Eur Arch Otorhinolaryngol DOI 10.1007/s00405-014-3324-8
MISCELLANEOUS
Skin adnexal carcinoma of the head and neck: a retrospective study in a tertiary referral center Hanneke Stam • Bart A. van de Wiel • W. Martin C. Klop • Biljana Zupan-Kajcovski • Soe Janssens • M. Baris Karakullukcu Vincent van der Noort • Peter J. F. M. Lohuis
•
Received: 25 April 2014 / Accepted: 6 October 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract The objective of this study is to give more insight in the diagnosis, clinical course and therapy of skin adnexal carcinoma of the head and neck. Forty cases of skin adnexal carcinoma of the head and neck treated from 1977 to 2011 were identified by searching the hospitals cancer registration database. After pathology review by a pathologist specialized in skin cancer, 17 cases were excluded. A retrospective chart review of the remaining 23 patients was performed. Clinical course was recorded by endpoints including survival, loco-regional control and recurrence free survival. Prognostic factors considered for analysis were differentiation of the tumor and location of the tumor. Five-year overall survival (OS) was 78 % (95 % CI 61–100 %). Five-year recurrence free survival (RFS) was 58 % (95 % CI 40–84 %). Poor differentiation of the tumor significantly reduced OS (p = 0.002) and RFS
(p = 0.01). Tumor location ‘face’ demonstrated a significantly better survival than other tumor locations (p \ 0.001). Local recurrence occurred in five cases, regional metastasis was seen in seven patients, distant metastasis in three patients. Three cases with distant metastases died of disease. Based on the findings of this small group of patients in a tertiary referral center, we conclude that skin adnexal carcinoma is a very rare skin carcinoma that can behave locally aggressive but also has the potential for regional and distant metastasis. The recognition of skin adnexal carcinoma and subsequent wide excision in an early stage of the disease is of major importance for loco-regional control and survival. Keywords Skin adnexal carcinoma Head and neck Clinical course Therapy
Introduction H. Stam W. M. C. Klop M. B. Karakullukcu P. J. F. M. Lohuis (&) Department of Head and Neck Oncology and Surgery, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands e-mail:
[email protected] B. A. van de Wiel Department of Pathology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands B. Zupan-Kajcovski S. Janssens Department of Dermatology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands V. van der Noort Department of Biometrics, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
Skin adnexal carcinomas (SACs) are a heterogeneous group of rare malignant tumors that arise in the appendages of the skin. They are classified as to their morphological differentiation: apocrine-eccrine, follicular and sebaceous [1]. SACs are uncommonly encountered in routine practice by the clinician as well as the pathologist which can result in undertreatment with a poor clinical outcome. Studies of SAC have been limited and consist mainly of case reports concerning specific subtypes of SAC. The rarity and difficulty to recognize SAC, in combination with its potential aggressive behavior makes SAC a challenging entity to treat. We conducted a retrospective case series in a tertiary referral center and a review of the literature to provide more insights into diagnosis, clinical course and therapy of SAC of the head and neck for a better recognition and proper treatment.
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Materials and methods A retrospective chart review was performed of patients treated for SAC of the head and neck from 1977 to 2011 with follow-up until June 2013 in The Netherlands Cancer Institute—Antoni van Leeuwenhoek Hospital Amsterdam, the Netherlands. Primary and referral cases were included. Cases were identified by searching the hospitals cancer registration database by using the International Classification of Diseases for Oncology, Third Edition (ICD-O-3) morphology codes for SAC. Codes representing Paget (code 8540) and extramammary Paget (code 8542) disease were excluded. The remaining cases with ICD-O-3 morphology codes (8102, 8110, 8200, 8211, 8390, 8400–8403, 8406–8410, 8413, 8481, 8940) that included a skin of the head and neck code (C44.0–C44.4) were included. Forty cases were identified with this methodology. The original pathology slides were reviewed by a pathologist, specialized in skin cancer (BvdW). Several cases were reviewed by a second pathologist who is also specialized in skin cancer (see acknowledgements). Clinical data of the eligible cases were reviewed to retrieve tumor location and clinical course. Standard therapy of SAC in our center started with a biopsy of the local tumor and an ultrasound of the neck, accompanied with fine needle aspiration cytology in case of suspicion of a pathological lymph node. In case of positive histology for SAC, a wide local excision with a surgical margin of at least 1 cm was performed, followed by histological assessment of the surgical margins. A neck dissection plus adjuvant radiotherapy of the neck was done if cytology was positive for SAC. Every patient was offered a follow-up with clinical lymph node assessment for at least 5 years after loco-regional therapy. Deviation of our standard therapy for SAC occurred as this study also includes referral cases that already received a form of treatment prior to referral to our center. Statistical analysis The rates of overall survival (OS), recurrence free survival (RFS), disease specific survival (DSS) and local– regional control were calculated by using the method of Kaplan and Meier, with censoring starting at last date of follow-up. OS was defined as the time from first treatment to death and DSS as the time from first treatment to death of SAC. RFS was defined as the time from primary treatment to the occurrence of local recurrence, regional disease, distant disease or death. Loco-regional control was defined as control at the site of the primary tumor or regional lymph stations of the head and neck after primary treatment. Prognostic factors considered for analysis were differentiation of the tumor, location of the tumor
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(grouped into four categories: ear, eyelid, face, scalp ? neck) and tumor type. The effect of these factors on relapse free survival was assessed using the log-rank test. The effects of location and differentiation on RFS were also considered simultaneously in a cox proportional hazard model.
Results Pathology review Forty cases of SAC were identified by searching the hospitals cancer registration database. Six out of the forty cases were excluded due to the inability to retrieve the corresponding histological slides in the hospitals tissue bank (all referral cases). Another eleven cases were excluded after review. Of these eleven cases, six were classified as a benign skin adnexal tumor, three were classified as basal cell carcinoma (BCC) or cutaneous squamous cell carcinomas (SCC) and two cases were too poorly differentiated to (sub)classify. A total of twentythree cases fulfilled the criteria of SAC, each with one lesion. After pathology review of the twenty-three cases, the subtype of seven cases of SAC changed. In three cases it was not possible to specify the subtype due to poor differentiation (SAC not otherwise specified). One case showed a SAC with multilineage differentiation and could therefore not be classified by subtype either. Of the total of twenty-three cases, apocrine-eccrine carcinoma occurred most commonly (57 %), with sebaceous (17 %), follicular (9 %) and SAC not otherwise specified (17 %) to a lesser extent. Ten out of twenty-three cases showed poor differentiation. It was not possible to assess the diameter and surgical margins of the primary tumors since the majority of the reviewed pathology slides were pathology slides of recurrent lesions and metastasic lesions. General patient characteristics Table 1 shows the clinical features of the total study population of twenty-three patients. The median age of the study population was 66 years (range 46–87). Fourteen patients (61 %) were female; nine (39 %) were male. Twenty-two out of twenty-three patients had Fitzpatrick skin type I–II. The most common site of presentation was the face (43 %), followed by scalp and neck (39 %), eyelid (9 %) and ear (9 %). Figure 1 presents a projection of the exact locations in the investigated group, extrapolated to one side.
Sex
Age (years)
F
F
F
M
F M F M
3
4
5
6
7 8 9 10
74 62 50 70
69
46
73
83
80
F F F
63 62 53
SAC with multilineage differentiation SAC NOS SAC NOS SAC NOS
Trichilemmal carcinoma Malignant proliferating tricholemmal tumor
– – Sebaceous cyst
–
Keratoacanthoma –
– Keratoacanthoma SCC SCC
Sebaceous Sebaceous Sebaceous Sebaceous
carcinoma carcinoma carcinoma carcinoma
Porocarcinoma Adenoid cystic carcinoma Syringoid eccrine carcinoma
BCC
–
BCC
BCC
BCC
Keratoacanthoma
Preoperative diagnosis
– – Sebaceous cyst Verruca seborrhoica – – SCC
Microcystic adnexal carcinoma Microcystic adnexal carcinoma Microcystic adnexal carcinoma Microcystic adnexal carcinoma Microcystic adnexal carcinoma Microcystic adnexal carcinoma Mucinous carcinoma Mucinous carcinoma Mucinous carcinoma Porocarcinoma
Type
Scalp Cheek Perioral
Cheek
Cheek Scalp
Neck Eyelid Eyelid Scalp
Scalp Scalp Scalp
Scalp Ear Scalp Ear
Cheek
Forehead
Periorbital
Perioral
Forehead
Forehead
Site
Scalp/neck Face Face
Face
Face Scalp/neck
Scalp/neck Eyelid Eyelid scalp/neck
Scalp/neck Scalp/neck Scalp/neck
Scalp/neck Ear Scalp/neck Ear
Face
Face
Face
Face
Face
Face
Subcategory tumor location
Yes Yes Yes
No
Yes No
Yes Yes Yes Yes
No Yes No
No No No Yes
No
No
No
No
No
No
Poor differentiation
No No No
No
No No
Yes No No Yes
No No Yes
No No Yes Yes
No
No
No
No
No
No
Local recurrencea
Yes No No
No
No No
Yes No Yes Yes
No Yes No
Yes No No Yes
No
No
No
No
No
No
Regional metastasisa
Yes No No
No
No No
Yes No No No
No No No
No No No Yes
No
No
No
No
No
No
Distant metastasisa
Yes Yes Yes
Yes
Yes Yes
Yes No Yes Yes
Yes No Yes
Yes No Yes Yes
No
Yes
No
No
No
No
Prior treatmentb
DOT NED NED
NED
DOOC NED
DOT DOOC NED NED
NED DOOC NED
DOOC NED NED DOT
NED
NED
NED
NED
DOOC
NED
Outcome
F female; M male, SAC skin adnexal carcinoma, NOS not otherwise specified, BCC basal cell carcinoma, SCC cutaneous squamous cell carcinoma, DOT dead of tumor, DOOC dead of other cause, NED no evidence of disease a On initial presentation or on follow up b Prior treatment before referral to our tertiary referral center
21 22 23
Not specified by type 20 F 62
11 F 64 12 F 71 13 F 64 Sebaceous origin 14 M 66 15 M 87 16 M 77 17 M 67 Follicular origin 18 F 85 19 F 51
M
2
Apocrine-eccrine origin 1 M 47
Patient
Table 1 Patient characteristics, tumor characteristics and outcome
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pathologic regional lymph nodes (n = 3). One patient was referred with local recurrence combined with the presence of regional disease. In one other case the reason for referral is unknown. The average time between first treatment and treatment in our center was almost 19 months (range 1–117 months). Treatment modalities and outcomes
Fig. 1 Projection of the location of 23 SACs. Two SACs not drawn: one retro auricular, one occipital
Only eight cases of the investigated group were primarily treated in our center, specialized in skin oncology. The remaining fifteen cases were referred to us for additional treatment. Reasons for referral were incomplete resection (n = 8), local recurrence (n = 2) and presence of
Treatment modalities and outcomes are summarized Table 1 and Fig. 2. Of the total population of twenty-three cases, five encountered local recurrence. All five patients with local recurrence are patients that were referred to our tertiary center. Three out of these five patients also developed regional metastases. Besides these three patients, four other patients developed regional metastases without local recurrence. Of these seven patients with regional metastases, six are referred patients. Four out of these seven patients with regional disease were cured after treatment. The remaining three developed distant metastases and died of disease. All three patients with distant metastasis are referred patients.
Fig. 2 Diagram depicting 23 SACs according to treatment and outcome. Prior treatment with cryotherapy and photodynamic therapy is not shown. RT radiotherapy
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SACs are mostly asymptomatic. Rarely they itch, bleed or cause pain. SACs predominantly occur in the fair skin population, mostly located on the head and neck [8, 9]. Literature demonstrates that SACs have a broad differential diagnosis [10]. Figures 5 and 6 show two different types of SACs and illustrate the variety of appearances and low specificity of SACs. SACs have an incidence rate of approximately, 5.3 per million persons per year in western countries [9, 11]. Extrapolating this to the Netherlands with 16 million inhabitants, this would mean 81 new cases per year. The incidence increases exponentially with age, with a peak in the eighth decade of life [9, 11]. Histo-pathological examination of a deep skin biopsy or a diagnostic excision is considered the gold standard for the diagnosis of SAC [12]. However, as SACs have a wide histo-pathological spectrum, it is often difficult to diagnose SAC histologically [13], even for an experienced pathologist. Figure 7 shows histological pictures of four different subtypes of SAC, including tumors with poor differentiation. Review in this study by a pathologist specialized in skin cancer of 34 cases of SAC that were identified by the hospitals cancer registry led to an alteration of diagnosis and exclusion of eleven cases. In another 7 of the 23 left eligible SAC cases the subtype changed. The amount of changes after the pathology review in this study confirms the difficulty in histological diagnosis of SAC, which we think can be explained by several reasons. First, the rarity of SACs makes it difficult for pathologists to obtain
Five-year OS was 78 % (95 % CI 61–100 %). With three of twenty-three patients dying of disease, all due to distant metastasis. Five-year RFS was 58 % (95 % CI 40–84 %). Furthermore, five-year DSS and five-year locoregional control were 82 % (95 % CI 66–100 %) and 63 % (95 % CI 46–87 %) respectively. Poor differentiation of the tumor reduced OS (p = 0.002, Fig. 3). Furthermore, both differentiation (p = 0.01) and site of the tumor (p = 0.004) reduced RFS. Tumor type did not influence survival in this small patient population. A second test comparing the four subcategories of tumor location (ear, eyelid, face, scalp ? neck), showed a significantly better survival for subcategory ‘face’ (p \ 0.001, Fig. 4).
Discussion This study showed that clinical diagnosis of SACs is very difficult, even for specialists who are experienced in skin cancer. Often SACs are misinterpreted as cutaneous squamous cell carcinoma (SCC), basal cell carcinoma (BCC) or a benign skin tumor (Table 1). The difficulty to diagnose SACs clinically can be attributed to the varying and often subtle appearance [2–7], whereas specialists also have limited exposure to SACs due to its rarity. Most SACs grow slowly and are red or skin colored. When diagnosed, the lesion has often been present for a long period since
Fig. 3 Kaplan–Meier survival curves indicating that patients with a poorly-differentiated SAC had a significantly worse overall survival than those patients with a betterdifferentiated SAC (p = 0.002)
0.6 0.4 0.2
Better differentiated Poorly differentiated
0.0
Survival Probability
0.8
1.0
Overall Survival
13
11
9
6
10
10
7
3
4
6
0
2
5
3
2
2
Better differentiated Poorly differentiated
8
10
12
14
Years
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1.0
Recurrence Free Survival by site Site
0.6 0.4 0.0
0.2
Survival Probability
0.8
Face Other
13
3
3
2
10
10
6
4
4
6
0
2
Other 2
2
1
1
8
10
12
14
Face
Years
Fig. 5 Picture of a sebaceous carcinoma
Fig. 6 Picture of a trichilemmal carcinoma
histological experience with SAC, which is presumably the most important explanation. Second, the histological appearances of a SAC and its benign counterpart can be very similar. Third SACs have a wide histopathological spectrum sometimes with multilineage differentiation and various subtypes of SACs bear histological resemblances to other skin tumors (for example BCCs). The outcome of the pathology review described above stresses the importance of pathology review in future research of SAC, preferably by a pathologist specialized in skin cancer.
Based on the findings of this small group of patients, this study demonstrates that the aggressiveness in biological behavior of SAC should not be underestimated. Local recurrence was seen in 5/23 cases, regional disease metastases in 7/23 cases and distant disease in 3/23 cases. Table 2 presents an overview of the biological behavior of the different SAC types, all based on level 4 evidence (case studies). This table also shows that the behavior of SAC is mostly locally aggressive, but it also has the potential for regional and distant metastasis. Patients with a poorly-
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Fig. 7 Histopathological pictures (Haematoxylin and Eosin, original magnification 2009) of several different adnexal carcinomas from this study. a Trichilemmal carcinoma: various growth patterns (solid, lobular and trabecular) and cells with abundant, clear cytoplasm. b Sebaceous carcinoma: lobular growth pattern with central necrosis
and only focally sebaceous cells with vacuolated cytoplasm. c Skin adnexal carcinoma not otherwise specified: irregular nests of atypical cells with no other differentiation features. d Microcystic adnexal carcinoma: infiltrative small nests with keratocysts within a desmoplastic stroma
differentiated SAC had a significantly worse OS and RFS than patients with a better-differentiated SAC in our study population. Previous studies showed a significantly poorer survival in poorly-differentiated eccrine carcinoma [14] and a higher incidence of metastasis in poorly-differentiated sebaceous carcinoma [15]. SACs located at the face showed a significantly better RFS than tumors located at the ear, eyelid or scalp and neck in our study. This better RFS for SACs located on the face might be due to earlier clinical recognition of these SACs. Earlier clinical recognition of SACs could reduce patient delay and may eventually result in a higher chance of local control at the time of treatment. However, six out of the ten SACs located at the face are classified as subtype microcystic adnexal carcinoma (MAC). Yu et al. [16] demonstrated that MAC has an excellent overall survival. Thus, the better RFS for SACs located at the face might also be due to the fact that more than half of the SACs located at the face are SACs with a good survival probability. Interestingly, subtype of SAC did not influence survival in our small study
population. Earlier epidemiological research of this study group on 2220 cases of full body SAC in the Netherlands showed that malignant mixed tumor was the only type that predicted a poorer survival [9]. Hidradenocarcinoma, digital papillary carcinoma, adenoid cystic carcinoma and apocrine carcinoma on the other hand, demonstrated a significantly better survival [9]. Local excision provides the best treatment outcome in SAC [8, 17], which was also the treatment modality provided in the majority of our population. There are three aspects in local therapy of SAC that should be discussed: the surgical margins, the role of Mohs micrographic surgery (MMS) and adjuvant radiotherapy. Regarding the surgical margins, there are no uniform guidelines available for SAC. Based on the experience in our specialized center in skin oncology, we recommend a surgical margin of at least 1 cm. Moreover, according to our opinion the surgical margin should correspond to the aggressiveness of the SAC: a wider surgical margin than 1 cm should be considered in SACs with a large diameter, in case of deep invasion, and in
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Eur Arch Otorhinolaryngol Table 2 Classification and biological behavior of skin adnexal carcinoma Ref
Localization
Biological behavior Locally aggressive
Local recurrence (%)
Regional metastasis (%)
Distant metastasis (%)
Eccrine-Apocrine differentiation Microcystic adnexal carcinoma
[2, 3, 19]
Head and neck
Yes
15–40
2.1b
2.1b
Mucinous carcinoma Adenoid cystic carcinoma
[26–28] [13, 27]
Scalp, face, eyelids Scalp
Yes Yes
30 50–60
10 Rarelya
3 Rarelya
Hidradenocarcinoma
[18, 27, 29]
Any area
Yes
40
Yesa
30–60
Apocrine carcinoma
[13, 27, 30]
Axilla (eyelid, ear, scalp)
Yes
30
40–50
24 %
Tubular carcinoma
[27]
Axilla
Yes
Unknown
48b
48b
Porocarcinoma
[27, 31, 32]
Leg, trunk
Yes
20
20
12
Spiradenocarcinoma
[17, 27]
Extremities, trunk
Yes
Higha
50
30
Digital papillary carcinoma
[27, 33]
Finger, toe, palm
Yes
48–50
Littlea
14–41
Malignant mixed tumour
[27, 34]
Extremities
Yes
C41
[50b
[50b
Follicular differentiation Pilomatrical carcinoma
[35–37]
Head, neck
Highly
42–60
11
10–16
Trichilemmal carcinoma
[7, 37, 38]
Face, ear
Rarely
Low
6
Rarely
Malignant proliferating tricholemmal tumour
[37, 39]
Scalp (90 %)
Possibly
5%
1–2 %b
1–2 %b
[6, 40]
Head, neck
Yes
18–35 %
5–18 %
20–25 %
Sebaceous differentiation Sebaceous carcinoma
Paget and extramammary Paget disease are not shown in this overview Ref reference a
Case based
b
Not possible to distinguish between regional and distant metastasis
case of poorly-differentiated SACs. In these locations where wide local excision might lead to high morbidity or organ loss (e.g. cheeck, ear, nose, under eyelid), every millimeter counts. MMS could be suitable in these cases because it certainly has the advantage over wide local excision with regard to maximal tissue conservation. However, clinical experience with MMS in SACs is limited and literature on this matter consists mostly of small case series [3, 12, 18–20]. A contraindication for the use of MMS is discontinuous growth of the tumor. In this study, infiltrative growth was seen in multiple cases. Furthermore, the pathology review already showed the difficulty to diagnose SAC with regular paraffin imbedded sections. MMS is based on assessment of frozen sections and this might be even more difficult and prone to mistakes. Because of the abovementioned reasons, we recommend to exercise restraint in the use of MMS in SAC. We would only recommend MMS if surgical morbidity would be unacceptably high with wide local excision. The third subject to discuss in the local treatment of SAC is adjuvant radiotherapy after excision. So far, there is no conclusive evidence that adjuvant local radiotherapy improves local disease control in SAC [8, 14, 16, 17, 21]. However, we suggest that local adjuvant radiotherapy might aid in selected cases of high
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risk SAC with multiple recurrences to reduce the risk of regional metastasis, especially if the primary tumor is located nearby organs like the orbit, ear, or nose. As in all skin carcinoma, local control is crucial for the further course of the disease. After the diagnosis of a local SAC, regional staging of the disease should always be performed; optimally this is performed with ultrasound guided fine-needle aspiration cytology [22]. The chance of a micrometastasis that remains unnoticed after ultrasound guided fine needle aspiration cytology is small. The advantage of sentinel biopsy versus the morbidity of the procedure is therefore low. Hence, treatment of the cN0 neck is not recommended. In this study population, 7/23 cases presented with regional metastasis. Four of these seven gained locoregional control whereas the remaining three developed distant metastasis and died of the disease. Provided distant metastasis does not occur, there is a solid chance of survival in regional disease of SAC. Therefore, it is important to start as soon as possible with adequate therapy in the presence of regional metastasis to prevent the development of distant metastasis. There are no guidelines for locoregional treatment of SAC. However, we advise a neck dissection in the presence of pathological regional lymph
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nodes. Also, we recommend adjuvant regional radiotherapy in case of C2 involved lymph nodes or if extra capsular rupture has occurred, similar to the protocol of cutaneous SCC and melanoma. Furthermore, frequent follow-up is important in the therapy of regional SAC. If distant metastasis of SAC occurs, the proper treatment remains uncertain as there are limited experiences with adjuvant therapies. Research in the field of metastatic SAC shows a potential role for specific pathway inhibitors [23–25]. Further studies are warranted in order to confirm the efficacy of adjuvant therapy in distant disease. It has not escaped our attention that this study consists of a special patient population. The majority of the population was referred to our tertiary referral center after primary treatment elsewhere. The patient group might therefore represent a skewed population with possibly a higher recurrence rate and more aggressive tumors. One must keep in mind though that the rarity of SAC may cause a higher referral rate due to unfamiliarity with SAC by specialists. Furthermore, this study had a limited sample size and the population consisted of a heterogeneous group of cases with different subtypes of SAC. Although the mean follow-up period was almost 6 years, ten of twentythree patients had a less than 5 years follow-up which may underestimate the failure rate.
Conclusion Based on the findings of this small group of patients in a tertiary referral center in combination with data from the literature we conclude that skin adnexal carcinoma is a very rare skin carcinoma that can behave locally aggressive but also has the potential for regional and distant metastasis. SAC is very well-curable with wide local excision. We therefore advice a surgical margin of minimal 1 cm and in large lesions even more. However, when SAC is poorly diagnosed and/or operated with limited surgical margins, this could result in multiple recurrences and increases the chance of regional and distant metastasis. We therefore conclude that timely recognition and diagnosis of SAC and subsequent wide excision in an early stage of the disease is of major importance in achieving loco-regional control and survival. A neck dissection is indicated in case of regional disease. Adjuvant radiotherapy seems to be able to favor the chance of survival in selected cases. Acknowledgments We thank dr. E.H. Jaspars, Department of Pathology, Tergooiziekenhuizen, Blaricum. The Netherlands for coreviewing several adnexal carcinomas. Furthermore, we would like to thank the Department of Dermatology of the Academic Medical Center Amsterdam, the Netherlands, for using photo material of SAC from their archive.
Conflict of interest No funds were received in support of this study. No benefits in any form have been or will be received from a commercial party related directly or indirectly to.
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