)
Calculated “free β-hCG” (mIU/ml)
QuickVue Qual hCG
Beckman Access total hCG (mIU/ml)
Case patient Control patient 1 Control patient 2 Control patient 3 Control patient 4
139 106 574 106 418
b0.5 103 541 104 371
139 3 33 2 47
Negative
129
tight squamous morules in a background of solid sheets of tumor cells (Fig. 1E). In areas, the cells form nodules composed of cells aligned in a more syncytial pattern and exhibiting slightly darker cytoplasm. It was postulated that, in light of the elevated hCG concentrations in this patient, that there may be paraneoplastic secretion of hCG arising from the locally aggressive thyroid carcinoma. The patient's previous two surgical specimens were retrieved and hCG immunostaining was performed on sections of all three specimens (β-hCG, Dako) using a
polyclonal antibody targeted against the β-subunit of the hormone (Fig. 1F). Staining was heterogeneous, ranging from negative to strongly positive. An absorption control assay was then performed. Following addition of plasma with elevated hCG concentration (49,000 mIU/ml), staining was decreased while addition of plasma with very high hCG concentration (850,000 mIU/ml) resulted in uniform failure of tumor staining. Additionally, TTF-1 staining demonstrated thyroid follicular differentiation in most cells, while β-catenin immunostain showed
Fig. 1. Grossly, the tumor was large (16 cm) and involved the overlying skin of the neck (A). On the cut section, there is infiltration of the surrounding soft tissues (B). Microscopically, there is ulceration of the skin due to the underlying cellular tumor (C), which demonstrates areas of cribriform architecture (D) and tight squamous morules (E). The intervening areas resemble the classic nuclear and architectural morphology of papillary thyroid carcinoma. Immunohistochemical staining for β-hCG showed focal strong positivity (F).
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nuclear and cytoplasmic positivity, consistent with the patient's history of Gardner syndrome. 3. Discussion Papillary thyroid carcinoma is the most common malignant neoplasm of the thyroid gland, accounting for N 95% of cases [17]. Other variants in addition to the conventional subtype include follicular, tall cell, encapsulated, columnar cell, oncocytic, and solid. One of the rarer subtypes of papillary carcinoma is the cribriform-morular variant (C-MV), characterized by the histologic presence of cribriform structures as well as morules or tight bundles of squamoid cells with abundant eosinophilic cytoplasm embedded in a background of solid sheets of cells that cytologically resemble papillary thyroid carcinoma. The C-MV may be either familial (related to APC gene mutation and Gardner syndrome/ FAP) or sporadic, although most cases of the C-MV are related to APC gene mutations. Conversely, although only about 1% of patients with FAP have thyroid malignancies [18], most patients with APC gene mutations who suffer from a thyroid neoplasm have the C-MV of papillary thyroid carcinoma [19]. It is for this reason that whenever the C-MV is diagnosed, a screening colonoscopy should be performed to search for other aspects of Gardner syndrome. The C-MV is thought to be a neoplasm that is often cured by thyroidectomy and without any significant risk of recurrence. In a recent case study of 31 patients, 12 were related to FAP while 19 were sporadic [20]. FAP-related lesions were more likely multinodular compared to those arising sporadically. Either hemithyroidectomy or total thyroidectomy was curative procedures for the group, with only two recurrences seen in patients who initially underwent hemithyroidectomy. No deaths were recorded among this patient population. These results were further verified in another case series of 18 FAP-related cases of papillary thyroid carcinoma [19]. It is unusual in the present case that the patient has progressive and aggressive disease. It is possible that her carcinoma developed additional genetic lesions and acquired a more aggressive phenotype early in its course. Her serum thyroglobulin concentration was much lower than would be expected given the tumor burden, suggesting de-differentiation. Paraneoplastic syndromes in thyroid carcinoma are rare (Table 2), and include N50 cases in the literature of paraneoplastic Cushing syndrome in association with medullary thyroid carcinoma (MTC) [21]. Paraneoplastic syndromes in papillary thyroid carcinoma are varied and include endocrine, dermatologic, hematologic, and neurologic abnormalities. To our knowledge, this case of paraneoplastic
secretion of hCG by thyroid carcinoma is the first to be reported in the literature. In a woman of childbearing age, an elevated β-hCG value is often indicative of pregnancy. In this patient, an obstetrical workup was appropriately undertaken. After a thorough physical exam and ultrasound analysis, a number of obstetrical and gynecologic disorders were excluded, including ectopic pregnancy, molar pregnancy (quiescent gestational trophoblastic disease), and ovarian neoplasms. At this point, relatively uncommon clinical and laboratory differential diagnoses were entertained and evaluated. Only after the exclusion of these possibilities was a paraneoplastic secretion considered. Immunohistochemical staining using a polyclonal antibody against the β-subunit of hCG showed variable but definite positivity and was verified by the absorption control study. Various other neoplasms may express hCG protein both clinically in blood and immunohistochemically in tissue sections. In some, the histologic findings recapitulate those seen in conventional choriocarcinoma, indicative of dedifferentiation or aberrant differentiation toward a choriocarcinomatous line. Examples include carcinomas of the uterus [10], breast [22], lung [23], colon [12,24], renal pelvis [25], bladder [26], and mesothelium [27]. There have also been reports of choriocarcinomatous differentiation in soft tissue tumors such as osteosarcoma [28,29] and phyllodes tumor of the breast [9]. In the patient described here, the portion of the tumor that stained strongly for β-hCG did not show histologic similarities with a conventional choriocarcinoma. There was increased overall cellularity with tumor cells exhibiting slightly decreased cytoplasm. No hemorrhage or necrosis was found in these areas. Additionally, they showed strong, uniform nuclear expression of TTF-1, indicating thyroid origin. In the laboratory hCG testing for this patient, there was an apparent discrepancy and differing results seen among the POC device, the quantitative Elecsys hCG assay and various other commercial hCG assays. One possible explanation for this phenomenon is the differential antibodies (with different epitopes specificities) that are employed in these assays. The binding of differential antibodies to modified paraneoplastic hCG molecules may alter the results of hCG testing [30, 31]. As modified hCG molecules are typically hyperglycosylated and often harbor additional carbohydrate groups, it may be prudent in such situations to confirm suspicious or discrepant hCG results by different assays to avoid false positive or negative results [32]. In this particular patient where the major form circulating form is free β-hCG (Table 1), the apparently false negative hCG results obtained by the qualitative Quick Vue was due to the POCT assay being preferentially designed to measure intact hCG, which is the predominant form in
Table 2 Selected cases of paraneoplastic syndromes in thyroid carcinoma. Thyroid neoplasm
Paraneoplastic syndrome
No. of reports
Year
References
Papillary
Acanthosis nigricans Syndrome of inappropriate antidiuresis Atrophoderma Polymyositis Dermatomyositis Myoclonus Polymyalgia rheumatica Opitcomyelopathy Neutrophilia & eosinophilia due to GM-CSF Ectopic parathyroid hormone secretion Perforating collagenosis Ectopic hCG secretion Ectopic ACTH secretion Diaphragmatic paralysis Coagulopathy Cholestasis Eosinophilia Opsoclonus/myoclonus Ectopic CRH secretion Leukocytosis Neuromyelitis optica
2 1 1 1 4 1 1 1 1 1 1 1 18 1 1 1 1 1 1 1 1
1992, 2010 2010 2010 2008 2011, 2008, 2005, 1996 2007 1994 1993 2006 1998 2010 2012 1980 (2), 1985 (3), 1982, 2005 (10), 2007, 2011 2011 2003 1994 1989 1986 1985 2011 2008
[33,34] [35] [36] [37] [38–41] [42] [43] [44] [45] [46] [47] This case [21,48–53] [54] [55,56] [56] [57] [58] [59] [60] [61]
Medullary
Follicular carcinoma Hürthle cell
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normal pregnancy. By using an assay that detects both free and intact hCG (as in the Elecsys total β-hCG), we were able to confirm the true presence of a circulating free β-hCG in our patient. The present case emphasizes discrepant plasma and urine β-hCG results in a woman of childbearing age. This may lead to additional serologic tests or other imaging procedures. Although C-MV is considered an indolent variant of PTC, this case, and reports of other tumors secreting hCG have noted that the clinical course was more aggressive than those not secreting the hormone. Finally, this patient demonstrated an exceptional paraneoplastic secretion of hCG by her thyroid malignancy. Acknowledgement The authors wish to acknowledge Dr. Jerome Taxy for his critical review of the manuscript. References [1] Lapthorn AJ, Harris DC, Littlejohn A, et al. Crystal structure of human chorionic gonadotropin. Nature 1994;369:455–61. [2] Cole LA. Biological functions of hCG and hCG-related molecules. 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Case report
Discrepant serum and urine β-hCG results due to production of β-hCG by a cribriform-morular variant of thyroid papillary carcinoma Mir Alikhan a, Anoopa Koshy b, Elizabeth Hyjek a, Kerstin Stenson c, Ronald N. Cohen b,1, Kiang-Teck J. Yeo a,⁎,1 a b c
Department of Pathology, Biological Sciences Division, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, United States Section of Endocrinology, Department of Medicine, Biological Sciences Division, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, United States Department of Surgery, Biological Sciences Division, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, United States
a r t i c l e
i n f o
Article history: Received 11 July 2014 Received in revised form 21 August 2014 Accepted 22 August 2014 Available online 30 August 2014 Keywords: Human chorionic gonadotrophin Thyroid papillary cancer hCG immunoassays
a b s t r a c t Background: Although patients with medullary thyroid cancer are known to present with paraneoplastic hormone production, this is much less common with papillary thyroid cancer. Methods: We present a patient with the cribriform morular variant of papillary thyroid cancer in association with familial adenomatous polyposis who developed a positive pregnancy test in the absence of known pregnancy. The patient had developed vaginal bleeding, and her laboratory testing was characterized by elevated serum human chorionic gonadotropin (β-hCG) concentrations, but negative qualitative urine results. After a thorough gynecological evaluation to exclude unexpected normal, ectopic, or molar pregnancy, we pursued an evaluation for other sources of β-hCG production. Results: We showed that the elevated serum β-hCG concentrations were not the result of heterophile antibody interferences, and ultimately we proved that her recurrent tumor produced the ectopic β-hCG. This is the first report of β-hCG production by papillary thyroid cancer. Thus, the possibility of ectopic production of β-hCG by papillary thyroid cancer needs to be included in the differential diagnosis of elevated hCG concentration in the absence of pregnancy. Conclusions: This study of an unusual paraneoplastic syndrome highlights the importance of investigating discrepancies in the clinical laboratory. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Human chorionic gonadotropin (hCG) is a 37 kDa glycoprotein primarily secreted by the fetal placenta following conception and implantation [1]. It functions to stimulate progesterone secretion by the corpus luteum during the first weeks of pregnancy, which promotes the viability of the fetus largely through thickening and maintenance of the uterine lining, providing adequate nourishment for the developing conceptus. Thereafter, concentrations of hCG decline as the placenta begins production of progesterone and estrogen [2]. hCG is also thought to have an immunosuppressant function [3], reducing the likelihood of fetal rejection by the maternal immune system. The hCG molecule is composed of 244 amino acids and consists of a heterodimer with an α and β subunit. The alpha subunit is identical among the glycoprotein hormones, namely LH, FSH, and TSH. The β subunit, however, is unique to the hCG molecule. It is the targeting of antibodies against various epitopes of the β subunit that confers relative ⁎ Corresponding author at: 5841 S. Maryland Ave., MC 0004, TW-010, Chicago, IL 60637, United States. E-mail address: [email protected] (K.-T.J. Yeo). 1 Co-senior authors.
http://dx.doi.org/10.1016/j.cca.2014.08.026 0009-8981/© 2014 Elsevier B.V. All rights reserved.
specificity for laboratory hCG testing, and this methodology is employed by most modern clinical chemistry assays [4]. The main physiologic role of hCG is within the context of normal pregnancy. As a result, increased hCG concentrations are essentially diagnostic of pregnancy; hCG testing can quickly and effectively rule in or rule out pregnancy in the appropriate clinical context. Recent development of point-of-care (POC) devices for its measurement in urine has provided rapid, simple methods for the detection of pregnancy, with sensitivities approaching that of serum in conventional laboratory analyzers [5]. Elevated hCG concentrations are most often due to pregnancy, whether intra-uterine or ectopic. However, the specificity is not perfect due to the uncommon occurrence of elevated concentrations seen in disease states, both benign and malignant. Rarely, the pituitary gland may secrete hCG in perimenopausal women due to release of negative feedback on gonadotropin releasing hormone (GnRH) secretion [6]. Gestational trophoblastic diseases (GTDs) are rare and comprise a spectrum of both benign (hydatidiform moles) and malignant (invasive moles, choriocarcinomas, placental site trophoblastic tumor, and epithelioid trophoblastic tumor) disorders. Each is characterized by the production by the lesional trophoblast of abnormally high concentrations of β-hCG [7]. Rarely, a non-pregnant woman with a history of
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gestational trophoblastic disease may have persistent low concentrations of hCG following treatment, termed “quiescent GTD.” [8]. An exceptionally rare cause of elevated hCG in a non-pregnant female is due to paraneoplastic secretion of the hormone by extraplacental tissues. Such cases have been reported in various neoplasms [9–14]. Paraneoplastic syndromes associated with thyroid carcinoma are rare, and hCG secretion has never been reported in association with this neoplasm. The present patient with papillary thyroid carcinoma (PTC) and subsequent vaginal bleeding had elevated plasma β-hCG concentrations due to secretion by her thyroid neoplasm. 2. Patient The patient is a 31-y-old woman with a history of Gardner syndrome (familial adenomatous polyposis; FAP). Due to her family history of colon cancer, she underwent colonoscopy at age 20 y and on biopsy, had multiple colonic tubular adenomas. She underwent total colectomy at the age of 22 y. She also developed a retroperitoneal desmoid tumor requiring surgical excision and repeated placement of ureteral stents due to hydronephrosis. The patient first presented to the Endocrinology Clinic at the University of Chicago at the age of 25 y for goiter. Physical exam revealed bilateral thyroid nodules. She was clinically euthyroid, and a TSH was 0.9 mIU/l (reference range, 0.3–3.8 mIU/l) with free thyroxine index (FTI) of 8.1 (reference range, 6.0–10.5). A thyroid ultrasound confirmed multiple bilateral thyroid nodules. Fine needle aspiration of two of these nodules was consistent with papillary thyroid carcinoma. She underwent a total thyroidectomy, which revealed multifocal papillary thyroid carcinoma (cribriform-morular variant), that extended to the inked margins of the surgical specimen. No nodes with metastatic carcinoma were identified. After surgery, she was treated with 30 mCi 131I (TSH was 130 mIU/l, and a thyroglobulin concentration was 3.0 ng/ml with negative anti-thyroglobulin antibodies); a post-therapy scan showed uptake only in the thyroid bed. She was lost to follow-up for about a year. When she returned back to clinic, her TSH was 0.7 mIU/l with a thyroglobulin of 2.0 ng/ml. On physical exam, multiple abnormal masses in her neck were identified. Fine needle aspiration of these lesions was consistent with recurrent carcinoma. She underwent neck dissection, and the pathology showed metastatic cribriform-morular variant (C-MV) of papillary thyroid carcinoma was present in the lymph nodes and neck musculature. She was taken off levothyroxine after surgery and her TSH increased to 170 mIU/l with a thyroglobulin concentration of b1.0 ng/ml. A dose of 100 mCi 131 I was given, and a post-therapy scan was negative for metastatic disease. She developed persistent macroscopic disease on cross-sectional imaging that increased in size. She declined further surgery at that time, as well as consideration of external beam radiation therapy. Over the next few years, she tried various alternative treatment strategies, and took her levothyroxine dose only intermittently. She returned to the Endocrine Clinic at age 29 y with large, bulky neck masses, a left pleural effusion, and pleural-based masses. The pleural fluid was drained, and cytology was consistent with reactive mesothelial cells. The patient continued to refuse radiation or consider chemotherapy, and preferred to experiment with alternative therapies. Her neck masses continued to grow and eventually broke through the overlying skin. A surgical debulking procedure was planned. She was seen at another institution for a second opinion and was scheduled for an MRI of the neck. A serum pregnancy test at this institution was positive and the MRI was canceled. The patient also recalled a recent episode of abnormal vaginal bleeding. She was subsequently seen at the Ob-Gyn clinic at the University of Chicago for further evaluation. A urine pregnancy test was negative. The patient was then referred to a family planning center for IUD placement; a plasma pregnancy test there was again positive. She was then referred back to the University of Chicago for further evaluation.
The clinical chemistry laboratory was consulted to address the apparent discrepancy between the urine and plasma hCG tests, as the sensitivity of the POC device is comparable with that of laboratory analyzers. This was resolved by a series of studies. First, a linearity study was set up to assess parallelism with serial dilutions of the patient's samples. Frozen serum samples received two and six months previously for thyroglobulin testing from the same patient were retrieved and also tested for β-hCG concentration as part of this study. The results demonstrated excellent parallelism in all samples, indicating good recovery for β-hCG (data not shown). The possibility of a falsely positive plasma β-hCG was considered due to heterophile antibodies - endogenous human anti-animal antibodies that may interfere non-specifically with immunometric assays by cross-linking the signal and capture antibodies [15,16]. The detection of heterophile antibodies in the context of hCG testing may be undertaken using three different approaches. The first employs the concept that heterophile antibodies are too large to be excreted in urine. Thus, a urine test for hCG would help confirm if the plasma test was truly positive. In our case, this was considered a possibility, but further testing of this patient's plasma on the QuickVue hCG POC device used in urine testing showed a negative hCG reading even though the quantitative value was ~ 160 mIU/l by an alternate hCG method. (A male control plasma showed negative reading while a pregnant female patient of hCG of 166 mIU/l showed a positive reading with the POC device). Additionally, a mixing study was carried out, where control pregnant patient plasma at a predetermined concentration of 437 mIU/l was added as an equal parts mixture to this patient plasma, yielding a βhCG of 282 mIU/l. When both the undiluted control and the equal parts mixture were tested on the QuickVue POC device, they gave a positive result, while the patient's undiluted plasma was negative. This verified that no endogenous interfering substances were present in the patient's plasma that could be interfering with the assay. A second approach is to measure the plasma sample by different quantitative hCG assays, since it is unlikely that all of them will show the same false positive results due to interference by heterophile antibodies. In our case patient, an hCG of 139 mIU/ml was obtained with the Elecsys total hCG, while b0.5 mIU/ml was obtained using the Elecsys intact hCG assay. Thus the calculated “free β-hCG”, (defined as total hCG-intact hCG) constitutes the predominant form of hCG in our patient. Another total hCG assay (Beckman Access) showed a similar value of ~ 129 mIU/ml, while various other commercial hCG assays yielded values of 50–346 mIU/ml (Table 1). A third, more specific approach, however, is the use of heterophile antibodies blocking agents (Scantibodies Laboratory). These are nonimmune, animal immunoglobins that are able to block heterophile antibodies in patient serum, preventing them from binding reagents antibodies in the assay. In our case, the addition of the blocking agents, however, did not appreciably affect the hCG results suggesting that heterophile antibodies were unlikely present to interfere with the hCG assay. Taken together, these results strongly suggest that the positive plasma hCG detected in this patient represents true, circulating hCG in this patient. Within the next couple of weeks, the patient agreed to undergo a surgical debulking procedure as palliative therapy to reduce tumor burden in her neck. The resected specimen was received by surgical pathology (Fig. 1A) and showed a 16 cm mass with tumor erupting through the overlying skin. The otherwise white-tan skin showed foci of hemorrhage and discoloration overlying the tumor. Serial sectioning of the tumor demonstrated an infiltrative, solid, heterogeneous cut surface with gross infiltration into fat and skeletal muscle and involvement of surgical margins (Fig. 1B). Microscopy of the tumor showed histology similar to the patient's previous thyroidectomy and resection specimens. More specifically, the lesion was composed of sheets and nests of malignant cells (Fig. 1C) with increased nucleus to cytoplasm ratio, elongated, grooved nuclei, and prominent nucleoli, indicative of PTC. Areas of cribriform architecture were identified (Fig. 1D) as well as
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Table 1 Case patient hCG results. Sample
Roche Elecsys total β-hCG (mIU/ml)
Roche Elecsys intact hCG (mIU/ml)
Calculated “free β-hCG” (mIU/ml)
QuickVue Qual hCG
Beckman Access total hCG (mIU/ml)
Case patient Control patient 1 Control patient 2 Control patient 3 Control patient 4
139 106 574 106 418
b0.5 103 541 104 371
139 3 33 2 47
Negative
129
tight squamous morules in a background of solid sheets of tumor cells (Fig. 1E). In areas, the cells form nodules composed of cells aligned in a more syncytial pattern and exhibiting slightly darker cytoplasm. It was postulated that, in light of the elevated hCG concentrations in this patient, that there may be paraneoplastic secretion of hCG arising from the locally aggressive thyroid carcinoma. The patient's previous two surgical specimens were retrieved and hCG immunostaining was performed on sections of all three specimens (β-hCG, Dako) using a
polyclonal antibody targeted against the β-subunit of the hormone (Fig. 1F). Staining was heterogeneous, ranging from negative to strongly positive. An absorption control assay was then performed. Following addition of plasma with elevated hCG concentration (49,000 mIU/ml), staining was decreased while addition of plasma with very high hCG concentration (850,000 mIU/ml) resulted in uniform failure of tumor staining. Additionally, TTF-1 staining demonstrated thyroid follicular differentiation in most cells, while β-catenin immunostain showed
Fig. 1. Grossly, the tumor was large (16 cm) and involved the overlying skin of the neck (A). On the cut section, there is infiltration of the surrounding soft tissues (B). Microscopically, there is ulceration of the skin due to the underlying cellular tumor (C), which demonstrates areas of cribriform architecture (D) and tight squamous morules (E). The intervening areas resemble the classic nuclear and architectural morphology of papillary thyroid carcinoma. Immunohistochemical staining for β-hCG showed focal strong positivity (F).
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nuclear and cytoplasmic positivity, consistent with the patient's history of Gardner syndrome. 3. Discussion Papillary thyroid carcinoma is the most common malignant neoplasm of the thyroid gland, accounting for N 95% of cases [17]. Other variants in addition to the conventional subtype include follicular, tall cell, encapsulated, columnar cell, oncocytic, and solid. One of the rarer subtypes of papillary carcinoma is the cribriform-morular variant (C-MV), characterized by the histologic presence of cribriform structures as well as morules or tight bundles of squamoid cells with abundant eosinophilic cytoplasm embedded in a background of solid sheets of cells that cytologically resemble papillary thyroid carcinoma. The C-MV may be either familial (related to APC gene mutation and Gardner syndrome/ FAP) or sporadic, although most cases of the C-MV are related to APC gene mutations. Conversely, although only about 1% of patients with FAP have thyroid malignancies [18], most patients with APC gene mutations who suffer from a thyroid neoplasm have the C-MV of papillary thyroid carcinoma [19]. It is for this reason that whenever the C-MV is diagnosed, a screening colonoscopy should be performed to search for other aspects of Gardner syndrome. The C-MV is thought to be a neoplasm that is often cured by thyroidectomy and without any significant risk of recurrence. In a recent case study of 31 patients, 12 were related to FAP while 19 were sporadic [20]. FAP-related lesions were more likely multinodular compared to those arising sporadically. Either hemithyroidectomy or total thyroidectomy was curative procedures for the group, with only two recurrences seen in patients who initially underwent hemithyroidectomy. No deaths were recorded among this patient population. These results were further verified in another case series of 18 FAP-related cases of papillary thyroid carcinoma [19]. It is unusual in the present case that the patient has progressive and aggressive disease. It is possible that her carcinoma developed additional genetic lesions and acquired a more aggressive phenotype early in its course. Her serum thyroglobulin concentration was much lower than would be expected given the tumor burden, suggesting de-differentiation. Paraneoplastic syndromes in thyroid carcinoma are rare (Table 2), and include N50 cases in the literature of paraneoplastic Cushing syndrome in association with medullary thyroid carcinoma (MTC) [21]. Paraneoplastic syndromes in papillary thyroid carcinoma are varied and include endocrine, dermatologic, hematologic, and neurologic abnormalities. To our knowledge, this case of paraneoplastic
secretion of hCG by thyroid carcinoma is the first to be reported in the literature. In a woman of childbearing age, an elevated β-hCG value is often indicative of pregnancy. In this patient, an obstetrical workup was appropriately undertaken. After a thorough physical exam and ultrasound analysis, a number of obstetrical and gynecologic disorders were excluded, including ectopic pregnancy, molar pregnancy (quiescent gestational trophoblastic disease), and ovarian neoplasms. At this point, relatively uncommon clinical and laboratory differential diagnoses were entertained and evaluated. Only after the exclusion of these possibilities was a paraneoplastic secretion considered. Immunohistochemical staining using a polyclonal antibody against the β-subunit of hCG showed variable but definite positivity and was verified by the absorption control study. Various other neoplasms may express hCG protein both clinically in blood and immunohistochemically in tissue sections. In some, the histologic findings recapitulate those seen in conventional choriocarcinoma, indicative of dedifferentiation or aberrant differentiation toward a choriocarcinomatous line. Examples include carcinomas of the uterus [10], breast [22], lung [23], colon [12,24], renal pelvis [25], bladder [26], and mesothelium [27]. There have also been reports of choriocarcinomatous differentiation in soft tissue tumors such as osteosarcoma [28,29] and phyllodes tumor of the breast [9]. In the patient described here, the portion of the tumor that stained strongly for β-hCG did not show histologic similarities with a conventional choriocarcinoma. There was increased overall cellularity with tumor cells exhibiting slightly decreased cytoplasm. No hemorrhage or necrosis was found in these areas. Additionally, they showed strong, uniform nuclear expression of TTF-1, indicating thyroid origin. In the laboratory hCG testing for this patient, there was an apparent discrepancy and differing results seen among the POC device, the quantitative Elecsys hCG assay and various other commercial hCG assays. One possible explanation for this phenomenon is the differential antibodies (with different epitopes specificities) that are employed in these assays. The binding of differential antibodies to modified paraneoplastic hCG molecules may alter the results of hCG testing [30, 31]. As modified hCG molecules are typically hyperglycosylated and often harbor additional carbohydrate groups, it may be prudent in such situations to confirm suspicious or discrepant hCG results by different assays to avoid false positive or negative results [32]. In this particular patient where the major form circulating form is free β-hCG (Table 1), the apparently false negative hCG results obtained by the qualitative Quick Vue was due to the POCT assay being preferentially designed to measure intact hCG, which is the predominant form in
Table 2 Selected cases of paraneoplastic syndromes in thyroid carcinoma. Thyroid neoplasm
Paraneoplastic syndrome
No. of reports
Year
References
Papillary
Acanthosis nigricans Syndrome of inappropriate antidiuresis Atrophoderma Polymyositis Dermatomyositis Myoclonus Polymyalgia rheumatica Opitcomyelopathy Neutrophilia & eosinophilia due to GM-CSF Ectopic parathyroid hormone secretion Perforating collagenosis Ectopic hCG secretion Ectopic ACTH secretion Diaphragmatic paralysis Coagulopathy Cholestasis Eosinophilia Opsoclonus/myoclonus Ectopic CRH secretion Leukocytosis Neuromyelitis optica
2 1 1 1 4 1 1 1 1 1 1 1 18 1 1 1 1 1 1 1 1
1992, 2010 2010 2010 2008 2011, 2008, 2005, 1996 2007 1994 1993 2006 1998 2010 2012 1980 (2), 1985 (3), 1982, 2005 (10), 2007, 2011 2011 2003 1994 1989 1986 1985 2011 2008
[33,34] [35] [36] [37] [38–41] [42] [43] [44] [45] [46] [47] This case [21,48–53] [54] [55,56] [56] [57] [58] [59] [60] [61]
Medullary
Follicular carcinoma Hürthle cell
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normal pregnancy. By using an assay that detects both free and intact hCG (as in the Elecsys total β-hCG), we were able to confirm the true presence of a circulating free β-hCG in our patient. The present case emphasizes discrepant plasma and urine β-hCG results in a woman of childbearing age. This may lead to additional serologic tests or other imaging procedures. Although C-MV is considered an indolent variant of PTC, this case, and reports of other tumors secreting hCG have noted that the clinical course was more aggressive than those not secreting the hormone. Finally, this patient demonstrated an exceptional paraneoplastic secretion of hCG by her thyroid malignancy. Acknowledgement The authors wish to acknowledge Dr. Jerome Taxy for his critical review of the manuscript. References [1] Lapthorn AJ, Harris DC, Littlejohn A, et al. Crystal structure of human chorionic gonadotropin. Nature 1994;369:455–61. [2] Cole LA. Biological functions of hCG and hCG-related molecules. 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