Primary cutaneous signet ring cell carcinoma (PCSRCC) is a very unusual but distinctive clinicopathologic entity that can simulate metastatic adenocarcinomas. It is defined as a diffuse malignant epithelial neoplasia localized in the dermis and subcutis without epidermal involvement, showing variable amounts of signet ring cells, without evidence of visceral adenocarcinoma. We present 2 cases of PCSRCC, which involved eyelids and axilla respectively. Despite thorough systemic workup, primary sources could not be demonstrated in either case. The tumor cells are positive for gross cystic disease fluid protein 15 in addition to a variety of glandular markers. Furthermore, both cases were immunostained with cytokeratin 20 (CK20). In conclusion, we report 2 cases of PCSRCC expressing CK20 immunoreactivity. CK20-positive primary cutaneous tumors should include PCSRCC in addition to Merkel cell carcinoma

ANSAI, Shinichi

KIYOHARA, Takahiro

KOURABA, Sachio

KUMAKIRI, Masanobu

TOKURIKI, Atsushi

Community Repository of Fukui

 1
Primary cutaneous signet ring cell carcinoma expressing cytokeratin 20 
immunoreactivity 
 
Takahiro Kiyohara, MD,a Masanobu Kumakiri, MD,a Sachio Kouraba, MD,a Atsushi 
Tokuriki, MD,a and Shinichi Ansai, MD,b Fukui and Sapporo, Japan 
 
From the Department of Dermatology, University of Fukui, Fukuia and the Sapporo 
Institute for Dermatopathology, Sapporo.b
 
Funding sources: None. 
 
Conflicts of interest: None identified. 
 
Reprint requests: Takahiro Kiyohara, MD, Department of Dermatology, University of 
Fukui, 23-3 Shimoaizuki, Matsuoka-cho, Yoshida-gun, Fukui 910-1193, Japan. 
E-mail: kiyo @ fmsrsa.fukui-med.ac.jp 
Tel. +81 776 61 3111 
Fax. +81 776 61 8112 
 
Word 2,260; References 21; Figures 5
  
 2
Abstract 
 
Primary cutaneous signet ring cell carcinoma (PCSRCC) is a very unusual but 
distinctive clinicopathologic entity that can simulate metastatic adenocarcinomas.  It is 
defined as a diffuse malignant epithelial neoplasia localized in the dermis and subcutis 
without epidermal involvement, showing variable amounts of signet ring cells, without 
evidence of visceral adenocarcinoma.  We present 2 cases of PCSRCC, which involved 
eyelids and axilla respectively.  Despite thorough systemic workup, primary sources 
could not be demonstrated in either case.  The tumor cells are positive for gross cystic 
disease fluid protein 15 in addition to a variety of glandular markers.  Furthermore, 
both cases were immunostained with cytokeratin 20 (CK20). 
   In conclusion, we report 2 cases of PCSRCC expressing CK20 immunoreactivity.  
CK20-positive primary cutaneous tumors should include PCSRCC in addition to 
Merkel cell carcinoma. 
 
Key words: Signet ring cell carcinoma, Cytokeratin 20, Metastatic adenocarcinoma, 
Mucin
  
 3
Cytokeratin (CK20) is a low-molecular-weight cytokeratin, that was originally 
identified by Moll et al.1-3 as protein IT in 2-dimensional gel electrophoresis of 
cytoskeletal extracts of intestinal epithelia.  In normal tissues, CK20 is expressed only 
in the gastrointestinal epithelium, urothelium, and Merkel cell.2-5  There has been 
recent interest in the application of CK20 antibody for determining the primary site of 
carcinomas.2,5,6
   Among skin tumors, Merkel cell carcinoma and metastatic adenocarcinomas may be 
positive for CK20, but CK20-positive primary cutaneous adenocarcinomas have not 
previously been reported.  We describe herein two cases of CK20-positive Primary 
cutaneous signet ring cell carcinoma (PCSRCC), a rare variant of primary cutaneous 
adenocarcinomas. 
 
MATERIALS AND METHODS 
 
     CASE REPORTS 
Case 1 
   We encountered a 73-year-old man with a 7-year history of multiple nodules and 
swelling around the right orbit.  Physical examination demonstrated diffuse swelling 
and erythema with a dozen of papules and nodules in the upper and lower eyelids (Fig 
1).  Each papule and nodule was 5 to 6 mm in diameter.  A few subcutaneous nodules 
were present.  The patient could not open his right eye.  There was no superficial 
lymphadenopathy.  The results of routine laboratory examinations were normal except 
for slight anemia.  Tumor markers, including squamous cell carcinoma, 
carcinoembryonic antigen (CEA), CA19-9, and alfa-fetoprotein were within the normal 
range in serum.  Magnetic resonance imaging (MRI) of the head demonstrated a 
well-defined lesion from the right orbit to the periorbital skin, which corresponded to 
the papules, nodules, and swelling.  Computed tomographic scans, MRI, various 
scintigrams, and gastrointestinal examinations did not demonstrate any evidence of 
other primary or metastatic lesions.  Radical surgery including exenteration plus the 
removal of any involved contiguous facial skin was performed, followed by 60Co 
irradiation (total 65Gy).  However, the tumor recurred in the left perioribital area 5 
years after resection. 
 
Case 2 
   A 62-year-old man presented with a brown tumor in the right axilla, which had 
progressively enlarged over about 14 years.  Physical examination demonstrated a 
5.7x3.7-cm, elastic hard tumor located in the right axilla.  The rough surface of the 
tumor was accompanied by red nodules (Fig 2).  The right axillary lymph node was 
swollen.  Laboratory examinations demonstrated several abnormal results caused by 
chronic NK-cell lymphocytosis: anemia, leukocytosis, thrombopenia, and liver 
dysfunction.  Various natural killer cell markers including CD2, 7, 16, 56, and 57, were 
elevated in the peripheral blood.  Clonal rearrangement of T-cell receptor genes was 
not detected by Southern blot analysis.  Among the tumor markers, serum CEA was 
slightly elevated.  Computed tomographic scans, MRI, various scintigrams, and 
gastrointestinal examinations did not demonstrate any evidence of other primary 
sources.  Despite the administration of combination chemotherapy, the patient died 9 
months after the initial consultation because of leukemia subsequent to chronic NK-cell 
  
 4
lymphocytosis. 
 
     HISTOPATHOLOGY 
   Skin lesions from both cases and the swollen axillary lymph node from patient 2 
were excised.  Both skin lesions had almost identical microscopic findings.  
Histological examinations demonstrated a solid tumor extending from the upper dermis 
to the subcutaneous tissue without connection to the epidermis or appendages.  The 
tumor cells were scattered singly, in groups of several cells, or arranged in a single file 
among collagen fibers, presenting a trabecular pattern (Fig 3).  Intercellular lumina 
were partly formed by several cells.  The tumors were composed of atypical cells with 
abundant eosinophilic, vacuolated cytoplasms.  Occasional signet ring cells were also 
seen (Fig 4).  Histological findings of the lymph node from patient 2 showed poorly 
differentiated adenocarcinoma. 
 
     HISTOCHEMISTRY 
   Both cases showed identical histochemical results.  The tumor cells, including the 
signet ring cells, were positive for diastase-resistant PAS and alcian blue. 
 
     IMMUNOHISTOCHEMISTRY 
   Sections cut from formalin-fixed, paraffin-embedded tissues were mounted on 
silanized glass slides.  Immunohistochemical staining was performed using the labeled 
streptavidin-biotin method as described previously.7  The antibodies included CK20 
(Dako Corporation, Carpinteria, CA; cytokeratin 20, clone Ks20.8, Code M7019; 
dilution: 1:100), MNF-116 (Dako Corporation; low-molecular-weight cytokeratin, clone 
MNF116; dilution: 1:50), 34 β E12 (Dako Corporation; high-molecular-weight 
cytokeratin, clone 34βE12; dilution: 1:50), BCA225 (Cambridge Laboratories; clone 
CU18; dilution: 1:10), GCDFP15 (Cambridge Laboratories; clone D6; dilution: 1:100), 
CEA (Dako Corporation; clone II-7; dilution: 1:25), CA125 (Immunotech; clone 
OC125; prediluted preparation), CA15-3 (Dako Corporation; clone DF3; dilution: 1:50), 
CA19-9 (Dako Corporation; clone 116-NS-19-9; prediluted preparation), S-100 protein 
(Dako Corporation; polyclonal; prediluted preparation), and CD15 (Becton-Dickinson, 
Franklin Lakes, NJ; clone LeuM1;dilution: 1:5).  Briefly, the sections were incubated 
with primary antibodies at room temperature for 60 minutes followed by biotinylated 
rabbit antimouse immunoglobulin for 60 minutes and then avidin-biotin-peroxidase 
complex for 60 minutes.  The color reaction was developed with 0.1% 
diaminobenzidine.  Appropriate positive and negative controls were used. 
   Both cases showed identical immunohistochemical results.  The tumor cells, 
including signet ring cells, were strongly positive for MNF116, CA15-3, BCA225, 
GCDFP15, and weakly for 34βE12, CEA, CA125.  They were negative for CA19-9, 
S-100 protein, and CD15.  Both cases demonstrated weak positivity for CK20 (Fig 5). 
 
     ELECTRON MICROSCOPY 
   Fresh tissue obtained from patient 1 was processed for electron microscopy by 
routine procedures.  The tumor cells showed cytoplasmic pseudolumens with 
microvilli and flocculent mucus material.  In addition, electron-dense granules were 
membrane-bound. 
 
  
 5
     RESULTS 
   Histologically, the tumors were localized in dermis and subcutis without epithelial 
involvement, showing variable amounts of signet ring cells.  The tumor cells were 
positive for GCDFP15 in addition to a variety of ductal and glandular markers, such as 
MNF116, BCA225, CEA, CA15-3, and CA125.  These cells were also positive for 
CK20. 
 
     DISCUSSION 
   CK20 is consistently present in colonic adenocarcinoma and their metastases to 
lymph nodes, liver, lung, and ovaries.5  Adenocarcinomas of the upper gastrointestinal 
tract, pancreas, and cholangiocarcinomas show variable reactivity.5  Hepatocellular 
carcinomas and carcinoid tumors often showed focal reactivity limited to scattered 
tumor cells.5  In contrast, CK20 is virtually absent in primary adenocarcinomas of lung, 
ovaries, and endometrium.2,5,6  Notable exceptions among ovarian tumors were 
mucinous neoplasms that showed variable, sometimes significant CK20 reactivity.5  
Transitional cell carcinoma is usually positive, while prostatic and renal 
adenocarcinomas are negative.  Typically, squamous cell carcinomas of all organs and 
carcinomas of the breast are also negative.  Merkel cell carcinomas of the skin show 
consistent reactivity, while small cell carcinomas of the lung are negative.  CK20 is a 
suitable adjunct marker especially to separate adenocarcinomas of gastrointestinal 
versus nongastrointestinal origin. 
   GCDFP15 was initially thought to be specific for apocrine glands and tumors with 
apocrine differentiation.8  However, the antigen is demonstrated in normal eccrine 
glands.9,10  Whether GCDFP15 is specific for apocrine tumors is currently under 
discussion.11  Although this antigen is found also in mammary and salivary glands, it is 
not found in gastrointestinal mucosa.12-14  Regardless, GCDFP15 is very useful for 
distinguishing between primary and metastatic adenocarcinomas of the skin. 
   The distinction between primary and metastatic adenocarcinomas has crucial 
therapeutic and prognostic implications.  CK20 and GCDFP15 are considered useful 
adjuncts in determining origin.  For example, it is possible to distinguish between 
primary and secondary perianal Paget’s disease.15   
   PCSRCC was first described by Rosen et al. in 1975.16  Thereafter, similar cases of 
PCSRCC have been reported, exclusively involving the eyelids.17-19  Recently, a few 
cases involving the axilla have been reported.20,21  None of the reported cases had any 
detectable primary internal malignancies.  Previous investigators have agreed that 
PCSRCC is of eccrine origin,14,16,18 while recent investigators have insisted on an 
apocrine origin.18,20  Either way, PCSRCC is a primary cutaneous, poorly differentiated, 
mucin-producing adenocarcinoma.18
   The lesions of these two patients demonstrated the range of clinical and histologic 
features of signet ring cell carcinoma.  Thorough systemic workup could not detect 
primary sources in either case.  Furthermore, tumor cells were positive for GCDFP15, 
suggesting a cutaneous origin.  Therefore, both cases were regarded as PCSRCC.  
Although CK20 is considered a marker of metastatic carcinomas of the skin, rare 
PCSRCC demonstrated immunoreactivity for CK20 in the present study.  
Histochemical and electron microscopic findings demonstrated mucin deposits.  
Interestingly, mucinous adenocarcinoma of the ovary could produce mucin and show 
variable, sometimes significant CK20 reactivity.5   
  
 6
   In conclusion, we report 2 cases of PCSRCC expressing CK20 immunoreactivity.  
CK20-positive primary cutaneous tumors should include PCSRCC in addition to 
Merkel cell carcinoma.
  
 7
     REFERENCES 
 
1. Moll R, Franke WW. Cytoskeletal differences between human neuroendocrine 
tumors: a cytoskeletal protein of molecular weight 46,000 distinguishes cutaneous 
from pulmonary neuroendocrine neoplasms. Differentiation 1985; 30: 165-75. 
2. Moll R, Lowe A, Laufer J, Franke WW. Cytokeratin 20 in human carcinomas: a new 
histodiagnostic marker detected by monoclonal antibodies. Am J Pathol 1992; 140: 
427-47. 
3. Moll R, Schiller DL, Franke WW. Identification of protein IT of the intestinal 
cytokeratin as a novel type I cytokeratin with unusual properties and expression 
patterns. J Cell Biol 1990; 111: 567-80. 
4. Harnden P, Allam A, Joyce AD, Patel A, Selby P, Southgate J. Cytokeratin 20 
expression by non-invasive transitional cell carcinomas: potential for distinguishing 
recurrent disease. Histopathology 1995; 27: 169-74. 
5. Miettinen M. Keratin 20: immunohistochemical marker for gastrointestinal, 
urothelial, and Merkel cell carcinomas. Mod Pathol 1995; 8: 384-8. 
6. Loy TS, Calaluce RD. Utility of cytokeratin immunostaining in separating 
pulmonary adenocarcinomas from colonic adenocarcinomas. Am J Clin Pathol 1994; 
102: 764-7.  
7. Giorno R. A comparison of two immunoperoxidase staining methods based on the 
avidin-biotin interaction. Diagn Immunol 1984; 2: 161-6. 
8. Mazoujian G, Pinkus GS, Davis S, Haagensen DE. Immunohistochemistry of a gross 
cystic disease fluid protein (GCDFP-15) of the breast: a marker of apocrine 
epithelium and breast carcinomas with apocrine features. Am J Pathol 1983; 110: 
105-12. 
9. Mazoujian G, Margolis R. Immunohistochemistry of gross cystic disease fluid 
protein (GCDFP-15) in 65 benign sweat gland tumors of the skin. Am J 
Dermatopathol 1988; 10: 28-35. 
10. Ordonez NG, Awalt H, MacKay B. Mammary and extramammary Paget’s disease: 
an immunohistochemical and ultrastructural study. Cancer 1987; 59: 1173-83. 
11. Ansai S, Koseki S, Hozumi Y, Kondo S. An immunohistochemical study of 
lysozyme, CD-15 (Leu M1), and gross cystic disease fluid protein-15 in various skin 
tumors: assessment of the specificity and sensitivity of markers of apocrine 
differentiation. Am J Dermatopathol 1995; 17: 249-55. 
12. Damiani S, Cattani MG, Buonamici L, Eusebi V. Mammary foam cells. 
Characterization by immunohistochemistry and in situ hybridization. Virchows Arch 
1998; 432: 433-40. 
13. de Almeida PC, Pestana CB. Immunohistochemical markers in the identification of 
metastatic breast cancer. Breast Cancer Res Treat 1992; 21: 201-10. 
14. Goldblum JR, Hart WR. Peranal Paget’s disease: a histologic and 
immunohistochemical study of 11 cases with and without associated rectal 
adenocarcinoma. Am J Surg Pathol 1998; 22: 170-9. 
15. Nowak MA, Guerriere-Kovach P, Pathan A, Campbell TE, Deppisch LM. Perianal 
Paget’s disease: distinguishing primary and secondary lesions using 
immunohistochemical studies including gross cystic disease fluid protein-15 and 
cytokeratin 20 expression. Arch Pathol Lab Med 1998; 122: 1077-81. 
16. Rosen Y, Kim B, Yermakov VA. Eccrine sweat gland tumor of clear cell origin 
  
 8
involving the eyelids. Cancer 1975; 36: 1034-41. 
17. Grizzard WS, Torczynski E, Edwards WC. Adenocarcinoma of eccrine sweat glands. 
Arch Ophthalmol 1976; 94: 2119-23. 
18. Jakobiec FA, Austin P, Iwamoto T, Trokel SL, Marquardt MD, Harrison W. Primary 
infiltrating signet ring carcinoma of the eyelids. Ophthalmology 1983; 90: 291-9. 
19. Thomas JW, Fu YS, Levine MR. Primary mucinous sweat gland carcinoma of the 
eyelid simulating metastatic carcinoma. Am J Ophthalmol 1979; 87: 29-33.Kuno Y, 
Numata T, Kanzaki T. Adenocarcinoma with signet ring cells of the axilla showing 
apocrine features: a case report. Am J Dermatopatol 1999; 21: 37-41. 
20. Kuno Y, Numata T, Kanzaki T. Adenocarcinoma with signet ring cells of the axilla 
showing apocrine features: a case report. Am J Dermatopathol 1999; 21: 37-41. 
21. Kuno Y, Tsuji T, Yamamoto K. Adenocarcinoma with signet ring cells of the axilla: 
two case reports and review of the literature. J Dermatol 1999; 26: 390-5.
  
 9
   Legends 
 
Fig 1. A dozen of papules and nodules were accompanied by diffuse swelling and 
erythema. (right eyelids of patient 1) 
Fig 2. A 5.7x3.7-cm, elastic hard tumor was accompanied by red nodules. (right axilla 
of patient 2) 
Fig 3. The scanning view shows a solid tumor from the upper dermis to the 
subcutaneous tissue without connection to the epithelia. (Hematoxylin-eosin stain of 
patient 1; original magnification x10) 
Fig 4. The tumor cells were scattered singly, in clusters of several cells, or arranged in a 
trabecular pattern.  Occasional signet ring cells were seen. (Hematoxylin-eosin stain of 
patient 1; original magnification x50) 
Fig 5. Positive reaction was seen in the cytoplasm of tumor cells. (Cytokeratin 20 
immunostain of patient 2; original magnification x100) 
  
Ｆｉｇ 1． Ｆｉｇ 2．
Ｆｉｇ 4．
Ｆｉｇ 3．
Ｆｉｇ 5．


Primary cutaneous signet ring cell carcinoma expressing cytokeratin 20 immunoreactivity

Abstract

Similar works

Full text

Available Versions

Community Repository of Fukui

University of Fukui Repository