Abstract
Salivary duct carcinoma with rhabdoid features (SDCRF) is a rare salivary tumor with poor prognosis and is proposed as a salivary counterpart of pleomorphic lobular carcinoma of the breast (PLCB). Here, we report three cases of SDC with rhabdoid features (SDCRF) mimicking PLCB. Pleomorphic adenoma (PA) component was accompanied in all the cases confirming carcinoma ex PA. One patient had frequent rhabdoid features and showed invasive growth into the surrounding tissue. The other two patients had intracapsular tumor but with rhabdoid features. The patients with intracapsular SDCRF survived for > 5 years after surgery with no evidence of recurrence, whereas the patient with extracapsular SDCRF died 10 months after biopsy, and autopsy revealed disseminated metastasis to the central nervous system. Histologically, tumor cells in all three cases resembled PLCB, with a discohesive appearance, abundant cytoplasm, enlarged hyperchromatic nuclei, and similar immunohistochemical profiles, namely loss of membranous E-cadherin, obscured expression of membranous β-catenin, diffuse positivity of androgen receptor, gross cystic disease fluid protein-15, mitochondrial adenosine triphosphate synthase subunit β, MUC1, and INI-1. Estrogen and progesterone receptors were negative, and HER2 immunoreactivities were variable. The tumor cells of extracapsular invasive SDCRF exhibited higher MIB-1 labeling index and more frequent intracytoplasmic lumina than those of intracapsular SDCRF. Ultrastructurally, rhabdoid cells contained intracytoplasmic lumina with microvillous structure, analogous to those reported in PLCB. No intracytoplasmic intermediate filament aggregation was observed. These observations indicate that SDCRF is a salivary counterpart of PLCB and under signet ring cell differentiation.
Electronic supplementary material
The online version of this article (10.1007/s12105-020-01186-4) contains supplementary material, which is available to authorized users.
Keywords: Salivary duct carcinoma with rhabdoid features, Pleomorphic lobular carcinoma of the breast, E-cadherin, Intracytoplasmic lumina with microvillous structure, Signet ring cell differentiation
Introduction
Salivary duct carcinoma (SDC) accounts for approximately 10% of salivary gland malignancies and occurs de novo or arises as a carcinoma ex pleomorphic adenoma (PA) [1]. Poorer prognosis is associated with the progression of an intracapsular tumor to a widely invasive extracapsular tumor [2]. Its histology usually resembles high-grade ductal carcinoma of the breast, not lobular carcinoma, in which non-coherent cancer cells diffusely proliferate with loss of E-cadherin expression [3]. An aggressive subtype of mammary lobular carcinoma is pleomorphic lobular carcinoma of the breast (PLCB) [3]. PLCB is distinct from classic lobular carcinoma in terms of abundant cytoplasm, nuclear morphology (e.g., increased nuclear size, nuclear polymorphism, nucleolar prominence, and increased mitoses) [3, 4] and immunohistochemical phenotype (estrogen and progesterone receptor negative and human epidermal growth factor receptor 2 [HER2] variably positive) [3–6].
Recently, SDC with rhabdoid features (SDCRF), an extremely rare SDC subtype, has been reported with only ten cases in English literature [7–9]. Eight out of the ten reported SDCRF cases were carcinoma ex PA, mostly widely invasive, showing poor prognosis (Table 1). SDCRF shows diffuse proliferation of non-coherent cancer cells that lack membranous E-cadherin expression and have large eosinophilic cytoplasm and eccentric nuclei with prominent nucleoli. Therefore, SDCRF has been proposed as a salivary counterpart of PLCB [8]. In only one SDCRF case, intracytoplasmic intermediate filament aggregation was shown in large rhabdoid tumor cells (Table 1) [7]. However, ultrastructural investigation has not been fully carried out in the other SDCRF cases. Moreover, one intracapsular case was merely included in the reported SDCRF cases (Table 1) [8]; further characterization of intracapsular cases is needed to clarify the development of SDCRF.
Table 1.
Summary of clinical features for previously and presently reported cases of salivary duct carcinoma with rhabdoid features ex pleomorphic adenoma
| Author | Age | Sex | Site | Progression from PA | Treatment | Follow up (mo) | Outcome | Metastasis | Comment |
|---|---|---|---|---|---|---|---|---|---|
| Kusafuka et al. [7, 8] | 44 | M | Lt PG | WI | TL, RT | 21 | DOD | LN, Bo | IF condensation |
| 66 | M | Rt SMG | WI | TL/TE | 26 | DOD | LN, Lu | ||
| Kusafuka et al. [8] | 39 | M | PG | WI | TL/TE, CRT* | 15 | NR | LN* | |
| 73 | M | PG | WI | TL/TE | Lost | LN | |||
| 36 | M | PG | IC | TL/TE | 78 | NR | |||
| 79 | M | SMG | WI | TL/TE | Lost* | LN* | |||
| 56 | M | SMG | WI | TL | 30 | DOD | LN | ||
| Otsuru et al. [9] | 82 | M | Rt SMG | WI | TE, CRT | 12 | DOD | LN, Lu, Bo, SC | MP feature |
| Patient 1 | 60 | M | Rt PG | IC | TL | 79 | NR | ||
| Patient 2 | 82 | M | Rt PG | IC | TL | 60 | NR | ||
| Patient 3 | 76 | M | Rt PG | EC | Biopsy, CRT | 10 | DOD | LN, CNS, Lt AG |
M Male, Lt left, PG parotid gland, Rt right, SMG submandibular gland, WI widely invasive, IC intracapsular carcinoma, EC extracapsular carcinoma, TL total lobectomy, RT postoperative radiotherapy, TE tumor excision, CRT postoperative chemoradiotherapy, mo months, Lost lost follow-up, DOD dead of disease, NR no recurrence, LN lymph node, Bo Bone, Lu lung, SC subcutaneous tissue, CNS central nervous system, AG adrenal gland, IF intermediate filament, MP micropapillary
*Data through personal communication, May 11th, 2020
Here, we report two intracapsular and one extracapsular SDCRF cases (Table 1) showing histological and immunohistochemical resemblance to PLCB. All three cases histologically exhibited intracytoplasmic lumina, which were also ultrastructurally shown with abundant microvilli in tumor cells of the extracapsular case, analogous to those reported in PLCB. The findings suggest tumor cells in the three cases were under signet ring cell differentiation, and may support the proposal that SDCRF is a salivary counterpart of PLCB.
Materials and Methods
Histology and Immunohistochemistry
The tissue specimen of patient 1 was fixed in 10% neutral buffered formalin. The tissue specimens of patients 2 and 3 were fixed in 20% formalin. They were embedded in paraffin blocks. Paraffin-embedded sections with 2- to 3-μm thickness were prepared, deparaffinized, and stained with hematoxylin and eosin. The immunohistochemical studies were also performed either manually or using an automated immunohistochemistry (IHC) instrument with a Bond Polymer Refine Detection™ system (Leica Biosystems, New Castle upon Tyne, United Kingdom). In the manual IHC procedure, the sections were heated in Immunosaver™ (Nissin EM Ltd., Tokyo, Japan) for antigen retrieval (Supplementary Table). The sections were then incubated with each primary antibody listed in Suppllementary Table, followed by treatment with secondary antibody conjugated to peroxidase-labeled dextran polymers. The reaction was visualized using 3, 3′-diaminobenzidine as the chromogen (Envision™ Detection System, Dako, Glostrup, Denmark).
The immunohistochemical results were evaluated by two independent pathologists (M.A. and H.T.). A few discordant results were discussed. The rates of protein expression on membrane (E-cadherin), in nuclei (androgen receptor [AR], estrogen receptor [ER], progesterone receptor [PgR], p53, and INI-1), in cytoplasm (gross cystic disease fluid protein-15 [GCDFP-15], mitochondrial ATP synthase subunit β [ATP5B], and MUC1), or both in cytoplasm and on membrane (β-catenin and DOG-1) of neoplastic cells were determined. The IHC score was defined as follows: ≥ 50% positive cells among all neoplastic cells (+++), 10–49% (++), 1–9% ( +), and 0% (−), except for HER2. The HER2 IHC score was estimated according to the criteria recommended by American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline [10], although the entire lesion, including the noninvasive component, was used for the estimation. MIB-1 labeling index was determined as the percentage of neoplastic cells with positive nuclear staining out of at least 1000 cancer cells in a hot spot. Regarding E-cadherin, β-catenin, GCDFP-15, ATP5B, MUC1, and INI-1, the immunoreactivity similar to or stronger than that of the surrounding parotid gland tissue was judged as positive. In DOG-1 IHC, neoplastic cells with immunoreactivity similar to or stronger than the apical immunoreactivity of co-existed intercalated ducts was counted as positive [11]. In cases of p53 IHC, only neoplastic cells with strong nuclear positivity are counted as positive cells.
Electron Microscopy
Formalin (20%)-fixed autopsy tissue specimens of patient 3 were used for the ultrastructural analysis. Briefly, the tumor tissue fragments were pre-fixed in 2% paraformaldehyde and 2.5% glutaraldehyde in cacodylate buffer, pH 7.4, and post-fixed in 1% osmium tetroxide in the same buffer. The fixed tissue was embedded in epoxy resin, ultra-sectioned, and applied for a transmission electron microscopy (Hitachi HT7700, Hitachi High-Technologies Corporation, Tokyo, Japan).
Case Report
Case 1
A 60-year-old Japanese man noticed a swelling in his right subaural area. Magnetic resonance imaging (MRI) revealed a mass between the superficial and deep lobes of the right parotid gland. The patient underwent right parotidectomy. The final pathological diagnosis was SDC in situ ex PA (intraductal carcinoma ex PA) [12]. The patient survived for 6 years and 7 months after surgery with no evidence of local recurrence or metastasis.
Case 2
An 82-year-old Japanese man noticed a mass at his right subaural area for 1 year. Cervical computed tomography (CT) imaging revealed a 3-cm-sized mass in the superficial lobe of the right parotid lobe. Because cytological diagnosis indicated a possibility of malignancy, right parotidectomy was performed. The lesion was pathologically diagnosed as SDC ex PA. The cancer cells showed extraductal invasion, but the lesion was confined within the PA capsule. The patient was followed up for 5 years after surgery with no evidence of local recurrence or metastasis.
Case 3
A 76-year-old Japanese man noticed a mass in his right subaural area for several months. On physical examination, multiple elastic hard and non-movable masses were found at the area. CT and MRI revealed nodules in the right parotid gland and multiple swollen cervical lymph nodes (Supplementary Figure). On echography, multiple hypoechoic masses with internal heterogeneity were noted, and the largest mass measured 25 × 11 mm in size. The largest mass and cervical lymph nodes were excised for biopsy purposes. The lesion was diagnosed as SDC ex PA. The SDC portion showed extensive rhabdoid features. The cancer invaded the PA capsule and surrounding striated muscle tissues. Lymphatic invasion was also observed. The patient then received radiotherapy (total dose: 60 Gy), followed by chemotherapy with six courses of docetaxel (30 mg/m2 as the first course, 70 mg/m2 as the second course, and 56 mg/m2 as the third to sixth course). Although the mass lesions in the right parotid gland and the metastatic lymph nodes regressed, as observed on CT and MRI, after the initial radiotherapy, metastatic tumors emerged in the medulla, right cerebral crus, and left frontal lobe of the cerebrum, as observed on CT, after the third course of chemotherapy; hence, the patient received a γ-knife therapy. Despite the treatment, he gradually exhibited impairment in balance. The patient died 10 months after the biopsy. Autopsy was performed 4 h after the patient died and revealed metastases to the central nervous system (cervical spinal cord, brain stem, cerebellum, and cerebrum) and left adrenal gland, which was associated with prominent carcinomatous meningitis. No cervical lymph node metastasis was noted.
Clinical findings of all three patients are summarized in Table 1. No medical history related to breast cancer was taken from any of them.
Histological Findings
The cancer lesions arose from PA in all cases. The PA component remained as a sclerotic area in patient 1 (Fig. 1a, b), chondromyxoid nodules in patient 2 (Fig. 1e, f), and hyalinized nodule in patient 3 (Fig. 1i, j). The entire lesions in patients 1 and 2 were confined within the PA capsule (Fig. 1a, e), whereas the capsule was inconspicuous in patient 3 (Fig. 1i). In patient 1, cancer cells were surrounded by myoepithelial cells, which were immunopositive for α-smooth muscle actin (α-SMA), suggesting intraductal carcinoma (Fig. 1c, d). In patient 2, cancer cells showed extraductal invasion, where α-SMA -immunopositive myoepithelial cells were partly lost (Fig. 1g, h), but the lesion was confined within the PA capsule, implying an intracapsular invasive carcinoma (Fig. 1e). In patient 3, cancer cells in nests lined by α-SMA-immunopositive myoepithelial cells were focally seen (Fig. 1k, l), but most cancer cells were dyscohesive with rhabdoid features invaded beyond the PA capsule (Fig. 1m), implying an extracapsular carcinoma. Although the cancer invasion to surrounding tissues and vessels was < 4 mm from the PA capsule within this biopsied specimen, the lesion could be more widely invasive if the entire lesion was resected and pathologically evaluated. The progression status from PA in patients 1–3 are summarized in Table 1.
Fig. 1.
Low magnification images of resected specimens of patient 1 (a–d), patient 2 (e–h), and patient 3 (i–m). a The lesion was confined to the PA capsule with a sclerotic area (an arrow). Hematoxylin and eosin stain [HE], bar: 5 mm. b Magnified view of the lesion in (a), showing the sclerotic area on the right side of the image. Cancer cells proliferated in tubules and low papillae on the left side of the image. HE, bar: 100 μm. c Magnified view of the lesion in (b). The tubules were surrounded by myoepithelial cells. HE, bar: 100 μm. d The myoepithelial cells in (c) were immunopositive for α-SMA. e The lesion was confined to the PA capsule, and chondromyxoid stroma was scattered (arrows). HE, bar: 5 mm f, Magnified view of the lesion in (e), showing the chondromyxoid stroma on the upper right side of the image. Cancer cells proliferated in nests, tubules and cribriform structure around the stroma. HE, bar: 100 μm g, Magnified view of the lesion in (e) Myoepithelial cells around tubules and nests were partly lost. HE, bar: 100 μm. h The myoepithelial cells in (g) were immunopositive for α-SMA. i The PA capsule was unclear, and a hyalinized nodule was noted (arrows). HE, bar: 5 mm. j Magnified view of the lesion in (i), showing the hyalinized nodule on the right side of the image. Rhabdoid cancer cells proliferated diffusely on the left side of the image, and were further magnified in inset. HE, bar: 100 μm. k Magnified view of the lesion in (i) Nests surrounded by myoepithelial cells (arrowheads) were seen on the left of the image. On the right side of the image, rhabdoid cancer cells infiltrated diffusely. HE, bar: 100 μm. l The myoepithelial cells in (k) were immunopositive for α-SMA. m Magnified view of the extracapsular portion in (i), showing cancer invasion into a lymphatic vessel outside the capsule. HE, bar: 100 μm
The cancer cells in patient 1 mainly formed intraluminal low papillary structures and tubules (Figs. 1b, c, 2a), while those in patient 2 proliferated forming nests and sheets, with cribriform structure and tubules in a small proportion (Figs. 1f, g, 3a). In both patients, the cancer cells partly showed a poorly cohesive appearance (≥ 50% of the entire lesion; Figs. 2a, g, l, 3a, g, l). The cancer cells in patient 3 proliferated more diffusely than those in patients 1 and 2 (Figs. 1j, k, 4a, g, l), lacking cellular cohesiveness in most area (≥ 95% of the entire lesion; Figs. 1j inset, 4 g, l). However, the cancer cells still focally exhibited nests, partly with cellular cohesion, as shown on the left side of Fig. 1k and on the lower right side of Fig. 4a (< 5% of the entire lesion). No apparent lesion akin to ductal carcinoma of the breast was observed in any patients, such as cribriform structure with comedonecrosis or Roman bridge architecture, usually seen in conventional SDC. The cancer cells in patients 1–3 cytologically resembled those observed in PLCB [13]. The cancer cells in the present cases were ≥ 4 times the size of lymphocytes, containing round- to irregular-shaped hyperchromatic nuclei with distinct nucleoli. Mitotic figures were occasionally seen in patient 1 (2 mitoses per 10 high-power fields) and patient 2 (4 mitoses per 10 high-power fields, including abnormal mitoses) but were frequently observed in patient 3 (approximately 40 per 10 high-power fields). They have abundant and eosinophilic cytoplasm exhibiting an apocrine appearance. In addition, occasionally in patients 1 and 2, intracytoplasmic lumina were found in some cancer cells resembling signet ring cells (Figs. 2l, 3l). Meanwhile, intracytoplasmic lumina were more frequently found in patient 3 than in patients 1 and 2; they were so large that the nuclei tended to be eccentrically placed, resembling signet ring cell features (Fig. 4l). In patients 1–3, the other cancer cells had no obvious intracytoplasmic lumina but eccentrically placed nuclei, indicating a rhabdoid appearance (Figs. 2l, 3l, 4l).
Fig. 2.
Histological and immunohistochemical findings of patient 1. a Low-power view (HE; bar, 100 μm), showing proliferation of cancer cells in lower papillae and tubules with a discohesive appearance. b–f Immunohistochemical images of E-cadherin, β-catenin, human epidermal growth factor receptor 2 (HER2), androgen receptor (AR), and p53 of the serial sections of (a). g High-power view (HE; bar, 50 μm). Cancer cells showed cellular discohesion. h–k Immunohistochemical images of gross cystic disease fluid protein-15 (GCDFP-15), mitochondrial ATP synthase subunit β (ATP5B), DOG1, and MUC1 of serial sections of (g). Inset in (i) shows ATP5B expression in intercalated ducts and acini of normal parotid glands. l Further magnified view in a part of (g) (HE; bar, 25 μm). Cancer cells had nuclei that are ≥ 4 times the size of lymphocyte nuclei. Several cancer cells showed intracytoplasmic lumina (arrowheads)
Fig. 3.
Histological and immunohistochemical findings of patient 2. a Low-power view (HE; bar, 100 μm). Cancer cells proliferated forming nests and sheets with cellular discohesion in part. b–f Immunohistochemical images of E-cadherin, β-catenin, human epidermal growth factor receptor 2 (HER2), androgen receptor (AR), and p53 of the serial sections of (a). g High-power view (HE; bar 50 μm). Cancer cells showed cellular discohesion. h–k Immunohistochemical images of gross cystic disease fluid protein-15 (GCDFP-15), mitochondrial ATP synthase subunit β (ATP5B), DOG1, and MUC1 of the serial sections of (g). Inset in (j) shows DOG1 expression in acini and intercalated ducts (arrowheads) of normal parotid gland. l Further magnified view in a part of (g) (HE; bar, 25 μm). The cancer cells had eosinophilic cytoplasm and enlarged hyperchromatic nuclei with nucleoli. A few cancer cells showed intracytoplasmic lumina (arrowheads)
Fig. 4.
Histological and immunohistochemical findings of patient 3. a Low-power view showing cancer cells proliferating diffusely with a discohesive appearance (HE; bar, 100 μm). A focal solid nest (an arrow) was seen on the lower right side of the image. b–f Immunohistochemical images of E-cadherin, β-catenin, human epidermal growth factor receptor 2 (HER2), androgen receptor (AR), and p53 of the serial sections of (a). g High-power view (HE; bar, 50 μm). The cancer cells show a discohesive and pleomorphic appearance. h–k Immunohistochemical images of gross cystic disease fluid protein-15 (GCDFP-15), mitochondrial ATP synthase subunit β (ATP5B), DOG1, and MUC1 of the serial sections of (g). l Further magnified view in a part of (g) (HE; bar, 25 μm). The cancer cells contained large eosinophilic cytoplasm and eccentric enlarged nuclei with prominent nucleoli, showing a rhabdoid feature. Several cancer cells had intracytoplasmic lumina (arrowheads)
Immunohistochemical Findings
Immunohistochemical results are summarized in Table 2. In all cases, most portions lacking cellular cohesion showed loss of E-cadherin expression (Figs. 2b, 3b, 4b), whereas membranous β-catenin immunoreactivity was obscured or lost (Figs. 2c, 3c, 4c). Conversely, the area with conspicuous E-cadherin expression (Figs. 2b, 3b, 4b) showed apparent membranous staining of β-catenin (Figs. 2c, 3c, 4c). Fibroblasts in stroma were also positive for β-catenin. Nuclear translocation of the β-catenin immunoreactivity was hardly observed. The HER2 expression pattern was not in accordance with E-cadherin and β-catenin expression (Figs. 2d, 3d, 4d). Diffuse nuclear expression of AR (Figs. 2e, 3e, 4e) and INI-1 (Table 2) was observed in patients 1–3. ER and PgR were hardly detectable in all patients (Table 2). Nuclear p53 immunoreactivity was occasionally observed in patient 1 (Fig. 2f), diffusely in patient 2 (Fig. 3f), and only focally in part of the solid nests in patient 3 (Fig. 4f, Table 2). Of note, the non-cohesive rhabdoid cancer cells found in patient 3 were all negative for p53 (Fig. 4f, Table 2).
Table 2.
Immunohistochemical results of the present three patients with salivary duct carcinoma with rhabdoid features
| Protein | Patient 1 | Patient 2 | Patient 3 |
|---|---|---|---|
| E-cadherin | − in ≥ 60% area | − in ≥ 50% area | − in ≥ 95% area |
| β-catenin |
c: − m: +++ |
c: − m: +++ |
c: + m: + |
| HER2 IHC score | – | 3 + | 2 + |
| AR | +++ | +++ | +++ |
| ER | – | – | – |
| PgR | – | – | – |
| p53 | + | ++ |
– in dyscohesive cells + in focal solid nests |
| GCDFP-15 | +++ | +++ | +++ |
| ATP5B | +++ | +++ | +++ |
| DOG1 |
c:– m:– |
c:+ m:– |
c:+++ m:++ |
| MUC1 | +++ | +++ | +++ |
| INI-1 | +++ | +++ | +++ |
| MIB-1 labeling index | 4.2% | 6.5% | 39.5% |
HER2 human epidermal growth factor receptor 2, IHC immunohistochemistry, AR androgen receptor, ER estrogen receptor, PgR progesterone receptor, GCDFP-15 gross cystic disease fluid protein-15, ATP5B mitochondrial ATP synthase subunit β, – negativity; + , 1–9% positivity; ++ , 10–49% positivity; +++ , ≥ 50% positivity, c cytoplasmic staining, m membranous staining
In all cases, GCDFP-15 (Figs. 2h, 3h, 4h), ATP5B (Figs. 2i, 3i, 4i), and MUC1 (Figs. 2k, 3k, 4k) were detected in the cytoplasm of the cancer cells, suggesting apocrine and oncocytic differentiation and mucinous cytoplasm. The cancer cells were negative for cytoplasmic DOG1 in patient 1 (Fig. 2j), but were focally and weakly positive for cytoplasmic DOG1 in patient 2 (Fig. 3j). In patient 3, weak DOG1 immunoreactivity was observed not only in the cytoplasm but also on the cell membrane, suggesting slight acinar/intercalated duct differentiation (Fig. 4j). The MIB-1 labeling index in patients 1–3 increased to 4.2%, 6.5%, and 39.5%, respectively (Table 2). This finding suggests that the patient with extracapsular invasion had higher proliferative activity than those with intracapsular tumor. The observed immunophenotypes were similar to those of PLCB [3–6].
Autopsy and Ultrastructural Findings
Autopsy of patient 3 revealed prominent cancer invasion in the subarachnoid cavity and metastatic spreading in the perivascular areas of the cervical spinal cord, brain stem, cerebellum, and cerebrum (Fig. 5a). Cancer cells were morphologically similar to those observed in the biopsy specimens displaying many rhabdoid cells (Figs. 1j inset, k, 4a, g, l), and cells with intracytoplasmic lumina, which resembled signet ring cell carcinoma, were evident (Fig. 5b). The lumina were filled with PAS-positive and diastase-resistant mucin (Fig. 5b inset). Formalin-fixed cerebral tissue was subsequently used in an ultrastructural study. Although cellular membrane was not properly preserved, intracytoplasmic lumina were well preserved and ultrastructurally analogous to those reported in PLCB (Fig. 5c) [14]. No intermediate filament aggregation was observed in cytoplasm. Mucin was more prominent in some intracytoplasmic lumina (Fig. 5d) but less prominent in others (Fig. 5e). The intracytoplasmic lumina with microvillous structure were mostly found within the perinuclear indented space and were more frequently detected under electron microscope in 65% of cancer cells (334 cancer cells of 515 cells including only focally sectioned cells) than under light microscope. The findings suggest that large intracytoplasmic lumina with microvillous structure occupy a space in cytoplasm and place nuclei at the periphery of the cells (eccentric nuclei). Moreover, the cancer cells containing the intracytoplasmic lumina with abundant mucin are likely to be signet ring cells, while the cancer cells with intracytoplasmic lumina with less mucin but prominent microvillous structure appear to be rhabdoid.
Fig. 5.
Histological and ultrastructural findings of patient 3 at autopsy. a Low-power view (HE; bar, 500 μm), showing massive infiltration of cancer cells in the subarachnoid cavity. They also spread into the cerebral tissue of left temporal lobe. b High-power view (HE; bar, 100 μm). The cancer cells resembled those observed in Figs. 1j inset, and 4g, l, but intracytoplasmic lumina (arrowheads) were more evident. Inset indicates that the intracytoplasmic lumina contained PAS-positive and diastase-resistant mucin. c Transmission electron micrograph (uranyl acetate-lead citrate staining; bar, 20 μm) suggests that most cancer cells contained intracytoplasmic lumina with microvillous structure with variable amount of mucin. d, e Higher magnification photos of the intracytoplasmic lumen of cancer cells at the center of (c). In (d), mucin was apparent and surrounded by microvilli; in (e), microvilli were prominent with less evident mucin, compared with the one in (d)
Discussion
In this report, we described three SDCRF cases mimicking PLCB. Among the three patients, one showed extracapsular invasion and exhibited a distinct rhabdoid appearance. This patient presented higher proliferative activity than those with intracapsular tumor, with loss of p53 immunoreactivity in the discohesive rhabdoid cells. Ultrastructural analysis revealed that the cancer cells in the patient with extracapsular SDCRF frequently contained large intracytoplasmic lumina with abundant microvilli and eccentric nuclei, suggesting signet ring cell differentiation.
In addition to this extracapsular invasive case, the present report also included two patients with intracapsular tumor, which showed a loss of E-cadherin expression and the presence of intracytoplastmic lumina, mimicking PLCB. To date, seven out of eight SDCRF ex PA cases were widely invasive with poor prognosis (Table 1), which were similar to the case of patient 3 in this report. Kusafuka et al. [8] included one intracapsular case in their study, however, no details were described. Cancer cells in the present three patients were all histologically similar to those of PLCB and shared similar immunohistochemical characteristics (Figs. 1, 2, 3, 4, 5, Table 2). Conversely, MIB-1 labeling index increased as invasion progressed (Table 2). The p53 immunoreactivity was occasionally observed in patient 1 and was more diffuse in patient 2 (Figs. 2f, 3f, Table 2). In patient 3, p53 immunoreactivity was only observed in cohesive cancer cells in focal solid nests, while discohesive rhabdoid cancer cells were totally negative, suggesting that the discohesive rhabdoid cells are p53 null type (Fig. 4f, Table 2). With regard to prognosis, patient 3 survived less than a year after the biopsy (Table 1). In contrast, patients 1 and 2 showed no recurrence or metastasis for > 5 years (Table 1). This finding is in agreement with the results of previous studies, which indicated that intracapsular carcinoma has good prognosis [2]. Altogether, it is possible that these intracapsular tumor cases may represent early-stage SDCRF.
The rhabdoid cancer cells in this report contained large eosinophilic cytoplasm and eccentric nuclei with prominent nucleoli, which morphologically resemble the cells of rhabdoid tumor in other organs, such as central nervous system. However, the rhabdoid cancer cells in this report contained large intracytoplasmic lumina with microvillous structure, which were analogous to the one reported in PLCB [14, 15]. These characteristics greatly differ from those of the cells in rhabdoid tumor of other organs, which show intracytoplasmic aggregation of the intermediate filaments [16]. Kusafuka, et al. [7] also reported that cancer cells in one SDCRF case ultrastructurally contained intermediate filament condensation in tumor cytoplasm (Table 1), which was not observed in the extracapsular case of this study. Since the only two SDCRF cases were ultrastructurally analyzed, more cases are required for further ultrastructural investigation.
Intracytoplasmic lumina with microvilli have been reported in various type of breast cancer [17] including PLCB [14, 15]. Cancer cells with a signet ring cell appearance in PLCB were characterized by mucin containing intracytoplasmic lumina with microvilli and immunoreactivity to GCDFP-15 and MUC1 [14, 15]. The results were in accordance with the extracapsular SDCRF case in this report. The findings would support the proposal that SDCRF is a salivary counterpart of PLCB. So far, a salivary counterpart of classic lobular carcinoma of the breast has not been proposed.
The intracytoplasmic lumen with microvilli was also reported in conventional SDC [18]. However, the intracytoplasmic lumen in the conventional SDC was not enough dilated to compress nuclei [18]. Our findings suggest that SDCRF is under signet ring cell differentiation and cancer cells in SDCRF with less mucin are likely to be observed as rhabdoid cells, due to intracytoplasmic lumina with abundant microvilli. Worse outcomes were resulted in SDCRF cases (both de novo and carcinoma ex PA) than conventional SDC [8], in our opinion, probably due to signet ring cell differentiation. Signet ring cell differentiation leads to aggressive behavior, which is ordinarily seen in other organs, such as gastrointestinal tumor. As above mentioned, intracapsular cases showed good prognosis, even with signet ring cell differentiation (Table 1).
SDC is believed to arise from striated, interlobular and excretory ducts of the salivary glands [19]. It is histologically similar to high-grade ductal carcinoma of the breast, showing cribriform structure, comedonecrosis, and Roman bridge architecture [1]. In contrast, SDCRF resembles PLCB rather than ductal carcinoma of the beast, because of the morphology of non-coherent cancer cells and loss of E-cadherin expression [8]. If salivary gland tumor is akin to PLCB, even dissimilar to ductal carcinoma of the breast, pathologists should conduct immunostaining of AR, GCDFP-15 and HER2, thinking of the possibility of SDCRF. The IHC pattern of AR+/GCDFP-15+/HER2variable in the present three cases (Figs. 2, 3, 4) agreed with the previous SDCRF reports [7–9], which was the same pattern as in conventional SDC [20]. We also reported negative ER and PgR expression in SDCRF cases (Table 2), in similar manner with most conventional SDC cases [20]. To distinguish SDCRF from conventional SDC, it is sufficient to recognize less coherent cancer cell morphology in hematoxylin and eosin stain. E-cadherin IHC may be optional to confirm loss of E-cadherin expression in routine diagnostic practice.
Due to the resemblance to PLCB, one of important differential diagnoses is metastatic breast cancer. Since the present cases were all male without any breast cancer history, the possibility of the metastatic breast cancer was low. However, in cases with medical history of breast cancer, especially in women, metastatic breast cancer should be ruled out thoroughly. Because of rhabdoid features, INI-1 deficient tumors are also considered in the differential diagnosis. To distinguish SDCRF from INI-1 deficient tumors, INI-1 immunostaining was useful that cancer cells in SDCRF were positive for INI-1 (Table 2) as also shown in the previous report [8].
We conclude that the present three cases shared morphological and immunohistochemical characteristics with PLCB. Furthermore, all three cases histologically show intracytoplasmic lumina. Ultrastructural analysis revealed that the rhabdoid cells in SDCRF frequently contained large intracytoplasmic lumina with abundant microvilli and eccentric nuclei. The findings indicate that SDCRF is a salivary counterpart of PLCB and under signet ring cell differentiation.
Electronic supplementary material
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Acknowledgements
The authors thank Dr. Shojiroh Morinaga, Department of Diagnostic Pathology, Hino Municipal Hospital, Japan, for the diagnosis of patient 2.
Funding
No funding obtained.
Compliance with Ethical Standards
Conflict of interest
No conflict of interest to disclose.
Footnotes
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