567331
research-article2015
IJSXXX10.1177/1066896914567331International Journal of Surgical PathologyWhite et al
Case Report
Periductal Stromal Sarcoma of the Breast With Liposarcomatous Differentiation: A Case Report With 10-Year Follow-up and Literature Review
International Journal of Surgical Pathology 2015, Vol. 23(3) 221–224 © The Author(s) 2015 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1066896914567331 ijs.sagepub.com
Sherrie Renee White, MD1, Louis J. Auguste, MD2, Hua Guo, MD2, and Tawfiqul Bhuiya, MD2
Abstract A biphasic tumor with features of benign ductal elements and a malignant stromal component that lacks the architecture of a phylloides tumor represents a diagnostic challenge. A 35-year-old woman presented with a painful mass located in the upper inner quadrant of the right breast. A biopsy revealed histologically that the tumor had a multinodular architecture with malignant spindle cells forming cuffs around multiple open benign ducts. No leaf-like architecture was present. In addition, liposarcomatous differentiation was seen in focal areas. Immunohistochemical staining showed positive for CD34, vimentin and CDK4, and negative for ER, PR, Her2/neu, CD10, CD117, p63, bcl-2, cytokeratin, and MDM2. A diagnosis of periductal stromal sarcoma with liposarcomatous differentiation was established. Following excision with mastectomy and adjuvant chemotherapy, the patient was disease-free for 10 years. To our knowledge, this is the first case report of periductal stromal sarcoma showing liposarcomatous differentiation. Keywords periductal stromal sarcoma, liposarcomatous differentiation, nonphylloides sarcoma of breast
Introduction Primary nonphylloides sarcomatous breast tumors are rare, accounting for less than 1% of breast malignancies.1 Angiosarcoma, undifferentiated high-grade pleomorphic sarcoma, stromal sarcoma, leiomyosarcoma, liposarcoma, and osteosarcoma have all been reported. The prognosis for breast sarcoma is poor, with 1 report showing 55% of patients developing recurrent disease and 43% of patients dying of the disease.1 The term periductal stromal sarcoma (PDSS) has been used synonymously with phylloides tumors, which were called periductal stromal tumors in most recent WHO Classification of Tumors of the Breast.2 However, studies suggested that PDSS should be defined as a distinct neoplasm.3 It is similar to phylloides tumor in that it is a biphasic tumor, but differs in the architecture. Additionally, in contrast to phylloides tumor, which appears to originate from the intralobular stroma, PDSS suggests an origin from the periductal stroma.3 Here, we present a case of PDSS with liposarcomatous differentiation.
Case Report This was a 35-year-old woman without a significant past medical history who complained of a right breast mass
with some pain for two months. She first noticed this mass in February 2004. She denied skin changes, nipple discharge, or adenopathy. The initial sonogram and mammogram in late March suspected a fibroadenoma at the 2 o’clock position, measuring 2 × 1.5 cm. Physical exam in mid-April showed a 4.4 × 3.3 cm mass at the same location. Fine-needle aspiration showed a proliferative fibrocystic condition without atypia, and mucoid-appearing extracellular substance was present. She had a remote history of fibroadenoma excision of right breast in 1984. There was no family history of breast cancer. A biopsy was then performed and she was found to have a mass located in the upper inner quadrant of the right breast that infiltrated the surrounding tissue at the lateral border and was adherent to the pectoralis major muscle. Given the histopathologic findings, a metastatic work up was ordered, 1
Jacobi Medical Center, Bronx, NY, USA Hofstra–North Shore Long Island Jewish School of Medicine, Hempstead, NY, USA 2
Corresponding Author: Tawfiqul Bhuiya, Anatomic Pathology Services, North Shore Long Island Jewish Health System, 6 Ohio Drive, Suite 202, Lake Success, NY 11042, USA. Email: [email protected]
222
Figure 1. Multiple nodules of atypical spindle cells forming cuffs around benign ducts with lack of leaf-like pattern. Multiple lymphoid aggregates were present (hematoxylin and eosin, 4×).
which included a computed tomography scan of the chest, abdomen, and pelvis; a positron emission tomography scan; and a bone scan, all negative for metastasis. Approximately one month later, the patient underwent a mastectomy with partial excision of the pectoralis major muscle, an axillary node dissection and breast reconstruction. All margins of resection were free of neoplastic tissue. After surgery, she received adjuvant chemotherapy with adriamycin and ifosfamide. No radiation was given. She is currently doing well without recurrence 10 years after presentation. Grossly, the tumor in the mastectomy specimen measured 10 × 6 × 2.5 cm with a pink-tan cut surface and illdefined borders. Microscopic low-power examination showed that the tumor involved only the stroma, with multiple nodules of atypical spindle cells forming cuffs around benign ducts. The nodules infiltrated into the adipose tissue coalescing at their interface. Multiple lymphoid aggregates were present (Figure 1). High power showed the stromal cells were large with hyperchromatic spindle shaped nuclei, multinucleation and atypical mitoses (>10/10 high-power field), surrounding open tubules and ducts (Figure 2). Adjacent to these areas were nests of atypical appearing lipoblasts in a myxoid matrix diagnostic of a liposarcoma (Figures 3 and 4). No leaf-like pattern was present. The remainder of the breast tissue contained non-proliferative fibrocystic changes and a fibroadenoma. The lymph nodes in the axilla were all negative for tumor. Immunohistochemistry showed the atypical spindle cells were positive for vimentin, patchy positivity for CD34, and negative staining for estrogen receptor (ER), progesterone receptor (PR), HER2, CD10, CD117, p63, Bcl-2, pan-keratin (AE1/AE3), and high molecular weight keratin (34BE12). The liposarcomatous component was positive for CDK4 and negative for MDM2.
International Journal of Surgical Pathology 23(3)
Figure 2. High power showed the stromal cells were large with hyperchromatic spindle-shaped nuclei, multinucleation and atypical mitoses (>10/10 high-power field), surrounding open tubules and ducts. (hematoxylin and eosin, 20×).
Figure 3. Focal nest of atypical lipoblasts in a myxoid matrix resembling a liposarcoma (hematoxylin and eosin, 20×).
Discussion Primary nonphylloides breast sarcomas are rare, accounting for less than 1% of breast malignancies.1 There is an extremely rare specific group of biphasic tumors that is devoid of the leaf-like growth pattern, but demonstrates cuffs of circumscribed periductal malignant spindle cell proliferation that infiltrates the surrounding adipose tissue. This type of tumor has come to be known as PDSS. It is differentiated from a stromal sarcoma due to the concentric growth of the tumor only around normal open ductal glands. In the past, periductal stromal tumor was a synonym for phylloides tumor.2 The largest report on this tumor was by Burga and Tavassoli,3 from the Armed Forces Institute of Pathology, who provided the criteria for the classification of PDSS.
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White et al
Figure 4. High power of multivacuolated lipoblasts with highly pleomorphic nuclei and atypical mitoses (hematoxylin and eosin, 40×).
These features included a predominantly spindle cell stromal proliferation of variable cellularity and atypia surrounding open tubules and ducts devoid of a phylloides pattern, one or multiple nodules separated by adipose tissue, stromal mitotic activity of >3/10 high-power fields, and stromal infiltration into surrounding breast tissue. Periductal stromal hyperplasia has similar features, but with a lesser degree of atypia, cellularity, and mitotic activity.3,4 So far, 25 cases of PDSS have been reported according to these criteria. The tumor sizes ranged from 0.2 to 6.5 cm, and patients ranged in age from 14 to 89 years (median age = 55.3 years).3-8 In the report by Burga and Tavassoli,3 immunohistochemistry showed an absence of nuclear staining for estrogen and progesterone receptors in the neoplastic spindle cells. Sixty percent showed diffuse, intense positivity for CD34 in the sarcomatous areas, 27% of cases were positive for CD117, and 2 cases were positive for HHF35.3 Our case showed positivity for vimentin, which supported the cells being of mesenchymal origin, patchy positive for CD34, but negative for CD117. The negativity of the tumor cells for p63, CD10, and cytokeratin excluded the possibility of a metaplastic carcinoma. In our case, areas of liposarcoma were present, which confirmed by CDK4 staining. To our knowledge, this is the first case report of PDSS, showing liposarcomatous differentiation. Studies have shown that similar to phylloides tumor, PDSS has a tendency for local recurrence when incompletely excised, and a potential to develop specific soft tissue sarcomas and even metastasis when showing more aggressive sarcomatous component.3 However, in present case, after 10-year follow-up, the patient is still disease free. The histology of one case with one or more presumable metastasis to the lungs 11 months later in the report by Burga and Tavassoli3 contained areas of angiosarcoma.
Heterologous elements such as liposarcoma, osteosarcoma, and chondrosarcoma have been found within malignant phylloides tumors.9 In phylloides tumors, the presence of heterologous elements is a sign of poor prognosis. Research by Cohn-Cedermark et al10 showed that the presence of stromal elements other than fibromyxoid tissue was 1 of 2 independent predicting factors of worse prognosis in phylloides tumors, the other being tumor necrosis. Additional cases need to be studied to determine whether this is true for patients with PDSS. In contrast to the other types of nonphylloides stromal tumors, PDSS is thought to have a better prognosis. Two out of 20 patients in the study by Burga and Tavassoli3 had recurrence of the tumor. One patient had probable metastasis to the lungs, but no biopsy was done for confirmation. The other patient had a recurrence 5 years later, which focally showed leaf-like formation suggesting that this tumor progressed to a phylloides tumor. These tumors are treated by surgical resection, primarily wide excision with clear margins, mastectomy being reserved for more extensive tumors like the one reported herein. Typically, these tumors do not metastasize to the regional lymph nodes and an axillary node dissection is not indicated, although a sentinel lymph node biopsy is indicated to stage the axilla. The role of chemotherapy or radiation in these cases is still under investigations.1,6 In a study by Blanchard et al,1 treating nonphylloides stromal tumors with adjuvant chemotherapy or radiation did not prolong disease-free survival or overall survival. In summary, the diagnosis of PDSS is based on the criteria established by the Armed Forces Institute of Pathology. Surgery with clear margins is important to prevent recurrence and possible progression. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Blanchard DK, Reynolds CA, Grant CS, Donohue JH. Primary nonphylloides breast sarcomas. Am J Surg. 2003;186:359-361. 2. Lakhani SR, Ellis IO, Schnitt SJ, Tan PH, van de Vijver MJ, eds. WHO Classification of Tumors of the Breast. Lyon, France: IARC Press; 2012. 3. Burga AM, Tavassoli FA. Periductal stromal tumor, a rare lesion with low-grade sarcomatous behavior. Am J Surg Pathol. 2003;27:343-348. 4. Tomas D, Janković D, Marusić Z, Franceschi A, Mijić A, Kruslin B. Low-grade periductal stromal sarcoma of the
224 breast with myxoid features: immunohistochemistry. Pathol Int. 2009;59:588-591. 5. Rao AC, Geetha V, Khurana A. Periductal stromal sarcoma of breast with lipoblast-like cells: a case report with review of the literature. Indian J Pathol Microbiol. 2008;51: 252-254. 6. Masbah O, Lalya I, Mellas N, et al. Periductal stromal sarcoma in a child: a case report. J Med Case Rep. 2011;5:249. 7. Caltabiano R, Magro G, Vecchio GM, Lanzafame S. Lowgrade periductal stromal sarcoma with marked sclera-elastosis. Pathology. 2011;43:509-510.
International Journal of Surgical Pathology 23(3) 8. Lan Y, Zhu J, Liu J, Yang H, Jiang Y, Wei W. Periductal stromal sarcoma of the breast: a case report and review of the literature. Oncol Lett. 2014;8:1181-1183. 9. Darryl C, Stuart JS, Rosemary RM. The breast. In: Mills SE, ed. Sternberg’s Diagnostic Surgical Pathology. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2010: 285-350. 10. Cohn-Cedermark G, Rutqvist LE, Rosendahl I, Silfversward C. Prognostic factors in cystosarcoma phyllodes. A clinicopathologic study of 77 patients. Cancer. 1991;68: 2017-2022.
Copyright of International Journal of Surgical Pathology is the property of Sage Publications Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
research-article2015
IJSXXX10.1177/1066896914567331International Journal of Surgical PathologyWhite et al
Case Report
Periductal Stromal Sarcoma of the Breast With Liposarcomatous Differentiation: A Case Report With 10-Year Follow-up and Literature Review
International Journal of Surgical Pathology 2015, Vol. 23(3) 221–224 © The Author(s) 2015 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1066896914567331 ijs.sagepub.com
Sherrie Renee White, MD1, Louis J. Auguste, MD2, Hua Guo, MD2, and Tawfiqul Bhuiya, MD2
Abstract A biphasic tumor with features of benign ductal elements and a malignant stromal component that lacks the architecture of a phylloides tumor represents a diagnostic challenge. A 35-year-old woman presented with a painful mass located in the upper inner quadrant of the right breast. A biopsy revealed histologically that the tumor had a multinodular architecture with malignant spindle cells forming cuffs around multiple open benign ducts. No leaf-like architecture was present. In addition, liposarcomatous differentiation was seen in focal areas. Immunohistochemical staining showed positive for CD34, vimentin and CDK4, and negative for ER, PR, Her2/neu, CD10, CD117, p63, bcl-2, cytokeratin, and MDM2. A diagnosis of periductal stromal sarcoma with liposarcomatous differentiation was established. Following excision with mastectomy and adjuvant chemotherapy, the patient was disease-free for 10 years. To our knowledge, this is the first case report of periductal stromal sarcoma showing liposarcomatous differentiation. Keywords periductal stromal sarcoma, liposarcomatous differentiation, nonphylloides sarcoma of breast
Introduction Primary nonphylloides sarcomatous breast tumors are rare, accounting for less than 1% of breast malignancies.1 Angiosarcoma, undifferentiated high-grade pleomorphic sarcoma, stromal sarcoma, leiomyosarcoma, liposarcoma, and osteosarcoma have all been reported. The prognosis for breast sarcoma is poor, with 1 report showing 55% of patients developing recurrent disease and 43% of patients dying of the disease.1 The term periductal stromal sarcoma (PDSS) has been used synonymously with phylloides tumors, which were called periductal stromal tumors in most recent WHO Classification of Tumors of the Breast.2 However, studies suggested that PDSS should be defined as a distinct neoplasm.3 It is similar to phylloides tumor in that it is a biphasic tumor, but differs in the architecture. Additionally, in contrast to phylloides tumor, which appears to originate from the intralobular stroma, PDSS suggests an origin from the periductal stroma.3 Here, we present a case of PDSS with liposarcomatous differentiation.
Case Report This was a 35-year-old woman without a significant past medical history who complained of a right breast mass
with some pain for two months. She first noticed this mass in February 2004. She denied skin changes, nipple discharge, or adenopathy. The initial sonogram and mammogram in late March suspected a fibroadenoma at the 2 o’clock position, measuring 2 × 1.5 cm. Physical exam in mid-April showed a 4.4 × 3.3 cm mass at the same location. Fine-needle aspiration showed a proliferative fibrocystic condition without atypia, and mucoid-appearing extracellular substance was present. She had a remote history of fibroadenoma excision of right breast in 1984. There was no family history of breast cancer. A biopsy was then performed and she was found to have a mass located in the upper inner quadrant of the right breast that infiltrated the surrounding tissue at the lateral border and was adherent to the pectoralis major muscle. Given the histopathologic findings, a metastatic work up was ordered, 1
Jacobi Medical Center, Bronx, NY, USA Hofstra–North Shore Long Island Jewish School of Medicine, Hempstead, NY, USA 2
Corresponding Author: Tawfiqul Bhuiya, Anatomic Pathology Services, North Shore Long Island Jewish Health System, 6 Ohio Drive, Suite 202, Lake Success, NY 11042, USA. Email: [email protected]
222
Figure 1. Multiple nodules of atypical spindle cells forming cuffs around benign ducts with lack of leaf-like pattern. Multiple lymphoid aggregates were present (hematoxylin and eosin, 4×).
which included a computed tomography scan of the chest, abdomen, and pelvis; a positron emission tomography scan; and a bone scan, all negative for metastasis. Approximately one month later, the patient underwent a mastectomy with partial excision of the pectoralis major muscle, an axillary node dissection and breast reconstruction. All margins of resection were free of neoplastic tissue. After surgery, she received adjuvant chemotherapy with adriamycin and ifosfamide. No radiation was given. She is currently doing well without recurrence 10 years after presentation. Grossly, the tumor in the mastectomy specimen measured 10 × 6 × 2.5 cm with a pink-tan cut surface and illdefined borders. Microscopic low-power examination showed that the tumor involved only the stroma, with multiple nodules of atypical spindle cells forming cuffs around benign ducts. The nodules infiltrated into the adipose tissue coalescing at their interface. Multiple lymphoid aggregates were present (Figure 1). High power showed the stromal cells were large with hyperchromatic spindle shaped nuclei, multinucleation and atypical mitoses (>10/10 high-power field), surrounding open tubules and ducts (Figure 2). Adjacent to these areas were nests of atypical appearing lipoblasts in a myxoid matrix diagnostic of a liposarcoma (Figures 3 and 4). No leaf-like pattern was present. The remainder of the breast tissue contained non-proliferative fibrocystic changes and a fibroadenoma. The lymph nodes in the axilla were all negative for tumor. Immunohistochemistry showed the atypical spindle cells were positive for vimentin, patchy positivity for CD34, and negative staining for estrogen receptor (ER), progesterone receptor (PR), HER2, CD10, CD117, p63, Bcl-2, pan-keratin (AE1/AE3), and high molecular weight keratin (34BE12). The liposarcomatous component was positive for CDK4 and negative for MDM2.
International Journal of Surgical Pathology 23(3)
Figure 2. High power showed the stromal cells were large with hyperchromatic spindle-shaped nuclei, multinucleation and atypical mitoses (>10/10 high-power field), surrounding open tubules and ducts. (hematoxylin and eosin, 20×).
Figure 3. Focal nest of atypical lipoblasts in a myxoid matrix resembling a liposarcoma (hematoxylin and eosin, 20×).
Discussion Primary nonphylloides breast sarcomas are rare, accounting for less than 1% of breast malignancies.1 There is an extremely rare specific group of biphasic tumors that is devoid of the leaf-like growth pattern, but demonstrates cuffs of circumscribed periductal malignant spindle cell proliferation that infiltrates the surrounding adipose tissue. This type of tumor has come to be known as PDSS. It is differentiated from a stromal sarcoma due to the concentric growth of the tumor only around normal open ductal glands. In the past, periductal stromal tumor was a synonym for phylloides tumor.2 The largest report on this tumor was by Burga and Tavassoli,3 from the Armed Forces Institute of Pathology, who provided the criteria for the classification of PDSS.
223
White et al
Figure 4. High power of multivacuolated lipoblasts with highly pleomorphic nuclei and atypical mitoses (hematoxylin and eosin, 40×).
These features included a predominantly spindle cell stromal proliferation of variable cellularity and atypia surrounding open tubules and ducts devoid of a phylloides pattern, one or multiple nodules separated by adipose tissue, stromal mitotic activity of >3/10 high-power fields, and stromal infiltration into surrounding breast tissue. Periductal stromal hyperplasia has similar features, but with a lesser degree of atypia, cellularity, and mitotic activity.3,4 So far, 25 cases of PDSS have been reported according to these criteria. The tumor sizes ranged from 0.2 to 6.5 cm, and patients ranged in age from 14 to 89 years (median age = 55.3 years).3-8 In the report by Burga and Tavassoli,3 immunohistochemistry showed an absence of nuclear staining for estrogen and progesterone receptors in the neoplastic spindle cells. Sixty percent showed diffuse, intense positivity for CD34 in the sarcomatous areas, 27% of cases were positive for CD117, and 2 cases were positive for HHF35.3 Our case showed positivity for vimentin, which supported the cells being of mesenchymal origin, patchy positive for CD34, but negative for CD117. The negativity of the tumor cells for p63, CD10, and cytokeratin excluded the possibility of a metaplastic carcinoma. In our case, areas of liposarcoma were present, which confirmed by CDK4 staining. To our knowledge, this is the first case report of PDSS, showing liposarcomatous differentiation. Studies have shown that similar to phylloides tumor, PDSS has a tendency for local recurrence when incompletely excised, and a potential to develop specific soft tissue sarcomas and even metastasis when showing more aggressive sarcomatous component.3 However, in present case, after 10-year follow-up, the patient is still disease free. The histology of one case with one or more presumable metastasis to the lungs 11 months later in the report by Burga and Tavassoli3 contained areas of angiosarcoma.
Heterologous elements such as liposarcoma, osteosarcoma, and chondrosarcoma have been found within malignant phylloides tumors.9 In phylloides tumors, the presence of heterologous elements is a sign of poor prognosis. Research by Cohn-Cedermark et al10 showed that the presence of stromal elements other than fibromyxoid tissue was 1 of 2 independent predicting factors of worse prognosis in phylloides tumors, the other being tumor necrosis. Additional cases need to be studied to determine whether this is true for patients with PDSS. In contrast to the other types of nonphylloides stromal tumors, PDSS is thought to have a better prognosis. Two out of 20 patients in the study by Burga and Tavassoli3 had recurrence of the tumor. One patient had probable metastasis to the lungs, but no biopsy was done for confirmation. The other patient had a recurrence 5 years later, which focally showed leaf-like formation suggesting that this tumor progressed to a phylloides tumor. These tumors are treated by surgical resection, primarily wide excision with clear margins, mastectomy being reserved for more extensive tumors like the one reported herein. Typically, these tumors do not metastasize to the regional lymph nodes and an axillary node dissection is not indicated, although a sentinel lymph node biopsy is indicated to stage the axilla. The role of chemotherapy or radiation in these cases is still under investigations.1,6 In a study by Blanchard et al,1 treating nonphylloides stromal tumors with adjuvant chemotherapy or radiation did not prolong disease-free survival or overall survival. In summary, the diagnosis of PDSS is based on the criteria established by the Armed Forces Institute of Pathology. Surgery with clear margins is important to prevent recurrence and possible progression. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Blanchard DK, Reynolds CA, Grant CS, Donohue JH. Primary nonphylloides breast sarcomas. Am J Surg. 2003;186:359-361. 2. Lakhani SR, Ellis IO, Schnitt SJ, Tan PH, van de Vijver MJ, eds. WHO Classification of Tumors of the Breast. Lyon, France: IARC Press; 2012. 3. Burga AM, Tavassoli FA. Periductal stromal tumor, a rare lesion with low-grade sarcomatous behavior. Am J Surg Pathol. 2003;27:343-348. 4. Tomas D, Janković D, Marusić Z, Franceschi A, Mijić A, Kruslin B. Low-grade periductal stromal sarcoma of the
224 breast with myxoid features: immunohistochemistry. Pathol Int. 2009;59:588-591. 5. Rao AC, Geetha V, Khurana A. Periductal stromal sarcoma of breast with lipoblast-like cells: a case report with review of the literature. Indian J Pathol Microbiol. 2008;51: 252-254. 6. Masbah O, Lalya I, Mellas N, et al. Periductal stromal sarcoma in a child: a case report. J Med Case Rep. 2011;5:249. 7. Caltabiano R, Magro G, Vecchio GM, Lanzafame S. Lowgrade periductal stromal sarcoma with marked sclera-elastosis. Pathology. 2011;43:509-510.
International Journal of Surgical Pathology 23(3) 8. Lan Y, Zhu J, Liu J, Yang H, Jiang Y, Wei W. Periductal stromal sarcoma of the breast: a case report and review of the literature. Oncol Lett. 2014;8:1181-1183. 9. Darryl C, Stuart JS, Rosemary RM. The breast. In: Mills SE, ed. Sternberg’s Diagnostic Surgical Pathology. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2010: 285-350. 10. Cohn-Cedermark G, Rutqvist LE, Rosendahl I, Silfversward C. Prognostic factors in cystosarcoma phyllodes. A clinicopathologic study of 77 patients. Cancer. 1991;68: 2017-2022.
Copyright of International Journal of Surgical Pathology is the property of Sage Publications Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
