Masood, Shahla MD; Davis, Cindy MD, MEd; Kubik, Melanie J. MD
Department of Pathology and Laboratory Medicine, College of Medicine-Jacksonville, University of Florida, Jacksonville, FL
The authors have no funding or conflicts of interest to disclose.
Reprints: Shahla Masood, MD, Department of Pathology and Laboratory Medicine, College of Medicine-Jacksonville, University of Florida, 655W, 8th Street, Jacksonville, FL 32209 (e-mail: firstname.lastname@example.org).
Papillary lesions of the breast continue to be a diagnostic challenge because of the wide morphologic spectrum that may be encountered in these lesions. A rare entity termed “breast tumor resembling the tall cell variant of papillary thyroid carcinoma” is considered to be a subtype of papillary carcinoma of the breast. It is characterized by distinct morphologic features, setting it apart from typical papillary carcinoma of the breast. Its resemblance to papillary thyroid carcinoma in conjunction with the established terminology may cause confusion, resulting in unnecessary ancillary studies to exclude the association of this lesion with papillary thyroid carcinoma. As immunohistochemical and molecular studies have shown no evidence to support any association between this entity and papillary thyroid carcinoma, we propose to change the current terminology of “breast tumor resembling the tall cell variant of papillary thyroid carcinoma” to the term “tall cell variant of papillary breast carcinoma.”
We recently encountered a case exemplifying the features of a “breast tumor resembling the tall cell variant of papillary thyroid carcinoma.” A 57-year-old woman with a 3-cm mass with pleomorphic microcalcifications in her left breast detected on screening mammography underwent diagnostic mammogram with targeted ultrasound showing a well-circumscribed, hypoechoic structure with mixed posterior shadowing and enhancement and increased vascularity (Fig. 1). The patient underwent core needle biopsy and the diagnosis of malignancy was established, leading to mastectomy.
Serial sectioning of the specimen revealed a well-circumscribed, firm tumor with a tan cut surface. Microscopically, the lesion showed a papillary architecture composed of tightly packed papillae with delicate fibrovascular stalks and abundant psammoma bodies (Fig. 2A). On higher magnification, the epithelial cells had a tall columnar configuration with granular eosinophilic cytoplasm, nuclear clearing, nuclear grooving, and stratification with palisading orientation along the basal pole of the cells (Figs. 2B, C), reminiscent of papillary thyroid carcinoma. Mitoses were readily appreciated (Fig. 2D). The lesion was positive for estrogen receptor and progesterone receptor, and negative for HER2/neu oncogene, thyroid transcription factor-1 (TTF-1), and thyroglobulin (Figs. 2E, F). All 14 lymph nodes within the specimen were negative for tumor. This lesion was diagnosed as “tall cell variant of papillary breast carcinoma.”
“Breast tumor resembling the tall cell variant of papillary thyroid carcinoma” was first reported in 2003 by Eusebi et al1 as a series of 5 cases of a breast lesion characterized by histologic features similar to those of the tall cell variant of papillary thyroid carcinoma. Subsequent immunostaining for TTF-1 and thyroglobulin as well as molecular studies for mutations of the RET protooncogene were negative.1,2 Since then, 6 additional cases of this entity have been reported,3–5 which were also negative for TTF-1 and thyroglobulin. Molecular studies performed on a case reported by Cameselle-Teijeiro et al3 were negative for BRAF mutations.
In general, these lesions can present as palpable nodules in the breast or they may be found on screening mammography with associated microcalcifications. On fine-needle aspiration cytology, the specimens are highly cellular, consisting of papillary groups or sheets as well as isolated cells with atypia, nuclear grooves, and cytoplasmic invaginations, or pseudoinclusions.3 Grossly, the tumors are well-circumscribed with a firm, tan-white cut surface. Histologically they strongly resemble papillary thyroid carcinoma. There may be areas of invasion, mucinous differentiation, and apocrine metaplasia. Immunostaining for thyroid-specific antigens and molecular studies for RET rearrangements typically found in papillary thyroid carcinoma are consistently negative. Estrogen receptor and progesterone receptor stains are variably positive (Table 1).
The reported cases of “breast tumor resembling the tall cell variant of papillary thyroid carcinoma” were all characterized by histologic features typically seen in papillary thyroid carcinoma. The characteristic eosinophilic cytoplasm found in these breast tumors is a reflection of the presence of abundant mitochondria.1 Of note, it has been reported that mitochondria-rich tumors of the breast are of indolent biological nature.1 Reported clinical follow-up of up to 9 years revealed that the majority of patients diagnosed with this variant of papillary breast carcinoma were alive and well (Table 1).1,4,5 Two patients had metastatic disease: 1 patient had both lymph node and bone metastasis3; the other patient was found to have metastasis to an intramammary lymph node.4 Both of these cases were stage pT2 tumors. Other reported cases had even larger primary lesions without evidence of metastasis.1,4,5 These findings suggest that the prognosis of this entity may be similar to that of classical papillary carcinoma of the breast.
Hameed et al6 demonstrated that the presence of architectural and cytologic features characteristic of papillary thyroid carcinoma are not limited to the reported cases of “breast tumor resembling the tall cell variant of papillary thyroid carcinoma,” but that one or more of these features may be found in classical papillary carcinoma of the breast, supporting the concept that this lesion is a variant of papillary carcinoma of the breast.
In papillary thyroid carcinoma, the typical clear nuclei are due to sparse chromatin secondary to the activation of the RET/PTC oncogene, which is a rearranged form of the RET gene.2 Molecular studies have shown that despite the morphologic resemblance to papillary thyroid carcinoma, the RET gene in these breast tumors is not rearranged, indicating that these breast tumors are genetically distinct.6 Other commonly found mutations in papillary thyroid carcinomas involve the BRAF gene.7 Considering that RET/PTC rearrangements and BRAF mutations are mutually exclusive pathogenetic events in papillary thyroid carcinomas, Cameselle-Teijeiro et al3 searched for evidence of BRAF mutation in their case of “breast tumor resembling the tall cell variant of papillary thyroid carcinoma” but found none.
Despite the small number of cases studied, the reported data suggest that the molecular mechanisms leading to the distinct picture of clear nuclei with grooves and pseudoinclusions in papillary breast carcinoma may be different from the molecular mechanisms leading to these features in papillary thyroid carcinoma, thus suggesting that there is no association between the tall cell variant of papillary breast carcinoma and the tall cell variant of papillary thyroid carcinoma, despite their morphologic resemblance.
Because the breast is not an uncommon site for metastatic tumors and 5% of these metastases are of thyroid origin,8 metastatic thyroid carcinoma is often considered in the differential diagnosis when encountering these features in a breast lesion. This trend of thinking has led to routinely ordering several thyroid-specific immunostains to exclude the possibility of metastatic thyroid lesions to the breast. However, as repeated immunohistochemical and molecular studies have failed to show any association between this lesion and papillary thyroid carcinoma, we believe that we need to consider this lesion as a primary breast carcinoma and delete the words “thyroid carcinoma” from the terminology of this tumor. This approach will eliminate the need for further ancillary studies and reduce the unnecessary financial burden to the patient. This is particularly important when there is no clinical and/or imaging evidence of primary thyroid carcinoma.
We therefore propose to rename the breast lesion “Tall cell variant of papillary breast carcinoma” to eliminate confusion about its association with papillary thyroid carcinoma and simplify the terminology surrounding this rare entity.
1. Eusebi V, Damiani S, Ellis IO, et al. Breast tumor resembling the tall cell variant of papillary thyroid carcinoma. Am J Surg Pathol. 2003;27:1114–1118
2. Eusebi V, Tallini G, Rosai J. Nuclear alterations and RET/PTC activation. Am J Surg Pathol. 2004;28:974–975
3. Cameselle-Teijeiro J, Abdulkader I, Barreiro-Morandeira F, et al. Breast tumor resembling the tall cell variant of papillary thyroid carcinoma: a case report. Int J Surg Pathol. 2006;14:79–84
4. Tosi A, Ragazzi M, Asioli S, et al. Breast tumor resembling the tall cell variant of papillary thyroid carcinoma: report of 4 cases with evidence of malignant potential. Int J Surg Pathol. 2007;15:14–19
5. Chang SY, Fleiszer DM, Mesurolle B, et al. Breast tumor resembling the tall cell variant of papillary thyroid carcinoma. Breast J. 2009;15:531–535
6. Hameed O, Perry A, Banerjee R, et al. Papillary carcinoma of the breast lacks evidence of RET rearrangements despite morphological similarities to papillary thyroid carcinoma. Mod Pathol. 2009;22:1236–1242
7. Trovisco V, Vieira De Castro I, Soares P, et al. BRAF
mutations are associated with some histological types of papillary thyroid carcinoma. J Pathol. 2004;202:247–251
8. Fiche M, Cassagnau E, Aillet G, et al. Breast metastasis from a “tall cell variant” of papillary thyroid carcinoma. Ann Pathol. 1998;18:130–132
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