carcinome intraductal

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 Sloan-
Kettering Cancer Center, New
York, New York.
The authors thank Mrs. R. Nelly Murillo for her
assistance in the preparation
of this manuscript.
Address for reprints: Ruby Delgado,
M.D., De-
partment
of Pathology, University of Texas
Southwestern Medical Ctr., 5323 Harry Hines
Blvd., Dallas.
TX 75235-9072.
Received February 16,
1996; revision received
May 23, 1996; accepted June 3, 1996.
BACKGROUND. Salivary duct carcinoma (SDC) has been established as a morpho-
logically 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 repre-
sent the
(1.G) counterpart of SDC. lrnmunoperoxidase stains were performed on
tive cases, and electron microscopy
oil 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. 1 he gross appearance was focally to
predominantly cystic. Microscopically, the tumors were characterized by intraduc-
tal proliferative lesions exhibiting three main patterns:
(1) cystic ducts with micro-
papillaq, 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 coex-
isted 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 cyto-
logic ductal atypia. Despite
gross circumscription, there was microscopic multifo-
cality, 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 mi-
croscopy
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 duct-
like cell phenotype. Its relationship
to 1IG-SL)C should be Purther explored. Cancer
1996; 78:958-67. 0 I996 American Curicer Society.
KEYWORDS salivary gland, duct carcinoma, low grade, high grade, immunohisto-
chemistry, electron microscopy.
lthough the histomorphogenesis of some salivary gland neo-
A plasms remains unclarified, the term salivary duct carcinoma
(SDC) has been restricted to tumors composed predominantly or ex-
clusively 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
c) 1996 American Cancer Society

Low Grade Salivary Duct Carcinoma/Delgado et al.
959
TABLE I
Immunohistouhemical Findings in Five Cases of LG-SDC
No. of
immunoreactive
Antibody CaSeS Pattern of immunoreactivity
S-100 protein 3
SM!\
1
membranous > cytoplasmic
diffusea;
i
menibrdnous > cpoplasniic
diffusea:
4 t14+*
luniinal diffuse; 7 - c
cpplasmic focahpocrine
metaplastic
cells; A +
nuclear & ryoplasmic diffiise"'';
cytoplasmic limited
to
T-4
myoepithelial cells; -4 +
I.G-SI)C: lowgradi salig dutr carcinoma; pCE4: polyclonal carcinoenibryonic anrign; CCIEP gross
c!\rir diww lluij prorein; !N\: smoorh muscle spPrific aciin
Inrludrr yacuol;i[rd c~lls.
liitl:itle(i some of [he nyqi~helial (ells.
Snurtv & I)iluunrl: (:\iokeraun Cnm 5.2 (Hecron-[)ickinson. \,luun[ain View. CAiPrediluredi: Cvokera-
iiii \lA(IOJ ;Em 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 tu-
mors characterized by the proliferation of salivary duct
structures and exhibiting ductal differentiation (by
light microscopy, immunohistochemistry, and elec-
tron microscopy), but lacking both the aggressive mor-
phologic features and clinical behavior of the high
grade
SIX We believe these tumors represent the low
grade end of the spectrum of salivary duct malignan-
cies.
MATERIALS AND METHODS
Four cases were accrued in consultation. A fifth case
was retrieved from the surgical pathology files of Park-
land Memorial Hospital in Dallas, Texas, and the re-
maining five from the surgical patholoby files of Me-
morial Hospital in New York, New York. Clinical infor-
mation and follow-up data were provided by the
referring physicians in three cases and from the pa-
tients' 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 acid-
Schiff (PAS), and mucicarmine, and immunohisto-
chemical analysis. Immunostains were performed us-
ing the standard avidin-biotin peroxidase method.
Commercially available antibodies were used with ap-
propriate controls (Table
1).
In one case fresh tissue was fixed in glutaralde-
hyde and routinely processed for transmission elec-
tron 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
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 in-
tracystic micropapillary and tufted formations focally
anastomosing and coalescing into solid plaque-like
epithelial stratification (Figs. IA-C). The micropapil-
lae were composed of cuboidal to small columnar cells
exhibiting conspicuous intracytoplasmic microvacu-
oles which increased in number from base
to lumen
and were accompanied by a fine granular yellow-
brown pigment. In its fullest expression the cells were
filled and distended by sharply outlined minute vacu-
oles causing indentation of the nucleus and accentua-
tion of the cytoplasmic rim, resulting in scallop-
shaped micropapillae (Figs.
2A, B). Better developed
papillae with fibrotic fibrovascular cores and psam-
moma bodies were also present. In the nonprolifera-
tive areas the cysts were lined by a simple apocrine
epithelium showing attenuation and squamous meta-
plasia.
(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 eosin-
ophilic cytoplasm, indistinct cell borders, and oval nu-
clei 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 re-
sulting 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 ac-
companied occasionally by the intracytoplasmic mi-
crovacuolar 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
Parotid [superficial lobe;
I cni Lowgrade papillocystic adeiiocarriiioma Superficial parotidectomy -
62iF Parotid
0.7 rni Papillocystic carcinoma Parotidectomy
-
?
3 32iF Right parotid (superfiria! lobe) 1.1 ciii Acinic cell carcinoma; positive margins Parotidectomy, radiotherapy NED at 12 yrs
4 63\11!
Right parotid (superficial lobel 1.3 ciii Aciiiic cell carcinoma Parotidectomy
NED at I1 yrs
6 56iF Right parotid
I cni Acinic cell carcinoma Parotidectomy NED
at 2 yrs
n 69iF
Right parotid (intraparotid lymph node1 4 cni LG-SDC Parotidectomy
NED a1 2 )rs
9 69 / M I.eR parotid 0.9 cm LG-SDC Parotidectomy
in 52iF Right parotid (deep lobe) 0.8 cm LG-SDC with focal invasion; positive margins Parotidectomy, radiotherapy NED at 9 mos
NED: no evidence of disease; LG-SDC: low gade salivary duct carcinoma,
J i4iM Left parotid
1.8 ciii Aciiiic ceil carcinoma Parotidectomy NED at
6 17s
I 4?/M
Left parorid (superficial lobe) 1.2 ciii LG-SDC
Parotideclomy NED at 2 ITS
FIGURE 1. Papillocystic pattern of low grade salivary duct carcinoma. (A)
Delicate filigreed intracystic micropapillae
with psamrnoma body rnicrocalcifi-
cation (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 arrange-
ment and focally communicating with the major cyst.
All tumors were nonencapsulated but somewhat cir-
cumscribed by a dense sclerotic stroma exhibiting sec-
ondary 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 infil-
trate (Fig.
I, bottom).
Despite the apparent circumscription of the tu-
mors, detached tumor foci were seen in the sur-
rounding glandular parenchyma (Fig.
5), best interpre-
ted as niultifocality, and in one case, stromal microin-
vasion (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 sur-
rounding but
not invading peripheral nerve branches.
Mitotic activity was negligible in
most cases, non-
atypical mitotic figures being identified in two cases.
Mucicarrnine and PAS stains highlighted the ma-
tctrial 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 gran-
ules were present but confined to foci of apocrine
m e 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 pat-
terns, and encompassed the vacuolated and nonvacu-
olated 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 neo-
plastic 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 form-
ing intercellular lumina and bound by a continuous
basal lamina. The ductal cells displayed apical micro-
villi and contained a modest number of organelles,
except for occasional cells showing an increased num-
ber 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 indenta-
tion of the nuclei and displaced the cytoplasmic organ-
elles to a subplasmalemmal location (Fig.
2R).
DISCUSSION
We report ten cases of a tumor which conforms to the
cytoarchitectural definition
of a salivary duct neo-
plasm (composed primarily of ductal luminal cells
with formation of distended salivary duct structures),
that, to
our knowledge, has not been previously char-
acterized as such. Because
it exhibits a bland histo-
morphology 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 HG-SDC,’-6 salivary duct neoplastic proliferations
grade salivary duct carcinoma
(HG-SDC), better have demonstrated a more aggressive behavior than
known for its reiterated similarity to breast duct carci- their morphologic counterparts in the breast. This ap-
noma (mainly comedo type),’-6
LG-SDC spans an ap- parent organ-specificity may be related to underlying
pearance reminiscent of florid to atypical ductal hy- structural differences
(i.e., regional anatomy or glan-
perplasia to
low grade intraductal breast carcinoma dular microanatomy), to biologic differences (i.e., hor-
(Table
3). Based on the accumulated experience with monal regulation), andlor to inherent tumor proper-