Highlights
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Ocular sebaceous adenomas and atypical sebaceous neoplasms are frequently MMR-deficient.
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Atypical sebaceous neoplasms share similar clinicopathologic features with sebaceous adenomas.
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Atypical sebaceous neoplasms are intermediate-grade, MMR-deficient, and distinct from organoid-pattern sebaceomas.
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Growth patterns may better reflect tumor biology than the 50% basaloid-cell cutoff.
Objective
To assess mismatch repair (MMR) deficiency in ocular sebaceous neoplasms that are not poorly differentiated sebaceous carcinomas, and to explore the characteristics of atypical lesions based on clinicopathologic and immunophenotypic findings.
Design
A retrospective observational case series.
Participants
Consecutive cases of 14 benign or atypical ocular sebaceous neoplasms diagnosed from January 2018 to June 2025.
Methods
Clinical and pathological data were reviewed and compared among three groups: sebaceous adenomas ( n = 6), atypical sebaceous neoplasms ( n = 3), and sebaceomas ( n = 5). The association with Muir-Torre syndrome (MTS) was also evaluated.
Main Outcome Measures
Clinical and histomorphological features (including growth pattern and ulceration), immunohistochemistry (MMR protein status, epithelial membrane antigen, adipophilin, Ki-67, and p53), and Mayo MTS risk scores.
Results
All atypical sebaceous neoplasms and 67% of adenomas were MMR-deficient, most commonly concurrent MSH2/MSH6 loss, versus none in sebaceomas ( P =.013). Atypical neoplasms also shared other key clinicopathologic features with adenomas, including ulceration, lobular/papillary growth, high proliferation, and strong epithelial membrane antigen expression, but differed from sebaceomas (all P <.05). Six patients had personal or family histories of visceral malignancy, and 4 had a Mayo score ≥2.
Conclusions
Ocular sebaceous neoplasms showed a relatively high rate of MMR deficiency. Lobular/papillary sebaceous adenomas and atypical neoplasms were frequently MMR-deficient and may carry implications for MTS, whereas organoid-pattern sebaceomas were typically MMR-proficient and showed no clinical evidence of MTS. Moreover, atypical sebaceous neoplasms, which are intermediate-grade and MMR deficiency-associated, may be classified separately from sebaceomas.
INTRODUCTION
M uir – Torre syndrome (MTS), a variant of Lynch syndrome characterized by visceral malignancies and cutaneous sebaceous neoplasms, is defined by germline pathogenic variants in mismatch repair (MMR) genes. These Lynch-associated cancers include colorectal, endometrial, ovarian, and small bowel cancers, as well as tumors of the urinary tract and biliary tract. The most common sebaceous neoplasm in the periocular region is conventional poorly differentiated sebaceous carcinoma, a high-grade basaloid carcinoma usually without any mature sebocytic differentiation and frequently showing TP53 mutation and/or RB1 loss, which is generally not related to MMR deficiency or MTS. , In benign ocular sebaceous neoplasms, namely sebaceous adenomas and sebaceomas arising in the meibomian glands and Zeis glands, MMR deficiency has been documented only in isolated case reports. ,, However, the prevalence and clinical significance of MMR deficiency in these tumors, especially those labeled “atypical,” remain poorly defined.
Current classification relies on a 50% basaloid-cell threshold to separate sebaceoma from adenoma, a criterion that remains controversial, particularly in tumors with ambiguous basaloid proportions and brisk mitotic activity. ,, This simplified, threshold-based classification does not reliably stratify MTS risk in such tumors. For lesions that fall between adenoma and sebaceoma, terms such as “atypical sebaceoma,” “borderline sebaceous neoplasm,” and “well-differentiated sebaceous carcinoma” have been used. ,,
In this study, we retrospectively reviewed a series of benign and atypical ocular sebaceous neoplasms excluding conventional poorly differentiated periocular-type sebaceous carcinoma. To assess MMR deficiency in these tumors and further characterize the atypical lesions, we compared morphological and immunohistochemical characteristics among sebaceous adenomas, atypical sebaceous neoplasms, and sebaceomas.
MATERIALS AND METHODS
Patients and Samples
Clinical and histopathological data of all 14 cases were collected from the archives of Eye & ENT Hospital of Fudan University from January 2018 to June 2025. All hematoxylin and eosin-stained sections were independently reviewed by two trained pathologists and classified according to the 5th edition of the WHO Classification of Eye and Orbit Tumors : sebaceous adenoma and sebaceoma are a spectrum of benign sebaceous tumors, in which sebocytes predominate over basaloid cells in sebaceous adenoma, whereas basaloid cells predominate over sebocytes in sebaceoma. Three well-circumscribed tumors with >50% basaloid/germinative cells that otherwise met WHO criteria for sebaceoma but showed conspicuous mitotic activity together with cytologic and architectural atypia, including multilayered germinative cells with enlarged, crowded, perpendicularly oriented nuclei, and abnormal sebaceous acinar structures, were categorized as atypical sebaceous neoplasms. This study was approved by the institutional review board of the Eye & ENT Hospital of Fudan University (EENT-IRB No.: 2021158).
MTS was defined according to Mayo MTS Risk Score; a score ≥2 indicates increased likelihood. Four factors included age <60 years (1 point), ≥2 sebaceous neoplasms (2 points), and personal or family history of LS-associated malignancies (1 point each). Outcomes were ascertained through electronic medical record review; telephone follow-up was performed when needed. Mitotic figures were recorded per 10 high-power fields (HPFs), after surveying all non-overlapping tumor areas. Tumors exhibiting enlarged or extended sebaceous alveoli with peripheral germinative cells and central mature sebocytes were defined as having a lobular pattern. Tumors with central fibrovascular cores surrounded by proliferating germinative cells lacking well-formed sebaceous alveoli were classified as papillary pattern, whether they were intracystic or exophytic. Tumors showing features of both were considered to have a mixed pattern. An organoid pattern was defined by predominant basaloid cells arranged in nests, cords, or in a rippled, trabecular, ribbon-like, labyrinthine, or carcinoid-like growth pattern, without discernible lobular or papillary architecture.
Immunohistochemistry
Immunohistochemistry was performed on 3-µm tissue sections from a formalin-fixed paraffin-embedded block using the Ventana Benchmark platform, following the manufacturer’s protocol. Primary antibodies: MLH1 (G168-15, Maixin, ready-to-use), MSH2 (FE11, Maixin, ready-to-use), MSH6 (44, Maixin, ready-to-use), and PMS2 (A16-4, Maixin, ready-to-use), p53 (DO-7, Gene Tech, 1:100), adipophilin (B6, Gene Tech, ready-to-use), EMA (epithelial membrane antigen; E29, Gene Tech, 1:200), Ki-67 (MIB-1, Gene Tech, 1:300). MMR deficiency was defined as a complete loss of nuclear staining for any MMR protein in tumor cells with intact internal controls. Aberrant p53 was defined as diffuse strong nuclear staining or complete absence. Adipophilin and EMA showed strong granular cytoplasmic positivity in sebocytes, with EMA also labeling epithelial membranes.
HPV testing
HPV testing was performed using the HPV Genotyping Kit for 23 Types (Yaneng Bio, Shenzhen), according to the manufacturer’s protocol. This kit allows detection of 23 human papilloma virus (HPV), including 18 high-risk types (HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, 73, 83, and 82) and 5 low-risk types (HPV 6, 11, 42, 43, and 44) by reverse dot blot method. Results were confirmed visually. A positive result appears as a dark-blue round dot at the corresponding HPV type; absence of a dot indicates a negative result.
Statistical analysis
Analyses were performed by SPSS, version 20 (IBM). Age, Ki-67 index, and mitotic count were analyzed as categorical variables; other continuous variables (e.g., tumor size) were summarized as median (range). Categorical variables were summarized as counts (%) and compared across diagnostic groups using 2-sided Fisher’s exact tests. P <.05 was considered statistically significant.
RESULTS
Clinical characteristics
Fourteen benign ocular sebaceous neoplasms from 14 patients were analyzed: 6 sebaceous adenomas, 3 atypical neoplasms, and 5 sebaceomas ( Fig. 1 and Table 1 ). Patients included 8 females and 6 males, with a median age of 64 years (range, 35–72 years). Tumors were predominantly located on the eyelid margin ( n = 10), followed by the tarsal conjunctiva ( n = 3) and caruncle ( n = 1). All three atypical neoplasms and five sebaceomas were confined to the eyelid margin; one atypical lesion arose on the cutaneous side of the margin. Surface ulceration was present in all atypical neoplasms and one adenoma but was absent in all sebaceomas ( P =.016). Tumor size ranged from 1 to 6 mm, with a median of 3.5 mm. Age and tumor location did not differ significantly among the three diagnostic groups (all P >.05). Sex distribution showed a marginal difference ( P =.049), with sebaceomas occurring exclusively in female patients.
Clinical and histologic features of ocular sebaceous tumors . (A, B) Sebaceous adenoma, lobular pattern . Clinical photograph shows a grayish-red mass involving tarsal conjunctiva and lid margin (yellow arrow), with adjacent pigmented nevi (white arrows). Histology shows lobules of mature sebocytes and peripheral basaloid cells arranged in 1-2 layers, with loss of p53 expression (H&E, × 40; inset, high magnification; p53 immunostaining not shown). (C, D) Sebaceous adenoma, papillary pattern . Clinical photograph shows a yellowish nodule on tarsal conjunctiva with surface ulceration. Histology reveals papillary structures surrounding fibrovascular cores, with extensive cystic holocrine secretion (H&E, × 40; inset, high magnification). (E, F) Atypical sebaceous neoplasm, lobular pattern . Clinical photograph shows a reddish nodular lesion at the eyelid margin with central ulceration. Histology shows lobular growth with thickened basaloid layers, enlarged nuclei, numerous ductal differentiations, and gradual loss of the maturation gradient (H&E, original magnifications × 40; inset, high magnification). (G, H) Sebaceoma, organoid pattern . Clinical photograph shows a smooth, yellow, firm nodule at the eyelid margin. Histology demonstrates a well-circumscribed, round nodule composed predominantly of basaloid cells arranged in a rippled pattern, with scattered focal sebocytes and characteristic infundibulocystic structures (H&E, × 40; inset, higher magnification).
Table 1
Clinicopathological Characteristics of 14 Ocular Sebaceous Neoplasms.
| Sebaceous Adenoma ( n = 6) | Atypical Sebaceous Neoplasm ( n = 3) | Sebaceoma ( n = 5) | P value | |
|---|---|---|---|---|
| Age, year | .650 | |||
| ≤64 | 4 | 1 | 2 | |
| >64 | 2 | 2 | 3 | |
| Sex | .049 | |||
| Female | 2 | 1 | 5 | |
| Male | 4 | 2 | 0 | |
| Location | .098 | |||
| Caruncle | 1 | 0 | 0 | |
| Lid margin | 2 | 3 | 5 | |
| Tarsal | 3 | 0 | 0 | |
| Ulceration | .016 | |||
| No | 5 | 0 | 5 | |
| Yes | 1 | 3 | 0 | |
| Growth pattern | .004 | |||
| Lobular | 3 | 2 | 0 | |
| Papillary | 2 | 1 | 0 | |
| Mixed | 1 | 0 | 0 | |
| Organoid | 0 | 0 | 5 | |
| Mitoses (per 10 HPFs) | .001 | |||
| <4 | 0 | 0 | 5 | |
| 4-10 | 2 | 2 | 0 | |
| >10 | 4 | 1 | 0 | |
| Ki-67 | <.001 | |||
| >15% | 6 | 3 | 0 | |
| <5% | 0 | 0 | 5 | |
| MMR deficiency | .013 | |||
| No | 2 | 0 | 5 | |
| Yes | 4 | 3 | 0 | |
| EMA | <.001 | |||
| + | 6 | 3 | 0 | |
| – | 0 | 0 | 5 |
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