958 Low Grade Salivary Duct Carcinoma A Distinctive Variant with a Low Grade Histology and a Predominant Intraductal Growth Pattern Ruby Delgado, M.D.’ David Klimstra, M.D.’ Jorge Albores-Saavedra, M.D.’ Division of Anatomic Pathology, Department of Pathology. University of Texas Southwestern Medical Center, Dallas, Texas. * Department of Pathology, Memorial SloanKettering Cancer Center, New York, New York. BACKGROUND. Salivary duct carcinoma (SDC) has been established as a morphologically distinct and highly aggressive (HG)malignancy of the major salivary glands. However, a low grade (LG) or intermediate grade salivary duct neoplasm has not been described. METHODS. We report the clinicopathologic findings of 10 cases believed to represent the (1.G) counterpart of SDC. lrnmunoperoxidase stains were performed on tive cases, and electron microscopy o i l three. RESULTS. hll of the tumors occurred in adult patients with no sex predilection, and presented as slow growing parotid gland lesions. Four cases involved the superficial lobe, one the deep lobe, and one arose within an intraparotid lymph node. The exact location of the tumor within the parotid gland was not stated in four cases. The size of the tumors ranged from 0.7 to 4 cm in greatest dimension, with most measuring between 1 and 2 cni. 1he gross appearance was focally to predominantly cystic. Microscopically, the tumors were characterized by intraductal proliferative lesions exhibiting three main patterns: (1) cystic ducts with micropapillaq, tufted, and plaque-like intralurninal projections; (2) ducts distended by a solid or pseudocribriform (fenestrated) cellular proliferation, with varied cystic dilatation; and (3) ducts exhibiting architectural atypia. The three patterns coexisted arid merged in most tumors, in varying proportions. All tumors shared bland to LG cytologic features, with the exception of one that had focal high-grade cytologic ductal atypia. Despite gross circumscription, there was microscopic multifocality, and in one case, stromal invasion. By immunohistochemistry the neoplastic cells expressed the conventional ductal and glandular epithelial cell markers in addition to strong positivity for S-100 with coexpression for CK-903. Electron microscopy contirmrd the ductal phenotype of the tumors and supported an in situ process evidenced by the presence of native myoepitlielial cells. Nine patients underwent total parotidectoniy and one superficial parotidectorny. One patient received radiation therapy following total parotidecotmy. Follow-up for 6 cases ranged from 2 to 12 years and revealed no evidence of disease. CONCLUSIONS. LG-SDC represents the LG end of the spectrum of salivary duct malignant neoplasms anti exhibits differentiation towards an intercalated ductlike cell phenotype. Its relationship to 1IG-SL)C should be Purther explored. Cancer 1996; 78:958-67. 0 I996 American Curicer Society. The authors thank Mrs. R. Nelly Murillo for her assistance in the preparation of this manuscript. KEYWORDS salivary gland, duct carcinoma, low grade, high grade, immunohistochemistry, electron microscopy. Address for reprints: Ruby Delgado, M.D., Department of Pathology, University of Texas Southwestern Medical Ctr., 5323 Harry Hines Blvd., Dallas. TX 75235-9072. A Received February 16, 1996; revision received May 23, 1996; accepted June 3, 1996. c) 1996 American Cancer Society lthough the histomorphogenesis of some salivary gland neoplasms remains unclarified, the term salivary duct carcinoma (SDC) has been restricted to tumors composed predominantly or exclusively of ductal cells with the formation of structures resembling distended salivary ducts. In most instances SDC has been recognized by its striking resemblance to mammary duct carcinoma. To date Low Grade Salivary Duct Carcinoma/Delgado et al. TABLE I Immunohistouhemical Findings in Five Cases of LG-SDC No. of immunoreactive CaSeS Pattern of immunoreactivity S-100 protein 3 membranous > cytoplasmic diffusea; i menibrdnous > cpoplasniic diffusea: 4 t14+* luniinal diffuse; 7 c c p p l a s m i c focahpocrine metaplastic cells; A + nuclear & ryoplasmic diffiise"''; SM!\ 1 Antibody - T-4 cytoplasmic limited to myoepithelial cells; - 4 959 In one case fresh tissue was fixed in glutaraldehyde and routinely processed for transmission electron microscopic examination. Selected tumoral tissue was retrieved from paraffin embedded blocks in the other two cases. The tissue was processed following deparaffinization in xylene and rehydration through graded ethanol solutions. All tumors were examined in a JEOL 1200 electron microscope (JEOL Ltd., Tokyo, Japan). CLINICAL FINDINGS A clinical summary of all cases is provided in Table 2. PATHOLOGIC FINDINGS + I.G-SI)C: lowgradi s a l i g dutr carcinoma; pCE4: polyclonal carcinoenibryonic anrign; CCIEP gross c!\rir d i w w lluij prorein; !N\: smoorh muscle spPrific aciin Inrludrr yacuol;i[rd c~lls. liitl:itle(i some of [he n y q i ~ h e l i a (ells. l Snurtv & I)iluunrl: (:\iokeraun Cnm 5.2 (Hecron-[)ickinson. \,luun[ain View. CAiPrediluredi: Cvokeraiiii \lA(IOJ ; E m lhgnoslicr Inc. Srw York, NI':I:?Ol: pCE4 il)ako Corporalion. Carpinierta. CNI:40;; HEY-?hignrt :abiiralorie, Inc, Dcdhani. S1hil:IOOi; S-I00 prolein :Dako Corporaiion, Carpinreria, C4i1.300!, 5\19 6ignia Ihgnosrics, Sr. 1.ouir. MOil:100i. only a high grade SIX has been recognized, showing the characteristic in situ and invasive growth phases.'." During our review of SDCs we encountered tumors characterized by the proliferation of salivary duct structures and exhibiting ductal differentiation (by light microscopy, immunohistochemistry, and electron microscopy), but lacking both the aggressive morphologic features and clinical behavior of the high grade S I X W e believe these tumors represent the low grade end of the spectrum of salivary duct malignancies. MATERIALS AND METHODS Four cases were accrued in consultation. A fifth case was retrieved from the surgical pathology files of Parkland Memorial Hospital in Dallas, Texas, and the remaining five from the surgical patholoby files of Memorial Hospital in New York, New York. Clinical information and follow-up data were provided by the referring physicians in three cases and from the patients' charts in four cases; three patients were lost to follow-up. Routine hematoxylin and eosin stained sections were examined. Additional sections from all cases were prepared for histochemical, periodic acidSchiff (PAS), and mucicarmine, and immunohistochemical analysis. Immunostains were performed using the standard avidin-biotin peroxidase method. Commercially available antibodies were used with appropriate controls (Table 1). Microscopically, the tumors were characterized by a heterogeneous intraductal proliferative process with three dominant patterns or components: (1) cystically dilated ducts exhibiting partial to circumferential intracystic micropapillary and tufted formations focally anastomosing and coalescing into solid plaque-like epithelial stratification (Figs. IA-C). The micropapillae were composed of cuboidal to small columnar cells exhibiting conspicuous intracytoplasmic microvacuoles which increased in number from base to lumen and were accompanied by a fine granular yellowbrown pigment. In its fullest expression the cells were filled and distended by sharply outlined minute vacuoles causing indentation of the nucleus and accentuation of the cytoplasmic rim, resulting in scallopshaped micropapillae (Figs. 2A, B). Better developed papillae with fibrotic fibrovascular cores and psammoma bodies were also present. In the nonproliferative areas the cysts were lined by a simple apocrine epithelium showing attenuation and squamous metaplasia. (2) Ducts distended by solid, pseudocribriform (fenestrated) or solid-papillary ductal proliferation (Fig. 3A). The cells comprising these neoplastic ducts were ovoid to cuboidal with dense pale to bright eosinophilic cytoplasm, indistinct cell borders, and oval nuclei with finely dispersed chromatin and pinpoint nucleoli. Foci of apocrine metaplasia were also seen (Fig. 313, inset). The cells were arranged in a somewhat loose to overlapping fashion forming solid sheets or slit-like to irregular luminal spaces or fenestrae resulting in a pseudocribriform appearance (Fig. 38). The spaces contained basophilic mucin alternating with hyaline colloid-like material. Many of the ducts showed cystic dilatation in varying degrees and were filled by basophilic mucin. This cystic change was accompanied occasionally by the intracytoplasmic microvacuolar change previously described. Other ducts had a solid-papillary appearance consisting of solid sheets traversed by delicate fibrovascular cores. (3) Ducts displaying conventional architectural atypia, spanning the entire range of mild to severe (Fig. 4). All 960 CANCER September 1,1996 I Volume 78 I Number 5 TABLE 2 Clinicopathologic Findings in Ten Patients with Low Grade Salivary Duct Carcinoma Case # Age (yrs)/sex Location Size Original diagnosis Treatment Follow-up 1 58iM 62iF 32iF 63\11! i4iM Parotid [superficial lobe; Parotid I cni 0.7 rni 1.1 ciii 1.3 ciii 1.8 ciii I cni 1.2 ciii 4 cni 0.9 cm 0.8 cm Lowgrade papillocystic adeiiocarriiioma Papillocystic carcinoma Acinic cell carcinoma; positive margins Aciiiic cell carcinoma Aciiiic ceil carcinoma Acinic cell carcinoma Superficialparotidectomy Parotidectomy Parotidectomy,radiotherapy Parotidectomy Parotidectomy Parotidectomy Parotideclomy Parotidectomy Parotidectomy Parotidectomy,radiotherapy - ? 3 4 J 6 I n 9 in 56iF 4?/M 69iF 69 / M 52iF Right parotid (superfiria! lobe) Right parotid (superficial lobel Left parotid Right parotid Left parorid (superficial lobe) Right parotid (intraparotid lymph node1 I.eR parotid Right parotid (deep lobe) LG-SDC LG-SDC LG-SDC LG-SDC with focal invasion; positive margins NED at 12 yrs NED at I 1 yrs NED at 6 17s NED at 2 yrs NED at 2 ITS NED a1 2 )rs NED at 9 mos NED: no evidence of disease; LG-SDC: low gade salivary duct carcinoma, FIGURE 1. Papillocystic pattern of low grade salivary duct carcinoma. (A) Delicate filigreed intracystic micropapillae with psamrnoma body rnicrocalcification (arrow). (8) Anastornosing micropapillae. (C) Mural tufting. three patterns coexisted and merged in most tumors in varying proportions and combinations. (The first pattern was observed in 100% of the cases, the second in 90%, and the third in 60%). In the cases where a large cyst dominated the histologic picture, the other two components were found in a pericystic arrangement and focally communicating with the major cyst. All tumors were nonencapsulated but somewhat circumscribed by a dense sclerotic stroma exhibiting secondary changes such as remote hemorrhage, choles- Low Grade Salivary Duct CarcinomalDelgado et al. 961 FIGURE 2. Intracytoplasrnic vacuolar change in papillocystic low grade salivary duct carcinoma. (A) Transition from apocrine-like cells to vacuolated cells, with progressive accumulation of intracytoplasmic microvacuoles. (B) Vacuolated ductal cells are filled and distended by nonmernbrane bound lipid droplets, anG show surface microvilli. terol granulomas, and dystrophic calcification. Also bordering the tumors was a marked lymphoid infiltrate (Fig. I , bottom). Despite the apparent circumscription of the tumors, detached tumor foci were seen in the surrounding glandular parenchyma (Fig. 5), best interpreted as niultifocality, and in one case, stromal microinvasion (Fig. CiB) was noted disclosing its malignant potent ial. Onc tumor was remarkable for having originated in an intraparotid lymph node, extending beyond it into the immediate parotid parenchyma and surrounding but not invading peripheral nerve branches. Mitotic activity was negligible in most cases, nonatypical mitotic figures being identified in two cases. Mucicarrnine and PAS stains highlighted the matctrial in intercellular spaces, with no intracytoplasmic niiicin positivity observed. No PAS-positive diastase resistant material suggestive of zymogen granules could be identified. Large PAS-diastase positive granules were present but confined to foci of apocrine me t a pl asia. Immunoperoxidase studies revealed the expected reactivity to conventional epithelial markers (Table 1). Of significance, however, was the strong nuclear and cytoplasmic positivity for S-100 protein (Fig. 7) and the cytoplasmic positivity for the high molecular weight cytokeratin (3413E12 or MA903). All three morphologic components exhibited similar immunostaining patterns, and encompassed the vacuolated and nonvacuolated cells. In addition, smooth muscle actin outlined the ductal proliferative lesions in a pattern indicative of a myoepithelial layer of pre-existing ducts involved by an intraductal neoplastic proliferation (Fig. 8A). Similarly, collagen type IV antibodies circled the neoplastic ducts. Immunoreactivity for antibodies to GCDFP-15, observed in two cases, correlated with foci of apocrine metaplasia. Ultrastructurally, the tumors were composed of ductal cells with interdigitating cell membranes forming intercellular lumina and bound by a continuous basal lamina. The ductal cells displayed apical microvilli and contained a modest number of organelles, except for occasional cells showing an increased number of mitochondria. Also identified in a peripheral or basal location were myoepithelial cells with long attenuated cytoplasmic prolongations (Fig. 8B). The vacuolated cells were characterized as plump ductal cells distended by what appeared as coalescing empty nonmembrane bound spaces in some cells and lipid droplets in others. These caused significant indentation of the nuclei and displaced the cytoplasmic organelles to a subplasmalemmal location (Fig. 2 R ) . DISCUSSION We report ten cases of a tumor which conforms to the cytoarchitectural definition of a salivary duct neoplasm (composed primarily of ductal luminal cells with formation of distended salivary duct structures), that, to our knowledge, has not been previously characterized as such. Because it exhibits a bland histomorphology and has thus far demonstrated a favorable behavior, we propose the term “low grade salivary duct carcinoma” (IG-SDC). 962 CANCER September 1,1996 / Volume 78 / Number 5 FIGURE 3. (A) Classic pseudocribriform pattern of low grade salivary duct carcinoma (B) Proliferating ductal cells show somewhat overlapping oval nuclei and indistinct cytoplasmic cell borders. Irregular intercellular spaces are filled with hyaline material. Focus of apocrine rnetaplasia (inset). In contrast to its aggressive counterpart, the high grade salivary duct carcinoma (HG-SDC), better known for its reiterated similarity to breast duct carcinoma (mainly comedo type),’-6LG-SDC spans an appearance reminiscent of florid to atypical ductal hyperplasia to low grade intraductal breast carcinoma (Table 3). Based on the accumulated experience with HG-SDC,’-6 salivary duct neoplastic proliferations have demonstrated a more aggressive behavior than their morphologic counterparts in the breast. This apparent organ-specificity may be related to underlying structural differences (i.e., regional anatomy or glandular microanatomy), to biologic differences (i.e., hormonal regulation), andlor to inherent tumor proper- Low Grade Salivary Duct CarcinomalDelgado et al. FIGURE 4. Architectural (cribriform) atypia in low grade duct salivary duct carcinoma. Spaces are filled with basophilic mucin. FIGURE 5. Isolated focus of low grade salivary duct carcinoma in adjacent parotid parenchyma (arrow), suggestive of multifocality. ties. The terminology applied to the ductal proliferations of the salivary glands should reflect these differences. Therefore, we propose the term “lowgrade salivary duct carcinoma” for the range of distinctive lesions we are describing. We acknowledge them as being pijrt of a morphologic continuum in salivary duct neoplasia. Progression was evidenced by the acquisition of a higher cytologic grade and focal microinvasion, observed in one case (Fig. 6A, B). The entities lo be considered in the differential diagnosis of LG-SDC vary from those of the HG-SDC. In those cases having a dominant cystic papillary component, LG-SDC has been often confused with papil- 963 lary-cystic acinic cell carcinoma (ACC).An additional feature shared by both entities and a likely source of confusion is the presence of vacuolated cells. Historically, vacuolated cells have been described as being unique to ACC.“’,’ They are reported to be observed in about one-third of the ACC and are the predominant cell type in a minority of the tumors. The nature of the vacuolated cells has not been elucidated. Several explanations have been postulated, including a retrogressive change in the zymogen granules and, the presence of dilated and distended profiles of rough endoplasmic reticulum (RER).’ Notwithstanding their elusive nature, the vacuolated cells in ACC are characterized by large cells with wispy or reticulated cytoplasm containing a single vacuole having the appearance of an intracytoplasmic pseudolumen or several macrovacuoles that coalesce into microcystic spaces (Fig. 9B). Conversely, LG-SDC shows fine vacuolation consisting of crowded punched-out microvacuoles having a somewhat refractile quality (Fig. 2A). These microvacuoles are associated with a pale yellowbrown pigment and are thus akin to the supravacuoles that have been reported to characterize and identify apocrine epithelium.” Another distinctive feature of apocrine epithelium is the presence of apical glycolipid granules,9 which were also identified in LG-SDC both by PAS-D and by electron microscopy. Conversely, in none of the tumors examined by light microscopy, histochemistry, or electron microscopy could acinar differentiation be documented. Failure to recognize LG-SDC as a distinct entity may also stem from the cellular composition of the ACC, alleged to be the result of a combination of five individual cell acinar, and its clear cell variant,12 nonspecific glandular, intercalated duct-like, and vacuolated. Such heterogeneity has been explained by its origin in or differentiation towards the terminal duct-acinar nit.^,'" Of the five cell types mentioned, only the nonspecific glandular and intercalated duct-like cells are the likely constituents of the LG-SDC. That is, LG-SDC appears to be the manifestation of a n entirely ductal proliferation/differentiation without the concomitant acinar component, whereas the latter by definition is expressed in the papillarycystic ACC. It is important to mention that tumors composed exclusively of intercalated duct-like cells have been documented; however, they have been reported as ACC on the basis of their papillary-cystic morphologic pattern.” Whereas, conceivably, a morphologic continuum may exist between papillary-cystic ACC and LG-SDC, we believe that in the majority of cases reproducible distinguishing criteria exist, including distinct vacuolated cell variants (Table 4, Figs. 9A, B). The quality of the microvacuolar change and its 964 CANCER September 1, 1996 / Volume 78 / Number 5 FIGURE 6. (A) Neoplastic duct with a higher cytologic grade resembling high grade salivary duct carcinoma (right) arising in a low grade salivary duct carcinoma (left) and associated with (B) a microscopic focus of stromal invasion. FIGURE 7. Distinctive immunoreactive pattern of low grade salivary duct carcinoma for S-100 protein antibody, with diffuse and intense nuclear and cytoplasmic positivity. prominence in some LG-SDC may raise the possibility of a sebaceous neoplasm. However, no other features of sebaceous differentiation such as the germinative epithelium"" are present and the resemblance is merely superficial. Because of the low grade cytology the diagnosis of a polymorphous low grade adenocarcinoma (PLGA) may be entertained. However, LG-SDC lacks the tubular, ductular, trabecular, and single file patterns so often observed in PLGA, as well as, the characteristic infiltrative appearance, mucohyaline stroma, and neurotropism. Finally, two entities that must be discussed in defining LG-SDC are papillary cystadenocarcinoma and papillary cystadenoma. According to the latest World Health Organization (WHO) histologic classification of salivary gland tumors,' papillary cystadenocarcinoma is a malignant tumor characterized by cysts with papillary endocystic projections. Like LG-SDC they are considered low grade malignant neoplasms with potential for infiltrative growth. Unlike LG-SDC they display well developed papillae with narrow, fibrous, sometimes hyalinized cores, covered with cuboidal or low columnar cells. Furthermore, they exhibit cytologic atypia, nuclear pleomorphism, and significant mitotic activity. Although it is tempting to view papillary cystadenocarcinoma as the papillary variant of LG-SDC, we believe its obvious more aggressive histologic features warrant its separate designation. Conversely, and not surprisingly, given their seemingly bland nature, cases of LG-SDC have been illustrated as examples of cystadenomas.5While not denying the existence of benign proliferative ductal lesions in the salivary gland, for the reasons previously discussed, in particular the noted progression to a higher cytologic grade lesion with invasion, we prefer to regard these tumors as potentially malignant. Fortuitously, in the latest WHO classification of salivary gland tumors,' the term papillary cystadenoma is given to a tumor that closely resembles Warthin tumor minus the lymphoid elements. Regarding the so-called salivary gland cystadenocarcinoma, we believe it is a nonspecific descriptive term that, like its counterpart, salivary gland adenocarcinoma, should only be used when a tumor eludes any of the heretofore established entities. Based on the histomorphogenetic classification Low Grade Salivary Duct Carcinoma/Delgado et at. 965 FIGURE 8. (A) The neoplastic ducts are silhouetted by a continuous layer of myoepithelial cells (immunoperoxidase stain for smooth muscle actin). as confirmed by electron microscopy, (6)cytoplasmic prolongations of a “native” myoepithelial cell circumscribe the neoplastic ductal cells TABLE 3 Distinguishing Histopathologic Features of Low Grade and High Grade Salivary Duct Carcinoma Cornedo necrosis Calcification Cell ;irrarigement Cell shape C!.toplasmic borders Cyzoplasm Suclci Cliroiiiatiii Suclcoli Mitotic figures Cellular composition Myoepithelial component IniniLnoliistochemist~ low grade SDC High grade SDC Pseudocribriform with slit-like spaces, solid, and cystically dilated: focal architectural atypia Absent Present (psainmoma bodies) 1.oose to overlapping Predomiiiaiiily ovoid Indistinct Dense pale 10 bright eosinophilic Oval, low grade Sormorhrorriatic Identifiable Negligible f leterogenous: ductal, apocrinc. vacuolared Peripheral: rim s-100 c 1vvlW-CK-903 * Cribriforni with geometric spaces scheme of salivary gland neoplasms proposed by some, ’ I ’ ’ the salivary duct carcinoma is a tumor composed predominantly of ductal luminal cells. In I,G-SL)C, both by immunohistochemistry and electron microscopy, myoepithelial participation is limited to a peripheral localization and of a seemingly non-neoplastic nature corresponding to an in situ phase (intraductal carcinoma). Alternatively, LGSDC may represent a highly organized bicellular ductal/myoepithelial growth. Of interest is the strong inimunoreactivity of I.G-SDC for S-100 and i t 5 coexpression with high-molecular weight cyto- I:rcquent Only associated with comedo necrosis Rigid I’redoniinaiitly polygonal Well-defined Powdery eosinophilic Round to oval, moderate to high-grade Vesicular Prominent Preseiit Moriomorphous: ductal Peripheral: scattered S-100 I~SlW-(X903T / keratin (CK-903). Based on immunohistochemical studies of the normal salivary gland, the former is more often associated with intercalated duct cells whereas the latter has been correlated with the basal cells found mainly in the interlextralobular ducts. However, such coexpression has been previously noted to identify the intercalated duct cell component in ACC, the acinar cells being negative for both anti bodies .‘I) Thus, this i mm u n o h is t o che m i cal find ing seems to characterize a neoplastic ductal phenotype morphologically akin to the intercalated duct cells, supporting our interpretation of these cases 966 CANCER September 1,1996 I Volume 78 I Number 5 FIGURE 9. Papillocystic variant of acinar cell carcinoma, included for comparison. (A) lntracystic papillary tumor masses exhibiting secondary follicular pattern. (B) Reticulated acinar and clear cells with macrovacuoles coalescing into microcystic spaces. TABLE 4 Distinguishing Histomorphologic Features of Low Grade Salivary Duct Carcinoma and Papillarv-CvsticAcinic Cell Carcinoma Low Grade SDC Papillary-Cystic ACC GroiLzh pattern Micropapillary to plaque-like (:ellular composition Partial intraluminal groulh ~pocritieivacuolated,intercalated duct-like, nonspecific glandular Papillay peninsulasimasses with secondary patterns: microcystic, follicular, etc. Fills and distends (expands1 cystic spaces Acinar, clear, intercalatedduct-like, nonspecific glandular, vacuolated, oncocpic Prominent nucleoli Readily identifiablr mitotic figures Derived from acinar cells, loose lreticulatedi macrovaciioles coalescing into mirrorystic spares Cplogic features of nunvacuolated ducral cells Cplogic features of vacuolated cells ldrntifiable nucleoli Infrequent iniitotic figures Derived from apocrine cells, well defined, crowded and refraclile intracellular microvacuoles Features shared by both entities: Secondary changes such as squamous nietaplasia of cyst lining, stromal fibrosis, sclerosis, remote heniorrhage with cholesterol cleftsigranulomaa.psammonia body-like and dystrophic calcification, marked lymphoid illfiltrate SDC: saliun duct carcinoma; ACC: acinic cell carcinoma. as salivary duct and not acinic cell neoplasms. Of interest, this immunohistochemical profile contrasts with that of high grade salivary duct carcinoma3," (Table 3 ) . Complete clinical information was available for 6 patients, none of whom showed local recurrence or metastatic disease at 2 (3 patients), 6 , 11, and 12 years following total parotidectomy. Only one had received postoperative radiotherapy based o n the diagnosis of ACC and positive surgical margins. Three patients were lost to follow-up. The last and most recent case in our series with only 9 months of follow-up was significant for exhibiting a focus of invasive ductal carcinoma extending to the surgical margin, for which postoperative radiotherapy was given. These clinical findings contrast with those of HG-SDC which has been reported to have a death rate of 70 to 75%, with a mean survival of 3 years after diagnosis.' We conclude that LG-SDC represents the low grade end of the spectrum of salivary duct neoplasms. LG-SDC appears to be primarily an in situ (intraductal) process and should be distinguished from the better known HG-SDC which is usually invasive, carries a poor prognosis, and warrants aggressive therapy. Furthermore, we especially emphasize the distinguishing features from an ACC, with which it is often confused. Recognition will enable further definition of this entity and of its natural course, given the protracted disease progression that characterizes many of the low grade salivary gland malig- Low Grade Salivary Duct Carcinoma/Delgado et al. nancies. In addition, the propensity of LG-SDC to become invasive an d/or to evolve to a HG-SDC also needs to be addressed. 8. 9. 1. 2. 3. 4. 5. ti. ,. -9 Lewis I E, McKinney BC, Weiland I.H. Ferreiro IA, Olsen KD. Salivary duct carcinoma: clinicopathologic and imniunohistochemical review of 26 cases. Cancer 199G; 77223-30. Hellquist HB, Karlsson MG, Nilsson C. 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