Sebaceous carcinoma in the clinical setting of non-Hodgkin lymphoma: the Mayo Clinic experience
Funding: JDB received a Dermatology Foundation Career Development Award for the study of lymphoma-associated skin cancer.
Conflicts of interest: None.
Jerry D. Brewer, md
Division of Dermatologic Surgery
200 First Street SW
Objectives Non-Hodgkin lymphoma is a hematologic malignancy associated with the more aggressive behavior of some forms of skin cancer. An association between sebaceous carcinoma and immunosuppression has been identified, but the behavior of sebaceous carcinoma in the setting of non-Hodgkin lymphoma has not been studied. This study aimed to increase understanding of the behavior of sebaceous carcinoma in patients with concomitant non-Hodgkin lymphoma.
Methods Six patients diagnosed with sebaceous carcinoma and non-Hodgkin lymphoma from 1976 to 2008 were identified at the Mayo Clinic in Rochester, Minnesota. Their charts were reviewed retrospectively.
Results All six patients were male and White and presented with sebaceous carcinoma on non-eyelid regions of the head and neck. Two patients had Muir–Torre syndrome; four had secondary cancers that included colon, prostate, transitional cell, and urothelial cancers. Skin cancers other than sebaceous carcinoma included basal cell carcinoma and squamous cell carcinoma. Three patients died of causes unrelated to sebaceous carcinoma; one died of an unknown cause and two were alive at the time of the study.
Conclusions Sebaceous carcinoma does not appear to behave more aggressively in the setting of non-Hodgkin lymphoma. Larger studies are needed to definitively understand how sebaceous carcinoma behaves in patients with lymphoma.
Sebaceous carcinoma is a rare, malignant cutaneous neoplasm that arises from sebaceous glands and frequently occurs around the eyelids.1–5 It may also be associated with Muir–Torre syndrome, a genetic disorder of the DNA mismatch repair genes MLH1 and MSH2, associated with internal malignancy.6–12 Sebaceous carcinoma can metastasize and result in death. These outcomes sometimes reflect a delayed diagnosis because this carcinoma commonly can appear as a benign condition of the eyelid.3,13 Over the past decade, however, the number of deaths from sebaceous carcinoma may have decreased because of earlier recognition.3,13–15
Sebaceous carcinoma is one of the cutaneous neoplasms associated with Muir–Torre syndrome, which include sebaceous hyperplasia, basal cell carcinoma (BCC), actinic keratosis (AK), squamous cell carcinoma (SCC) and melanoma.16 An association between sebaceous carcinoma and immunosuppression has also been identified and has been particularly observed in organ transplant recipients.17,18 An increased incidence of skin cancers has been associated with lymphoma-related immunosuppression.19–21 Muir–Torre syndrome may also be associated with hematologic cancers, which represent some of the visceral cancers in the syndrome.22,23 Despite a potential association between this rare cutaneous malignancy and lymphoma-related immunosuppression, few studies in the medical literature look at the behavior of sebaceous carcinoma in the clinical setting of lymphoma.
We report six patients treated at the Mayo Clinic in Rochester, Minnesota, from January 1, 1976, to December 31, 2008, with concomitant diagnoses of sebaceous carcinoma and non-Hodgkin lymphoma. A retrospective chart review of these patients’ data was conducted to further understand the behavior of sebaceous carcinoma in the clinical setting of non-Hodgkin lymphoma. The Mayo Clinic Institutional Review Board approved this study.
Materials and methods
Table 1 summarizes patient characteristics, including the timing of sebaceous carcinoma and non-Hodgkin lymphoma diagnoses, the presence of Muir–Torre syndrome, BCC and SCC tumor burden, history of multiple AKs (i.e. three or more at one visit or more than five within two years), secondary cancers, treatment, and clinical outcomes in the present sample.
Table 1. Patient characteristics and details of sebaceous carcinoma (SC) and non-Hodgkin lymphoma (NHL)
|1||M||90 (8/1990)||Central scalp||89 (7/1989)||No||0||4||Yes||Prostatic carcinoma||CO2 laser; no recurrence or metastasis; died of congestive heart failure (5/1991)|
|2||M||82 (4/2004)||Left cheek||75 (2/1997)||Yes||1||4||Yes||Colon cancer||Mohs excision; no recurrence or metastasis; died of pneumonia and CLL (11/2004)|
|3||M||74 (9/2009)||Right forehead||70 (3/2006)||No||1||0||No||None||Mohs excision; no recurrence or metastasis; died of infection, CLL and PE (2/2011)|
|4||M||79 (11/2009)||Left scalp||66 (6/1996)||Yes||18||2||Yes||Prostatic carcinoma||Mohs excision; no recurrence or metastasis; alive|
|5||M||77 (7/2004)||Right neck||77 (7/2004)||No||5||5||Yes||Transitional cell carcinoma, urothelial carcinoma||Mohs excision; no recurrence or metastasis; cause of death unknown (10/2008)|
|6||M||84 (5/2010)||Right cheek||79 (12/2005)||No||7||0||No||None||Mohs excision; no recurrence or metastasis; alive|
A 90-year-old man with a history of large B cell lymphoma of the stomach diagnosed in July 1989 presented one year later with a biopsy-proven sebaceous carcinoma on the central scalp. The lesion was treated with carbon dioxide laser, and there was no recurrence or metastasis. Lymphoma treatment included radiation therapy. Muir–Torre syndrome was not found to be associated. Tumor burden of the skin included four SCCs and multiple AKs. A secondary malignancy was prostatic carcinoma with bone metastasis. The patient died of congestive heart failure in 1991.
An 82-year-old man with a history of chronic lymphocytic leukemia diagnosed in February 1997 presented with a biopsy-proven sebaceous carcinoma on the left cheek in April 2004. The lesion was treated with Mohs micrographic surgery, and there was no recurrence or metastasis. Lymphoma treatment included prednisone, chlorambucil, fludarabine, rituximab, methylprednisolone, and IV immunoglobulin. The patient had a history of colon cancer (invasive grade 3) and Muir–Torre syndrome. Tumor burden of the skin included one BCC, four SCCs, and multiple AKs. The patient died of pneumonia and chronic lymphocytic leukemia in November 2004.
A 74-year-old man with a history of chronic lymphocytic leukemia diagnosed in March 2006 presented with a biopsy-proven sebaceous carcinoma on the right forehead in September 2009. The lesion was treated with Mohs surgery, and there was no recurrence or metastasis. Lymphoma treatment included cyclophosphamide, rituximab, pentostatin, and allopurinol. Muir–Torre syndrome was not found to be associated, and no secondary cancers were found. Tumor burden of the skin included one BCC. The patient died of an infection, chronic lymphocytic leukemia, and pulmonary embolism in February 2011.
A 79-year-old man with a history of chronic lymphocytic leukemia and small lymphocytic lymphoma diagnosed in June 1996 presented with biopsy-proven sebaceous carcinoma on the left scalp in November 2009. The lesion was treated with Mohs surgery, and no recurrence or metastasis occurred. Lymphoma treatment included rituximab. The patient was positive for Muir–Torre syndrome with the MLH1 gene on genetic testing. A secondary malignancy was prostatic carcinoma (Gleason grade 3/4). Tumor burden of the skin included 18 BCCs, two SCCs, and multiple AKs. The patient is alive with multiple comorbidities.
A 77-year-old man with a history of chronic lymphocytic leukemia diagnosed in July 2004 presented with a biopsy-proven sebaceous carcinoma in the same month on the right neck. The lesion was treated with Mohs surgery, and there was no recurrence or metastasis. The patient required treatment for chronic lymphocytic leukemia. Muir–Torre syndrome was not found to be associated. Secondary cancers included transitional cell carcinoma and urothelial carcinoma in situ of the genitourinary tract. Tumor burden of the skin included five BCCs, five SCCs, and multiple AKs. The patient died in October 2008 of unknown causes.
An 84-year-old man with a history of large granular lymphocytic leukemia diagnosed in December 2005 presented with biopsy-proven sebaceous carcinoma on the right cheek in May 2010. The lesion was treated with Mohs surgery, and the patient had no recurrence or metastasis. Lymphoma treatment included chlorambucil and rituximab. Muir–Torre syndrome was not found to be associated, and no secondary malignancies were observed. Tumor burden of the skin included seven BCCs. The patient is alive currently.
We identified six patients with diagnoses of both sebaceous carcinoma and non-Hodgkin lymphoma. At the time of non-Hodgkin lymphoma diagnosis, the average age in this sample was 76 years (range: 66–89 years). The average age at the diagnosis of sebaceous carcinoma was 81 years (range: 74–90 years). All six patients were male and Caucasian. Three patients had sebaceous carcinoma lesions on the scalp or forehead; the others had sebaceous carcinoma lesions on the cheek or neck.
Muir–Torre syndrome was found in two patients, one of whom was MLH1 gene-positive and had a history of prostate cancer. Secondary cancers were found in four patients and included colon, prostate, transitional cell, and urothelial cancers. Non-Hodgkin lymphoma subtypes included chronic lymphocytic leukemia or small lymphocytic lymphoma or both in four patients, gastric large B cell lymphoma in one patient, and large granular lymphocytic leukemia in one patient. Tumor burden of the skin other than sebaceous carcinoma was as follows: three patients had five or more BCCs (including one patient with 18 BCCs); three patients had four or more SCCs; and four patients had multiple AKs.
Sebaceous carcinoma treatment consisted of Mohs surgery in five patients and carbon dioxide laser in one patient. There was no evidence of sebaceous carcinoma recurrence or metastasis in any of the six patients. Three patients died of causes unrelated to sebaceous carcinoma, one died of an unknown cause, and two remained alive at the time of the present study.
Sebaceous carcinoma is a rare tumor arising in sebaceous glands of the skin. In a review of sebaceous carcinoma, Dores and colleagues24 observed that 90% of patients were aged >50 years, that men and Caucasian individuals were most commonly affected, and that the head and neck represented the most frequent sites of occurrence. Clinical presentation is most commonly a painless subcutaneous nodule arising on the eyelid. These lesions are often confused with other eyelid conditions, such as chalazions or blepharoconjunctivitis, which may delay diagnosis and lead to metastasis or a poorer prognosis at later diagnosis.3,23
Sebaceous carcinoma is generally managed with surgical resection to ensure adequate tumor-free margins. Spencer and colleagues25 demonstrated lower recurrence rates of 11% with Mohs surgery, compared with 30% in standard excision. Compared with an age-matched population, 5- and 10-year overall survival rates were 92% and 79%.24 Like the patients in the previous reports, our six subjects were all male, Caucasian aged >50 years, and displayed lesions on the head and neck. Interestingly, none of our patients had sebaceous carcinoma lesions on the eyelid. It has been suggested that sebaceous carcinoma found in certain patients with Muir–Torre syndrome may manifest at sites other than the eyelid. Five of our patients were treated with Mohs surgery and had no recurrence or metastasis; for them, sebaceous carcinoma was not a specific cause of death. Instead, death appeared to result from non-Hodgkin lymphoma or chronic lymphocytic leukemia-related comor-bidities.
Sebaceous carcinoma is associated with the autosomal dominant genodermatosis Muir–Torre syndrome. In a study of patients with sebaceous tumors, 30.5% were found to have Muir–Torre syndrome.26 Two of our six patients (33%) were found to have Muir–Torre syndrome. Internal malignancies are observed in Muir–Torre syndrome, and the colorectal and genitourinary systems are most commonly involved (50% and 25%, respectively).22 This observation was consistent with findings in our two patients with Muir–Torre syndrome, who had concurrent sebaceous carcinoma with either colon or prostate cancer. Of the four patients without Muir–Torre syndrome, two patients had bladder, ureter, or prostate cancer, and two had no secondary internal malignancy.
The relationship among sebaceous carcinoma, Muir–Torre syndrome, and lymphoma has not been widely studied despite the 9–11% representation of hematologic cancers in Muir–Torre syndrome.22,23 Case reports in the literature include those of a 27-year-old Caucasian man with a history of Hodgkin lymphoma, in whom sebaceous carcinoma developed three years later,22 a 61-year-old Caucasian woman who presented with sebaceous adenomas six months after a diagnosis of non-Hodgkin lymphoma,27 and a 54-year-old man who received a simultaneous diagnosis of non-Hodgkin lymphoma and sebaceoma.28 One study observed that in patients aged >50 years with primary malignancy of non-Hodgkin lymphoma or chronic lymphocytic leukemia, sebaceous carcinoma appeared mostly on non-eyelid sites.24 Landis and colleagues29 reported a case of sebaceous carcinoma presenting in a patient with Muir–Torre syndrome after kidney transplantation. They also reviewed previous reports of patients who underwent cardiac or renal transplantation and patients with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) in whom Muir–Torre syndrome seemed to have been “unmasked”, resulting in sebaceous carcinoma.29
In addition, it is of interest to consider whether the chemotherapeutic regimen used to treat lymphoma has a carcinogenic effect that may increase the chances of sebaceous carcinoma development. In our small case series of six patients, four patients had undergone chemotherapeutic treatment for lymphoma. Although this concept has been debated in the medical literature, evidence is lacking that lymphoma-related chemotherapy is associated with subsequent secondary cutaneous malignancy.21,30,31
In lymphoma patients with Muir–Torre syndrome, sebaceous carcinoma may reflect both immunosuppression and abnormalities in tumor suppression. The DNA mismatch or absence of repair genes MLH1 or MSH2, or both, results in decreased tumor surveillance, high microsatellite instability, and greater predisposition for sebaceous carcinoma formation in immunosuppressed patients with Muir–Torre syndrome.32 Because certain skin tumors are known to increase in frequency and become more aggressive in the immunosuppressed state, it is possible that sebaceous carcinoma may behave similarly in lymphoma-induced immunosuppression. In Patient 4, who had Muir–Torre syndrome, the skin tumor burden was substantial and included 18 BCCs, two SCCs, and multiple AKs. The combination of immunosuppression by lymphoma and the genetic predisposition indicated by the presence of Muir–Torre syndrome may represent the cause of the increased overall skin tumor burden in this patient. However, Patient 2, who also had Muir–Torre syndrome, had a history of AK, SCC, and BCC similar to those of patients who did not have Muir–Torre syndrome.
In conclusion, this study presents a series of six patients with sebaceous carcinoma and non-Hodgkin lymphoma that covered >30 years of follow-up at Mayo Clinic in Rochester. This case series should not be used as conclusive evidence for the behavior of sebaceous carcinoma in the clinical setting of non-Hodgkin lymphoma. Although larger studies are necessary for a definitive understanding of how sebaceous carcinoma behaves in patients with lymphoma, these patients may have an increased risk for this disease. Lymphoma-related immunosuppression and Muir–Torre syndrome-related abnormal tumor surveillance may predispose such patients to sebaceous carcinoma formation. Although immunosuppression has been associated with the increased aggressiveness of many types of cutaneous neoplasm, sebaceous carcinoma does not appear to behave more aggressively in the setting of non-Hodgkin lymphoma or chronic lymphocytic leukemia. In our six patients, no metastasis or death were caused by sebaceous carcinoma. Mohs micrographic surgery provides much lower rates of recurrence than standard excision and represents the likely choice of treatment.