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Breast metastasis by medullary thyroid carcinoma detected by FDG positron emission tomography
Available online at www.sciencedirect.com
Annals of Diagnostic Pathology 12 (2008) 67 – 71
Breast metastasis by medullary thyroid carcinoma detected by FDG positron emission tomography Sharon Nofech-Mozes, MDa,b, Robert Mackenzie, MD, FRCPCc, Harriette J. Kahn, MD, FRCPCa,b, Lisa Ehrlich, MD, FRCPCd, Simon J. Raphael, MD, FRCPCa,b,4 a Department of Anatomical Pathology, Sunnybrook Health Sciences Center, Toronto, ON, Canada M4N 3M5 Department of Pathobiology and Laboratory Medicine, University of Toronto, Toronto, ON, Canada M5G 1L5 c Department of Radiation Oncology, Toronto Sunnybrook Regional Cancer Center, Toronto, ON, Canada M4N 3M5 d Department of Medical Imaging, Sunnybrook Health Sciences Center, Toronto, ON, Canada M4N 3M5 b
Abstract
Medullary thyroid carcinoma (MTC) is an uncommon thyroid cancer comprising 5% to 8% of thyroid neoplasms. In contrast to common thyroid tumors, this tumor originates from the calcitoninproducing C cells. Regional metastases to cervical lymph nodes occur early in the disease, whereas distant metastasis occurs late. Common metastatic sites include the liver, bone, brain, and adrenal medulla. We present a case of MTC metastatic to the breast. We report on this case for the following reasons: (1) metastasis to the breast is an extremely rare occurrence and could be easily confused clinically and pathologically with a primary breast neoplasm and (2) this is the first reported case of detection of breast metastasis by an MTC using FDG (18F-fluoro-2-deoxy-d-glucose) positron emission tomography with an accompanying histologic description. D 2008 Elsevier Inc. All rights reserved.
Keywords:
Medullary thyroid carcinoma; Breast metastasis; FDG-PET
1. Introduction Histopathologic evaluation of breast masses is one of the most common tasks in surgical pathology. Most of these masses represent primary breast lesions, but pathologists rarely encounter metastatic involvement of the breast by extramammary neoplasms. Breast metastases comprise 0.5% to 2% of all breast tumors [1,2]. Autopsy reports have indicated that the incidence of breast metastases is between 1.7% and 6.6%. The diagnosis of a metastatic tumor should be considered in patients with known extramammary malignancy and whenever the morphology does not correspond to the patterns typical for primary breast tumors. Metastases to the breast have been associated with poor prognosis, with most patients dying within 1 year of diagnosis [2]. Recognizing a breast tumor as being metastatic is of great clinical significance in
4 Corresponding author. Department of Anatomical Pathology, Sunnybrook Health Sciences Center, Toronto, ON, Canada M4N 3M5. Tel.: +1 416 480 6100x2124; fax: +1 416 480 4271. E-mail address: [email protected] (S.J. Raphael). 1092-9134/$ – see front matter D 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.anndiagpath.2006.08.004
terms of treatment and prognosis. Accurate diagnosis can spare patients unnecessary surgical procedures and is essential in the selection of the most effective chemotherapeutic regimen for them. The diagnosis is particularly challenging for pathologists when fine needle aspiration cytology or core needle biopsy is used because each technique provides only limited amounts of tissue. Needle biopsy may be applied particularly when the clinical diagnosis is locally advanced breast cancer. If the correct diagnosis of a secondary tumor is not made, then inappropriate neoadjuvant systemic therapy may be administered before further definitive surgical excision. We present the first case of metastasis to the breast from a medullary thyroid carcinoma (MTC) that was identified on FDG (18F-fluoro-2-deoxy-d-glucose) positron emission tomography with a description of histologic, immunohistochemical, and ultrastructural features. 2. Case history The patient was a 50-year-old woman. Her significant past clinical history included bilateral fibroadenomas
68
S. Nofech-Mozes et al. / Annals of Diagnostic Pathology 12 (2008) 67 – 71
diagnosed with core biopsy in 2002. In 2003, she presented with a right thyroid mass that was diagnosed as a Hqrthle cell neoplasm on fine needle aspiration. The frozen section revealed an MTC, and the patient was treated with total thyroidectomy without neck dissection. The thyroid tumor was unencapsulated and measured 2 cm. No angiolymphatic invasion was seen; however, a right parapharyngeal lymph node contained metastatic MTC. Two weeks after the operation, the patient complained of discomfort on her right upper neck; a postoperative computed tomographic scan demonstrated a soft tissue mass. This was diagnosed as an MTC on core needle aspiration. The residual disease was treated with external beam radiotherapy. Her serum calcitonin level however remained persistently elevated in the presence of repeated physical examinations that had unremarkable findings and computed tomographic scans of the neck and chest that had normal results. The results of a technetium sestamibi scan were negative. To investigate this further, we performed an FDG-PET; it revealed a 1.9-cm left upper inner-quadrant breast mass and 2 hepatic masses (Fig. 1). An ultrasound of the breast showed a hypoechoic irregular heterogeneous mass corresponding to the area of increased activity noted on the FDG-PET. The lesion was further evaluated by mammography, which demonstrated a dense indistinct lobulated mass measuring 3 cm. An ultrasound-guided core needle biopsy revealed a high-grade carcinoma, and the initial working diagnosis based on microscopic examination of hematoxylin-eosin sections alone was that of primary breast carcinoma. However, after further discussions with clinicians, we performed immunohistochemical studies, and the diagnosis of the core biopsy was that of a metastatic MTC. A palliative excisional biopsy was performed to control local pain and to prevent local progression of the disease.
Fig. 1. An FDG-PET computed tomographic scan image showing a focal FDG-avid left breast ovoid mass slightly superior and medial to the nipple. This demonstrates a peak standardized uptake value of 5.46.
Fig. 2. A representative section from the breast core biopsy specimen with a high-grade invasive tumor surrounding the nonneoplastic duct (original magnification 100).
Pathologic evaluation of the mass confirmed the diagnosis of metastatic MTC. The patient received 4 cycles of cisplatinum and doxorubicin with mild shrinkage of the liver lesions. She is alive but has a persistent disease confined to the liver 8 months after the diagnosis of breast and liver metastases. 3. Pathologic findings The excised tumor appeared grossly as a hard tan mass with ill-defined borders that measured 4 3.2 3 cm. A present discrete 1-cm nodule adjacent to the tumor grossly most resembled a fibroadenoma. The hematoxylin-eosin– stained section of the tumor showed clusters of neoplastic cells that were distributed haphazardly within the breast parenchyma surrounding intact ducts and lobules (Fig. 2). The neoplastic cells had a high nuclear-to-cytoplasmic ratio with irregular nuclear contours, vesicular chromatin, and single or multiple prominent nucleoli (Fig. 3). Occasional
Fig. 3. A high-power view illustrating marked nuclear pleomorphism. Note the atypical mitosis depicted (original magnification 400).
S. Nofech-Mozes et al. / Annals of Diagnostic Pathology 12 (2008) 67 – 71
69
Table 1 Antibodies used for immunohistochemistry and staining results Antibody
Clone
Source
Dilution
Staining in the tumor cells
Cytokeratin 7 Synaptophysin Chromogranin Calcitonin Thyroid transcription factor 1 Monoclonal carcinoembryonic antigen E-cadherin
OV-TL 12/30 27G12 Catalog no. A0430 Catalog no A576 8G7G3/1 Col-1 36
1:400 1:100 1:200 1:500 1:400 1:200 1:200
+++ +++ ++ +++ +++ ++ +++
ER PR HER2/neu
6F11 312 CB11 TAB 250
Dako, Glostrup, Denmark Vector, Burlingame, Calif Dako, Glostrup, Denmark Dako, Glostrup, Denmark Neuromarkers, Fremont, Calif Biomeda, San Jose, Calif BD Biosciences Pharmingen, Mississauga, ON, Canada Novocastra, New Castle, England Novocastra, New Castle, England Novocastra, New Castle, England Zymed, San Francisco, Calif
1:50 1:100 1:400 1:100
multinucleated cells were present. Mitoses were atypical and easily identified. The stroma was fibrotic and slightly eosinophilic with a few dystrophic calcifications present. Lymphovascular invasion was identified. These microscopic features were identical to those seen on the earlier core biopsy specimen. Congo red stain was negative for amyloid. Immunohistochemical studies performed on formalin-fixed and paraffin-embedded tissue sections (Table 1) showed that the neoplastic cells were positive for cytokeratin 7, synaptophysin, calcitonin (Fig. 4), chromogranin, monoclonal carcinoembryonic antigen, E-cadherin, and thyroid transcription factor 1. The neoplastic cells were negative for estrogen receptor (ER) and progesterone receptor (PR) expressions as well as for HER2/neu oncoprotein overexpression. This profile was identical to the patient’s primary thyroid tumor. Electron microscopy demonstrated tumor cells with multiple cytoplasmic dense-core secretory granules. Each granule was composed of a single membrane separated by a clear zone from an electron-dense central portion (Fig. 5). Small numbers of amyloid fibers were found on ultrastructural examination. The surrounding breast parenchyma showed a fibroadenoma and nonproliferative fibrocystic changes.
4. Discussion
Fig. 4. Positive calcitonin immunostaining in the tumor. The native breast ducts yielded negative results (original magnification 100).
Fig. 5. Electron microscopy demonstrating neurosecretory granules in the cytoplasm (original magnification 20 000).
Metastatic disease to the breast is uncommon; thus, it may not be considered in the differential diagnosis of breast tumors by clinicians and pathologists. A secondary tumor is especially difficult to diagnose in cases in which breast metastasis is the first manifestation of an occult extramammary malignancy. This occurs in approximately 25% of patients who have metastatic tumors to the breast [3]. Moreover, even in patients with a history of malignancy presenting with a single breast mass, a second primary breast lesion is always considered more probable than a metastasis. It is important to consider metastatic tumors in the differential diagnosis when the breast lesion has unusual clinical, radiologic, or pathologic features. At present, there is a lack of reliable and specific clinical or radiologic tests to indicate that a tumor is a metastasis rather than a primary lesion. Metastases to the breast are multifocal in 11% to 35% and bilateral in 26% of cases and may be accompanied by axillary lymph node involvement, features often seen in primary tumors as well [4]. The mammographic appearance of secondary tumors is as a
70
S. Nofech-Mozes et al. / Annals of Diagnostic Pathology 12 (2008) 67 – 71
well-circumscribed mass without spiculation. These lesions are often indistinguishable from primary breast cancer [5]. It has been suggested that lack of tumor-associated acoustic shadowing is a characteristic ultrasonographic feature of metastatic tumors in the breast [2]. In the current case, the patient’s breast lesion was initially imaged with FDG-PET. Recent studies [6-8] have found that this tool is useful in detecting recurrent or occult metastatic diseases in patients with MTC and anaplastic thyroid carcinoma, providing higher sensitivity (66%-100%) and specificity (79%-90%) as compared with conventional nuclear imaging methods. Nevertheless, the differentiation between a primary and a secondary malignancy cannot be based on the PET image. Given the lack of reliable noninvasive diagnostic tools, histologic diagnosis plays a major role in the distinction of primary from secondary breast tumors. A recent review of the literature listed the most common extramammary solid tumors that metastasize to the breast in order of frequency as lymphoma and malignant melanoma, followed by lung cancer, ovarian carcinoma, soft tissue sarcoma, gastrointestinal tumor, and genitourinary tumor [5]. Case reports of metastatic involvement from osteosarcoma, thyroid neoplasms, as well as cervical, vaginal, and endometrial carcinoma have been described in the literature. In view of the infrequency of primary breast cancer in men, the possibility of a metastasis should always be considered. The prostate is the most common primary source of metastatic tumors in the male breast. Based on a case series in 1973, the incidence of breast metastases from prostatic carcinoma was estimated at 5%; however, in that study, microscopic breast involvement was found in autopsies in approximately one fourth of the men with clinically diagnosed prostatic carcinoma [9]. Bartella et al [5] studied the radiologic-histologic correlation of metastatic tumors to the breast and estimated that approximately 4% of these originate from the thyroid. We are aware of 8 cases of MTC reported in the literature as case reports or as part of a series of secondary breast tumors, all occurring in women. In the present case, metastasis to the breast from an MTC was identified on FDG-PET. This imaging modality was selected for our patient because of her persistent elevated calcitonin level after treatment and the failure of other imaging modalities to detect a residual disease. It has been suggested that subdetectable tumoral foci are responsible for the unexplained high plasma tumor marker levels in patients [6]. One patient with breast metastasis from an MTC was mentioned among 36 patients with an MTC investigated by FDG-PET as a result of elevated calcitonin levels [6]. That patient had multiple bone and lymph node lesions detected using this modality. A biopsy of the breast mass confirmed the diagnosis of metastatic MTC; however, a pathologic description of this case is not available. Several histologic features warrant the consideration of metastasis to the breast. Multifocality, especially with an
unusual histologic pattern, should raise the possibility of a metastatic tumor being in place. One clue for a metastatic origin, as observed in our case, is that the metastatic tumors surround and displace ducts and lobules, which typically show little or no hyperplasia. The presence of an in situ carcinoma component would support a primary breast lesion. Care must be taken to distinguish true in situ carcinoma from metastatic lesions with confluent necrosis that may mimic comedo necrosis. In difficult cases, immunohistochemical markers such as smooth muscle myosin and p63 can be used to demonstrate a continuous myoepithelial layer surrounding the ductal structures of ductal carcinoma in situ, which would not be seen in metastatic lesions. Immunohistochemistry plays an important role in the accurate identification of metastatic lesions. Because the most common secondary breast tumors are lymphoma and melanoma, an initial panel of antibodies should be directed to exclude these lesions. Primary breast carcinomas are positive for cytokeratin 7, and those of ductal origin express E-cadherin. However, this latter characteristic is shared by diverse neoplasms, including those of thyroid origin, as in the case of our patient. The ER, PR, and HER2/neu are expressed in a subset of invasive breast carcinoma and in some other carcinomas; thus, their presence or absence cannot determine whether a breast neoplasm is of metastatic origin. The data regarding ER, PR, and HER2/neu expressions in MTCs, although based on a limited number of cases, suggest that MTCs are negative for ER and PR [10-12] expressions, at least by immunohistochemistry, as well as for HER2/neu oncoprotein overexpression and gene amplification. Recent studies reported that HER2/neu is overexpressed in approximately one third of papillary thyroid carcinomas [13] and in anaplastic thyroid carcinoma cell lines [14]. Neuroendocrine markers may be expressed by primary breast carcinomas with neuroendocrine differentiation and by various metastatic lesions, especially those of gastrointestinal origin, as well as by MTCs. Because no single immunohistochemical marker can specifically identify a primary breast lesion, we suggest that a panel of antibodies be selected based on each patient’s history and sex as well as the frequency of possible primaries. The role of ultrastructural studies in diagnostic histopathology is limited in the era of immunohistochemistry. Nevertheless, they have a role as an adjunct tool for diagnosis, as demonstrated in our case. Although repeated Congo red stains were negative for amyloid in our case, few amyloid fibers were identified using electron microscopy. In summary, breast metastases from extramammary malignancies are infrequent. Breast metastasis usually indicates a disseminated metastatic disease and a poor prognosis. This report illustrates the difficulties in diagnosing MTC metastatic to the breast. The source of the increased serum calcitonin level was unknown until FDGPET was used. A high level of suspicion based on the patient’s history in combination with a panel of immuno-
S. Nofech-Mozes et al. / Annals of Diagnostic Pathology 12 (2008) 67 – 71
histochemical markers, including calcitonin, pan-endocrine markers, and thyroid markers such as thyroid transcription factor 1, led to the correct diagnosis.
References [1] Hajdu SI, Urban JA. Cancers metastatic to the breast. Cancer 1972;29(6):1691 - 6. [2] Yeh CN, Lin CH, Chen MF. Clinical and ultrasonographic characteristics of breast metastases from extramammary malignancies. Am Surg 2004;70(4):287 - 90. [3] Rosen PP. Rosen’s breast pathology, 2nd ed. 2004. p. 689. [4] Akcay MN. Metastatic disease in the breast. Breast 2002;11(6):526 - 8. [5] Bartella L, Kaye J, Perry NM, et al. Metastases to the breast revisited: radiological-histopathological correlation. Clin Radiol 2003;58(7): 524 - 31. [6] Esik O, Szavcsur P, Szakall Jr S, et al. Angiography effectively supports the diagnosis of hepatic metastases in medullary thyroid carcinoma. Cancer 2001;91(11):2084 - 95. [7] de Groot JW, Links TP, Jager PL, Kahraman T, Plukker JT. Impact of 18 F-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-
[8]
[9] [10]
[11]
[12]
[13]
[14]
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PET) in patients with biochemical evidence of recurrent or residual medullary thyroid cancer. Ann Surg Oncol 2004;11(8):786 - 94. Khan N, Oriuchi N, Higuchi T, Endo K. Review of fluorine-18-2fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) in the follow-up of medullary and anaplastic thyroid carcinomas. Cancer Control 2005;12(4):254 - 60. Salyer WR, Salyer DC. Metastases of prostatic carcinoma to the breast. J Urol 1973;109(4):671 - 5. Bur M, Shiraki W, Masood S. Estrogen and progesterone receptor detection in neoplastic and non-neoplastic thyroid tissues. Mod Pathol 1993;6(4):469 - 72. Colomer A, Martinez-Mas JV, Matias-Guiu X, et al. Sex-steroid hormone receptors in human medullary thyroid carcinoma. Mod Pathol 1996;9(1):68 - 72. Arain SA, Shah MH, Meo SA, Jamal Q. Estrogen receptors in human thyroid gland. An immunohistochemical study. Saudi Med J 2003;24(2):174 - 8. Freudenberg LS, Sheu S, Gorges R, et al. Prognostic value of c-erbB-2 expression in papillary thyroid carcinoma. Nuklearmedizin 2005; 44(5):179-182, 184. Kurebayashi J, Okubo S, Yamamoto Y, et al. Additive antitumor effects of gefitinib and imatinib on anaplastic thyroid cancer cells. Cancer Chemother Pharmacol 2006;25:1 - 11.
Annals of Diagnostic Pathology 12 (2008) 67 – 71
Breast metastasis by medullary thyroid carcinoma detected by FDG positron emission tomography Sharon Nofech-Mozes, MDa,b, Robert Mackenzie, MD, FRCPCc, Harriette J. Kahn, MD, FRCPCa,b, Lisa Ehrlich, MD, FRCPCd, Simon J. Raphael, MD, FRCPCa,b,4 a Department of Anatomical Pathology, Sunnybrook Health Sciences Center, Toronto, ON, Canada M4N 3M5 Department of Pathobiology and Laboratory Medicine, University of Toronto, Toronto, ON, Canada M5G 1L5 c Department of Radiation Oncology, Toronto Sunnybrook Regional Cancer Center, Toronto, ON, Canada M4N 3M5 d Department of Medical Imaging, Sunnybrook Health Sciences Center, Toronto, ON, Canada M4N 3M5 b
Abstract
Medullary thyroid carcinoma (MTC) is an uncommon thyroid cancer comprising 5% to 8% of thyroid neoplasms. In contrast to common thyroid tumors, this tumor originates from the calcitoninproducing C cells. Regional metastases to cervical lymph nodes occur early in the disease, whereas distant metastasis occurs late. Common metastatic sites include the liver, bone, brain, and adrenal medulla. We present a case of MTC metastatic to the breast. We report on this case for the following reasons: (1) metastasis to the breast is an extremely rare occurrence and could be easily confused clinically and pathologically with a primary breast neoplasm and (2) this is the first reported case of detection of breast metastasis by an MTC using FDG (18F-fluoro-2-deoxy-d-glucose) positron emission tomography with an accompanying histologic description. D 2008 Elsevier Inc. All rights reserved.
Keywords:
Medullary thyroid carcinoma; Breast metastasis; FDG-PET
1. Introduction Histopathologic evaluation of breast masses is one of the most common tasks in surgical pathology. Most of these masses represent primary breast lesions, but pathologists rarely encounter metastatic involvement of the breast by extramammary neoplasms. Breast metastases comprise 0.5% to 2% of all breast tumors [1,2]. Autopsy reports have indicated that the incidence of breast metastases is between 1.7% and 6.6%. The diagnosis of a metastatic tumor should be considered in patients with known extramammary malignancy and whenever the morphology does not correspond to the patterns typical for primary breast tumors. Metastases to the breast have been associated with poor prognosis, with most patients dying within 1 year of diagnosis [2]. Recognizing a breast tumor as being metastatic is of great clinical significance in
4 Corresponding author. Department of Anatomical Pathology, Sunnybrook Health Sciences Center, Toronto, ON, Canada M4N 3M5. Tel.: +1 416 480 6100x2124; fax: +1 416 480 4271. E-mail address: [email protected] (S.J. Raphael). 1092-9134/$ – see front matter D 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.anndiagpath.2006.08.004
terms of treatment and prognosis. Accurate diagnosis can spare patients unnecessary surgical procedures and is essential in the selection of the most effective chemotherapeutic regimen for them. The diagnosis is particularly challenging for pathologists when fine needle aspiration cytology or core needle biopsy is used because each technique provides only limited amounts of tissue. Needle biopsy may be applied particularly when the clinical diagnosis is locally advanced breast cancer. If the correct diagnosis of a secondary tumor is not made, then inappropriate neoadjuvant systemic therapy may be administered before further definitive surgical excision. We present the first case of metastasis to the breast from a medullary thyroid carcinoma (MTC) that was identified on FDG (18F-fluoro-2-deoxy-d-glucose) positron emission tomography with a description of histologic, immunohistochemical, and ultrastructural features. 2. Case history The patient was a 50-year-old woman. Her significant past clinical history included bilateral fibroadenomas
68
S. Nofech-Mozes et al. / Annals of Diagnostic Pathology 12 (2008) 67 – 71
diagnosed with core biopsy in 2002. In 2003, she presented with a right thyroid mass that was diagnosed as a Hqrthle cell neoplasm on fine needle aspiration. The frozen section revealed an MTC, and the patient was treated with total thyroidectomy without neck dissection. The thyroid tumor was unencapsulated and measured 2 cm. No angiolymphatic invasion was seen; however, a right parapharyngeal lymph node contained metastatic MTC. Two weeks after the operation, the patient complained of discomfort on her right upper neck; a postoperative computed tomographic scan demonstrated a soft tissue mass. This was diagnosed as an MTC on core needle aspiration. The residual disease was treated with external beam radiotherapy. Her serum calcitonin level however remained persistently elevated in the presence of repeated physical examinations that had unremarkable findings and computed tomographic scans of the neck and chest that had normal results. The results of a technetium sestamibi scan were negative. To investigate this further, we performed an FDG-PET; it revealed a 1.9-cm left upper inner-quadrant breast mass and 2 hepatic masses (Fig. 1). An ultrasound of the breast showed a hypoechoic irregular heterogeneous mass corresponding to the area of increased activity noted on the FDG-PET. The lesion was further evaluated by mammography, which demonstrated a dense indistinct lobulated mass measuring 3 cm. An ultrasound-guided core needle biopsy revealed a high-grade carcinoma, and the initial working diagnosis based on microscopic examination of hematoxylin-eosin sections alone was that of primary breast carcinoma. However, after further discussions with clinicians, we performed immunohistochemical studies, and the diagnosis of the core biopsy was that of a metastatic MTC. A palliative excisional biopsy was performed to control local pain and to prevent local progression of the disease.
Fig. 1. An FDG-PET computed tomographic scan image showing a focal FDG-avid left breast ovoid mass slightly superior and medial to the nipple. This demonstrates a peak standardized uptake value of 5.46.
Fig. 2. A representative section from the breast core biopsy specimen with a high-grade invasive tumor surrounding the nonneoplastic duct (original magnification 100).
Pathologic evaluation of the mass confirmed the diagnosis of metastatic MTC. The patient received 4 cycles of cisplatinum and doxorubicin with mild shrinkage of the liver lesions. She is alive but has a persistent disease confined to the liver 8 months after the diagnosis of breast and liver metastases. 3. Pathologic findings The excised tumor appeared grossly as a hard tan mass with ill-defined borders that measured 4 3.2 3 cm. A present discrete 1-cm nodule adjacent to the tumor grossly most resembled a fibroadenoma. The hematoxylin-eosin– stained section of the tumor showed clusters of neoplastic cells that were distributed haphazardly within the breast parenchyma surrounding intact ducts and lobules (Fig. 2). The neoplastic cells had a high nuclear-to-cytoplasmic ratio with irregular nuclear contours, vesicular chromatin, and single or multiple prominent nucleoli (Fig. 3). Occasional
Fig. 3. A high-power view illustrating marked nuclear pleomorphism. Note the atypical mitosis depicted (original magnification 400).
S. Nofech-Mozes et al. / Annals of Diagnostic Pathology 12 (2008) 67 – 71
69
Table 1 Antibodies used for immunohistochemistry and staining results Antibody
Clone
Source
Dilution
Staining in the tumor cells
Cytokeratin 7 Synaptophysin Chromogranin Calcitonin Thyroid transcription factor 1 Monoclonal carcinoembryonic antigen E-cadherin
OV-TL 12/30 27G12 Catalog no. A0430 Catalog no A576 8G7G3/1 Col-1 36
1:400 1:100 1:200 1:500 1:400 1:200 1:200
+++ +++ ++ +++ +++ ++ +++
ER PR HER2/neu
6F11 312 CB11 TAB 250
Dako, Glostrup, Denmark Vector, Burlingame, Calif Dako, Glostrup, Denmark Dako, Glostrup, Denmark Neuromarkers, Fremont, Calif Biomeda, San Jose, Calif BD Biosciences Pharmingen, Mississauga, ON, Canada Novocastra, New Castle, England Novocastra, New Castle, England Novocastra, New Castle, England Zymed, San Francisco, Calif
1:50 1:100 1:400 1:100
multinucleated cells were present. Mitoses were atypical and easily identified. The stroma was fibrotic and slightly eosinophilic with a few dystrophic calcifications present. Lymphovascular invasion was identified. These microscopic features were identical to those seen on the earlier core biopsy specimen. Congo red stain was negative for amyloid. Immunohistochemical studies performed on formalin-fixed and paraffin-embedded tissue sections (Table 1) showed that the neoplastic cells were positive for cytokeratin 7, synaptophysin, calcitonin (Fig. 4), chromogranin, monoclonal carcinoembryonic antigen, E-cadherin, and thyroid transcription factor 1. The neoplastic cells were negative for estrogen receptor (ER) and progesterone receptor (PR) expressions as well as for HER2/neu oncoprotein overexpression. This profile was identical to the patient’s primary thyroid tumor. Electron microscopy demonstrated tumor cells with multiple cytoplasmic dense-core secretory granules. Each granule was composed of a single membrane separated by a clear zone from an electron-dense central portion (Fig. 5). Small numbers of amyloid fibers were found on ultrastructural examination. The surrounding breast parenchyma showed a fibroadenoma and nonproliferative fibrocystic changes.
4. Discussion
Fig. 4. Positive calcitonin immunostaining in the tumor. The native breast ducts yielded negative results (original magnification 100).
Fig. 5. Electron microscopy demonstrating neurosecretory granules in the cytoplasm (original magnification 20 000).
Metastatic disease to the breast is uncommon; thus, it may not be considered in the differential diagnosis of breast tumors by clinicians and pathologists. A secondary tumor is especially difficult to diagnose in cases in which breast metastasis is the first manifestation of an occult extramammary malignancy. This occurs in approximately 25% of patients who have metastatic tumors to the breast [3]. Moreover, even in patients with a history of malignancy presenting with a single breast mass, a second primary breast lesion is always considered more probable than a metastasis. It is important to consider metastatic tumors in the differential diagnosis when the breast lesion has unusual clinical, radiologic, or pathologic features. At present, there is a lack of reliable and specific clinical or radiologic tests to indicate that a tumor is a metastasis rather than a primary lesion. Metastases to the breast are multifocal in 11% to 35% and bilateral in 26% of cases and may be accompanied by axillary lymph node involvement, features often seen in primary tumors as well [4]. The mammographic appearance of secondary tumors is as a
70
S. Nofech-Mozes et al. / Annals of Diagnostic Pathology 12 (2008) 67 – 71
well-circumscribed mass without spiculation. These lesions are often indistinguishable from primary breast cancer [5]. It has been suggested that lack of tumor-associated acoustic shadowing is a characteristic ultrasonographic feature of metastatic tumors in the breast [2]. In the current case, the patient’s breast lesion was initially imaged with FDG-PET. Recent studies [6-8] have found that this tool is useful in detecting recurrent or occult metastatic diseases in patients with MTC and anaplastic thyroid carcinoma, providing higher sensitivity (66%-100%) and specificity (79%-90%) as compared with conventional nuclear imaging methods. Nevertheless, the differentiation between a primary and a secondary malignancy cannot be based on the PET image. Given the lack of reliable noninvasive diagnostic tools, histologic diagnosis plays a major role in the distinction of primary from secondary breast tumors. A recent review of the literature listed the most common extramammary solid tumors that metastasize to the breast in order of frequency as lymphoma and malignant melanoma, followed by lung cancer, ovarian carcinoma, soft tissue sarcoma, gastrointestinal tumor, and genitourinary tumor [5]. Case reports of metastatic involvement from osteosarcoma, thyroid neoplasms, as well as cervical, vaginal, and endometrial carcinoma have been described in the literature. In view of the infrequency of primary breast cancer in men, the possibility of a metastasis should always be considered. The prostate is the most common primary source of metastatic tumors in the male breast. Based on a case series in 1973, the incidence of breast metastases from prostatic carcinoma was estimated at 5%; however, in that study, microscopic breast involvement was found in autopsies in approximately one fourth of the men with clinically diagnosed prostatic carcinoma [9]. Bartella et al [5] studied the radiologic-histologic correlation of metastatic tumors to the breast and estimated that approximately 4% of these originate from the thyroid. We are aware of 8 cases of MTC reported in the literature as case reports or as part of a series of secondary breast tumors, all occurring in women. In the present case, metastasis to the breast from an MTC was identified on FDG-PET. This imaging modality was selected for our patient because of her persistent elevated calcitonin level after treatment and the failure of other imaging modalities to detect a residual disease. It has been suggested that subdetectable tumoral foci are responsible for the unexplained high plasma tumor marker levels in patients [6]. One patient with breast metastasis from an MTC was mentioned among 36 patients with an MTC investigated by FDG-PET as a result of elevated calcitonin levels [6]. That patient had multiple bone and lymph node lesions detected using this modality. A biopsy of the breast mass confirmed the diagnosis of metastatic MTC; however, a pathologic description of this case is not available. Several histologic features warrant the consideration of metastasis to the breast. Multifocality, especially with an
unusual histologic pattern, should raise the possibility of a metastatic tumor being in place. One clue for a metastatic origin, as observed in our case, is that the metastatic tumors surround and displace ducts and lobules, which typically show little or no hyperplasia. The presence of an in situ carcinoma component would support a primary breast lesion. Care must be taken to distinguish true in situ carcinoma from metastatic lesions with confluent necrosis that may mimic comedo necrosis. In difficult cases, immunohistochemical markers such as smooth muscle myosin and p63 can be used to demonstrate a continuous myoepithelial layer surrounding the ductal structures of ductal carcinoma in situ, which would not be seen in metastatic lesions. Immunohistochemistry plays an important role in the accurate identification of metastatic lesions. Because the most common secondary breast tumors are lymphoma and melanoma, an initial panel of antibodies should be directed to exclude these lesions. Primary breast carcinomas are positive for cytokeratin 7, and those of ductal origin express E-cadherin. However, this latter characteristic is shared by diverse neoplasms, including those of thyroid origin, as in the case of our patient. The ER, PR, and HER2/neu are expressed in a subset of invasive breast carcinoma and in some other carcinomas; thus, their presence or absence cannot determine whether a breast neoplasm is of metastatic origin. The data regarding ER, PR, and HER2/neu expressions in MTCs, although based on a limited number of cases, suggest that MTCs are negative for ER and PR [10-12] expressions, at least by immunohistochemistry, as well as for HER2/neu oncoprotein overexpression and gene amplification. Recent studies reported that HER2/neu is overexpressed in approximately one third of papillary thyroid carcinomas [13] and in anaplastic thyroid carcinoma cell lines [14]. Neuroendocrine markers may be expressed by primary breast carcinomas with neuroendocrine differentiation and by various metastatic lesions, especially those of gastrointestinal origin, as well as by MTCs. Because no single immunohistochemical marker can specifically identify a primary breast lesion, we suggest that a panel of antibodies be selected based on each patient’s history and sex as well as the frequency of possible primaries. The role of ultrastructural studies in diagnostic histopathology is limited in the era of immunohistochemistry. Nevertheless, they have a role as an adjunct tool for diagnosis, as demonstrated in our case. Although repeated Congo red stains were negative for amyloid in our case, few amyloid fibers were identified using electron microscopy. In summary, breast metastases from extramammary malignancies are infrequent. Breast metastasis usually indicates a disseminated metastatic disease and a poor prognosis. This report illustrates the difficulties in diagnosing MTC metastatic to the breast. The source of the increased serum calcitonin level was unknown until FDGPET was used. A high level of suspicion based on the patient’s history in combination with a panel of immuno-
S. Nofech-Mozes et al. / Annals of Diagnostic Pathology 12 (2008) 67 – 71
histochemical markers, including calcitonin, pan-endocrine markers, and thyroid markers such as thyroid transcription factor 1, led to the correct diagnosis.
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