Sarcomatoid Variant of Salivary Duct Carcinoma Clinicopathologic and Immunohistochemical Study of Eight Cases With Review of the Literature

Anatomic Pathology / SARCOMATOID SALIVARY DUCT CARCINOMA Sarcomatoid Variant of Salivary Duct Carcinoma Clinicopathologic and Immunohistochemical Study of Eight Cases With Review of the Literature Toshitaka Nagao, MD, 1* Thomas A. Gaffey, MD, 1 Hiromi Serizawa, MD, 2 Keiichi Iwaya, MD, 2 Akinori Watanabe, CT, IAC, 2 Tomoyuki Yoshida, MD, 3 Kazuto Yamazaki, MD, 4 Masato Sageshima, MD, 5 and Jean E. Lewis, MD 1 Key Words: Carcinosarcoma; p53; Parotid gland; Salivary duct carcinoma; Salivary gland; Sarcomatoid carcinoma DOI: 10.1309/5J4008QRY1HWW5W4 Abstract Salivary duct carcinoma (SDC) is an uncommon, high-grade tumor. We present 8 cases of sarcomatoid SDC, which has been defined recently as a rare variant of SDC. The 8 patients (5 men, 3 women) had a mean age of 63.6 years. Histologically, all tumors were characterized by a biphasic neoplasm composed of both SDC and sarcomatoid elements. In 3 cases, sarcomatoid components showed osteosarcomatous heterologous differentiation. A residual pleomorphic adenoma was detected in 5 tumors. The sarcomatoid component showed focal immunoreactivity for cytokeratin in 4 cases and epithelial membrane antigen in all 8 cases. Diffuse p53 immunostaining was detected in 3 cases, and it was coexpressed in both components. Our observations support the histogenetic theory of a common origin of the carcinomatous and sarcomatoid populations. Of the 13 patients, including our 8, reported to have sarcomatoid SDC arising in a major salivary gland and for whom long-term follow-up data were available, 7 have died of disease (mean survival, 15.6 months). These results indicate that sarcomatoid SDC is a highly aggressive tumor, similar to conventional SDC. Salivary duct carcinoma (SDC) is an uncommon, distinctive, high-grade malignant tumor that arises predominantly in a major salivary gland. 1-3 Kleinsasser et al 4 originally described this entity in 1968, and it was included in the second version of the World Health Organization classification of salivary gland tumors. 5 Histologically, SDC bears a striking resemblance to ductal carcinoma of the breast, with intraductal and invasive components. The intraductal component is described as a cribriform, papillary, or solid growth pattern, often with comedolike central necrosis. The invasive carcinoma consists of irregular glands and cords of cells that frequently elicit a prominent desmoplastic reaction. SDC can occur de novo or as the malignant component of carcinoma ex pleomorphic adenoma. 6 Several histologic variants of SDC have been described, including documentation of their biologic behavior. 7-9 Sarcomatoid SDC has been defined recently as one of these variants, characterized histologically by a biphasic neoplasm with SDC and sarcomatoid elements. 9 Although only 4 cases have been reported as sarcomatoid SDC, 9,10 we have identified several additional cases that were termed carcinosarcoma or true malignant mixed tumor in earlier reports. 11-17 The clinicopathologic and immunohistochemical characteristics of these tumors have not been well defined. In the present study, we documented the clinicopathologic and immunohistochemical features of 8 cases of sarcomatoid SDC. In addition, we attempted to clarify the diagnostic criteria of this neoplasm and its possible histogenesis. Materials and Methods We identified 8 cases of the sarcomatoid variant of SDC from the pathology files of Mayo Clinic, Rochester, MN 222 Am J Clin Pathol 2004;122:222-231 222 DOI: 10.1309/5J4008QRY1HWW5W4

Anatomic Pathology / ORIGINAL ARTICLE (cases 1-3), and Tokyo Medical University Hospital, Tokyo, Japan (case 4), and the consultation files of the authors (T.N., cases 5 and 6; J.E.L., cases 7 and 8). The 8 cases fulfilled the criteria for sarcomatoid SDC defined by Henley et al, 9 except for the presence of heterologous differentiation in several of our cases. Tumor tissue samples were fixed in 10% buffered formalin, processed by routine histologic techniques, and stained with H&E. From the slides available for each case, the percentage of carcinomatous and sarcomatoid zones in the primary lesion was estimated semiquantitatively and expressed as a percentage of the surface area involved. Clinical details and follow-up data were obtained when possible from medical records, referring pathologists, and treating physicians. Formalin-fixed, paraffin-embedded tissue samples from the primary tumors were available for immunohistochemical staining in 7 of 8 cases. In 1 case, only the recurrent sarcomatoid neoplasm was available for this analysis. The deparaffinized and rehydrated slides were stained immunohistochemically using the labeled streptavidin-biotin peroxidase method with an automated immunostainer (Ventana, Tucson, AZ). To enhance immunostaining, a heat epitope retrieval procedure or enzyme digestion method was performed. The primary antibodies used are listed in Table 1. The antigen-antibody reaction was visualized with the chromogen 3,3'-diaminobenzidine. The sections were lightly counterstained with hematoxylin. The cases were regarded as positive for HER-2/neu when staining of the membrane or of both the membrane and cytoplasm was positive in more than 10% of tumor cells. A lesion was considered p53-positive when more than 10% of tumor cell nuclei showed strong reactivity. The percentage of Ki-67 positive cells was determined by counting at least 1,000 tumor cells, and the value was recorded as the Ki-67 labeling index. Results Clinical Findings The clinicopathologic features of the sarcomatoid variant of SDC are summarized in Table 2. The 8 patients (5 men, 3 women) had a mean age of 63.6 years (range, 42-82 years). In 7 cases, sarcomatoid SDC involved the parotid gland, and in 1 case, the tumor arose in the submandibular gland. The mean size of the tumors was 3.4 cm (range, 1.5-6.0 cm). All patients underwent total sialoadenectomy as the initial treatment, except 1 patient who underwent superficial parotidectomy. Neck dissection was performed in 4 patients, 2 of whom had cervical lymph node metastases. Postoperatively, 5 patients received radiotherapy. Pathologic Findings Microscopically, all tumors formed a solitary mass in the salivary gland and had a dimorphic pattern of carcinomatous and sarcomatoid components Image 1. The proportion of each component within the tumor varied from case to case, with the sarcomatoid areas predominating in 6 cases (Table 2). In all cases, carcinomatous elements were characteristic of SDC and resembled ductal carcinoma of the breast, with a cribriform ( Roman bridge ), papillary, or solid growth pattern Image 2A. Frequently, the central portion of the cell clusters showed comedo-like necrosis, and sometimes a scirrhous growth pattern was observed Image 2B. Table 1 Antibodies Used in the Study Antigen (Antibody) Source Clonality Dilution Cytokeratin (AE1/AE3) Zymed, San Francisco, CA M 1:200 Cytokeratin (CAM5.2) Becton Dickinson, San Jose, CA M 1:50 Cytokeratin (34βE12) DAKO, Carpinteria, CA M 1:10 Cytokeratin 7 DAKO M 1:100 Wide-spectrum screening keratin DAKO P 1:800 Epithelial membrane antigen DAKO M 1:20 α-smooth muscle actin DAKO M 1:150 Calponin DAKO M 1:100 S-100 protein DAKO P 1:800 Vimentin DAKO M 1:500 Desmin DAKO M 1:100 CD68 (KP-1) DAKO M 1:200 BRST-2 (GCDFP-15) Signet Laboratories, Dedham, MA M 1:200 Carcinoembryonic antigen DAKO M 1:50 Androgen receptor Novocastra, Newcastle upon Tyne, England M 1:20 Estrogen receptor Ventana, Tucson, AZ M 1:150 Progesterone receptor Ventana M 1:50 p53 (DO7) DAKO M 1:200 HER-2/neu Novocastra M 1:50 Ki-67 (MIB-1) DAKO M 1:400 GCDFP-15, gross cystic disease fluid protein 15; M, monoclonal; P, polyclonal. Am J Clin Pathol 2004;122:222-231 223 223 DOI: 10.1309/5J4008QRY1HWW5W4 223

Nagao et al / SARCOMATOID SALIVARY DUCT CARCINOMA Table 2 Clinicopathologic Features of Sarcomatoid Salivary Duct Carcinoma Tumor Proportion (%) Case No./ Heterologous Residual Therapy for Cervical LN Sex/Age (y) Site Size (cm) CC SC Elements PA Initial Tumor Metastasis Outcome 1/M/52 P 2.5 20 80 No No TP + RND + Rx No NED at 13 y 3 mo 2/M/69 P 1.5 60 40 No No TP + RND + Rx Yes DOD at 21 mo with mediastinal LN, brain, and bone metastases 3/M/73 P 3.0 10 80 Yes Yes SP + Rx No Locally recurred at 16 mo; NED 2 mo later 4/M/65 P 6.0 40 60 No No TP + RND + Rx Yes NED at 18 mo 5/F/66 P 3.0 30 70 No Yes TP + RND No NED at 22 mo 6/M/60 P 5.0 10 90 Yes Yes TP Yes Recurred in the cervical LNs at 18 and 22 mo; NED 12 mo later 7/F/42 S 3.0 70 30 No Yes TG + Rx No DOD at 19 mo 8/F/82 P 3.0 20 80 Yes Yes TP NA Lost to follow-up CC, carcinomatous component; DOD, died of disease; LN, lymph node; NA, not available; NED, no evidence of disease; P, parotid gland; PA, pleomorphic adenoma; RND, radical neck dissection; Rx, radiotherapy; S, submandibular gland; SC, sarcomatoid component; SP, superficial parotidectomy; TG, total glandectomy; TP, total parotidectomy. Image 1 Sarcomatoid salivary duct carcinoma. Low-power view of the tumor shows a biphasic feature with carcinomatous (left) and sarcomatoid (right) components (H&E, 40). The tumor cells exhibited marked atypia, with eosinophilic cytoplasm and prominent nucleoli. Apocrinelike metaplasia sometimes was seen when cells displayed a papillary intracystic arrangement. However, sarcomatous elements were composed of highly atypical spindle cells arranged in a fascicular manner Image 3A. In every case, scattered multinucleated, malignant bizarre cells also were observed among the spindle cells Image 3B. In 1 case (case 4), rhabdoid tumor cells characterized by an abundance of eosinophilic cytoplasm and eccentric nuclei were identified focally Image 3C. Some myxoid areas were present in 2 cases (cases 5 and 6) Image 3D. Of 8 cases, 3 had heterologous malignant osteoid deposition, extensively (case 3) or focally (cases 6 and 8) Image 3E. Osteoclastlike giant cells were seen among the tumor cells in 1 case (case 2) Image 3F. Although the carcinomatous and sarcomatoid components usually were distinct, a transitional zone was recognized between them in all cases Image 4. The metastatic lymph nodes available for review contained biphasic neoplasm in 1 of 3 cases and monophasic neoplasm, either carcinomatous or sarcomatoid tumor, in the other 2. Remnants of a pleomorphic adenoma were identified in 5 of 8 cases (cases 3, 5-8) Image 5. The results of immunohistochemical staining are given in Table 3. All carcinomatous components that we examined stained diffusely for cytokeratins (AE1/AE3, CAM5.2, and 7) Image 6A, wide-spectrum screening keratin, and epithelial membrane antigen (EMA) Image 6B, but they were negative for cytokeratin 34βE12 in 2 of 7 cases. In comparison, sarcomatoid cells expressed immunoreactivity for cytokeratins AE1/AE3 and 34βE12 in 4 of 8 cases and for cytokeratin 7 or wide-spectrum screening keratin in 3 of 7 cases, and the expression pattern usually was focal (Image 6A). Sarcomatoid components in every case were negative for cytokeratin CAM5.2 but expressed EMA in all cases, although the immunoreactivity often was focal (Image 6B). Although no cytokeratin-positive cells were identified in a sarcomatoid component with heterologous malignant osteoid formation, no significant differences in the EMA staining pattern were noted between cases with and cases without the heterologous elements. 224 Am J Clin Pathol 2004;122:222-231 224 DOI: 10.1309/5J4008QRY1HWW5W4

Anatomic Pathology / ORIGINAL ARTICLE A B Image 2 Carcinomatous component of sarcomatoid salivary duct carcinoma showing cribriform pattern with central comedolike necrosis (A, H&E, 400) and scirrhous pattern of growth (B, H&E, 400). Note carcinoma cells exhibiting eosinophilic cytoplasm and prominent nucleoli. α-smooth muscle actin, S-100 protein, and desmin were expressed in 1 case each, restricted to the sarcomatoid cells. In 2 cases, calponin-positive tumor cells were observed only in the sarcomatoid component. Rhabdoid-like cells were positive for EMA but negative for desmin and S-100 protein. Vimentin was always expressed in the sarcomatoid area and was focally positive in the carcinomatous area in 2 of 7 cases Image 6C. Osteoclast-like giant cells were positive for CD68 (KP-1). Carcinomatous cells in 6 of 7 cases were positive for BRST-2 (gross cystic disease fluid protein [GCDFP]- 15) Image 6D and carcinoembryonic antigen, whereas sarcomatoid areas were largely negative for these markers, except for 2 cases focally positive for BRST-2 (GCDFP-15). Androgen receptor protein was expressed only in carcinomatous areas in 4 of 6 cases Image 6E, whereas focal immunoreactivity for estrogen receptor protein and progesterone receptor protein was seen in 1 case each in the carcinomatous area. Strong membranous immunoreactivity for HER-2/neu was detected only in the carcinomatous component of 4 of 7 cases. Diffuse nuclear p53 immunostaining was detected in 3 of 7 cases, and the positive immunoreactivity was concordant in both carcinomatous and sarcomatoid components Image 6F. Typically, many tumor cells expressed Ki-67 (MIB-1), and the Ki-67 labeling index was higher in the sarcomatoid component than in the carcinomatous component in 6 of 7 cases. Follow-up Data Clinical follow-up information was available for 7 of 8 patients. Postoperatively, 1 patient had local recurrence of the tumor. Metastatic lesions occurred in cervical and mediastinal lymph nodes postoperatively in 1 case each. Distant organ metastasis developed in 2 patients, who died of disease at 19 and 21 months after the initial diagnosis. Discussion Some issues about the diagnostic criteria and nomenclature for the entity sarcomatoid SDC are controversial, especially its distinction from carcinosarcoma. Neoplasms composed of both malignant epithelial and mesenchymal components are designated as carcinosarcomas in the World Health Organization classification of the salivary gland tumors. 5 Carcinosarcoma, also referred to as true malignant mixed tumor, is a very rare neoplasm that can occur de novo or arise in a preexisting pleomorphic adenoma. 18,19 Heterologous elements, such as malignant bone and cartilage, often are seen in the mesenchymal components of these tumors. 18,19 Carcinomatous elements in carcinosarcoma often are called ductal carcinoma, 20 which is used as an equivalent term for more precisely designated high-grade adenocarcinoma, not otherwise specified (NOS) of salivary gland origin. True SDC histologically mimics intraductal carcinoma of the breast with a high nuclear grade and of solid, cribriform, or papillary type. In our review of the carcinosarcoma literature, we found cases with ductal carcinoma, a term used for high-grade adenocarcinoma, NOS, or applied to an insufficiently described tumor. 18,21-24 Other examples fulfilled the criteria of true SDC Table 4. 11-17 In 2000, Henley et al 9 reported 3 cases of SDC that contained malignant spindle cell Am J Clin Pathol 2004;122:222-231 225 225 DOI: 10.1309/5J4008QRY1HWW5W4 225

Nagao et al / SARCOMATOID SALIVARY DUCT CARCINOMA A B C D E F Image 3 Variation of sarcomatoid components in sarcomatoid salivary duct carcinoma. A, Fascicular pattern of spindle cells (H&E, 400). B, Several multinucleated, bizarre giant neoplastic cells (H&E, 400). C, Rhabdoid cells with abundant eosinophilic cytoplasm and eccentric nuclei (H&E, 400). D, Myxoid stroma (H&E, 400). E, Lace-like malignant osteoid formation (H&E, 400). F, Scattered osteoclast-like giant cells (H&E, 400). 226 Am J Clin Pathol 2004;122:222-231 226 DOI: 10.1309/5J4008QRY1HWW5W4

Anatomic Pathology / ORIGINAL ARTICLE Image 4 Transitional zone between carcinomatous and sarcomatoid elements in sarcomatoid salivary duct carcinoma (H&E, 400). Image 5 Preexisting pleomorphic adenoma element with myxoid stroma (left) and carcinomatous element of sarcomatoid salivary duct carcinoma (right) (H&E, 400). Table 3 Immunohistochemical Results for Sarcomatoid Salivary Duct Carcinoma Case No. 1 2 3 * 4 5 6 7 8 Antigen (Antibody) CC SC CC SC SC CC SC CC SC CC SC CC SC CC SC Cytokeratin (AE1/AE3) + F+ + F+ + F+ + + + F+ + Cytokeratin (CAM5.2) + + + + + + + Cytokeratin (34βE12) + F+ + F+ + + + F+ + Cytokeratin 7 + F+ + F+ + ND ND + + F+ + Wide-spectrum screening keratin + + F+ F+ + ND ND + + F+ + Epithelial membrane antigen + F+ + + F+ + + + F+ + F+ + F+ + F+ α-smooth muscle actin F+ Calponin ND ND + + S-100 protein F+ Vimentin F+ + + + + + F+ + F+ + Desmin F+ BRST-2 (GCDFP-15) + + F+ + F+ + + F+ Carcinoembryonic antigen + + + F+ + + Androgen receptor + + + ND ND + Estrogen receptor ND ND ND F+ Progesterone receptor ND ND ND F+ p53 (DO7) + + + + ND + + HER-2/neu + ND + + + Ki-67 (MIB-1), % 40.8 52.5 32.3 38.5 ND 25.2 33.1 10.6 39.6 47.1 62.4 80.7 49.6 11.2 44.2 CC, carcinomatous component; F, focally; GCDFP-15, gross cystic disease fluid protein-15; ND, not done; SC, sarcomatoid component; +, positive;, negative. * For case 3, only the recurrent lesion, which represented the sarcomatoid component, was available for immunohistochemical examination. elements; the authors designated these neoplasms sarcomatoid SDC. However, heterologous elements were not identified in these cases. 9 In the present study, we used the term sarcomatoid SDC to designate biphasic neoplasms with or without heterologous differentiation, provided that the carcinomatous components fulfilled the criteria for true SDC. The histogenesis of carcinosarcoma in various organs has been addressed, 25,26 but the articles provided little information specifically about salivary gland carcinosarcoma. Accumulated ultrastructural, immunohistochemical, and molecular evidence supports a monoclonal nature for carcinosarcoma in general. 25-30 Our 8 cases of sarcomatoid SDC showed concordance of p53 expression in both carcinomatous and sarcomatoid components, supporting a monoclonal origin of these tumors. 28 We established a more detailed immunoprofile for sarcomatoid SDC by using antibodies against a wide Am J Clin Pathol 2004;122:222-231 227 227 DOI: 10.1309/5J4008QRY1HWW5W4 227

Nagao et al / SARCOMATOID SALIVARY DUCT CARCINOMA A B C D E F Image 6 Immunohistochemical analysis of sarcomatoid salivary duct carcinoma. A and B, Diffuse and focal immunoreactivity is shown in carcinomatous (left) and sarcomatous (right) components, respectively (A, cytokeratin [AE1/AE3], 400; B, epithelial membrane antigen, 400). C, Vimentin is expressed diffusely in the sarcomatoid element (right) but is negative in the carcinomatous element (left) ( 400). D and E, Carcinomatous components are strongly positive for BRST-2 (gross cystic disease fluid protein-15) (D, 400) and androgen receptor (E, 400). F, Strong nuclear p53 immunoreactivity is observed in both carcinomatous (upper portion) and sarcomatous (lower portion) cells ( 400). 228 Am J Clin Pathol 2004;122:222-231 228 DOI: 10.1309/5J4008QRY1HWW5W4

Anatomic Pathology / ORIGINAL ARTICLE Table 4 Reported Cases Regarded as Sarcomatoid Salivary Duct Carcinoma Tumor Heterologous Residual Cervical LN Reference Sex/Age(y) Site Size(cm) Original Diagnosis Elements PA Treatment Metastasis Outcome Talmi et al, 11 1990 M/76 P 1.5 True malignant No No TP + Rx No NED at 11 mo mixed tumor Bleiweiss et al, 12 1992 M/64 S 2.0 Carcinosarcoma Yes No TG No Recurred at 7 mo Grenko et al, 13 1993 F/66 P 5.0 Carcinosarcoma Yes No TP Yes DOD at 13 mo with pulmonary metastases Carson et al, 14 1995 F/51 P 5.5 Carcinosarcoma Yes No TP No Recurred at 7 mo; DOD 2 mo later Alvarez-Canas and F/86 P 9.5 Carcinosarcoma Yes Yes TP + No DOD at Rodilla, 15 1996 (true malignant (chondrosarcoma) RND 8 mo with local mixed tumor) recurrence Henley et al, 9 2000 M/56 P 1.5 Sarcomatoid SDC No No SP + Rx NA NED at 12 mo M/68 P 3.5 Sarcomatoid SDC No No TP + NA DOD at 36 mo RND with pulmonary metastases M/70 P 1.5 Sarcomatoid SDC No No TP + NA NED at 7 mo RND + Rx Sironi et al, 16 2000 M/77 P 8.0 Carcinosarcoma Yes No TP + Yes DOD at 3 mo RND with metastatic disease Pang et al, 17 2001 M/37 P 4.0 Carcinosarcoma Yes No TP + No NED at 36 mo (malignant mixed (chondrosarcoma) RND tumor) Ide et al, 10 2003 F/45 O 1.5 Sarcomatoid SDC No No Wide No NED at 11 y excision DOD, died of disease; LN, lymph node; NA, not available; NED, no evidence of disease; O, oral minor salivary gland; P, parotid gland; PA, pleomorphic adenoma; RND, radical neck dissection; Rx, radiotherapy; S, submandibular gland; SDC, salivary duct carcinoma; SP, superficial parotidectomy; TG, total glandectomy; TP, total parotidectomy. range of epithelial and mesenchymal markers to better understand the histogenesis of these tumors. Generally, the carcinomatous and sarcomatoid elements were diffusely immunoreactive for cytokeratin and vimentin, respectively. However, the sarcomatoid elements also expressed epithelial markers by showing occasional staining for cytokeratin and consistent, focal positivity for EMA. Similar observations have been reported for previous cases of sarcomatoid SDC. 9,10 Our immunohistochemical data in 8 cases of the sarcomatoid variant of SDC, with or without heterologous elements, support the concept of mesenchymal differentiation in conventional SDC histology. Several investigators have suggested that sarcomatoid carcinoma or metaplastic carcinoma is a more appropriate designation than carcinosarcoma. 25,26,31,32 Although the term carcinosarcoma is widely used for biphasic carcinomatous and mesenchymal neoplasms in the field of salivary gland pathology, we recommend the term sarcomatoid variant of SDC (sarcomatoid SDC) instead of carcinosarcoma when the carcinomatous component of those lesions is SDC and the term sarcomatoid carcinoma, NOS for lesions in which the carcinoma component is not a distinct type of tumor. Rarely, sarcomatoid features also have been described in other distinct types of salivary gland carcinoma, including mucoepidermoid carcinoma, 33 acinic cell carcinoma, 34 squamous cell carcinoma, 35,36 and epithelial-myoepithelial carcinoma. 37 Because metaplasia, by definition, is a reversible change in which one adult cell type is replaced by another adult cell type, 38 we believe that metaplastic carcinoma is an inappropriate term to designate biphasic carcinomatous and mesenchymal neoplasms. In addition, the term metaplastic carcinoma is used only in reference to the breast, and the term sarcomatoid carcinoma seems to be widely and properly used for such a tumor in other organs. 25,39 Furthermore, in the breast, the term metaplastic carcinoma has been used to encompass several different and apparently unrelated neoplastic conditions such as ductal carcinoma with squamous differentiation and adenosquamous carcinoma. 39 For these reasons and to prevent ambiguity, we propose use of the term sarcomatoid carcinoma instead of metaplastic carcinoma in reference to the salivary glands. In our series of sarcomatoid SDC sarcomatoid cells expressed calponin in 2 cases and α-smooth muscle actin and S-100 protein in 1 case each; thus, some sarcomatoid SDC might exhibit a myoepithelial differentiation. Evidence of a myoepithelial phenotype also has been reported in similar tumors of the breast but not of other organs. 39,40 Histologically, carcinomatous elements of our cases showed features specific for SDC, ie, proliferation of pleomorphic carcinoma cells with eosinophilic cytoplasm and Am J Clin Pathol 2004;122:222-231 229 229 DOI: 10.1309/5J4008QRY1HWW5W4 229

Nagao et al / SARCOMATOID SALIVARY DUCT CARCINOMA prominent nucleoli and cribriform (so-called Roman bridge) or solid growth patterns accompanied by comedo necrosis. 1-5 Immunohistochemically, the carcinoma elements in our cases showed frequent positivity for carcinoembryonic antigen, BRST-2 (GCDFP-15), and androgen receptor and only rare expression of estrogen receptor and progesterone receptor, features of conventional SDC. 41,42 The loss or lack of expression of BRST-2 and androgen receptor in the sarcomatoid component of sarcomatoid SDC observed in the present study might indicate that some molecular changes related to these proteins are associated with a sarcomatoid differentiation. Five (63%) of 8 cases of sarcomatoid SDC in our series and 6 (32%) of the 19 cases reported in the literature 9,11-17 (and including our cases) arose from a preexisting pleomorphic adenoma. These rates of occurrence are higher than those reported (up to 14%) for conventional SDCs in the review by Barnes et al. 2 SDCs arising in a preexisting pleomorphic adenoma might be more prone to undergo sarcomatoid change than de novo SDCs. However, because only a small number of cases have been examined, additional case studies are necessary to determine whether this is true. Sarcomatoid SDC must be distinguished from several neoplasms. The differential diagnosis includes collision tumors and hybrid carcinomas. 31,43 Collision tumors, a fusion of 2 malignant neoplasms arising from independent topographic sites, lack a transitional zone, which commonly is found in sarcomatoid SDC. 31 Rarely, a hybrid carcinoma consisting of SDC and myoepithelial carcinoma has been reported. 43 Because myoepithelial carcinoma can exhibit spindle cell morphologic features and occasionally can have chondromatous features, 44 this tumor should be distinguished from sarcomatoid SDC. However, myoepithelial carcinomas do not show osteosarcomatous heterologous differentiation. Negative results for the expression of α-smooth muscle actin, calponin, and S-100 protein in our cases, which lacked osteosarcomatous differentiation, might exclude the possibility of myoepithelial carcinoma, which usually is positive for these markers. 44 In our 8 cases and the previously reported 11 cases that we regarded as sarcomatoid SDC, this rare neoplasm affected 12 men and 7 women, who had a mean age of 63.4 years (range, 37-86 years). 9-17 The tumors developed preferentially in major salivary glands, especially the parotid gland. The mean tumor size was 3.7 cm (range, 1.5-9.5 cm). Treatment usually consisted of total glandectomy (16 cases), accompanied by radical neck dissection (9 cases) and radiotherapy (8 cases). A residual pleomorphic adenoma was found in 6 of 19 cases. Histologically, 9 of 19 cases exhibited heterologous elements, often osteosarcoma. Cervical lymph node and distant metastases were observed in 5 of 15 cases. Of 17 patients with sarcomatoid SDC arising in the major salivary glands for whom follow-up was available, 7 died of disease at 3 to 36 months (mean, 15.6 months) after the initial diagnosis. 9,11-17 Although the 5-year survival rate and median survival time of sarcomatoid SDC (32.6% and 21 months, respectively; n = 13) 9,11-17 seemed to be somewhat less and shorter than those of conventional SDC (39.1% and 52 months, respectively; n = 48), in our institution (Mayo Clinic), the difference between them in overall survival was not significant (P =.307; log-rank test). These data indicate that sarcomatoid SDC has a highly aggressive behavior, similar to that of conventional SDC. 1,2 From the 1 Division of Anatomic Pathology, Mayo Clinic, Rochester, MN; the Departments of 2 Surgical Pathology and 3 Otolaryngology, Tokyo Medical University Hospital, Tokyo, Japan; 4 Department of Surgical Pathology, Teikyo University Ichihara Hospital, Ichihara, Japan; and 5 Department of Pathology, Akita City Hospital, Akita, Japan. Address reprint requests to Dr Gaffey: Division of Anatomic Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. * Dr Nagao is a visiting clinician in the Division of Anatomic Pathology. References 1. Brandwein MS, Jagirdar J, Patil J, et al. Salivary duct carcinoma (cribriform salivary carcinoma of excretory ducts): a clinicopathologic and immunohistochemical study of 12 cases. Cancer. 1990;65:2307-2314. 2. Barnes L, Rao U, Krause J, et al. Salivary duct carcinoma, part I: a clinicopathologic evaluation and DNA image analysis of 13 cases with review of the literature. Oral Surg Oral Med Oral Pathol. 1994;78:64-73. 3. Lewis JE, McKinney BC, Weiland LH, et al. Salivary duct carcinoma: clinicopathologic and immunohistochemical review of 26 cases. Cancer. 1996;77:223-230. 4. Kleinsasser O, Klein HJ, Hübner G. Salivary duct carcinoma: a group of salivary gland tumors analogous to mammary duct carcinoma [in German]. Arch Klin Exp Ohren Nasen Kehlkopfheilkd. 1968;192:100-105. 5. Seifert G, Sobin LH. Histological Typing of Salivary Gland Tumours. 2nd ed. Berlin, Germany: Springer-Verlag; 1991. World Health Organization International Histological Classification of Tumours. 6. Lewis JE, Olsen KD, Sebo TJ. Carcinoma ex pleomorphic adenoma: pathologic analysis of 73 cases. Hum Pathol. 2001;32:596-604. 7. Delgado R, Klimstra D, Albores-Saavedra J. Low grade salivary duct carcinoma: a distinctive variant with a low grade histology and a predominant intraductal growth pattern. Cancer. 1996;78:958-967. 8. Simpson RH, Prasad AR, Lewis JE, et al. Mucin-rich variant of salivary duct carcinoma: a clinicopathologic and immunohistochemical study of four cases. Am J Surg Pathol. 2003;27:1070-1079. 9. Henley JD, Seo IS, Dayan D, et al. Sarcomatoid salivary duct carcinoma of the parotid gland. Hum Pathol. 2000;31:208-213. 230 Am J Clin Pathol 2004;122:222-231 230 DOI: 10.1309/5J4008QRY1HWW5W4

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