Aggressive Pilomatrixoma: A Diagnostic Dilemma on Fine-Needle Aspiration Cytology With Review of Literature Mamta Gupta, M.D.,* Rani Bansal, M.D., Gaurav Tiwari, M.D., and Suprabha Sharma, M.D.
We report a case of aggressive pilomatrixoma (PMX) in a 25-year-old male who presented with swelling in left supraclavicular region of 2-month duration. A diagnosis of small round cell tumor was suggested on fine-needle aspiration cytology. He underwent wide excision of the mass. On histomorphological examination, a diagnosis of aggressive PMX was made. The swelling recurred after 3 months of complete resection and on examination had similar morphological features. The case is presented because of the potential diagnostic difficulties on cytological examination and rare occurrence of aggressive variant of PMX. Diagn. Cytopathol. 2014;42:906–911. VC 2014 Wiley Periodicals, Inc. Key Words:
aggressive; pilomatrixoma; cytology; histopathology
Pilomatrixoma (PMX) is a benign cutaneous adnexal neoplasm with differentiation toward the matrix and inner sheath of a normal hair follicle as well as hair cortex.1 PMX with atypical histologic features and a tendency for local invasiveness and local recurrence have been designated as aggressive PMXs.2 It presents as a solitary, slow growing dermal or subcutaneous nodule and is rarely diagnosed clinically. Although histologic features of lesion are well recognized, it continues to pose difficulty in diagnosis on aspiration cytology.3 Up to 45% of cases are incorrectly diagnosed as either benign neoplasms (cysts, adnexal tumors, granulomatous inflammation) or as malignant tumors (e.g., squamous cell carcinoma, small round blue cell tumors, malignant adnexal tumors).4,5
Department of Pathology, Subharti Medical College, Meerut, Uttar Pradesh, India *Correspondence to: Dr. Mamta Gupta, M.D., Department of Pathology, Subharti Medical College, Swami Vivekanand Subharti University, Subhartipuram NH-58, Meerut, Uttar Pradesh, India. E-mail: [email protected] Received 30 August 2013; Revised 11 March 2014; Accepted 11 June 2014 DOI: 10.1002/dc.23192 Published online 26 June 2014 in Wiley Online Library (wileyonlinelibrary.com).
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Several cases on cytological features of PMX have been reported. However, only a small number of aggressive variant of PMX have been reported in literature that could recur if not widely excised. The key histologic features of aggressive PMX are a high mitotic rate and presence of excessive basaloid proliferation with discrete nodules distant from main lesion.5,6 We review a case of aggressive PMX, misdiagnosed as small round cell tumor on fine-needle aspiration cytology. We discuss this case because of its potential diagnostic pitfall on cytology, distinctive histomorphological features, and a tendency for recurrence.
Case Report A 25-year-old male presented with complaints of swelling on left side of neck of 2 months duration. It was insidious in onset and gradually increased in size. There was no history of fever, cough, difficulty in swallowing, hoarseness of voice, or associated pain. On examination, a 2 3 2 cm firm, mobile, nontender nodule with normal overlying skin was palpated in left supraclavicular region. Systemic and ear, nose, and throat examination was normal. Hematological profile, chest radiograph, and ultrasound examination were normal. With clinical impression of enlarged left supraclavicular lymph node, a differential diagnosis of tubercular lymphadenitis/metastasis from unknown primary for further evaluation was suggested. Fine-needle aspiration cytology was performed using 23gauge needle. The smears prepared were stained with May-Gr€unwald Giemsa (MGG), Papanicolaou (Pap), and hematoxylin–eosin (H&E) stain. Smears were cellular showing predominantly monotonous population of uniform small round cells with high nuclear:cytoplasmic (N:C) ratio, round nuclei with finely granular chromatin and inconspicuous nucleoli, cytoplasm was scant delicate and ill-defined. These cells were arranged predominantly in loose and tight clusters with few places showing rosetteC 2014 WILEY PERIODICALS, INC. V
Diagnostic Cytopathology DOI 10.1002/dc
AGGRESSIVE PILOMATRIXOMA
Fig. 1. A: Cellular smear with small round cells in sheets, loose and tight clusters (Papanicolaou, 3100). B: Monotonous population of uniform small round cells with high N:C ratio, round nuclei with finely granular chromatin, inconspicuous nucleoli and scant cytoplasm (MGG, 3400). C: Aggregations of basaloid cells, few squamoid cells and centrally filled with large masses of eosinophilic cornified material containing shadow cells and necrosis (H&E, 340). D: Growth component of basolid cells with increased mitotic activity (arrow-head) and transition zone of retained nuclei (H&E, 3400), Inset—mitotic figures (arrow) seen in basaloid component (H&E, 31000). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
like appearance and microacinar pattern (Figs. 1A and B). Numerous naked nuclei, lymphocytes, neutrophils, and macrophages were present in the background. A cytological diagnosis of small round cell tumor was suggested. The nodule was excised and submitted for histopathological examination. Gross examination revealed a single, globular, firm nodule measuring 2 3 2 3 1 cm with a white granular cut surface and few specks of hemorrhage. Microscopic examination showed a partly circumscribed tumor composed of nests, columns, and stellate shaped areas of small basaloid cells with round to oval hyperchromatic nucleus and scant cytoplasm. There was abrupt keratinization into squamous cells, islands of ghost cells, and necrosis (Fig. 1C). Many aggregates of basaloid cells showed frequent mitotic figures ranging from 1 to 7/highpower field (HPF; Fig. 1D). However, cytological atypia or atypical mitosis was not observed. There was focal foreign body giant cell reaction with lymphocytes, plasma cells, and few eosinophils. The tumor was surrounded by inflamed cellular stroma, fibroadipose tissue, and skeletal
muscle bundles. The tumor was extending close to the resected margins (Figs. 2A–D). A retrospective review of the aspiration cytology smears revealed an occasional aggregate of anucleate and nucleated squamous cells (Fig. 3A). A diagnosis of aggressive (atypical) PMX was made, with close follow-up of the patient. The swelling recurred at the same place 3 months after complete resection. Wide excision of the tumor with overlying skin was done and microscopic examination revealed similar findings. Resection margins were free of tumor. The patient is on follow-up since 1 year and the lesion has not recurred.
Discussion PMX was first described by Malherbe and Chenantais in 1880 as calcified epithelioma of sebaceous glands.7 However, this concept was changed when Forbis and Helwig in 1961 introduced the term PMX, following histochemical and electron microscopic studies, that the neoplasm is derived from primitive basal cells of the Diagnostic Cytopathology, Vol. 42, No 10
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Diagnostic Cytopathology DOI 10.1002/dc
GUPTA ET AL.
Fig. 2. A: Aggregates of basaloid cells reaching close to surrounding skeletal muscle bundles (H&E, 3100). B: Tumor tissue reaching close to the resected margins (inked) (H&E, 3100). C: The infiltrating portion of the tumor is largely composed of basaloid cells, few shadow cells and squamous cells with occasional keratin pearl formation (H&E, 3100). D: Shadow cells with adjacent foreign body giant cell reaction (H&E, 3100). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
epidermis and differentiate toward hair matrix with uncontrolled tumor type of proloiferation.8 A less commonly described unclear entity is aggressive or proliferating PMX, first described by Nield et al.9 in 1986 as a neoplasm of hair matrix differentiation and also showing perineural and vascular involvement. Saussez et al.5 in 2005 further characterized the histological characteristics of these tumors and clarified the limits between the spectrum ranging from PMX and pilomatrical carcinoma. The present case was classified based on these features as aggressive pilomaticoma. Most typical clinical picture of PMX is occurrence of solitary, small, firm nodule with normal overlying skin and measuring 5–30 mm in size. The lesions are commonly skin colored, but may show a bluish purple to reddish hue or pigmentation. The most affected skin regions are the face, scalp, neck, chest, and upper limbs.1,10 In reports of Wells et al.,11 diagnosis was improper in 94% of cases and in 57% cases it was misdiagnosed preoperatively. The clinical differential diagnosis in children includes epidermal inclusion cyst (EIC), ossifying hamartoma, branchial remnant, preauricular sinus, lymphadenopathy, degenerating fibroxanthoma, foreign body 908
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reaction, and osteoma cutis. In adults and elderly, differential diagnosis also includes metastatic lymphadenopathy as in present case or a primary cutaneous neoplasm.12 The cytology of PMX was first described by Woyke et al. in 1982. The aspirates of these tumors contained small basophilic cells, singly or in clusters admixed with nucleated and anucleated squames, the latter forming clusters of yellowish ghost cells. Numerous error in diagnosis have been made in the past, at times leading to a false positive cytological diagnosis.13 Fine-needle aspiration cytology of PMX contain a variety of cells including basaloid cells, ghost (or shadow) cells, foreign body-type giant cells, nucleated squamous cells, and calcium deposits frequently in a background of amorphous debris and chronic inflammatory cells. The basaloid component is arranged as single cells or cohesive to loose monolayer clusters with irregular edges. The basaloid cells are uniform and small, with high N/C ratios, round to oval nuclei, and smooth nuclear borders. Their nuclei have open, finely granular chromatin and prominent nucleoli. The cytoplasm of the basaloid cells is scant, delicate, and ill-defined. Variable numbers of naked nuclei are present in the background. The ghost cells are
Diagnostic Cytopathology DOI 10.1002/dc
AGGRESSIVE PILOMATRIXOMA
Fig. 3. A: A retrospective review of the aspiration cytology smears revealed an occasional aggregate of anucleate (arrowhead) and nucleated (arrow) squamous cells (Papanicolaou, 3400). B: Corresponding cells seen in histopathology (H&E, 3100). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
present in clumps or as single anucleated squamous cells that are often fragmented.14 This diagnostic triad of basaloid cells, ghost cells, and foreign body giant cell reaction is usually not present in all cases.15 In the present case, the smears were dominated by basaloid cells leading to a potential diagnostic pitfall. Ieni et al.4 in a study observed that a correct diagnosis of PMX on cytology could be made in only 44% of the cases, and in 40% the pathogonomic ghost cells, giant cells and calcium deposits were absent leading to inaccurate preoperative diagnosis with erroneous clinical management. Several other lesions may contain a mixture of basaloid cells, squamous cells or reactive granulomas may mimic PMX on aspiration smears.16 In cases with predominance of basaloid cells, the lesion may be mistaken for small round blue cell tumor,17 rhabdomyosarcoma, basal cell carcinoma, Merkel cell carcinoma, or metastatic small cell carcinoma of lung. Primitive small blue round cells and spindle cells, with rhabdomyoblastic differentiation is present in rhabdomyosarcoma. Basal cell carcinoma is characterized by sheets of basaloid cells with peripheral palisading, nuclear over-
lapping, and inconspicuous or absence of nucleoli. Merkal cell neuroendocrine tumor of skin is usually seen in elderly, cytologically cells are mostly dispersed to loosely structured clusters and forming rosettes. Nucleus is granular with inconspicuous to absent nucleoli. Cytoplasm is scant with presence of spherical, eosinophilic pink inclusions. Small cell carcinoma is characterized by monotonous population of small, spherical, ovoid, or elongated cancer cells, singly or in short groups, with vesicular or hyperchromatic, coarsely granular nuclei.13,16 Also, predominantly basaloid cells in groups with hyperchromatic nuclei are found in skin appendage tumors such as cylindroma, spiradenoma, hidroadenoma, or adenoid cystic carcinoma. Monomorphic adenoma and adenoid cystic carcinoma of salivary gland show sheets of basaloid cells with clumps of eosinophilic stromal material. In these neoplasms, there is absence of ghost cells, acellular calcific deposits, and multinucleated giant cells, findings observed in PMX.4,16 Rarely, PMX has been misdiagnosed as squamous cell carcinoma. However, absence of atypical mitosis, nuclear pleomorphism, and coarse clumping of chromatin may help us to rule out a malignant neoplasm.4 When the aspirate contains numerous keratinized squamous cells with scarcity of basaloid or shadow cells, the smears may be misinterpreted as benign cystic lesion, EIC, trichelemmal cyst, and fibrohistiocytic lesion. Like PMX, EIC is superficial in location, consist of nucleated and anucleated squamous cells and keratin, basaloid cells are not seen. The appearance of shadow cells has been reported also in other cutaneous and visceral neoplasm, particularly, ovarian endometrioid adenocarcinomas. A granulomatous inflammation may be suspected if inflammatory cells and foreign body giant cells predominate the lesions as in keratinous cysts, ruptured benign cysts, panniculitis to squamous cell carcinoma.3–5 In the present case, there was predominance of basaloid cells leading to a diagnosis of small round cell tumor. This can happen if the aspiration is done from periphery of the tumor or from an early lesion with predominance of basaloid cells. Finding occasional squames on reexamination was an indicator to categorize it as PMX. The presence of these shadow cells with central pale nuclear zone has been repeatedly mentioned as the most important cytologic feature for diagnosis of PMX. However, despite their abundance in histologic sections, finding in cytologic smears is not reported in many cases. This is probably due to difficulty in detaching these cells during aspiration, leading to sampling error.15 Also, lack of familiarity with the lesion on cytology as observed by Bansal et al.3 is one of the reasons that pure adnexal tumors are under-reported or misdiagnosed. The presence of shadow cells is an important finding which if present helps in establishing cytologic diagnosis of Diagnostic Cytopathology, Vol. 42, No 10
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PMX. Although mentioned briefly in previous reports, its importance is under-emphasized.16 Wong et al.18 has described them as sharply outlined masses of refractile keratin clumps (sheets of ghost cells), feature mainly visualized in Pap stain. There is a study suggesting that apoptosis is the main mechanism leading to development of dead shadow cells and is responsible for the banal behavior of PMX.19 A repeat aspiration or aspiration from multiple sites may increase sampling of different histologic components.20 Few authors have recommended use of cell blocks because the ghost cells are fragmented or obscured in smears, but are readily identified in cell-block sections.14 A spectrum of histopathologic features reflecting different stages of development is observed. PMX is a relatively well-circumscribed, deep dermal or dermalsubcutaneous, cystic neoplasm surrounded by a variable connective tissue stroma.1 Kaddu et al.21 categorized the evolution of this cystic neoplasm into four distinct and chronological stages: early, fully developed, early regressive, and late regressive. Early lesions are characterized by small to largesized, cystic lesions lined focally by aggregations of basaloid cells (matrical and supramatrical cells) and few squamoid cells and filled centrally with large masses of eosinophilic cornified material (faulty hair matrix) containing shadow (ghost) cells and few keratin filaments. Basaloid cells exhibit deeply basophilic oval or round nuclei and a variable number of mitotic figures. Fully developed lesions are large neoplasms lined by basaloid epithelium at their periphery, and within, composed of irregularly shaped, densely packed zones of cornified masses containing shadow cells. Early regressive lesions have no apparent epithelial lining but have basaloid cell foci at the periphery; within, they were composed of pink hair matrix material with shadow cells surrounded by granulation tissue with inflammatory infiltrate and multinucleated histiocytic giant cells. Late regressive lesions have no epithelial component and are composed of irregularly shaped, partially confluent masses of faulty hair material, and calcified to sometimes ossified shadow cells embedded in a desmoplastic stroma, with little or no inflammatory infiltrate. Thus, the lesion begins as an infundibular matrix cyst and ends up as a calcified and ossified nodule with no visible epithelial component.1,2,21 Saussez et al.5 observed that histologically aggressive PMX are characterized by cellular atypia and prominent mitotic activity in the basaloid cells arranged in sheets and irregular islands or bands and infiltrating the surrounding tissues. The shadow squamous cells and basaloid cells are surrounded by background of inflammatory cells and fragments of calcified material. According to Inglefield et al.,6 aggressive PMX in addition to the presence of excessive basaloid cell proliferation shows discrete nodules distant from main lesion and a high 910
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mitotic rate. It has the ability to infiltrate the surrounding tissues and a capacity to recur.5,22 Therefore, treatment involves wide surgical excision of mass with overlying skin.5 A subset of PMX’s termed “proliferating PMX” was described by Kaddu et al.21 It is characterized by presence of a large, lobular proliferation of basaloid cells in association with small to large foci of shadow cells. Cytomorphologically, the basaloid cells exhibited variable nuclear atypia and mitotic figures.23 Saussez et al.5 pointed that both proliferating and aggressive PMX may be morphologically close entities.1,5 Histologically, aggressive PMX may be confused with basal cell carcinoma with matrical differentiation, proliferating pilar tumor, and pilomatrical carcinoma.5 Pilomatrical carcinoma is clinically not a distinctive lesion. The tumor is a large, asymmetrical, poorly circumscribed dermal, or dermal subcutaneous mass composed of several, irregularly shaped and variously sized aggregations of basaloid cells with foci of cornified material containing shadow cells. Basaloid cells exhibit hyperchromatic nuclei, with prominent nucleoli and ill-defined cytoplasmic margins. Variable numbers of atypical mitotic figures (up to 10 mitoses per HPF). Foci of geographical necrosis, calcification, and ossification are observed. They have a potential for distant metastases.1,24 Mitotic activity is not a reliable indicator of malignancy or aggressive behavior, as it may be seen in banal PMX.1 However, Sari et al.25 observed that an increased mitotic rate, an uncommon feature of PMX, may be a marker for more aggressive biologic behavior. Also, Lopansri and Mihm26 had observed that PMX with numerous basaloid cell proliferation and mitosis should not always be guarded as part of histologic feature of benign PMX. These lesions should be more carefully evaluated as to its potential aggressive behavior and possible recurrences, as was also observed in the present case. In conclusion, PMX should be considered in the differential diagnosis of small round cell tumors especially when primitive appearing cells are aspirated on fineneedle aspiration cytology. A diagnostic dilemma on cytology arises most commonly due to predominance of one component over the other. Appropriate clinical correlation with constellation of cytologic features and familiarity with lesion will help in considering this uncommon neoplasm of skin in the differential diagnosis. Aggressive variant of PMX is a histopathological entity characterized by increased number of mitosis, presence of necrosis, and infiltration into surrounding region. These tumors require a close follow-up, as they have a tendency to recur.
References 1. Hurt MA, Kaddu S, Kutzner H, Cribier B, Schulz T, Hartschuh W. Benign tumors with follicular differentiation. In: Leboit PE, Burg
Diagnostic Cytopathology DOI 10.1002/dc
AGGRESSIVE PILOMATRIXOMA G, Weedon D, Sarasin A, editors. World health organization classification of tumors. Pathology and genetics of skin tumors. Lyon: IARC Press; 2006. p 152–159.
15. Preethi TR, Jayasree K, Abraham EK. A case of PMX misdiagnosed as metastatic carcinoma on fine needle aspiration cytology. J Cytol 2007;24:207–208.
2. Rosai J. Skin: Dermatosis, tumors and tumorlike conditions. In: Rosai J, editor. Rosai and Ackerman’s surgical pathology. 10th ed. New York: Elsevier; 2011. p 95–235.
16. Tulbah A, Akhtar M. Pilomatrixoma: FNAC A report of three cases. Ann Saudi Med 1997;17:88–91.
3. Bansal C, Handa U, Mohan H. Fine needle aspiration cytology of PMX. J Cytol 2011;28:1–6. 4. Ieni A, Todaro P, Bonanno AM, Catalano F, Catalano A, Tuccari G. Limits of fine-needle aspiration cytology in diagnosing PMX: A series of 25 cases with clinico-pathologic correlations. Indian J Dermatol 2012;57:152–155. 5. Saussez S, Mahillon V, Blaivie C, Haller A, Chantrain G, Thill M. Aggressive PMX of the infra-auricular area: A case report. Auris Nasus Larynx 2005;32:407–410.
18. Wong MP, Yuen ST, Collins RJ. Fine needle aspiration biopsy of pilomatrixoma: Still a diagnostic trap for the unwary. Diagn cytopathol 1994;10:365–369.
6. Inglefield CJ, Muir IF, Gray ES. Aggressive PMX in childhood. Ann Plast Surg 1994;33:656–658. 7. Malherbe A, Chenantais J. Note sur epithelioma calcifedes glandes sebacees. Prog Med 1880;8:826–837. 8. Forbis R, Helwig EB. Pilomatrixoma (calcifying epithelioma). Arch Dermatol 1961;83:606–618. 9. Nield DV, Saad MN, Ali MH. Aggressive PMX in a child: A case report. Br J Plast Surg 1986;39:139–144. 10. WygleR dowska-Kania M, Kaminska-Winciorek G, Krauze E, Brzezinska-Wcislo L, Kajor M. Multifocal type of PMX. Adv Med Sci 2007;52:251–253. 11. Wells NJ, Blair GK, Magee JF, Whiteman DM. PMX: A common, benign childhood skin tumor. Can J Surg 1994;37:483–486. 12. Prendes BL, Kangelaris GT, Zante AV, Wang SJ. PMX masquerading as metastatic squamous cell carcinoma. Paediatr Surg 2012;12:17–22. 13. Koss LG, Melamed MR. The skin. In: Koss LG, Melamed MR, editors. Koss’s diagnostic cytology and its histopathologic bases. 5th ed. Philadelphia: Lippincott Williams & Wilkins; 2005. p 1286–1301. 14. Lin O, Zakowski MF. Cytology of soft tissue, bone, and skin. In: Bibbo M, Wilbur DC, editors. Comprehensive cytopathology. 3rd ed. China: Elsevier; 2008. p 741–513.
17. Thapliyal N, Joshi U, Vaibhav G, Sayana A, Srivastava AK, Jha RS. PMX mimicking small round cell tumor on fine needle aspiration cytology: A case report. Acta Cytol 2008;52: 627–630.
19. Fayyazi A, Soruri A, Radzum HJ, Peters JH, Berger H. Cell renewal, cell differentiation and programmed cell death (apoptosis) in pilomatricoma. Br J Dermatol 1997;137:714–720. 20. Ma KF, Tsui MS, Chan SK. Fine needle aspiration diagnosis of pilomatrixoma. A monomorphic population of basaloid cells with squamous differentiation not to be mistaken for carcinoma. Acta Cytol 1991;35:570–574. 21. Kaddu S, Soyer HP, H€ odl S, Kerl H. Morphological stages of pilomatricoma. Am J Dermatopathol 1996;18:333–338. 22. Upile T, Jerjes W, Sipaul F, et al. A patient with ulcerated calcifying epithelioma of Malherbe in the pinna: Case report. Head Neck Oncol 2012;4:25. doi:10.1186/1758-3284-4-25. 23. Kaddu S, Soyer HP, Wolf IH, Kerl H. Proliferating pilomatricoma. A histopathologic simulator of matrical carcinoma. J Cutan Pathol 1997;24:228–234. 24. Hardisson D, Linares MD, Cuevas-Santos J, Contreras F. Pilomatrix carcinoma: A clinicopathologic study of six cases and review of the literature. Am J Dermatopathol 2001;23:394–401. 25. Sari A, Yavuzer R, Isik I, Latıfoglu O, Ataoglu O. Atypical presentation of PMX: A case report. Dermatol Surg 2002;28: 603–605. 26. Lopansri S, Mihm MC. Pilomatrix carcinoma or calcifying epitheliocarcinoma of Malherbe. A case report and review of literature. Cancer 1980;45:2368–2373.
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We report a case of aggressive pilomatrixoma (PMX) in a 25-year-old male who presented with swelling in left supraclavicular region of 2-month duration. A diagnosis of small round cell tumor was suggested on fine-needle aspiration cytology. He underwent wide excision of the mass. On histomorphological examination, a diagnosis of aggressive PMX was made. The swelling recurred after 3 months of complete resection and on examination had similar morphological features. The case is presented because of the potential diagnostic difficulties on cytological examination and rare occurrence of aggressive variant of PMX. Diagn. Cytopathol. 2014;42:906–911. VC 2014 Wiley Periodicals, Inc. Key Words:
aggressive; pilomatrixoma; cytology; histopathology
Pilomatrixoma (PMX) is a benign cutaneous adnexal neoplasm with differentiation toward the matrix and inner sheath of a normal hair follicle as well as hair cortex.1 PMX with atypical histologic features and a tendency for local invasiveness and local recurrence have been designated as aggressive PMXs.2 It presents as a solitary, slow growing dermal or subcutaneous nodule and is rarely diagnosed clinically. Although histologic features of lesion are well recognized, it continues to pose difficulty in diagnosis on aspiration cytology.3 Up to 45% of cases are incorrectly diagnosed as either benign neoplasms (cysts, adnexal tumors, granulomatous inflammation) or as malignant tumors (e.g., squamous cell carcinoma, small round blue cell tumors, malignant adnexal tumors).4,5
Department of Pathology, Subharti Medical College, Meerut, Uttar Pradesh, India *Correspondence to: Dr. Mamta Gupta, M.D., Department of Pathology, Subharti Medical College, Swami Vivekanand Subharti University, Subhartipuram NH-58, Meerut, Uttar Pradesh, India. E-mail: [email protected] Received 30 August 2013; Revised 11 March 2014; Accepted 11 June 2014 DOI: 10.1002/dc.23192 Published online 26 June 2014 in Wiley Online Library (wileyonlinelibrary.com).
906
Diagnostic Cytopathology, Vol. 42, No 10
Several cases on cytological features of PMX have been reported. However, only a small number of aggressive variant of PMX have been reported in literature that could recur if not widely excised. The key histologic features of aggressive PMX are a high mitotic rate and presence of excessive basaloid proliferation with discrete nodules distant from main lesion.5,6 We review a case of aggressive PMX, misdiagnosed as small round cell tumor on fine-needle aspiration cytology. We discuss this case because of its potential diagnostic pitfall on cytology, distinctive histomorphological features, and a tendency for recurrence.
Case Report A 25-year-old male presented with complaints of swelling on left side of neck of 2 months duration. It was insidious in onset and gradually increased in size. There was no history of fever, cough, difficulty in swallowing, hoarseness of voice, or associated pain. On examination, a 2 3 2 cm firm, mobile, nontender nodule with normal overlying skin was palpated in left supraclavicular region. Systemic and ear, nose, and throat examination was normal. Hematological profile, chest radiograph, and ultrasound examination were normal. With clinical impression of enlarged left supraclavicular lymph node, a differential diagnosis of tubercular lymphadenitis/metastasis from unknown primary for further evaluation was suggested. Fine-needle aspiration cytology was performed using 23gauge needle. The smears prepared were stained with May-Gr€unwald Giemsa (MGG), Papanicolaou (Pap), and hematoxylin–eosin (H&E) stain. Smears were cellular showing predominantly monotonous population of uniform small round cells with high nuclear:cytoplasmic (N:C) ratio, round nuclei with finely granular chromatin and inconspicuous nucleoli, cytoplasm was scant delicate and ill-defined. These cells were arranged predominantly in loose and tight clusters with few places showing rosetteC 2014 WILEY PERIODICALS, INC. V
Diagnostic Cytopathology DOI 10.1002/dc
AGGRESSIVE PILOMATRIXOMA
Fig. 1. A: Cellular smear with small round cells in sheets, loose and tight clusters (Papanicolaou, 3100). B: Monotonous population of uniform small round cells with high N:C ratio, round nuclei with finely granular chromatin, inconspicuous nucleoli and scant cytoplasm (MGG, 3400). C: Aggregations of basaloid cells, few squamoid cells and centrally filled with large masses of eosinophilic cornified material containing shadow cells and necrosis (H&E, 340). D: Growth component of basolid cells with increased mitotic activity (arrow-head) and transition zone of retained nuclei (H&E, 3400), Inset—mitotic figures (arrow) seen in basaloid component (H&E, 31000). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
like appearance and microacinar pattern (Figs. 1A and B). Numerous naked nuclei, lymphocytes, neutrophils, and macrophages were present in the background. A cytological diagnosis of small round cell tumor was suggested. The nodule was excised and submitted for histopathological examination. Gross examination revealed a single, globular, firm nodule measuring 2 3 2 3 1 cm with a white granular cut surface and few specks of hemorrhage. Microscopic examination showed a partly circumscribed tumor composed of nests, columns, and stellate shaped areas of small basaloid cells with round to oval hyperchromatic nucleus and scant cytoplasm. There was abrupt keratinization into squamous cells, islands of ghost cells, and necrosis (Fig. 1C). Many aggregates of basaloid cells showed frequent mitotic figures ranging from 1 to 7/highpower field (HPF; Fig. 1D). However, cytological atypia or atypical mitosis was not observed. There was focal foreign body giant cell reaction with lymphocytes, plasma cells, and few eosinophils. The tumor was surrounded by inflamed cellular stroma, fibroadipose tissue, and skeletal
muscle bundles. The tumor was extending close to the resected margins (Figs. 2A–D). A retrospective review of the aspiration cytology smears revealed an occasional aggregate of anucleate and nucleated squamous cells (Fig. 3A). A diagnosis of aggressive (atypical) PMX was made, with close follow-up of the patient. The swelling recurred at the same place 3 months after complete resection. Wide excision of the tumor with overlying skin was done and microscopic examination revealed similar findings. Resection margins were free of tumor. The patient is on follow-up since 1 year and the lesion has not recurred.
Discussion PMX was first described by Malherbe and Chenantais in 1880 as calcified epithelioma of sebaceous glands.7 However, this concept was changed when Forbis and Helwig in 1961 introduced the term PMX, following histochemical and electron microscopic studies, that the neoplasm is derived from primitive basal cells of the Diagnostic Cytopathology, Vol. 42, No 10
907
Diagnostic Cytopathology DOI 10.1002/dc
GUPTA ET AL.
Fig. 2. A: Aggregates of basaloid cells reaching close to surrounding skeletal muscle bundles (H&E, 3100). B: Tumor tissue reaching close to the resected margins (inked) (H&E, 3100). C: The infiltrating portion of the tumor is largely composed of basaloid cells, few shadow cells and squamous cells with occasional keratin pearl formation (H&E, 3100). D: Shadow cells with adjacent foreign body giant cell reaction (H&E, 3100). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
epidermis and differentiate toward hair matrix with uncontrolled tumor type of proloiferation.8 A less commonly described unclear entity is aggressive or proliferating PMX, first described by Nield et al.9 in 1986 as a neoplasm of hair matrix differentiation and also showing perineural and vascular involvement. Saussez et al.5 in 2005 further characterized the histological characteristics of these tumors and clarified the limits between the spectrum ranging from PMX and pilomatrical carcinoma. The present case was classified based on these features as aggressive pilomaticoma. Most typical clinical picture of PMX is occurrence of solitary, small, firm nodule with normal overlying skin and measuring 5–30 mm in size. The lesions are commonly skin colored, but may show a bluish purple to reddish hue or pigmentation. The most affected skin regions are the face, scalp, neck, chest, and upper limbs.1,10 In reports of Wells et al.,11 diagnosis was improper in 94% of cases and in 57% cases it was misdiagnosed preoperatively. The clinical differential diagnosis in children includes epidermal inclusion cyst (EIC), ossifying hamartoma, branchial remnant, preauricular sinus, lymphadenopathy, degenerating fibroxanthoma, foreign body 908
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reaction, and osteoma cutis. In adults and elderly, differential diagnosis also includes metastatic lymphadenopathy as in present case or a primary cutaneous neoplasm.12 The cytology of PMX was first described by Woyke et al. in 1982. The aspirates of these tumors contained small basophilic cells, singly or in clusters admixed with nucleated and anucleated squames, the latter forming clusters of yellowish ghost cells. Numerous error in diagnosis have been made in the past, at times leading to a false positive cytological diagnosis.13 Fine-needle aspiration cytology of PMX contain a variety of cells including basaloid cells, ghost (or shadow) cells, foreign body-type giant cells, nucleated squamous cells, and calcium deposits frequently in a background of amorphous debris and chronic inflammatory cells. The basaloid component is arranged as single cells or cohesive to loose monolayer clusters with irregular edges. The basaloid cells are uniform and small, with high N/C ratios, round to oval nuclei, and smooth nuclear borders. Their nuclei have open, finely granular chromatin and prominent nucleoli. The cytoplasm of the basaloid cells is scant, delicate, and ill-defined. Variable numbers of naked nuclei are present in the background. The ghost cells are
Diagnostic Cytopathology DOI 10.1002/dc
AGGRESSIVE PILOMATRIXOMA
Fig. 3. A: A retrospective review of the aspiration cytology smears revealed an occasional aggregate of anucleate (arrowhead) and nucleated (arrow) squamous cells (Papanicolaou, 3400). B: Corresponding cells seen in histopathology (H&E, 3100). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
present in clumps or as single anucleated squamous cells that are often fragmented.14 This diagnostic triad of basaloid cells, ghost cells, and foreign body giant cell reaction is usually not present in all cases.15 In the present case, the smears were dominated by basaloid cells leading to a potential diagnostic pitfall. Ieni et al.4 in a study observed that a correct diagnosis of PMX on cytology could be made in only 44% of the cases, and in 40% the pathogonomic ghost cells, giant cells and calcium deposits were absent leading to inaccurate preoperative diagnosis with erroneous clinical management. Several other lesions may contain a mixture of basaloid cells, squamous cells or reactive granulomas may mimic PMX on aspiration smears.16 In cases with predominance of basaloid cells, the lesion may be mistaken for small round blue cell tumor,17 rhabdomyosarcoma, basal cell carcinoma, Merkel cell carcinoma, or metastatic small cell carcinoma of lung. Primitive small blue round cells and spindle cells, with rhabdomyoblastic differentiation is present in rhabdomyosarcoma. Basal cell carcinoma is characterized by sheets of basaloid cells with peripheral palisading, nuclear over-
lapping, and inconspicuous or absence of nucleoli. Merkal cell neuroendocrine tumor of skin is usually seen in elderly, cytologically cells are mostly dispersed to loosely structured clusters and forming rosettes. Nucleus is granular with inconspicuous to absent nucleoli. Cytoplasm is scant with presence of spherical, eosinophilic pink inclusions. Small cell carcinoma is characterized by monotonous population of small, spherical, ovoid, or elongated cancer cells, singly or in short groups, with vesicular or hyperchromatic, coarsely granular nuclei.13,16 Also, predominantly basaloid cells in groups with hyperchromatic nuclei are found in skin appendage tumors such as cylindroma, spiradenoma, hidroadenoma, or adenoid cystic carcinoma. Monomorphic adenoma and adenoid cystic carcinoma of salivary gland show sheets of basaloid cells with clumps of eosinophilic stromal material. In these neoplasms, there is absence of ghost cells, acellular calcific deposits, and multinucleated giant cells, findings observed in PMX.4,16 Rarely, PMX has been misdiagnosed as squamous cell carcinoma. However, absence of atypical mitosis, nuclear pleomorphism, and coarse clumping of chromatin may help us to rule out a malignant neoplasm.4 When the aspirate contains numerous keratinized squamous cells with scarcity of basaloid or shadow cells, the smears may be misinterpreted as benign cystic lesion, EIC, trichelemmal cyst, and fibrohistiocytic lesion. Like PMX, EIC is superficial in location, consist of nucleated and anucleated squamous cells and keratin, basaloid cells are not seen. The appearance of shadow cells has been reported also in other cutaneous and visceral neoplasm, particularly, ovarian endometrioid adenocarcinomas. A granulomatous inflammation may be suspected if inflammatory cells and foreign body giant cells predominate the lesions as in keratinous cysts, ruptured benign cysts, panniculitis to squamous cell carcinoma.3–5 In the present case, there was predominance of basaloid cells leading to a diagnosis of small round cell tumor. This can happen if the aspiration is done from periphery of the tumor or from an early lesion with predominance of basaloid cells. Finding occasional squames on reexamination was an indicator to categorize it as PMX. The presence of these shadow cells with central pale nuclear zone has been repeatedly mentioned as the most important cytologic feature for diagnosis of PMX. However, despite their abundance in histologic sections, finding in cytologic smears is not reported in many cases. This is probably due to difficulty in detaching these cells during aspiration, leading to sampling error.15 Also, lack of familiarity with the lesion on cytology as observed by Bansal et al.3 is one of the reasons that pure adnexal tumors are under-reported or misdiagnosed. The presence of shadow cells is an important finding which if present helps in establishing cytologic diagnosis of Diagnostic Cytopathology, Vol. 42, No 10
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GUPTA ET AL.
PMX. Although mentioned briefly in previous reports, its importance is under-emphasized.16 Wong et al.18 has described them as sharply outlined masses of refractile keratin clumps (sheets of ghost cells), feature mainly visualized in Pap stain. There is a study suggesting that apoptosis is the main mechanism leading to development of dead shadow cells and is responsible for the banal behavior of PMX.19 A repeat aspiration or aspiration from multiple sites may increase sampling of different histologic components.20 Few authors have recommended use of cell blocks because the ghost cells are fragmented or obscured in smears, but are readily identified in cell-block sections.14 A spectrum of histopathologic features reflecting different stages of development is observed. PMX is a relatively well-circumscribed, deep dermal or dermalsubcutaneous, cystic neoplasm surrounded by a variable connective tissue stroma.1 Kaddu et al.21 categorized the evolution of this cystic neoplasm into four distinct and chronological stages: early, fully developed, early regressive, and late regressive. Early lesions are characterized by small to largesized, cystic lesions lined focally by aggregations of basaloid cells (matrical and supramatrical cells) and few squamoid cells and filled centrally with large masses of eosinophilic cornified material (faulty hair matrix) containing shadow (ghost) cells and few keratin filaments. Basaloid cells exhibit deeply basophilic oval or round nuclei and a variable number of mitotic figures. Fully developed lesions are large neoplasms lined by basaloid epithelium at their periphery, and within, composed of irregularly shaped, densely packed zones of cornified masses containing shadow cells. Early regressive lesions have no apparent epithelial lining but have basaloid cell foci at the periphery; within, they were composed of pink hair matrix material with shadow cells surrounded by granulation tissue with inflammatory infiltrate and multinucleated histiocytic giant cells. Late regressive lesions have no epithelial component and are composed of irregularly shaped, partially confluent masses of faulty hair material, and calcified to sometimes ossified shadow cells embedded in a desmoplastic stroma, with little or no inflammatory infiltrate. Thus, the lesion begins as an infundibular matrix cyst and ends up as a calcified and ossified nodule with no visible epithelial component.1,2,21 Saussez et al.5 observed that histologically aggressive PMX are characterized by cellular atypia and prominent mitotic activity in the basaloid cells arranged in sheets and irregular islands or bands and infiltrating the surrounding tissues. The shadow squamous cells and basaloid cells are surrounded by background of inflammatory cells and fragments of calcified material. According to Inglefield et al.,6 aggressive PMX in addition to the presence of excessive basaloid cell proliferation shows discrete nodules distant from main lesion and a high 910
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mitotic rate. It has the ability to infiltrate the surrounding tissues and a capacity to recur.5,22 Therefore, treatment involves wide surgical excision of mass with overlying skin.5 A subset of PMX’s termed “proliferating PMX” was described by Kaddu et al.21 It is characterized by presence of a large, lobular proliferation of basaloid cells in association with small to large foci of shadow cells. Cytomorphologically, the basaloid cells exhibited variable nuclear atypia and mitotic figures.23 Saussez et al.5 pointed that both proliferating and aggressive PMX may be morphologically close entities.1,5 Histologically, aggressive PMX may be confused with basal cell carcinoma with matrical differentiation, proliferating pilar tumor, and pilomatrical carcinoma.5 Pilomatrical carcinoma is clinically not a distinctive lesion. The tumor is a large, asymmetrical, poorly circumscribed dermal, or dermal subcutaneous mass composed of several, irregularly shaped and variously sized aggregations of basaloid cells with foci of cornified material containing shadow cells. Basaloid cells exhibit hyperchromatic nuclei, with prominent nucleoli and ill-defined cytoplasmic margins. Variable numbers of atypical mitotic figures (up to 10 mitoses per HPF). Foci of geographical necrosis, calcification, and ossification are observed. They have a potential for distant metastases.1,24 Mitotic activity is not a reliable indicator of malignancy or aggressive behavior, as it may be seen in banal PMX.1 However, Sari et al.25 observed that an increased mitotic rate, an uncommon feature of PMX, may be a marker for more aggressive biologic behavior. Also, Lopansri and Mihm26 had observed that PMX with numerous basaloid cell proliferation and mitosis should not always be guarded as part of histologic feature of benign PMX. These lesions should be more carefully evaluated as to its potential aggressive behavior and possible recurrences, as was also observed in the present case. In conclusion, PMX should be considered in the differential diagnosis of small round cell tumors especially when primitive appearing cells are aspirated on fineneedle aspiration cytology. A diagnostic dilemma on cytology arises most commonly due to predominance of one component over the other. Appropriate clinical correlation with constellation of cytologic features and familiarity with lesion will help in considering this uncommon neoplasm of skin in the differential diagnosis. Aggressive variant of PMX is a histopathological entity characterized by increased number of mitosis, presence of necrosis, and infiltration into surrounding region. These tumors require a close follow-up, as they have a tendency to recur.
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AGGRESSIVE PILOMATRIXOMA G, Weedon D, Sarasin A, editors. World health organization classification of tumors. Pathology and genetics of skin tumors. Lyon: IARC Press; 2006. p 152–159.
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6. Inglefield CJ, Muir IF, Gray ES. Aggressive PMX in childhood. Ann Plast Surg 1994;33:656–658. 7. Malherbe A, Chenantais J. Note sur epithelioma calcifedes glandes sebacees. Prog Med 1880;8:826–837. 8. Forbis R, Helwig EB. Pilomatrixoma (calcifying epithelioma). Arch Dermatol 1961;83:606–618. 9. Nield DV, Saad MN, Ali MH. Aggressive PMX in a child: A case report. Br J Plast Surg 1986;39:139–144. 10. WygleR dowska-Kania M, Kaminska-Winciorek G, Krauze E, Brzezinska-Wcislo L, Kajor M. Multifocal type of PMX. Adv Med Sci 2007;52:251–253. 11. Wells NJ, Blair GK, Magee JF, Whiteman DM. PMX: A common, benign childhood skin tumor. Can J Surg 1994;37:483–486. 12. Prendes BL, Kangelaris GT, Zante AV, Wang SJ. PMX masquerading as metastatic squamous cell carcinoma. Paediatr Surg 2012;12:17–22. 13. Koss LG, Melamed MR. The skin. In: Koss LG, Melamed MR, editors. Koss’s diagnostic cytology and its histopathologic bases. 5th ed. Philadelphia: Lippincott Williams & Wilkins; 2005. p 1286–1301. 14. Lin O, Zakowski MF. Cytology of soft tissue, bone, and skin. In: Bibbo M, Wilbur DC, editors. Comprehensive cytopathology. 3rd ed. China: Elsevier; 2008. p 741–513.
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19. Fayyazi A, Soruri A, Radzum HJ, Peters JH, Berger H. Cell renewal, cell differentiation and programmed cell death (apoptosis) in pilomatricoma. Br J Dermatol 1997;137:714–720. 20. Ma KF, Tsui MS, Chan SK. Fine needle aspiration diagnosis of pilomatrixoma. A monomorphic population of basaloid cells with squamous differentiation not to be mistaken for carcinoma. Acta Cytol 1991;35:570–574. 21. Kaddu S, Soyer HP, H€ odl S, Kerl H. Morphological stages of pilomatricoma. Am J Dermatopathol 1996;18:333–338. 22. Upile T, Jerjes W, Sipaul F, et al. A patient with ulcerated calcifying epithelioma of Malherbe in the pinna: Case report. Head Neck Oncol 2012;4:25. doi:10.1186/1758-3284-4-25. 23. Kaddu S, Soyer HP, Wolf IH, Kerl H. Proliferating pilomatricoma. A histopathologic simulator of matrical carcinoma. J Cutan Pathol 1997;24:228–234. 24. Hardisson D, Linares MD, Cuevas-Santos J, Contreras F. Pilomatrix carcinoma: A clinicopathologic study of six cases and review of the literature. Am J Dermatopathol 2001;23:394–401. 25. Sari A, Yavuzer R, Isik I, Latıfoglu O, Ataoglu O. Atypical presentation of PMX: A case report. Dermatol Surg 2002;28: 603–605. 26. Lopansri S, Mihm MC. Pilomatrix carcinoma or calcifying epitheliocarcinoma of Malherbe. A case report and review of literature. Cancer 1980;45:2368–2373.
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