Diagnosis: Primary signet ring carcinoma of the eyelid
Primary signet ring carcinoma of the eyelid is a unique malignant neoplasm that is derived from the sweat glands. It is an extremely rare tumor, with only 23 reported cases, excluding the one described herein.1A variety of names have been used to describe it, including eccrine sweat gland tumor of clear cell origin,2primary mucinous sweat gland carcinoma of the eyelid,3and histiocytoid variant of eccrine sweat gland carcinoma.4The variability in nomenclature reflects the tumor's debated histogenesis, with authors differing in opinion regarding an apocrine or eccrine origin. Despite the differences in terminology, the reported cases share a common morphological appearance, immunohistochemical profile, and clinical behavior. We have chosen to use the term primary signet ring carcinoma of the eyelid, which was recently coined in 2008.1
The tumor has been described only in the middle-aged and elderly, with patients ranging in age from 47 to 87 years. It also has a clear male predominance, as was shown in a recent study by Mortensen et al,1in which 18 of the 23 cases reviewed involved men. Although several cases, including the one described herein, presented as thickening of a single eyelid, the most common presenting feature is diffuse thickening of both upper and lower eyelids, which creates the appearance that the involved eye is squinting.1This feature has led some authors to dub it the monocle tumor.1The rate of disease progression is variable, in that the time from symptom onset to presentation to a physician ranges from 3 months to 5 years.5It has also been reported that the tumor may undergo a prolonged and indolent course, with a sudden, rapid progression.4Metastases at diagnosis are common. In the study by Mortensen and colleagues,1regional lymph node metastases were found in 30% of patients and involved preauricular, cervical, submandibular, and parotid nodes. Distant metastasis occurred in 17% of patients and involved the skin, spine, contralateral orbit, and lungs.1
Reports on imaging are limited. The findings of magnetic resonance imaging were reported in only 1 case, which describes the tumor as “a well-defined lesion from the right orbit to the periorbital skin.”6Swinson et al7reported a case involving a tumor that measured 15×10 mm on gross examination but was not highlighted by positron emission tomography. Kramer et al4described a patient with “nonspecific findings” on a computed tomographic scan of the head. To our knowledge, our case is the first one that describes the tumor as an enhancing soft-tissue lesion limited to the eyelid on magnetic resonance imaging.
Microscopically, the tumors consist of a diffuse or vaguely nodular infiltrate of single cells with hyperchromatic nuclei, prominent nucleoli, eosinophilic cytoplasm, and intracytoplasmic mucin, which creates the characteristic signet ring appearance that is seen in a few of the cells. The microscopic appearance is reminiscent of lobular carcinoma of the breast and signet ring carcinoma of the stomach. The immunohistochemical staining profile is consistent with the tumor's purported sweat gland derivation. Specifically, it shows reactivity with antibodies directed against gross cystic disease fluid protein 15, a marker of apocrine and breast epithelium.5Also, the cells show reactivity with antibodies against CK7, carcinoembryonic antigen, and epithelial membrane antigen.1,5Tumor cells show no expression of neuroendocrine markers such as synaptophysin and chromogranin.1Melanocytic markers, including S-100 protein, HMB-45, and melan-A, are not expressed, nor is CK20, although a CK20-positive tumor has been reported.6Estrogen receptor expression has been described in 3 cases, 2 of which showed concomitant progesterone receptor expression.4,5Two cases that showed a lack of expression of estrogen receptor and progesterone receptor have also been reported.1
The most important entity in the differential diagnosis is metastasis, especially from a lobular breast carcinoma or signet ring carcinoma of the intestinal tract. Gross cystic disease fluid protein 15 is useful evaluating these tumors, because, while it shows reactivity in signet ring carcinomas of breast origin and in primary signet ring carcinoma of the eyelid, it does not show reactivity for morphologically similar carcinomas of gastrointestinal tract or pulmonary derivation.8Staining with p63 is helpful in distinguishing most primary skin adnexal neoplasms, except mucinous carcinoma and apocrine carcinoma, from carcinoma that is metastatic to the skin.9Our case did not stain with antibodies against p63, and we are not aware of reports on p63 expression in this tumor type. However, because primary signet ring carcinoma of the eyelid is likely an apocrine tumor, the lack of staining is not surprising.
Apart from the case presented herein, to our knowledge there have been no reports on evaluation with antibodies against E-cadherin. Our case showed strong, diffuse expression of E-cadherin. Lobular breast carcinoma rarely expresses E-cadherin, and the exceptional positive cases tend to show focal staining that is limited to solid areas of the tumor.10E-cadherin may therefore be a useful marker in differentiating primary signet ring carcinoma of the eyelid from metastatic lobular breast carcinoma.
Signet ring carcinomas of the eyelid tend to be very aggressive and may invade the orbit to extensively involve the ocular adnexa. When possible, resection with negative margins is considered the treatment of choice. Orbital exenteration was required in 10 of the 19 reported cases (or 11 of the 20 cases, including ours) for which treatment data are available.1Several adjuvant treatments, including radiation, fluorouracil, and tamoxifen therapy, have been used.1Given the small number of cases, however, definitive recommendations for adjuvant treatment have not been made. In our case, we opted not to perform elective parotidectomy and selective neck dissection at the time of exenteration because we were planning to administer postoperative radiation to the primary site. Instead, we chose to expand the adjuvant radiation field to include these routes of possible lymphatic spread.
Long-term outcomes have been variable. In a review by Langel et al5that looked at long-term follow-up in 8 cases, 1 patient died of disease 26 months after treatment, 1 patient showed no evidence of disease 1.5 years after treatment, 3 patients were alive with disease between 4.5 and 6 years after treatment, and 3 patients died of other causes 10 years after treatment. Follow-up was not available on the remaining 2 patients.
In summary, primary signet ring carcinoma of the eyelid is a rare and distinct malignant neoplasm that occurs primarily in middle-aged and elderly men, is locally aggressive, and carries a significant risk of nodal and distant metastasis. It is important to rule out metastatic carcinoma to the eyelid from another site, especially the breast, before making a diagnosis. Treatment should be aimed at completely excising the tumor, which often requires orbital exenteration.
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Pathology Quiz Case 2: Diagnosis. Arch Otolaryngol Head Neck Surg. 2010;136(11):1148-1149. doi:10.1001/archoto.2010.199-b