Periocular Histiocytoid Carcinoma: Potential Diagnostic Challenges

• Histiocytoid carcinomas can arise as primary lesions around the eye.

• Metastatic histiocytoid carcinoma can also involve the periocular region.

• No immunohistochemical or molecular markers that discriminate between these two possibilities are known.

• GATA-3 can be expressed in primary periocular histiocytoid carcinoma.

• Histiocytoid carcinoma can occasionally show minimal cytological atypia and mimic nonneoplastic lesions.

Periocular histiocytoid/signet-ring cell carcinomas are rare tumors. They can arise locally or metastasize from distant sites. Of the approximately 52 primary cutaneous histiocytoid/signet-ring cell carcinoma cases reported, 39 arose in the eyelid and/or orbit, whereas 13 arose in axillary skin [1-17]. These tumors are most common in elderly males [2, 12]. Metastases have occurred in around half of the reported cases, usually to nearby lymph nodes [2, 12]. Tumor-related deaths have also been described [6, 13, 18, 19]. The periorbital lesions often present as diffuse swelling and thickening of the involved lid, with normal or erythematous skin, and tend to infiltrate circumferentially around the eyelid, leading to their “monocle-like” appearance [20]. Clinical misdiagnosis is common, as benign inflammatory conditions, such as chalazion or chronic blepharoconjunctivitis have a similar presentation.

A histiocytoid variant of breast carcinoma has been documented but is also rare. Shimizu et al. [21] reviewed 1,010 primary breast cancer cases diagnosed between 1972 and 1996 and found only 6 with histiocytoid changes. One case of histiocytoid carcinoma in the male breast has been reported [22]. The tumors are most commonly regarded as a variant of lobular carcinoma, and their occasional occurrence with apocrine lobular carcinoma in situ and expression of GCDFP-15 suggest apocrine differentiation [23, 24]. Both lobular and histiocytoid breast cancers can metastasize to the periocular region, often with bilateral involvement [25, 26]. Hood and colleagues published the first series in 1973, which included 8 metastatic mammary carcinomas in the eyelid with a histiocytoid appearance. In several of these cases, the eyelid metastasis was identified before the primary tumor [27].

Unfortunately, primary and metastatic histiocytoid carcinomas can be morphologically and immunohistochemically indistinguishable from one another. Both are characterized by round to oval or polyhedral tumor cells with abundant histiocytoid cytoplasm showing variable vesicular or signet-ring features. Tumor cells generally diffusely percolate through the soft tissues in single-file formations or as individual cells, sometimes forming cohesive sheets, and express epithelial and apocrine markers. It can be a challenging diagnosis to make when only a few individual tumor cells are present in a biopsy. The histiocytoid cells can be misinterpreted as macrophages, especially when other inflammatory cells are present (Fig. 1). In this study, we present 3 cases of periocular histiocytoid carcinoma, which illustrate the challenges of differentiating primary and metastatic lesions.

A 68-year-old Caucasian male presented with a 2-year history of gradual decrease in vision and the sensation of a mass ‘pushing’ on his right eye. His past medical history was significant for non-insulin-dependent diabetes, hypertension, hypercholesteremia, and chronic obstructive pulmonary disease. On examination, he had limitation of extraocular motility and 4 mm of ptosis on the right side compared to the left. Magnetic resonance imaging (MRI) showed a 2.2 × 4.9 × 2.6 cm enhancing mass in the right superior, lateral, and anterior orbit extending along the superior and lateral aspect of the globe with ill-defined intraconal enhancement (Fig. 2). An extensive clinical workup, including whole-body positron emission tomography, failed to identify lesions outside the right periocular region.

An incisional biopsy of the right lower eyelid was taken and revealed a poorly differentiated adenocarcinoma. Orbital exenteration was subsequently performed. Microscopic examination revealed tumor cells involving the upper and lower eyelids, conjunctiva, lacrimal gland, extraocular muscles, and outer one-third of the sclera. No intraocular tumor was observed, and the optic nerve margin was negative. There were multifocal positive soft-tissue margins involving the superior, inferior, medial, and lateral orbit. The cells displayed a histiocytoid appearance with occasional signet-ring cells noted. The cells diffusely percolated through the dermis as solid collections, in single-file formations and as individual cells, sparing involvement of the epidermis. A mucicarmine stain highlighted signet-ring cells. Immunohistochemistry showed positivity for cytokeratin 7 (CK7), CAM 5.2, gross cystic disease fluid protein 15 (GCDFP-15), GATA-3, ER, PR, p63, carcinoembryonic antigen, EMA, and E-cadherin (Table 1). Immunohistochemical stains against CK20, CD68, CDX2, D2–40, S-100, HMB-45, Ber-EP4, mammaglobin, HER2/neu, thyroid transcription factor 1 (TTF-1), and prostate-specific antigen were negative. The Ki-67 proliferation index was low. A diagnosis of primary periocular histiocytoid/signet-ring cell carcinoma was made. The patient declined adjuvant radiotherapy and passed away 20 months after diagnosis from chronic obstructive pulmonary disease and hypercalcemia.

A 46-year-old female presented with a 4-month history of bilateral periorbital edema and firm nodules in both lower eyelids. The patient had experienced intermittent pain around both eyes during this period. She had a history of infiltrating histiocytoid lobular breast carcinoma and was treated by mastectomy 11 years before. Corresponding to the development of her lid nodules, she had a recurrence of her breast cancer and was found to have cervical lymph node metastases for which she received a 6-month regimen of Abraxane® chemotherapy. Clinical examination revealed firm masses involving the upper and lower lids bilaterally (Fig. 3). An ill-defined enhancement within the right orbit was seen on MRI, and the patient underwent an orbitotomy for biopsy.

Microscopically, the lesion consisted of round to oval cells with predominantly mild nuclear pleomorphism infiltrating in a single-file pattern and in small clusters through orbital muscle and fat. Most cells were notable for their pronounced histiocytic features, including abundant vacuolated cytoplasm, but were immunonegative for the macrophage marker CD68. The immunophenotype was strongly positive for CK7, CAM 5.2, cytokeratin AE1/AE3, GATA-3, and weakly positive for GCDFP-15, E-cadherin, and p63 (Table 1). ER stains were positive in the tumor cytoplasm but not in the nucleus. Immunostaining for CK20, PR, D2–40, TTF-1, and CDX2 were negative. HER2neu overexpression analysis was negative. The Ki67 proliferation index was 20–30%. The histopathological and immunohistochemical findings of the lesion were consistent with a diagnosis of orbital metastases of the histiocytoid variant of lobular breast cancer. The patient was lost to follow-up.

An 83-year-old female presented with double and blurry vision. Her past medical history included in situ lobular carcinoma 35 years prior to presentation as well as invasive ductal carcinoma diagnosed 25 years ago and treated with lumpectomy and a radium implant. Her family history included breast carcinoma in her sister and daughter. Clinical examination revealed bilateral, asymmetrical limitation of upward gaze and 3 mm of right-sided proptosis. Computed tomography (CT) imaging demonstrated enlargement of the right superior, medial, and inferior recti muscles as well as the right lacrimal gland (Fig. 4). Contralaterally, the left lateral rectus muscle was enlarged. MRI also suggested involvement of the posterior sclera, optic nerve sheath, and lacrimal gland, and the patient was noted to have multiple punctate foci throughout the calvarium and the upper cervical vertebrae consistent with diffuse bony metastatic disease. These punctate foci were not seen on a previous MRI conducted 10 years before. Systemic evaluation was unrevealing including serologies and a CT/positron emission tomography scan; there was no evidence of breast cancer recurrence.

Right lateral orbitotomy with an incisional muscle biopsy was performed. Microscopic examination revealed sheets of histiocytoid cells with abundant granular cytoplasm and bland nuclei infiltrating through the muscle and fat of the biopsies. The tumor cells were strongly positive for cytokeratin AE1/AE3 and CK7 and negative for CK20. The Ki67 proliferation index was moderate. GATA-3 and GCDFP-15 immunostains were both positive, while mammaglobin, ER, PR, and HER2neu immunostains were negative (Table 1). CD68, S100, TTF-1, CD1A, p63, and D2–40 immunostains were also negative. While the histology and immunohistochemistry (ER negative, PR positive) of her previous ductal carcinoma did not match that of the orbital lesion, the findings could be consistent with a diagnosis of infiltrating histiocytoid carcinoma of either primary or metastatic origin, including metastases from an undetected breast lesion. She received 40 Gy of palliative radiation split into 2 doses of 20 Gy delivered over a 2-week period but refused chemotherapy. Over the next 3 years, she developed ascites, abdominal carcinomatosis, and passed away.

These 3 cases document the similarities between primary histiocytoid carcinoma (Case 1), metastatic histiocytoid carcinoma (Case 2), and patients for whom this distinction is difficult (Case 3). Unfortunately, molecular and immunohistochemical markers that clearly differentiate primary and metastatic tumors are not known. In both, the neoplastic cells are immunopositive for cytokeratins CK7, AE1/AE3, CAM 5.2, and EMA, whereas they are generally immunonegative for CK20 [2, 24]. Positive immunoreactivity for GCDFP-15, carcinoembryonic antigen, and Ber-EP4 has also been reported [2, 24]. E-cadherin is immunopositive in around 80% of the primary periocular histiocytoid carcinoma cases, whereas immunoreactivity is seen in only 25% of the histiocytoid breast carcinomas cases [1-5, 20, 22, 28-34]. Among the 17 cases of primary periocular histiocytoid carcinoma, which assessed ER and PR, there was immunoreactivity in 35 and 33%, respectively [1-6, 20, 35-42]. HER2neu overexpression was negative in all 6 reported cases [1, 3, 5, 39]. In comparison, immunoreactivity for ER, PR, and HER2neu in 29 cases of histiocytoid breast carcinoma was 44, 19, and 57%, respectively [21, 22, 26, 29, 31-34, 43-46].

GATA-3, a transcription factor involved in maintaining luminal epithelial differentiation in the adult mammary gland, represents a possible marker for discriminating primary from metastatic disease not previously assessed in primary periocular histiocytoid carcinoma [47, 48]. Miettinen et al. [49] observed GATA-3 expression in 92% of the primary ductal carcinomas (n = 179), in 96% of the metastatic ductal carcinomas (n = 51), and in 100% of the primary lobular carcinomas (n = 38). However, there was positive immunoreactivity to GATA-3 in all our cases, including the primary tumor. Other skin adnexal tumors are known to express GATA-3; thus, this is not completely unexpected [49, 50]. The marker may have diagnostic utility if metastatic gastrointestinal signet-ring cell carcinoma is on the differential diagnosis, as this neoplasm should be negative.

The histogenesis of primary cutaneous histiocytoid/signet-ring cell carcinoma is still debated. In earlier reports, the neoplasm was thought to originate from eccrine sweat glands. Rosen et al. [51] and Thomas et al. [19] conducted ultrastructural studies and found both clear and dark cells and intracytoplasmic lumina with villi, which favored an eccrine origin. More recent reports have favored apocrine differentiation because the tumor has Periodic Acid-Schiff-positive diastase-resistant secretions and positive immunostaining for the apocrine marker GCDFP-15 [1]. In addition, Jakobiec et al. [52] observed abundant smooth and rough endoplasmic reticulum, granular cytoplasmic inclusions, cytoplasmic lumina, and lipid droplets at the ultrastructural level, which is suggestive of an apocrine origin. However, the neoplasm lacks morphological apocrine secretion, and GCDFP-15 immunoreactivity has been reported in normal eccrine glands [38, 53, 54]. From a theoretical viewpoint, it is possible that these tumors can arise from either eccrine or apocrine glands. Further research is therefore needed before definitive conclusions can be drawn.

With regards to Case 3, a diagnosis of recurrent metastatic breast carcinoma was favored given the family history, bilateral involvement, pathological findings, and evidence of extensive bony metastases seen on imaging. However, it should be noted that imaging and clinical examination failed to reveal a primary breast lesion. Prolonged follow-up was recommended as the primary breast lesion may become apparent in the future. Interestingly, her previous invasive ductal carcinoma was ER negative and PR positive, whereas the periocular lesion was ER and PR negative. It is possible for the metastatic profile of the tumor to be different from the primary process, so this would not rule out recurrence. An invasive focus in her prior lobular carcinoma in situ could also have been missed. Finally, the periocular lesion may represent a new occult histiocytoid breast carcinoma. This would explain the differences in histopathology between the original primary ductal carcinoma and the suspected periocular metastasis. Primary periocular histiocytoid carcinoma should also remain on the differential diagnosis, as a primary origin for the suspected metastatic lesion was not found.

While both primary and metastatic histiocytoid carcinomas of the eyelid and orbit are uncommon, other histiocytic lesions are not [55]. Noncancerous granulomatous lesions composed of histiocytes, potentially similar in appearance to histiocytoid carcinoma cells, can be seen in various processes including xanthelasma. Case 2 highlights how some regions of these carcinomas can mimic nonneoplastic histiocytes and show rather minimal atypia. Cytokeratin or CD68 immunohistochemical staining is a useful discriminator if diagnostic doubt exists.

The study complied with the guidelines for human studies and was approved by the institute’s committee on human research.

The authors have no conflicts of interest to declare.