Primary Cutaneous Adenoid Cystic Carcinoma

DERMATOPATHOLOGY

Primary cutaneous adenoid cystic carcinoma Elizabeth Naylor, BA,a Papri Sarkar, MD,b Clifford S. Perlis, MD,c Dilip Giri, MD,d Douglas R. Gnepp, MD,a and Leslie Robinson-Bostom, MDa Providence, Rhode Island; Boston, Massachusetts; Philadelphia, Pennsylvania; and New York, New York Primary cutaneous adenoid cystic carcinoma is a rare, slow-growing malignancy first described by Boggio in 1975. This tumor characteristically consists of basophilic cells with a distinct adenoid or cribriform pattern in the mid to deep reticular dermis. Modified myoepithelial cells with prominent basement membrane material often surround true lumina. Definitive diagnosis relies on the characteristic histologic features and the exclusion of metastatic disease. We describe two patients who presented with painful papules of the scalp and were successfully treated with wide local excision. ( J Am Acad Dermatol 2008;58:636-41.)

CASE REPORTS Case 1 An 85-year-old man presented with a painful scalp papule that he had originally noticed 1 month before coming for treatment. He denied any history of trauma, pruritus, or bleeding in the area. His medical history was significant for hypertension, hypercholesterolemia, myasthenia gravis, rheumatoid arthritis, and a coronary artery bypass graft. Physical examination revealed a firm, tender, 5-mm, flesh-colored papule on the left posterior aspect of his scalp. No overlying skin changes or regional lymphadenopathy were appreciated. Biopsy findings revealed an intradermal neoplasm without an overlying epidermal connection. Tumor lobules were composed of basaloid cells with minimal cytoplasm, arranged in cords and strands in a multifocal growth pattern. There was mild nuclear pleomorphism and inconspicuous nucleoli. Many lobules demonstrated a cribriform pattern surrounded by basement membrane material (Fig 1).

From the Departments of Dermatology and Pathology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providencea; Department of Dermatology, Harvard University, Bostonb; Department of Medical Oncology, Fox Chase Cancer Center, Philadelphiac; and Memorial Sloan-Kettering Cancer Center, New York.d Funding sources: None. Conflicts of interest: None declared. Reprints not available from the authors. Correspondence to: Leslie Robinson-Bostom, MD, Associate Professor, Warren Alpert Medical School of Brown University, Rhode Island Hospital, Department of Dermatology, 593 Eddy St, APC 10, Providence, RI 02903. E-mail: lrobinson-bostom@ lifespan.org. 0190-9622/$34.00 ª 2008 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2007.12.005

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Abbreviations used: BCC: CEA: CT: EMA: PCACC:

basal cell carcinoma carcinoembryonic antigen computed tomographic epithelial membrane antigen primary cutaneous adenoid cystic carcinoma

Tubular and focally solid basaloid nests with focal intercalated ductal type differentiation were noted (Fig 1, B). Mucin, true lumina, and eosinophilic hyaline material were also appreciated (Fig 1, A-D). Perineural invasion was conspicuous (Fig 1, B, inset). Immunohistochemical analysis revealed strong luminal and pseudocystic space epithelial membrane antigen (EMA) staining. S-100 stained 75% of luminal and nonluminal cells. Cytokeratin AE1/AE3 stained 90% of cells in the tumor lobules. High-molecular weight cytokeratin stained 85% of epithelial cells. Calponin stained nonluminal myoepithelial cells. Smooth muscle actin also stained the majority of the nonluminal cells, while true luminal cells were negative. Strong true luminal staining was noted with monoclonal and polyclonal carcinoembryonic antigen (CEA). The lesion was diagnosed as adenoid cystic carcinoma. A metastatic work-up, including chest roentgenography and computed tomographic (CT) scanning of the head and neck, revealed a 1.0-cm nodule in the right lobe of the thyroid and asymmetry to the posterolateral left oropharynx and hypopharynx. This latter finding was evaluated clinically and no definitive lesion was seen. A right-sided thyroidectomy revealed no evidence of neoplastic change. The parotid and salivary glands appeared normal on CT scan. There were no intracranial lesions, and the visualized lung apices were clear. Because of

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extensive perineural invasion, wide local re-excision of the scalp lesion was performed. Forty-four months after the re-excision, the patient remains asymptomatic without any evidence of recurrence or metastasis. Case 2 A 67-year-old woman presented with a tender scalp papule of 2 years’ duration. Her medical history was significant for bilateral wrist ganglion cysts, Morton’s neuroma, hyperlipidemia, rosacea, gastroesophageal reflux disease, Dupuytren’s disease, and peritoneal cyst excision. Physical examination revealed a 5-mm flesh-colored papule on the left posterior aspect of her scalp. A local excision was performed. Histopathologic examination demonstrated islands of basaloid cells in a cribriform pattern located in the reticular dermis and subcutis with no connection to the overlying epidermis (Fig 2, A and B). Tumor cells were mildly to moderately pleomorphic with focally prominent nucleoli and a moderate amount of cytoplasm; mitotic figures were not observed. Scattered true lumina were seen. Cystic spaces contained abundant basophilic mucin. Perineural invasion was not present. EMA strongly stained true lumina. S-100 was patchy, staining 5% to 10% of the luminal and nonluminal cells. Cytokeratin AE1/AE3 strongly stained 95% of the tumor cells (Fig 2, A, inset). High-molecular weight cytokeratin staining was weaker, staining 75% of the tumor cells. Calponin was diffusely positive in luminal and nonluminal cells (Fig 2, C ). Smooth muscle actin stained 75% of the nonluminal cells; true lumina were negative (Fig 2, D). Polyclonal CEA staining revealed strong positivity in true lumina. Monoclonal CEA was also positive but stained only weakly (Fig 2, E ). A wide reexcision was performed 3 weeks later because of the positive deep margins on the original excision. Work-up for metastasis included a neck and chest CT scan, which revealed stable pulmonary nodules. The patient has been followed up for 10 months with no evidence of recurrence or metastasis.

DISCUSSION Adenoid cystic carcinoma is most commonly seen as a neoplasm of the salivary glands and seromucinous glands of the upper respiratory tract. It has also been reported to arise in the breast, trachea, major bronchi, uterine cervix, prostate, lacrimal gland, external auditory canal, and the skin.1 PCACC was first reported by Boggio2 in 1975. Since Boggio’s initial report, 48 additional cases, including the two presented herein, have been reported in the Englishlanguage literature (Table I).3-35

Fig 1. A, Infiltrating intradermal basaloid tumor with cribriform pattern, mucinous secretion, and basement membrane material. B, Detail of tumor demonstrates tubular, cribriform, and focally solid basaloid nests. Inset, Highlighting of perineural invasion in adjacent area. C, Higher magnification of cribriform area with prominent mucinous secretion. D, Focus of tumor demonstrates prominent basement membrane material in pseudocystic spaces. (A-D, Hematoxylin-eosin stain; original magnifications: A, 340; B, 3100 [includes inset]; C and D, 3200.)

PCACC most commonly arises in the seventh decade of life with a mean reported age of 59 years. Women account for 53% of reported cases. PCACC appears clinically as a firm, poorly circumscribed, slow growing nodule. The size of the tumor averages 3.5 cm and the tumor most often occupies an intradermal and subcutaneous location, with 41% of PCACCs arising on the scalp. Other reported locations include the chest, abdomen, back, eyelid, and perineum. Patients may be asymptomatic or may present with local hair loss, tenderness, or, rarely, pruritus.14

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Fig 2. A, Intradermal and subcutaneous basaloid tumor with prominent cribriform pattern. Inset, Strong staining of myoepithelial cells. B, Higher magnification highlights the cribriform pattern with prominent mucinous secretion and a few intercalated ducts. C, Diffuse staining and highlighting of myoepithelial cells. D, Moderate staining of myoepithelial cells. E, Staining of intercalated duct lumina. (A and B, Hematoxylin-eosin stain [A, inset, cytokeratin AE1/AE3]; C, calponin stain; D, SMA stain; E, CEA-monoclonal stain; original magnifications: A, 340 [inset, 3100]; B, C, and E, 3200; D, 3100.)

Histologic examination of PCACC characteristically shows intensely basophilic cells with a distinct adenoid or cribriform pattern occupying the mid to reticular dermis. Cells have hyperchromatic nuclei but lack prominent nuclear atypia. True lumina are surrounded by modified myoepithelial cells, often with prominent basement membrane material. Cystic spaces are occupied by alcian blueepositive mucin. Perineural invasion, which is seen in 76% of cases, is associated with an increased rate of

recurrence (46% recurrence in cases with perineural invasion vs 22% recurrence in cases without perineural invasion) (Table I). Immunochemical analysis reveals strong staining with EMA. Immunoperoxidase staining with S-100 and cytokeratin is generally positive. Some authors employing monoclonal antibodies to CEA have reported positive staining,18 whereas others have reported a lack of staining of tumor cells.1,23 Urso et al17 reported positive staining of luminal cells and intraluminal material with polyclonal CEA.17 The microscopic differential diagnosis of PCACC includes metastatic cutaneous adenoid cystic carcinoma, cylindroma, adenoid basal cell carcinoma (BCC), mucinous apocrine carcinoma, and apocrine mixed tumor of the skin. Salivary gland adenoid cystic carcinoma rarely metastasizes to the skin. Extracutaneous adenoid cystic carcinoma stains positively with EMA, S-100, and cytokeratin. In contrast to PCACC, which stains variably positively with CEA, extracutaneous adenoid cystic carcinoma stains consistently positive with CEA. PCACC should only be considered if there is no history or current evidence of extracutaneous adenoid cystic carcinoma.12 Cylindromas are distinguished from PCACC histologically by their lack of perineural invasion and invasive growth pattern. The tumor islands of cylindroma have an outer palisading cell type and an inner group of large cells with vesicular nuclei and focal ductal differentiation. In addition, their clinical behavior is that of a benign neoplasm in contrast to the low-grade malignant behavior of PCACC.26 Adenoid BCC may show a cribriform growth pattern and areas of cystic degeneration similar to PCACC. These two entities can be differentiated histologically by the contiguity of adenoid BCC with the overlying epidermis or hair follicle. PCACC usually does not demonstrate any connection between the neoplastic cells and the overlying epidermis.23 Epithelial connection has, however, been reported in upper respiratory tract adenoid cystic carcinoma.36 The presence of retraction artifact, elongation of cells, and palisading nuclei in the solid tumor masses of adenoid BCC also distinguish it from PCACC.1 Immunohistochemically, PCACC expresses EMA, whereas adenoid BCC does not.1 Mucinous apocrine carcinoma is recognized as having islands of eosinophilic tumor cells with cuboidal nuclei surrounded by large pools of basophilic mucin with thin fibrovascular septa. Cutaneous apocrine mixed tumor characteristically displays decapitation secretion. In general, the prognosis of adenoid cystic carcinoma of the salivary and lacrimal glands depends on various factors, including clinical stage, the location

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Table I. Cases of primary cutaneous adenoid cystic carcinoma in the English-language literature Reference

Boggio2 (1975) Sanderson and Batten3 (1975) Headington et al4 (1978) Dissayanake and Salm5 (1980) Cooper, Adelson, and Holthaus6 (1984) Boggio7 (1985) Wick and Swanson8 (1986) Beck, Lechner, and Wunsch9 (1986) Lang, Metcalf, and Maize10 (1986) Seab and Graham11 (1987)

Meyrick Thomas, Lowe, and Munro12 (1987) van der Kwast et al1 (1988) Ikegawa et al13 (1989) Kuramoto and Tagami14 (1990) Salzman and Eades15 (1991) Fukai et al16 (1990) Urso et al17 (1991) Bergman et al18 (1991) Chesser et al19 (1992) Matsumura et al20 (1993) Yoshihara et al21 (1993) Irvine et al22 (1996) Kato, Yasukawa, and Onozuka23 (1998) Zimmerman and Bibbo24 (1998) Chang et al25 (1999) Weekly et al26 (2000) Mencia-Gutierrez et al27 (2001) Koh et al28 (2001) Chu, Chang, and Lou29 (2001) Krunic et al30 (2003) Marback et al31 (2003) Duzova et al32 (2004) Doganay et al33 (2004) Fueston, Gloster, and Mutasim34 (2006) Goto et al35 (2006) Present report Present report NS, Not stated. *Length of follow-up.

Age (y)

Gender

Perineural invasion

66 46 60 41 47 61

F F F F M F

Scalp Scalp Scalp Axilla Scalp Arm

Recurrence*

8 5 NS 2.5 3 8

Yes NS Yes Yes NS Yes

NS Yes/11 y Yes/21 mo No/18 mo No/30 mo Yes/30 mo

No/14 y Yes/Lung No/21 mo No/18 mo No/30 mo NS

59 76 41 40 63 90 54 51 43 74 48 90 38 59 79 66

F F F M F M M M M M F F M M M F

Abdomen Scalp Back Hand Back Chest Chest Cheek Chest Scalp Scalp Perineum Chest Thigh Hip Scalp

7 2 NS NS NS NS NS NS NS NS NS NS NS NS NS 2.5

Yes No NS NS No Yes Yes Yes Yes No Yes Yes Yes Yes Yes NS

Yes/5 y No/10 y Yes/35 y No/9 mo Yes/78 mo No/3 y Yes/7.5 y Yes/21 mo Yes/20 y No/13.5 y Yes/9 y Yes/9 mo Yes/6.5 y No/1 mo Yes/5 mo Yes/16 y

No/5 y No/10 y NS NS No/78 mo No/3 y No/7.5 y No/21 mo No/20 y No/13.5 y Yes/Lung, pleura No/9 mo No/6.5 y No/1 mo No/5 mo NS

75 14 72 67 74 83 40 63 65 66 14 65 52

M F M M F M F F M M F F F

Chest Face Scalp Retroauricular Buttock Chest Abdomen Shoulder Scalp Face Scalp Abdomen Scalp

2 5 4 3 3 4 9 NS 1.2 2 2 1.5 3

Yes No Yes No Yes Yes Yes Yes No Yes NS Yes Yes

Yes/9 mo Yes/23 y NS No/3 mo No/3 y No/36 mo No/25 mo NS No/10 mo No/24 mo No/2 y NS No/3.5 y

NS Yes/Lungs NS No/4 mo No/3 y No/36 mo No/25 mo NS No/10 mo No/14 mo No/2 y NS Yes/Lymph nodes

82 70 40 70 60 64 45 57 55 55 57

F M M F M M F M F F F

Scalp Scalp Scalp Eyelid Scrotum Infra-auricular Scalp Eyelid Scalp Axilla Scalp

NS 2.5 0.9 1.2 NS 8 NS NS 2 5 3.5

NS No NS NS Yes Yes No NS Yes Yes No

Yes/3 y Yes/1 y No/4 y No/16 mo Yes/2 mo No/2 y No/18 mo No/18 mo No/10 mo Yes/2 y No/28 mo

Yes/Lung Yes/Lung, lymph node Yes/Lymph nodes No/16 mo NS Yes/Lymph nodes No/18 mo No/18 mo No/10 mo Yes/Lung, lymph nodes No/28 mo

39 85 67

M M F

Eyelid Scalp Scalp

NS 0.5 0.5

NS Yes No

No/20 mo No/44 mo No/10 mo

No/20 mo No/44 mo No/10 mo

Location

Size (cm)

Metastases*

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of the primary lesion, and the histologic growth pattern. Adenoid cystic carcinomas may be classified into 3 different histologic variants: tubular, solid, and cribriform. Adenoid cystic carcinomas with a solid growth pattern have a worse prognosis than those with a cribriform or tubular growth pattern. Accordingly, the solid subtype is characterized by a relatively high incidence of aneuploidy, a higher dividing cell fraction, and overexpression of p53.37 Adenoid cystic carcinoma of the breast represents less than 1% of all breast cancers and is associated with a favorable prognosis. One series of 120 patients reported metastatic disease in only 8 patients.38 Similarly, adenoid cystic carcinomas of the lung are usually confined to the site of origin at diagnosis and are characterized by a slow infiltrative growth and local recurrence.39 Unlike lung and breast adenoid cystic carcinoma, adenoid cystic carcinoma of the salivary glands is an aggressive tumor in which local recurrence and widespread metastases cause death in the majority of patients. One study calculated the onset of pulmonary metastases to occur an average of 227 months before the patient’s initial presentation.40 Surgery in combination with irradiation improves local disease control.41 PCACC characteristically follows an indolent course but has a high tendency to recur locally after excision. The reported interval between surgery and recurrence has ranged from 1 month to 35 years with extended tumor-free intervals necessitating longterm follow-up. The present review found 44% of reported PCACC cases to recur with an average of 58 months of follow-up. Lymph node and pulmonary metastases have been reported in a total of 5 and 6 cases, respectively. Discontinuous perineural involvement may produce false-negative margins, leading to inadequate resection.30 Because of the frequency of local recurrence, wide local excision with tumor-free margins is recommended. Some authors advocate a combination of excision, radiation, and chemotherapy.23 Combination cisplatin and doxorubicin hydrochloride chemotherapy has been successfully used to treat PCACC with pulmonary metastases.13 Four reported cases of PCACC have been treated with Mohs surgery.10,19,30,34 Although a metastatic work-up is warranted, lymph node dissection is not currently recommended unless there is evidence of lymphadenopathy. REFERENCES 1. van der Kwast TH, Vuzevski VD, Ramaekers F, Bousema MT, Van Joost T. Primary cutaneous adenoid cystic carcinoma: case report, immunohistochemistry, and review of the literature. Br J Dermatol 1988;118:567-77.

2. Boggio R. Adenoid cystic carcinoma of scalp [letter]. Arch Dermatol 1975;111:793-4. 3. Sanderson KV, Batten JC. Adenoid cystic carcinoma of the scalp with pulmonary metastasis. Proc R Soc Med 1975;68: 649-50. 4. Headington JT, Teears R, Niederhuber JE, Slinger RP. Primary adenoid cystic carcinoma of skin. Arch Dermatol 1978;114: 421-4. 5. Dissanayake RV, Salm R. Sweat-gland carcinomas: prognosis related to histological type. Histopathology 1980;4:445-66. 6. Cooper PH, Adelson GL, Holthaus WH. Primary cutaneous adenoid cystic carcinoma. Arch Dermatol 1984;120:774-7. 7. Boggio RR. Primary adenoid cystic carcinoma of the skin. Arch Pathol Lab Med 1985;109:707. 8. Wick MR, Swanson PE. Primary adenoid cystic carcinoma of the skin. A clinical, histological and immunocytochemical comparison with adenoid cystic carcinoma of salivary glands and adenoid basal cell carcinoma. Am J Dermatopathol 1986;8:2-13. 9. Beck HG, Lechner W, Wunsch PH. Adenoid cystic sweat gland cancer. Hautarzt 1986;37:405-9. 10. Lang PG Jr, Metcalf JS, Maize JC. Recurrent adenoid cystic carcinoma of the skin managed by microscopically controlled surgery (Mohs surgery). J Dermatol Surg Oncol 1986;12:395-8. 11. Seab JA, Graham JH. Primary cutaneous adenoid cystic carcinoma. J Am Acad Dermatol 1987;17:113-8. 12. Meyrick Thomas RH, Lowe DG, Munro DD. Primary adenoid cystic carcinoma of the skin. Clin Exp Dermatol 1987;12: 378-80. 13. Ikegawa S, Saida T, Obayashi H, Sasaki A, Esumi H, Ikeda S, et al. Cisplatin combination chemotherapy in squamous cell carcinoma and adenoid cystic carcinoma of the skin. J Dermatol 1989;16:227-30. 14. Kuramoto Y, Tagami H. Primary adenoid cystic carcinoma masquerading as syringoma of the scalp. Am J Dermatopathol 1990;12:169-74. 15. Salzman MJ, Eades E. Primary cutaneous adenoid cystic carcinoma: a case report and review of the literature. Plast Reconstr Surg 1991;88:140-4. 16. Fukai K, Ishii M, Kobayashi H, Chanoki M, Furukawa M, Nakagawa K, et al. Primary cutaneous adenoid cystic carcinoma: ultrastructural study and immunolocalization of types I, III, IV, V collagens and laminin. J Cutan Pathol 1990;17:374-80. 17. Urso C, Giannini A, Rubino I, Bondi R. Adenoid cystic carcinoma of sweat glands: report of two cases. Tumori 1991; 77:264-7. 18. Bergman R, Lichtig C, Moscona RA, Friedman-Birnbaum R. A comparative immunohistochemical study of adenoid cystic carcinoma of the skin and salivary glands. Am J Dermatopathol 1991;13:162-8. 19. Chesser RS, Bertler DE, Fitzpatrick JE, Mellette JR. Primary cutaneous adenoid cystic carcinoma treated with Mohs micrographic surgery toluidine blue technique. J Dermatol Surg Oncol 1992;18:175-6. 20. Matsumura T, Kumakiri M, Ohkawara A, Yoshida T. Adenoid cystic carcinoma of the skin—an immunohistochemical and ultrastructural study. J Dermatol 1993;20:164-70. 21. Yoshihara T, Ikuta H, Hibi S, Todo S, Imashuku S. Second cutaneous neoplasms after acute lymphoblastic leukemia in childhood. Int J Hematol 1993;59:67-71. 22. Irvine AD, Kenny B, Walsh MY, Burrows D. Primary cutaneous adenoid cystic carcinoma. Clin Exp Dermatol 1996;21:249-50. 23. Kato N, Yasukawa K, Onozuka T. Primary cutaneous adenoid cystic carcinoma with lymph node metastasis. Am J Dermatopathol 1998;20:571-7.

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33. Doganay L, Bilgi S, Aygit C, Altaner S. Primary cutaneous adenoid cystic carcinoma with lung and lymph node metastases. J Eur Acad Dermatol Venereol 2004;18:383-5. 34. Fueston JC, Gloster HM, Mutasim DF. Primary cutaneous adenoid cystic carcinoma: a case report and literature review. Cutis 2006;77:157-60. 35. Goto H, Yamamoto T, Ishiyama Z, Usui M, Okada S. Adenoid cystic carcinoma arising from the lower eyelid. Jpn J Ophthalmol 2006;50:374-6. 36. Gnepp DR, Heffner DK. Mucosal origin of sinonasal tract adenomatous neoplasms. Mod Pathol 1989;2:365-71. 37. Yamamoto Y, Wistuba II, Kishimoto Y, Virmani AK, Vuitch F, Albores-Saavedra J, et al. DNA analysis at p53 locus in adenoid cystic carcinoma: comparison of molecular study and p53 immunostaining. Pathol Int 1998;48:273-80. 38. Sumpio BE, Jennings TA, Merino MJ, Sullivan PD. Adenoid cystic carcinoma of the breast. Data from the Connecticut Tumor Registry and a review of the literature. Ann Surg 1987;205:295-301. 39. Dalton ML, Gatling RR. Peripheral adenoid cystic carcinoma of the lung. South Med J 1990;83:577-9. 40. Umeda M, Nishimatsu N, Masago H, Ishida Y, Yokoo S, Fujioka M, et al. Tumor-doubling time and onset of pulmonary metastasis from adenoid cystic carcinoma of the salivary gland. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999;88:473-8. 41. Simpson JR, Thawley SE, Matsuba HM. Adenoid cystic salivary gland carcinoma: treatment with irradiation and surgery. Radiology 1984;151:509-12.