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Signet Ring Basal Cell Carcinoma
PATHOLOGY
Teaching Case
RESEARCH AND PRACTICE © Urban & Fischer Verlag http://www.urbanfischer.de/journals/prp
Signet Ring Basal Cell Carcinoma A Case Study Emphasizing the Differential Diagnosis of Neoplasms with Signet Ring Cell Formation Kyriaki Aroni, Andreas Ch. Lazaris, Irene Nikolaou, Angelica Saetta, Nikolaos Kavantzas, Panagiotis S. Davaris Department of Pathology, School of Medicine, The National and Capodistrian University of Athens, Greece
Summary Signet ring cells are cells in which the nucleus is crescentically compressed to the cellular border so that the cells look like signet rings. Due to the pluripotential nature of the basal cells of the epidermis, basal cell carcinoma displays many histopathological variants. We herein report the rare case of a middle-aged woman who had a basal cell carcinoma on the skin of the upper lip. The neoplasm was predominantly composed of cells with signet ring configuration. Histochemically, the latter were mucinnegative. Immunohistochemistry demonstrated intracytoplasmic reactivity for cytokeratin MNF116 with strong staining intensity, as well as for smooth muscle actin. The signet ring tumor cells were S100 protein-negative and carcinoembryonic antigen-negative. The lack of ploidy abnormality as well as of molecular alterations in K-ras and p53 genes may explain in part the non-aggressive biological behavior of the present tumor. Because of potential diagnostic difficulties, the pathologist should be aware of this unusual form of basal cell carcinoma. A brief review of the literature on the differential diagnosis of signet ring cell cutaneous tumors is presented. Key words: Basal cell carcinoma – Signet ring – Differential diagnosis – Immunohistochemistry – DNA cytometry
Introduction Basal cell carcinoma (BCC), the most common malignant cutaneous neoplasm [3], arises from a pluropotential stem cell that can exhibit a wide spectrum of differPathol. Res. Pract. 197: 853–856 (2001)
entiation [2]. A signet ring is a finger ring containing a signet or seal that can be used as a signature by an official for marking documents. Signet ring cell formation is a well-known phenomenon in carcinomas of the gastrointestinal tract and pancreas. These cells are so named because a round space, inclusion, or accumulation distorts the nuclei of affected cells so that the rim of cytoplasm resembles an annulus and the compressed nucleus a signet [1]. We herein report a distinctly unusual variant of BCC of the signet ring cell type with emphasis on its differential diagnosis and on the absence of potential markers of tumor aggressiveness.
Report of a Case A 45-year-old woman presented with a 0.4 cm, pearly papule on the upper lip that had been very slowly enlarging for several years. The lesion was diagnosed as BCC by two shave biopsies; a wide excision was performed, and the patient’s postoperative course was uneventful. She has been free of disease 18 months after surgery.
Materials and Methods The tissue was fixed in 10% neutral buffered formaldehyde solution. In addition to hematoxylin and eosin, sections were
Address for correspondence: Kyriaki Aroni, Dept. of Pathology, The Athens National University Medical School, 75 Mikras Asias str., Goudi, GR-115 27 Athens, Greece. Tel.: 003-010-7771206, Fax: 003-010-7462157. E-mail: [email protected] 0344-0338/01/197/12-853 $15.00/0
854 · K. Aroni et al. stained with alcian blue (pH 2.5), periodic acid Schiff reaction with diastase (PAS-D) and without diastase (PAS) and Congo red for amyloid deposits. Feulgen stain was used for the assessment of nuclear DNA content. Immunohistochemical studies were done on deparaffinized sections using the standard avidin-biotin complex method (all reagents from Dako, Glostrup, Denmark) and diaminobenzidine as a chromogen. The sources and working dilutions of the primary antisera used are shown in the Table 1. Normal sera were substituted for “negative” controls. Molecular Analysis DNA extracted from the tumor biopsy was examined for the presence of K-ras and p53 mutations. K-ras codon 12 mutations were analyzed by PCR-RFLPs. The primers used for amplification of K-ras exon 1 encompass two restriction sites for BstNI. The mutant allele could be defined by the presence of a 143 bp band. p53 gene mutations at exons 7-9 were determined using the Non Isotopic RNase Cleavage Assay (NIRCA, Ambion, USA). DNA was amplified, and during a second cycle of amplification, promoters for transcription were integrated into the PCR product, which was then transcribed and hybridized to the normal sequences, followed by cleavage with RNAses. The latter enzymes recognize and cleave mismatches due to the presence of mutations in the amplified fragments. The limited size of the specimen did not allow further investigation. DNA Image Cytometry Images were acquired using a Zeiss Axiolab microscope (Carl Zeiss Jena GmbH, Jena, Germany) with a mechanical stage, fitted with a SONY-iris CCD videocamera (SONY corporation, Tokyo, Japan). The latter was connected to a Pentium II personal computer loaded with the Image Scan Pro Software (Science, Erkrath, Germany). Slides were examined at low power magnification (×40) to identify the areas with the highest cellularity. A total number of ≥300 nuclei stained with Feulgen was selected at high power magnification (×400) and stored as JPEG file [1550 × 1070 pixels, 16.7 million colours (24-bit)]. The images were then converted to grayscale, and the staining intensity of the Feulgen-stained nuclei was measured semiautomatically, followed by a classification of the nuclei in pairs according to their staining intensity. Finally, the graphic presentation of the nuclei demonstrating their distribution according to the DNA content was performed.
Pathological Findings On light microscopy, the tumor consisted of infiltrating angulated lobules of basaloid keratinocytes with focal peripheral palisading (Fig. 1) and clefts separating neoplastic epithelium and intervening fibroblastic stroma (retraction artifact). Cells showing a signet ring configuration were predominantly observed among the total of neoplastic cells (Fig. 2), located mainly at the center of the tumor nests. Some of these cells’ vacuoles appeared empty. No mucin histochemical stain showed any positively stained material within the vacuoles; PAS was almost totally negative. Congo-red was also negative. Mitoses were not encountered among the neoplastic cells. Immunohistochemical staining results are given in the Table. Interestingly, among all keratins examined, keratin MNF116 demonstrated the strongest staining intensity among neoplastic cells (Fig. 3). Neoplastic cells were S100- and vimentin-immunonegative. Rare, dispersed S-100- and vimentin-positive cells were detectable within the tumor formations; they probably corresponded to Langerhans’ dendritic cells. Despite the negative staining for S100 protein of the neoplastic cells, their positive staining for smooth muscle actin argues in favor of their myoepithelial differentiation. A molecular biological examination revealed that no mutation was present either at codon 12 of the K-ras gene or in exons 7–9 of the p53 gene. DNA image cytometry revealed a nearly diploid graphic presentation.
Discussion Signet ring cell BCC does not appear to differ clinically from ordinary BCC; the very few patients with signet ring cell BCC reported so far are elderly, and all tumors occurred on the face. The clinical behavior of signet ring cell BCC is expectedly mild, and the lack of genetic defects, at least in the two genes examined in the present case, as well as the absence of aneuploidy, probably reinforce this concept.
Table 1. Immunohistochemical features of the tumor Antibody
Type
Clone
Dilution
Expression
Source
Keratin (wide spectrum screening) CK8, low molecular weight CK, high molecular weight Cytokeratin 45 & 56 KD Cytokeratin 45,46,56.5 CEA Smooth muscle actin S100 protein Vimentin CD68
Poly Mon Mon Mon Mon Mon Mon Poly Mon Mon
– 35β11 34β12 LP34 MNF116 II-7 1A4 – V9 KP1
1:500 1:25 1:50 1:50 1:50 1:50 1:25 1:200 1:25 1:50
± – ± – ± – ± – – –
Dako Dako Dako SkyTek SkyTek Dako Dako Dako Dako Dako
Poly = polyclonal, Mon = monoclonal, + positive, – negative, ± positivity of low staining intensity
Signet Ring Basal Cell Carcinoma · 855
The histological diagnosis of a signet ring cell BCC can be quite difficult, especially in punch biopsy material when architectural features cannot be readily assessed. The overall pattern of growth is probably the most important criterion in the histopathological assessment of the neoplasm. The characteristic histological features that allow for the identification of a BCC are well known [4]; when none are observed in a skin neoplasm with signet ring cells, the pathologist may consider the diagnosis of a metastatic adenocarcinoma. Cutaneous metastases are seen in 9% of patients with internal malignancies and for the most part do not represent a real differential diagnosis of BCC with signet ring-like cells. However, some metastases may exhibit basaloid features; breast carcinoma in the dermis may most closely resemble BCC. Nuclear pleomorphism, hyperchromatism, increased mitotic activity and clinical correlation should allow for histopathological distinction [4]. In cutaneous metastases of visceral adenocarcinomas, abundant mucin can be found in the cytoplasm of cells; the latter stains with PAS and PAS-D. Indeed, in gastric carcinoma, for instance, nuclear displacement in signet ring cells is due to the cytoplasmic accumulation of mucin. These lesions contain neoplastic cells that are keratinpositive, and most have vacuoles that express CEA at the edges. Mucin as well as CEA were undetectable in the neoplastic cells of the present case. In metastatic lesions, histology typically shows diffuse dermal infiltrate, sometimes with extension into the subcutis. Typically, the overlying epidermis is intact, and there is an underlying spared zone of uninvolved dermis. The tumor cells are often found in narrow strands between bundles of collagen. None of the above mentioned findings was detected in this case. Apart from metastatic adenocarcinomas, rare cases of other primary cutaneous signet ring cell neoplasms occur [1]. Signet ring cells can be detected in few benign neoplasms as well as in quite a lot of malignant ones [i.e. lymphoma, clear cell sweat gland carcinoma, trichilemmocarcinoma, signet ring cell squamous cell carcinoma (SSC), sebaceous carcinoma]. Signet ring melanoma
Fig. 1. The tumour’s architectural pattern (H & E, ×100). Fig. 2. Numerous signet ring cells among the neoplastic population (H & E, ×400). Fig. 3. MNF116 immunopositivity of neoplastic cells (ABComplex/HRP, ×400).
856 · K. Aroni et al.
has been reported in extracutaneous locations to date, and must also be considered. Immunohistochemical stains are essential for reaching a diagnosis by identifying the cell type. In signet ring cell melanoma, staining for vimentin is thought to be consistently positive while, paradoxically, staining for S100 protein and HMB45 is not [9]. In signet ring cell lymphomas, either B- or Tcell markers are positive. CEA is reported to be positive in sweat gland carcinoma, and mucin stains are invariably positive. In general, duct-like structures and not hair follicles within the islands of tumour cells are shown [2]. In trichilemmocarcinoma, areas of replacement of the epidermis by clear cells (merely resembling the signet ring type) and budding along the lower onethird of the epidermis with formation of abnormal pilar complexes or abortive hair follicles are noticed. Normal pilar structures are absent [2]. Immunolabeling for CEA is frequently positive in SCC and sebaceous carcinoma (and negative in BCC). In sebaceous carcinoma, the sebaceous neoplastic cells show foamy, microvesicular cytoplasm rather than a signet ring appearance [2]. Finally, we have to point out that the difference setting signet ring cell BCC apart from all the others is morphological. This morphological difference lies in the overall architecture of the tumor nests, some degree of peripheral palisading and the characteristic participation of the stroma. These features form the basis for the diagnosis of BCC regardless of its line of differentiation. The vacuoles of the present case were PAS (and PAS-D)-negative as well as keratin-negative, indicating that signet ring cell formation in BCC may not be caused by glycogen or mucin. The MNF116-positive reaction of neoplastic cells observed favors the keratinous nature of the signet ring cells’ content. Actually, cytokeratin MNF116 has been reported to be strongly expressed on the basal cells of the epidermis and adnexae of normal skin [6] as well as on the vacuolated basal keratinocytes in epidermolysis bullosa simplex [5]. It is noteworthy that signet ring cells of the present case expressed smooth muscle actin. Although positive staining of neoplastic cells for smooth muscle actin does not imply a myoepithelial differentiation per se [8], this staining characteristic has been observed in other BCCs as well [8].
To sum up, the signet ring appearance of tumor cells is merely based on morphology and does not necessarily indicate the presence of cytoplasmic mucin as in poorlydifferentiated adenocarcinoma of the stomach. Cells can acquire a signet ring-like shape by the accumulation of substances other than mucin [7]. Signet ring cells are not characteristic of any particular primary or secondary cutaneous neoplasm, but rather can be encountered in a variety of processes of different nature. Signet ring cells in cutaneous tumors are not necessarily indicative of glandular differentiation, nor are they necessarily a sign of malignancy. Acknowledgment. The authors acknowledge the excellent technical assistance of the biologist A. Goudopoulou.
References 1. Bastian BC, Kutzner H, Yen TSB, LeBoit PE (1999) Signet-ring cell formation in cutaneous neoplasms. J Am Acad Dermatol 41: 606–613 2. Cohen RE, Zaim MT (1988) Signet-ring clear-cell basal cell carcinoma. J Cutan Pathol 15: 183–187 3. Johnson TM, Tschen J, Ho C, Lowe L, Nelson BR (1994) Unusual basal cell carcinomas. Cutis 54: 85–92 4. Lowe L, Rapini RP (1991) Newer variants and simulants of basal cell carcinoma. J Dermatol Surg Oncol 17: 641–648 5. Prieto VG, McNutt NS (1994) Immunohistochemical detection of keratin with the monoclonal antibody MNF116 is useful in the diagnosis of epidermolysis bullosa simplex. J Cutan Pathol 21: 118–122 6. Prieto VG, Lugo J, McNutt NS (1996) Intermediate- and low-molecular-weight keratin detection with the monoclonal antibody MNF116. An immunohistochemical study on 232 paraffin-embedded cutaneous lesions. J Cutan Pathol 23: 234–241 7. Sook Seo I, Warner TFCS, Priest JB (1979) Basal cell carcinoma-signet ring type. J Cutan Pathol 6: 101–107 8. Suster S, y Cajal SR (1991) Myoepithelial differentiation in basal cell carcinoma. Am J Dermatopathol 13: 350–357 9. White GM, Barr RJ, Liao S-Y (1991) Signet ring cell basal cell carcinoma. Am J Dermatopathol 13: 288–292 Received: June 25, 2001 Accepted in revised version: October 1, 2001
Teaching Case
RESEARCH AND PRACTICE © Urban & Fischer Verlag http://www.urbanfischer.de/journals/prp
Signet Ring Basal Cell Carcinoma A Case Study Emphasizing the Differential Diagnosis of Neoplasms with Signet Ring Cell Formation Kyriaki Aroni, Andreas Ch. Lazaris, Irene Nikolaou, Angelica Saetta, Nikolaos Kavantzas, Panagiotis S. Davaris Department of Pathology, School of Medicine, The National and Capodistrian University of Athens, Greece
Summary Signet ring cells are cells in which the nucleus is crescentically compressed to the cellular border so that the cells look like signet rings. Due to the pluripotential nature of the basal cells of the epidermis, basal cell carcinoma displays many histopathological variants. We herein report the rare case of a middle-aged woman who had a basal cell carcinoma on the skin of the upper lip. The neoplasm was predominantly composed of cells with signet ring configuration. Histochemically, the latter were mucinnegative. Immunohistochemistry demonstrated intracytoplasmic reactivity for cytokeratin MNF116 with strong staining intensity, as well as for smooth muscle actin. The signet ring tumor cells were S100 protein-negative and carcinoembryonic antigen-negative. The lack of ploidy abnormality as well as of molecular alterations in K-ras and p53 genes may explain in part the non-aggressive biological behavior of the present tumor. Because of potential diagnostic difficulties, the pathologist should be aware of this unusual form of basal cell carcinoma. A brief review of the literature on the differential diagnosis of signet ring cell cutaneous tumors is presented. Key words: Basal cell carcinoma – Signet ring – Differential diagnosis – Immunohistochemistry – DNA cytometry
Introduction Basal cell carcinoma (BCC), the most common malignant cutaneous neoplasm [3], arises from a pluropotential stem cell that can exhibit a wide spectrum of differPathol. Res. Pract. 197: 853–856 (2001)
entiation [2]. A signet ring is a finger ring containing a signet or seal that can be used as a signature by an official for marking documents. Signet ring cell formation is a well-known phenomenon in carcinomas of the gastrointestinal tract and pancreas. These cells are so named because a round space, inclusion, or accumulation distorts the nuclei of affected cells so that the rim of cytoplasm resembles an annulus and the compressed nucleus a signet [1]. We herein report a distinctly unusual variant of BCC of the signet ring cell type with emphasis on its differential diagnosis and on the absence of potential markers of tumor aggressiveness.
Report of a Case A 45-year-old woman presented with a 0.4 cm, pearly papule on the upper lip that had been very slowly enlarging for several years. The lesion was diagnosed as BCC by two shave biopsies; a wide excision was performed, and the patient’s postoperative course was uneventful. She has been free of disease 18 months after surgery.
Materials and Methods The tissue was fixed in 10% neutral buffered formaldehyde solution. In addition to hematoxylin and eosin, sections were
Address for correspondence: Kyriaki Aroni, Dept. of Pathology, The Athens National University Medical School, 75 Mikras Asias str., Goudi, GR-115 27 Athens, Greece. Tel.: 003-010-7771206, Fax: 003-010-7462157. E-mail: [email protected] 0344-0338/01/197/12-853 $15.00/0
854 · K. Aroni et al. stained with alcian blue (pH 2.5), periodic acid Schiff reaction with diastase (PAS-D) and without diastase (PAS) and Congo red for amyloid deposits. Feulgen stain was used for the assessment of nuclear DNA content. Immunohistochemical studies were done on deparaffinized sections using the standard avidin-biotin complex method (all reagents from Dako, Glostrup, Denmark) and diaminobenzidine as a chromogen. The sources and working dilutions of the primary antisera used are shown in the Table 1. Normal sera were substituted for “negative” controls. Molecular Analysis DNA extracted from the tumor biopsy was examined for the presence of K-ras and p53 mutations. K-ras codon 12 mutations were analyzed by PCR-RFLPs. The primers used for amplification of K-ras exon 1 encompass two restriction sites for BstNI. The mutant allele could be defined by the presence of a 143 bp band. p53 gene mutations at exons 7-9 were determined using the Non Isotopic RNase Cleavage Assay (NIRCA, Ambion, USA). DNA was amplified, and during a second cycle of amplification, promoters for transcription were integrated into the PCR product, which was then transcribed and hybridized to the normal sequences, followed by cleavage with RNAses. The latter enzymes recognize and cleave mismatches due to the presence of mutations in the amplified fragments. The limited size of the specimen did not allow further investigation. DNA Image Cytometry Images were acquired using a Zeiss Axiolab microscope (Carl Zeiss Jena GmbH, Jena, Germany) with a mechanical stage, fitted with a SONY-iris CCD videocamera (SONY corporation, Tokyo, Japan). The latter was connected to a Pentium II personal computer loaded with the Image Scan Pro Software (Science, Erkrath, Germany). Slides were examined at low power magnification (×40) to identify the areas with the highest cellularity. A total number of ≥300 nuclei stained with Feulgen was selected at high power magnification (×400) and stored as JPEG file [1550 × 1070 pixels, 16.7 million colours (24-bit)]. The images were then converted to grayscale, and the staining intensity of the Feulgen-stained nuclei was measured semiautomatically, followed by a classification of the nuclei in pairs according to their staining intensity. Finally, the graphic presentation of the nuclei demonstrating their distribution according to the DNA content was performed.
Pathological Findings On light microscopy, the tumor consisted of infiltrating angulated lobules of basaloid keratinocytes with focal peripheral palisading (Fig. 1) and clefts separating neoplastic epithelium and intervening fibroblastic stroma (retraction artifact). Cells showing a signet ring configuration were predominantly observed among the total of neoplastic cells (Fig. 2), located mainly at the center of the tumor nests. Some of these cells’ vacuoles appeared empty. No mucin histochemical stain showed any positively stained material within the vacuoles; PAS was almost totally negative. Congo-red was also negative. Mitoses were not encountered among the neoplastic cells. Immunohistochemical staining results are given in the Table. Interestingly, among all keratins examined, keratin MNF116 demonstrated the strongest staining intensity among neoplastic cells (Fig. 3). Neoplastic cells were S100- and vimentin-immunonegative. Rare, dispersed S-100- and vimentin-positive cells were detectable within the tumor formations; they probably corresponded to Langerhans’ dendritic cells. Despite the negative staining for S100 protein of the neoplastic cells, their positive staining for smooth muscle actin argues in favor of their myoepithelial differentiation. A molecular biological examination revealed that no mutation was present either at codon 12 of the K-ras gene or in exons 7–9 of the p53 gene. DNA image cytometry revealed a nearly diploid graphic presentation.
Discussion Signet ring cell BCC does not appear to differ clinically from ordinary BCC; the very few patients with signet ring cell BCC reported so far are elderly, and all tumors occurred on the face. The clinical behavior of signet ring cell BCC is expectedly mild, and the lack of genetic defects, at least in the two genes examined in the present case, as well as the absence of aneuploidy, probably reinforce this concept.
Table 1. Immunohistochemical features of the tumor Antibody
Type
Clone
Dilution
Expression
Source
Keratin (wide spectrum screening) CK8, low molecular weight CK, high molecular weight Cytokeratin 45 & 56 KD Cytokeratin 45,46,56.5 CEA Smooth muscle actin S100 protein Vimentin CD68
Poly Mon Mon Mon Mon Mon Mon Poly Mon Mon
– 35β11 34β12 LP34 MNF116 II-7 1A4 – V9 KP1
1:500 1:25 1:50 1:50 1:50 1:50 1:25 1:200 1:25 1:50
± – ± – ± – ± – – –
Dako Dako Dako SkyTek SkyTek Dako Dako Dako Dako Dako
Poly = polyclonal, Mon = monoclonal, + positive, – negative, ± positivity of low staining intensity
Signet Ring Basal Cell Carcinoma · 855
The histological diagnosis of a signet ring cell BCC can be quite difficult, especially in punch biopsy material when architectural features cannot be readily assessed. The overall pattern of growth is probably the most important criterion in the histopathological assessment of the neoplasm. The characteristic histological features that allow for the identification of a BCC are well known [4]; when none are observed in a skin neoplasm with signet ring cells, the pathologist may consider the diagnosis of a metastatic adenocarcinoma. Cutaneous metastases are seen in 9% of patients with internal malignancies and for the most part do not represent a real differential diagnosis of BCC with signet ring-like cells. However, some metastases may exhibit basaloid features; breast carcinoma in the dermis may most closely resemble BCC. Nuclear pleomorphism, hyperchromatism, increased mitotic activity and clinical correlation should allow for histopathological distinction [4]. In cutaneous metastases of visceral adenocarcinomas, abundant mucin can be found in the cytoplasm of cells; the latter stains with PAS and PAS-D. Indeed, in gastric carcinoma, for instance, nuclear displacement in signet ring cells is due to the cytoplasmic accumulation of mucin. These lesions contain neoplastic cells that are keratinpositive, and most have vacuoles that express CEA at the edges. Mucin as well as CEA were undetectable in the neoplastic cells of the present case. In metastatic lesions, histology typically shows diffuse dermal infiltrate, sometimes with extension into the subcutis. Typically, the overlying epidermis is intact, and there is an underlying spared zone of uninvolved dermis. The tumor cells are often found in narrow strands between bundles of collagen. None of the above mentioned findings was detected in this case. Apart from metastatic adenocarcinomas, rare cases of other primary cutaneous signet ring cell neoplasms occur [1]. Signet ring cells can be detected in few benign neoplasms as well as in quite a lot of malignant ones [i.e. lymphoma, clear cell sweat gland carcinoma, trichilemmocarcinoma, signet ring cell squamous cell carcinoma (SSC), sebaceous carcinoma]. Signet ring melanoma
Fig. 1. The tumour’s architectural pattern (H & E, ×100). Fig. 2. Numerous signet ring cells among the neoplastic population (H & E, ×400). Fig. 3. MNF116 immunopositivity of neoplastic cells (ABComplex/HRP, ×400).
856 · K. Aroni et al.
has been reported in extracutaneous locations to date, and must also be considered. Immunohistochemical stains are essential for reaching a diagnosis by identifying the cell type. In signet ring cell melanoma, staining for vimentin is thought to be consistently positive while, paradoxically, staining for S100 protein and HMB45 is not [9]. In signet ring cell lymphomas, either B- or Tcell markers are positive. CEA is reported to be positive in sweat gland carcinoma, and mucin stains are invariably positive. In general, duct-like structures and not hair follicles within the islands of tumour cells are shown [2]. In trichilemmocarcinoma, areas of replacement of the epidermis by clear cells (merely resembling the signet ring type) and budding along the lower onethird of the epidermis with formation of abnormal pilar complexes or abortive hair follicles are noticed. Normal pilar structures are absent [2]. Immunolabeling for CEA is frequently positive in SCC and sebaceous carcinoma (and negative in BCC). In sebaceous carcinoma, the sebaceous neoplastic cells show foamy, microvesicular cytoplasm rather than a signet ring appearance [2]. Finally, we have to point out that the difference setting signet ring cell BCC apart from all the others is morphological. This morphological difference lies in the overall architecture of the tumor nests, some degree of peripheral palisading and the characteristic participation of the stroma. These features form the basis for the diagnosis of BCC regardless of its line of differentiation. The vacuoles of the present case were PAS (and PAS-D)-negative as well as keratin-negative, indicating that signet ring cell formation in BCC may not be caused by glycogen or mucin. The MNF116-positive reaction of neoplastic cells observed favors the keratinous nature of the signet ring cells’ content. Actually, cytokeratin MNF116 has been reported to be strongly expressed on the basal cells of the epidermis and adnexae of normal skin [6] as well as on the vacuolated basal keratinocytes in epidermolysis bullosa simplex [5]. It is noteworthy that signet ring cells of the present case expressed smooth muscle actin. Although positive staining of neoplastic cells for smooth muscle actin does not imply a myoepithelial differentiation per se [8], this staining characteristic has been observed in other BCCs as well [8].
To sum up, the signet ring appearance of tumor cells is merely based on morphology and does not necessarily indicate the presence of cytoplasmic mucin as in poorlydifferentiated adenocarcinoma of the stomach. Cells can acquire a signet ring-like shape by the accumulation of substances other than mucin [7]. Signet ring cells are not characteristic of any particular primary or secondary cutaneous neoplasm, but rather can be encountered in a variety of processes of different nature. Signet ring cells in cutaneous tumors are not necessarily indicative of glandular differentiation, nor are they necessarily a sign of malignancy. Acknowledgment. The authors acknowledge the excellent technical assistance of the biologist A. Goudopoulou.
References 1. Bastian BC, Kutzner H, Yen TSB, LeBoit PE (1999) Signet-ring cell formation in cutaneous neoplasms. J Am Acad Dermatol 41: 606–613 2. Cohen RE, Zaim MT (1988) Signet-ring clear-cell basal cell carcinoma. J Cutan Pathol 15: 183–187 3. Johnson TM, Tschen J, Ho C, Lowe L, Nelson BR (1994) Unusual basal cell carcinomas. Cutis 54: 85–92 4. Lowe L, Rapini RP (1991) Newer variants and simulants of basal cell carcinoma. J Dermatol Surg Oncol 17: 641–648 5. Prieto VG, McNutt NS (1994) Immunohistochemical detection of keratin with the monoclonal antibody MNF116 is useful in the diagnosis of epidermolysis bullosa simplex. J Cutan Pathol 21: 118–122 6. Prieto VG, Lugo J, McNutt NS (1996) Intermediate- and low-molecular-weight keratin detection with the monoclonal antibody MNF116. An immunohistochemical study on 232 paraffin-embedded cutaneous lesions. J Cutan Pathol 23: 234–241 7. Sook Seo I, Warner TFCS, Priest JB (1979) Basal cell carcinoma-signet ring type. J Cutan Pathol 6: 101–107 8. Suster S, y Cajal SR (1991) Myoepithelial differentiation in basal cell carcinoma. Am J Dermatopathol 13: 350–357 9. White GM, Barr RJ, Liao S-Y (1991) Signet ring cell basal cell carcinoma. Am J Dermatopathol 13: 288–292 Received: June 25, 2001 Accepted in revised version: October 1, 2001