Combination treatment of bilateral periocular sebaceous carcinomas with microsatellite instability with neoadjuvant pembrolizumab and Mohs surgery.

This case highlights the successful use of pembrolizumab for neoadjuvant treatment of MMR-deficient sebaceous carcinoma of bilateral eyelids to reduce tumour burden allowing smaller defect post-Mohs surgery and better reconstructive outcome. Microsatellite stability, tumour mutational burden and PD-L1 expression are important prognostic factors to be considered for the use of neoadjuvant pembrolizumab. Further studies are needed to determine if neoadjuvant pembrolizumab consistently improves surgical and cosmetic outcomes and reduces local recurrence and metastasis.

Could Extension Into the Lacrimal Gland and Sac Thwart Topical Chemotherapy for Intraepithelial Sebaceous Carcinoma?

PURPOSE: To identify the frequency of intraepithelial (Pagetoid) spread beyond the ocular surface-namely beyond conjunctiva and cornea-in patients undergoing orbital exenteration for advanced periocular Sebaceous carcinoma (SC). DESIGN: A retrospective, noncomparative observational case series. SUBJECTS: Patients undergoing orbital exenteration for biopsy-proven SC, at Moorfields Eye Hospital between 1997 and 2013. METHODS: Review of clinical records and histological specimens, with particularly reference to involvement of conjunctiva and the extent of Pagetoid infiltration beyond the examinable ocular surface-here termed "hidden" disease. MAIN OUTCOME MEASURES: Histological evidence of intraepithelial SC within the lacrimal sac or lacrimal gland. RESULTS: Twenty-nine patients had clinical data and histological specimens adequate for review. Seventeen (59%) did not have a discrete mass (clinically or histologically) and, on clinical examination, were thought to only have extensive intraepithelial carcinoma; foci of microscopic invasion were, however, detected histologically in 11/17 (65%) of these specimens. Moreover, the in situ carcinoma was found to have invaded far in lacrimal gland ductules in 1/17 patients, in the lacrimal sac (in 2 patients; 12%) or in both the gland and sac (in 2 patients); these 5/17 (29%) cases all showed extensive poorly differentiated intraepithelial SC. Of the 12 other patients who had both Pagetoid spread and a clinically evident nodule, 3 had histological evidence of "hidden" disease. CONCLUSION: Although-due to their being operated in the era prior to the accepted usage of topical therapy for this condition-some of these exenterations might have had particularly advanced in situ SC, over a quarter of patients with periocular SC warranting orbital exenteration show "hidden" intraepithelial tumor within the lacrimal gland and sac. This important finding might significantly reduce the efficacy (particularly in the lacrimal gland) of the various topical therapies used for in situ SC of the ocular surface, and it also emphasizes the importance of excising both the lacrimal gland and sac in all orbital exenterations for this particular tumor.

Identification of potentially druggable molecular alterations in skin adnexal malignancies.

Skin adnexal cancers (SAC) are a heterogeneous group of rare malignancies with histological differentiation towards epithelial adnexa, which lack effective systemic treatments. The aim of this work is to identify any potentially druggable genomic alterations for possible targeted therapies. Cases of primary or recurrent/metastatic (RM) SAC between 2002 and 2014 were identified by searching the institutional cancer registration database. Histological sections of all referral cases were reviewed by a dedicated pathologist to confirm diagnosis. Immunohistochemistry was performed to assess the expression of androgen receptors (AR) and human epidermal growth factor receptor type 2 (HER2). Targeted next-generation sequencing (T-NGS) was performed to identify targetable mutations (panel of 50 genes analyzed by Cancer Hotspot Panel, Ion-Torrent Personal Genome Machine). Mutational analysis of the PTCH1 gene not present in the T-NGS panel was assessed by Sanger sequencing. A total of 45 cases with available histological samples were identified (35 primary, 10 RM). The most frequent histological type was porocarcinoma (n = 12). Globally, 14 cases (31%) were AR+ (6/10 RM, 60%; 8/35 primary, 23%). HER2 was shown as 2+ in eight of 42 (19%) cases (2/9 RM, 22%; 6/33 primary, 18%). DNA was adequate for T-NGS analysis in 25 cases. In the majority of cases (17 cases, 68%) at least one mutation in oncogenes or tumor suppressor genes was found: the most frequent ones involved TP.53 (13 cases, 76% of mutated SAC) and PIK3CA (three cases, 18%). The rate of PTCH1 mutation was 30%. These findings support the use of molecular screening in patients with advanced SAC.

A Case Report of Recurrent Metastatic Sebaceous Carcinoma Which Showed Favorable Response Tt Non-Fluorouracil Based Chemotherapy.

BACKGROUND Sebaceous carcinoma is a rare malignant tumor of the skin adnexa. While surgical resection is a treatment of choice in localized disease, frequent recurrence and distant metastasis make treatment difficult. Moreover, due to its rarity, optimal systemic treatment has not been determined. CASE REPORT A 59-year-old female presented with disseminated subcutaneous nodules. Past history indicated she received repeated surgery, radiation therapy, and fluorouracil-based systemic chemotherapy for recurrent sebaceous carcinoma. Following a subcutaneous nodule biopsy, histopathologic examination confirmed recurrent metastasis of sebaceous carcinoma. Because there was no established regimen as salvage chemotherapy, we decided to administer paclitaxel plus Adriamycin as a combination regimen after a thorough search of previous reports on PubMed. After the patient received 6 cycles of chemotherapy, all masses dramatically regressed. Unfortunately, several new lesions appeared 3 months after cessation of chemotherapy. Therefore, she was treated with anti-HGF antibody through a clinical trial. After that, she received nivolumab. But treatment with all the new agents did not show any response. Furthermore, her disease progressed rapidly. We re-challenged with the paclitaxel and Adriamycin regimen, 2 cycles of chemotherapy, and the follow-up positron emission tomography - computed tomography revealed marked decrement of multiple metastatic nodules. CONCLUSIONS Although several clinical reports have shown the effectiveness of fluorouracil, especially 5-fluorouracil-based chemotherapy, there has been a paucity of reports on other chemotherapeutic agents. We report a case of metastatic sebaceous carcinoma which showed favorable response to non-fluorouracil-based chemotherapy.

Carboplatin and Pembrolizumab Chemoimmunotherapy Achieves Remission in Recurrent, Metastatic Sebaceous Carcinoma.

A 72-year-old Caucasian woman who had recurrent sebaceous carcinoma of the right orbit with bilateral cervical lymph node involvement 24 months after orbital exenteration was treated with carboplatin (area under the curve of 5) and pembrolizumab (2 mg/kg) for 6 cycles, followed by maintenance pembrolizumab. She obtained a complete pathological remission and remains free of local, regional, and systemic disease at 15 months.

Near complete response to Pembrolizumab in microsatellite-stable metastatic sebaceous carcinoma.

BACKGROUND: Sebaceous carcinoma is an aggressive adnexal skin tumor with a predilection for the eyelids and sebaceous glands of the head and neck. CASE PRESENTATION: A 73 year-old man presented with confusion and was found to have widely disseminated sebaceous carcinoma with metastases to brain, lungs, liver, bowel, lymph nodes, and bone. Following initial treatment of the brain metastases with surgery he received post-operative radiosurgery. He then began systemic immunotherapy with pembrolizumab. After 6 months, he developed a near complete response to therapy by irRECIST and RECIST v.1.1. The response was associated with circulating CD8+ T cells with central memory (CM) and effector memory (EM) phenotype and mature CD16 + CD57+ NK cells. During treatment the patient developed adrenal insufficiency requiring high-dose systemic corticosteroids and later adrenal replacement therapy. After 12-months of follow-up he showed imaging evidence of progression in liver, mediastinum, and abdominal lymph nodes. Given persistent, strong PD-L1 expression he resumed pembrolizumab therapy and showed radiographic evidence of an ongoing response to therapy. CONCLUSIONS: This is the first report describing objective clinical and radiographic responses following immunotherapy for widely metastatic sebaceous carcinoma. The dramatic therapeutic response to pembrolizumab was associated with peripheral blood circulating memory T cells and mature Natural Killer cells after 6 months (24 weeks) of therapy. This report supports prospective clinical trials of anti-PD1 checkpoint blockade for metastatic sebaceous carcinoma.

Palliative 5-fluorouracil and cisplatin chemotherapy in recurrent metastatic sebaceous carcinoma: Case report and literature review.

Sebaceous carcinoma is a rare malignant tumor of the skin. Although this tumor is not completely understood due to its rarity and the paucity of published reports, it is known to be an aggressive tumor with a high incidence in Asia. Sebaceous carcinomas occur preferentially in the periocular region and require attention not to miss the associated Muir-Torre syndrome. In the case of localized disease, a wide local excision with clear margin followed by adjuvant radiation therapy is usually considered the standard treatment strategy but there is no agreed treatment strategy or standard chemotherapeutic regimen for recurrent metastatic sebaceous carcinoma. We report here two cases of recurrent metastatic sebaceous carcinoma patients who responded to 5-fluorouracil and cisplatin combination chemotherapy, and review the literature. We suggest that 5-fluorouracil-cisplatin can be considered a feasible and effective treatment modality for recurrent sebaceous carcinoma.

Neoadjuvant Systemic Chemotherapy in the Management of Extensive Eyelid Sebaceous Gland Carcinoma: A study of 10 Cases.

PURPOSE: To report the efficacy of neoadjuvant systemic chemotherapy in the management of eyelid sebaceous gland carcinoma (SGC). METHODS: Retrospective study of 10 patients that received neoadjuvant systemic chemotherapy (Cisplatin/Carboplatin and 5-Fluorouracil) for eyelid SGC. RESULTS: The mean age at presentation of eyelid SGC was 58 years (median, 55 years; range, 45 to 72 years). There were 6 females and 4 males. The mean tumor basal diameter was 36 mm (median, 31 mm, range, 20 to 65 mm), with orbital tumor extension in 9 cases. On the basis of TNM Classification, the tumors were classified as T3 (n = 10), N1 (n = 6), and M1 (n = 2). The mean number of cycles of neoadjuvant systemic chemotherapy per patient was 3 (median, 3; range, 3 to 4). The mean percentage reduction of tumor basal diameter after neoadjuvant chemotherapy was 74% (median, 80%; range, 30% to 100%). None of them had any major systemic side-effects of neoadjuvant chemotherapy. Postchemotherapy, surgical treatment for residual tumor was performed in 7 cases. Five cases underwent excision biopsy and 2 cases with residual orbital component underwent eyelid-sparing orbital exenteration. No tumor recurrence was noted in any of the 7 cases at a mean follow-up period of 18 months (median, 14 months; range, 3 to 63 months). One patient died due to systemic metastasis. CONCLUSION: Neoadjuvant systemic chemotherapy is effective and safe in the management of eyelid sebaceous gland carcinoma.

New pharmaceutical concepts for sebaceous gland diseases: implementing today's pre-clinical data into tomorrow's daily clinical practice.

The human sebaceous gland is a microscopic branched type multiacinar gland been present everywhere on the body except on the palms and soles, whereas they are sparsely located on the dorsum of hands and feet. Several medical conditions are related with sebaceous gland pathology, such as acne, sebaceous hyperplasia, sebaceous adenoma and sebaceous carcinoma. Acne is a common, complex, chronic disorder of the human pilosebaceous unit that mostly occurs in adolescence and young adulthood. The sebaceous gland plays an exquisite role in the initiation of the disease. The multifactorial nature of the pathogenesis of acne includes increased sebum production, alteration of the quality of sebum lipids, inflammatory processes, interaction with neuropeptides and dysregulation of the hormone microenvironment, follicular hyperkeratinization and inflammation maintained by Propionbacterium acnes products within the follicle. On the other hand, the sebaceous gland, as a major and critical compartment of human skin, is also affected through ageing, both intrinsic and extrinsic, which lead to distinct clinical and histological changes. Intrinsic ageing of the sebaceous gland is determined primarily by genetic factors and hormonal status, with androgens playing a major role. A clinical manifestation associated with intrinsic ageing changes is skin xerosis. Extrinsic ageing of human sebaceous gland is mainly caused by accumulating UV irradiation, especially UVA. Photoageing of sebaceous gland is expressed with a wide spectrum of benign and malignant sebaceous tumours, such as sebaceous hyperplasia, sebaceous carcinoma and Muir-Torre syndrome. This review will focus on the pathogenesis of the most common sebaceous gland diseases and their molecular pathways which may represent future pharmaceutical targets.

[Effect of S-1 in a patient with metastatic eyelid sebaceous carcinoma].

We report a 68-year-old female with a history of repeated right cervical lymph node metastasis secondary to eyelid sebaceous carcinoma. She had undergone right neck dissection due to lymph node metastasis at the department of surgery in an other local hospital. After the orbital exenteration, she underwent multiple operations, including 2 right partial parotidectomy and then total parotidectomy, 4 right cervical lymph node excisions and 1 left upper neck dissection due to lymph node metastasis. Adjuvant chemotherapy with S-1(at a dose of 80 mg per day)alone was applied as tumor dormancy therapy on an outpatient basis. Any adverse events during S-1 medication were observed. New metastatic lesions were not found until 29 months after the beginning of chemotherapy with S-1 alone. Although the effectiveness of S-1 for eyelid sebaceous carcinoma has not been demonstrated, S-1 might be useful in patients with recurrent eyelid sebaceous carcinoma based on our patient's recurrence-free survival.

Neoadjuvant chemotherapy in recurrent sebaceous carcinoma of eyelid with orbital invasion and regional lymphadenopathy.

A 35-year-old man presented with a recurrent temporal conjunctival mass (25 × 12 mm) involving about six-clock hours of the limbus in the left eye. The mass encroached onto the temporal half of cornea and showed surface keratin, large intrinsic and feeder vessels. It infiltrated the deep corneal stroma. There were no cells in the anterior chamber. Ultrasound biomicroscopy confirmed infiltration of deep corneal stroma without intraocular invasion. Surgery involved excision of the conjunctival component with 4-mm margin, lamellar sclerectomy and a penetrating sclerokeratoplasty with 3 mm of healthy corneal margin. Cryotherapy (double-freeze-thaw) was done to the conjunctival margins. Histopathology showed it to be invasive sebaceous cell carcinoma. A thin layer of deep corneal stroma and all conjunctival margins were uninvolved. At thirty-six weeks after treatment the left eye recorded a visual acuity of finger counting at 1 meter distance and no recurrence.

Topical mitomycin C chemotherapy in the management of ocular surface neoplasia: a 10-year review of treatment outcomes and complications.

INTRODUCTION: The use of topical mitomycin C (MMC) has gained popularity in the management of ocular surface neoplasia. The aim of this study is to determine outcomes and complications following such treatment. METHODS: This study is a retrospective review of patients treated with topical MMC for ocular surface neoplasia, including primary acquired melanosis (PAM), melanoma, corneal-conjunctival intraepithelial neoplasia (CCIN), squamous cell carcinoma (SCC) and sebaceous gland carcinoma (SGC). Data regarding diagnosis, short- and long-term outcomes, and short- and long-term complications, were recorded. RESULTS: 58 patients were identified, with a mean age of 63 years and mean follow-up of 36 months. 21 received MMC as primary therapy and 37 as surgical adjuvant. The regimen was 0.04% MMC four times a day for 3 weeks on, 3 weeks off, 3 weeks on, with topical steroid and lubricants throughout. Initial clinical response was either partial or complete in 93%. Overall, 26% developed recurrent disease at a mean of 13 months post treatment. Recurrence rates by pathology were 20% PAM, 25% melanoma, 0% CCIN, 67% SCC and 57% SGC. Short-term complications occurred in 52%, but only 7% required treatment cessation. Long-term complications such as persisting keratoconjunctivitis, epiphora and corneal problems, occurred in 31%. CONCLUSION: The results confirm the effectiveness of topical MMC chemotherapy in the management of ocular surface neoplasia. Self-limiting short-term complications were common; however, limbal stem cell deficiency appears to be a significant long-term complication of treatment, occurring in 12%.

Mitomycin-C as adjuvant therapy in the treatment of sebaceous gland carcinoma in high-risk locations.

PURPOSE: To report on the use of Mitomycin-C as adjuvant therapy to excision and cryotherapy in patients with sebaceous gland carcinoma (SGC) in high-risk locations. DESIGN: Retrospective, consecutive, case series. PARTICIPANTS: Three patients with SGC of the upper palpebral conjunctiva or caruncle, but without clinical pagetoid spread. METHODS: Following excision and double freeze-thaw cryotherapy, patients with histology demonstrating SGC of the ocular surface were treated with topical Mitomycin-C (0.04%). Follow-up was conducted over an average of 30 months (range: 24-37 months). MAIN OUTCOME MEASURES: Postoperative evidence of local recurrence, lymph node or distant organ metastasis. RESULTS: No patients had evidence of local recurrence or systemic disease. CONCLUSIONS: Wide surgical excision with cryotherapy is the basis of treatment of SGC without pagetoid spread. The use of Mitomycin-C as adjuvant therapy remains controversial, although there is some rationale for its use in high-risk situations.

Topical medical therapies for ocular surface tumors.

We review the use of three topical medications for the therapy of ocular surface tumors: mitomycin C, 5-fluorouracil, and interferon alpha-2B. One hundred sixty patients with histologically or cytologically proven epithelial and melanocytic tumors were identified in the literature. Side effects occurred most often with mitomycin C, followed by 5-fluorouracil, and interferon alpha-2B. Patients most frequently experienced transient keratitis, redness, and irritation. Topical agents were used as both primary and adjuvant therapy. Rates of tumor regression for CIN and squamous cell carcinoma ranged from 80 to 96%, and 70% of pigmented tumors regressed after an average follow-up of 27 months.