Anatomic Pathology / Microcystic SCC of the Lung Microcystic Squamous Cell Carcinoma of the Lung A Clinicopathologic Study of Three Cases Annikka Weissferdt, MD, and Cesar A. Moran, MD Key Words: Squamous cell carcinoma; Lung; Microcystic adnexal carcinoma; Adnexal tumors; Microcystic change DOI: 10.1309/AJCP61QPWAZSPJAO Abstract Three cases of pulmonary squamous cell carcinoma (SCC) are described displaying a prominent microcystic pattern closely resembling microcystic adnexal carcinoma of the skin (MAC). The patients were 2 women and 1 man aged 72 to 83 years. Histologically, in addition to conventional SCC, all tumors showed striking microcystic changes characterized by nests and strands of basaloid squamous cells with central cystic spaces, peripheral palisading, and cytoplasmic clearing of the central tumor portions. Follow-up available for 2 patients revealed that 1 was alive at 76 months and 1 had died 38 months after diagnosis. Microcystic SCC is an unusual variant of SCC of the lung histologically mimicking tumors with glandular or adnexal differentiation and a particularly striking resemblance to MAC of the skin. The importance of the recognition of this growth pattern lies in the separation from other often less aggressive pulmonary neoplasms or metastatic disease from a cutaneous tumor. Squamous cell carcinoma (SCC) of the lung is a tumor that may show different growth patterns. The main variants include papillary, clear cell, small cell, and basaloid SCC in addition to other less commonly seen patterns. 1 We report 3 cases of an undescribed variant of pulmonary SCC characterized by prominent microcystic changes. The microcystic change seen in our cases was so pronounced as to mimic glandular and duct-like adnexal differentiation and was strikingly reminiscent of the growth pattern seen in the so-called microcystic adnexal carcinoma (MAC) of the skin, a rare but distinct cutaneous neoplasm with locally aggressive behavior and an ability to give rise to metastasis. 2,3 The importance of the recognition of microcystic changes in SCC of the lung lies in the potential for misdiagnosis as a tumor with a true glandular component or neoplasm of adnexal derivation. We provide a detailed pathologic description to facilitate the differential diagnosis of this unusual variant and its closest mimics. Materials and Methods Three cases of SCC of the lung showing a prominent microcystic growth pattern were identified from the surgical pathology files of the M.D. Anderson Cancer Center, Houston, TX. In each case, 5 or 6 H&E-stained tumor sections from resection specimens were available for review. Clinical and follow-up information was obtained from the patients charts or from referral information. Results Clinical Features The clinical features are summarized in Table 1. Of the patients, 2 were women and 1 was a man; their age range was 436 Am J Clin Pathol 2011;136:436-441 436 DOI: 10.1309/AJCP61QPWAZSPJAO
Anatomic Pathology / Original Article Table 1 Clinical Features of Three Patients With Microcystic Squamous Cell Carcinoma of the Lung Case No./ Tumor Tumor Sex/Age (y) Size (cm) Location Follow-up 1/F/82 3.8 Right lower lobe Not available 2/F/73 2.1 Left upper lobe Died, 38 mo 3/M/72 2.8 Left lower lobe Alive, 76 mo from 72 to 83 years (mean, 75.7 years). The main symptoms included cough, chest pain, and hemoptysis. All 3 patients underwent resection of their tumors through lobectomy; 1 patient received adjuvant chemotherapy. Follow-up available for 2 patients showed that 1 was alive 76 months after diagnosis and 1 had died 38 months after diagnosis. The third patient was lost to follow-up. Gross Features Grossly, all 3 tumors were described as nonencapsulated and poorly circumscribed masses located in the periphery of the lungs. The size ranged from 2.1 to 3.8 cm. The cut surfaces were gray-brown and had a firm consistency. Areas of hemorrhage or necrosis were not identified. Complete surgical resection was achieved in all 3 cases. Histologic Features The histologic features were similar in all 3 cases. At low magnification, all tumors were located in the periphery of the lung and exhibited infiltrative growth into the surrounding A parenchyma Image 1. At higher power, the tumors were shown to be composed of irregular islands, nests, and strands of mild to moderately pleomorphic keratinocytes Image 2. Characteristically, these tumor nests demonstrated central cystic changes often imparting a glandular appearance to the lesion Image 3. In some nests, the cyst lining consisted barely of a single layer of cuboidal epithelium reminiscent of adnexal duct-like structures Image 4. In addition, the keratinocytes often had basaloid features characterized by hyperchromatic nuclei, scant cytoplasm, and peripheral palisading. In other areas, the epithelial cells showed prominent cytoplasmic clearing toward the central portions of the neoplastic islands Image 5. The cystic lumina were often filled with amorphous material or cellular debris. The tumors were largely embedded in a prominent desmoplastic stroma that appeared to compress some of the tumor nests into thin, slender strands of neoplastic cells. All tumors showed increased proliferation with mitotic counts ranging from 4 to 19 mitoses per 10 high-power fields. Large areas of necrosis were not a conspicuous feature, although focal comedo-type necrosis was noted in 1 case. Vascular invasion was noted in 2 cases. In addition to the features described, all tumors showed areas of more conventional SCC with evidence of keratinization and/or intercellular bridge formation Image 6. Overall, the histologic features were reminiscent to the ones described for MAC of the skin Image 7. Discussion Lung cancer is the most common primary malignancy worldwide, and SCC accounts for the second most common B Image 1 A and B, Low-power view of microcystic squamous cell carcinoma showing an infiltrative growth pattern in the lung parenchyma (A, H&E, 2; B, H&E, 4). Am J Clin Pathol 2011;136:436-441 437 437 DOI: 10.1309/AJCP61QPWAZSPJAO 437
Weissferdt and Moran / Microcystic SCC of the Lung Image 2 Microcystic squamous cell carcinoma of lung composed of irregular tumor nests set in a sclerotic background (H&E, 10). histologic type of this disease, with an incidence of roughly one third of all pulmonary carcinomas. 4,5 SCC of the lung is strongly associated with tobacco exposure and has a poor 5-year survival rate of approximately 15%. 4,6 The histologic hallmark of SCC is the presence of keratinization or intercellular bridges, the identification of which allows distinction from other non small cell carcinomas. Pulmonary SCC may display a variety of different growth patterns, including more common subtypes like exophytic, cystic, A small cell, spindle cell, and basaloid SCC 1,4,7-10 and rarer variants like adenoid, ameloblastic-like, clear cell, granularlike, or papillary SCC. 4,8,11,12 We describe a new, unusual, but distinct subtype of SCC of the lung characterized by the formation of microcystic duct-like structures reminiscent of the growth pattern seen in the so-called MAC that has been described in the skin. MAC was first described in 1982 by Goldstein and colleagues 2 as a rare cutaneous neoplasm of adnexal differentiation. Clinically, this tumor most often manifests as a slow-growing nodule in the head and neck area of middle-aged patients. Histologically, MAC exhibits pilar and eccrine differentiation and characteristically forms nests and strands of squamous or basaloid cells containing horn cysts or abortive follicles and ducts or gland-like structures lined by 1 or 2 layers of cuboidal epithelial cells. The surrounding stroma typically shows dense desmoplastic or sclerotic changes. Despite its locally aggressive behavior (subcutaneous infiltration, perineural invasion, or perichondrial involvement), cytologic atypia or mitotic activity is usually inconspicuous. Clinically and histologically, MAC is often misdiagnosed as a benign adnexal neoplasm, basal cell carcinoma, or SCC. 2,3 Although metastasis is exceedingly rare, isolated case reports describing regional lymph node or lung metastasis have been published. 3,13 The microcystic changes seen in our series of SCC of the lung morphologically show a striking resemblance to MAC of the skin. The growth pattern, small cystic spaces in the tumor nests, the often basaloid or clear-appearing keratinocytes, and a dense sclerotic stroma can easily mimic the presence of a glandular neoplasm or adnexal differentiation. It is B Image 3 A and B, Prominent central cystic change in the tumor nests mimicking gland or duct formation (A, H&E, 20; B, H&E, 10). 438 Am J Clin Pathol 2011;136:436-441 438 DOI: 10.1309/AJCP61QPWAZSPJAO
Anatomic Pathology / Original Article Image 4 Extensive cystic change reminiscent of adnexaltype ductal structures (H&E, 20). important, however, to distinguish microcystic SCC from tumors with similar growth patterns because treatment and prognosis vary depending on the exact tumor type. The main differential diagnoses include adenosquamous carcinoma, primary adnexal-type or salivary gland type neoplasms of the lung, and metastatic cutaneous MAC. Adenosquamous carcinoma of the lung is a subtype of non small cell carcinoma with a more aggressive clinical behavior than adenocarcinoma or SCC by itself. 4 It is defined as a carcinoma showing areas that by themselves would be diagnosed as SCC and adenocarcinoma, with each element constituting at least 5% of the tumor. 4 Very often, SCCs showing a glandular growth pattern or solid adenocarcinomas with squamoid morphologic features are misdiagnosed as adenosquamous carcinoma. In fact, 2 of our cases were initially diagnosed as adenosquamous carcinoma based on the glandular or duct-like appearance of the tumors. If one applies the strict criteria set out for a diagnosis of true adenosquamous carcinoma, the distinction from microcystic SCC should not be too difficult. Primary adnexal or salivary gland type neoplasms of the lung are rare. Mucoepidermoid carcinoma, sebaceous carcinoma, and pleomorphic adenoma may be neoplasms with morphologic features similar to those of microcystic SCC. In mucoepidermoid carcinoma, the presence of intermediate cells and absence of keratinization should be the most distinguishing features in the separation from true SCC. Sebaceous carcinoma is an extremely rare neoplasm of the lung composed of a cellular proliferation of basaloid, eosinophilic, and clear cells containing intracytoplasmic lipid. Focal areas of squamous differentiation can be present in Image 5 High-power view of tumor nests with prominent peripheral palisading and lighter cytoplasmic staining properties in the central portions of the tumor nests (H&E, 20). Image 6 Areas of more conventional squamous cell carcinoma with conspicuous keratinization (H&E, 20). these tumors, but glandular spaces or duct-like structures are not a typical finding. 14 Pleomorphic adenoma may feature prominent duct-like structures similar to the growth pattern seen in microcystic SCC. The former, however, is a benign biphasic neoplasm lacking cytologic atypia and mitotic activity and containing a characteristic chondromyxoid mesenchymal component that will not be present in microcystic SCC. Last, albeit rare, metastatic cutaneous MAC to the lung has to be excluded. This tumor usually shows bland cytologic features and no or low mitotic activity, thereby distinguishing Am J Clin Pathol 2011;136:436-441 439 439 DOI: 10.1309/AJCP61QPWAZSPJAO 439
Weissferdt and Moran / Microcystic SCC of the Lung A B Image 7 A and B, Microcystic adnexal carcinoma of the skin showing microcystic duct-like structures, abortive follicles, and horn cysts in a sclerotic stroma (A, H&E, 10; B, H&E, 10). it from true SCC. In addition, a thorough clinical history should exclude a previous or existing cutaneous lesion. Although immunohistochemical studies may not have a major role in the differential diagnosis of microcystic SCC of the lung, in difficult cases, immunomarkers may facilitate separation from its closest mimics Table 2. 4,15-18 We have described 3 cases of SCC of the lung showing a prominent microcystic growth pattern strongly resembling the histologic features of MAC of the skin. This study expands the morphologic spectrum of pulmonary SCC and highlights the importance of the correct diagnosis of this subtype to exclude other tumors with similar growth patterns but different prognostic or therapeutic implications. From the Department of Pathology, M.D. Anderson Cancer Center, Houston, TX. Table 2 Immunohistochemical Reactivity of Microcystic Squamous Cell Carcinoma, Microcystic Adnexal Carcinoma, and Pleomorphic Adenoma Tumor Reactivity Squamous cell carcinoma CK, CK5/6, p63 4 Microcystic adnexal carcinoma EMA, CK7, CEA, S-100 (A6), Pleomorphic adenoma CD15 15,16 Epithelial cells: CK, CEA, EMA; myoepithelial cells: p63, calponin, WT1, SMA, S-100, GFAP 17,18 CEA, carcinoembryonic antigen; CK, cytokeratin; EMA, epithelial membrane antigen; GFAP, glial fibrillary acidic protein; SMA, smooth muscle actin; WT1, Wilms tumor 1. Address reprint requests to Dr Weissferdt: Dept of Pathology, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030. References 1. Travis WD, Brambilla E, Müller-Hermelink HK, et al, eds. Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. Lyon, France: IARC Press; 2004:26-30. WHO Classification of Tumours; vol 10. 2. Goldstein DJ, Barr RJ, Santa Cruz DJ. Microcystic adnexal carcinoma: a distinct clinicopathologic entity. Cancer. 1982;50:566-572. 3. Gabillot-Carré M, Weill F, Mamelle G, et al. Microcystic adnexal carcinoma: report of seven cases including one with lung metastasis. Dermatology. 2006;212:221-228. 4. Moran CA, Suster S. Non small cell carcinoma of the lung. In: Moran CA, Suster S, eds. Tumors and Tumor-like Lesions of the Lung and Pleura. Philadelphia, PA: Saunders Elsevier; 2010:51-110. 5. Wahbah M, Boroumand N, Castro C, et al. Changing trends in the distribution of the histologic types of lung cancer: a review of 4,439 cases. Ann Diagn Pathol. 2007;11:89-96. 6. American Cancer Society. Cancer Facts & Figures, 2009. Atlanta, GA: American Cancer Society; 2009. 7. Sherwin RP, Laforet EG, Strieder JW. Exophytic endobronchial carcinoma. J Thorac Cardiovasc Surg. 1962;43:716-730. 8. Dulmet-Brender E, Jaubert F, Huchon G. Exophytic endobronchial epidermoid carcinoma. Cancer. 1986;57:1358-1364. 9. Churg A, Johnston WH, Stulbarg M. Small cell squamous and mixed small cell squamous: small cell anaplastic carcinomas of the lung. Am J Surg Pathol. 1980;4:255-263. 10. Suster S, Huszar M, Herczeg E. Spindle cell squamous carcinoma of the lung: immunocytochemical and ultrastructural study of a case. Histopathology. 1987;11:871-878. 440 Am J Clin Pathol 2011;136:436-441 440 DOI: 10.1309/AJCP61QPWAZSPJAO
Anatomic Pathology / Original Article 11. Katzenstein AL, Prioleau PG, Askin FB. The histologic spectrum and significance of clear-cell change in lung carcinoma. Cancer. 1980;45:943-947. 12. Nappi O, Swanson PE, Wick MR. Pseudovascular adenoid squamous cell carcinoma of the lung: clinicopathologic study of three cases and comparison with true pleuropulmonary angiosarcoma. Hum Pathol. 1994;25:373-378. 13. Bier-Laning CM, Hom DB, Gapany M, et al. Microcystic adnexal carcinoma: management options based on long-term follow-up. Laryngoscope. 1995;105:1197-1201. 14. Borczuk AC, Sha KK, Hisler SE, et al. Sebaceous carcinoma of the lung: histologic and immunohistochemical characterization of an unusual pulmonary neoplasm: report of a case and review of the literature. Am J Surg Pathol. 2002;26:795-798. 15. Wick MR, Cooper PH, Swanson PE, et al. Microcystic adnexal carcinoma: an immunohistochemical comparison with other cutaneous appendage tumors. Arch Dermatol. 1990;126:189-194. 16. Weedon D. Tumors of cutaneous appendages. In: Weedon D, ed. Skin Pathology. 3rd ed. Philadelphia, PA: Churchill Livingstone Elsevier; 2009:758-807. 17. Wenig BM. Neoplasms of the salivary glands. In: Wenig BM, ed. Atlas of Head and Neck Pathology. 2nd ed. Philadelphia, PA: Saunders Elsevier; 2008:582-702. 18. Langman G, Andrews CL, Weissferdt A. WT1 expression in salivary gland pleomorphic adenomas: a reliable marker of the neoplastic myoepithelium. Mod Pathol. 2011;24:168-174. Am J Clin Pathol 2011;136:436-441 441 441 DOI: 10.1309/AJCP61QPWAZSPJAO 441