Pleomorphic basal cell carcinoma: case reports and review.

Abstract: Pleomorphic basal cell carcinoma is a pathologic variant of basal cell carcinoma characterized by the presence of atypical-appearing, mononuclear or multinucleated giant cells. Including our 3 patients, a total of 52 pleomorphic basal cell carcinomas have been described in 48 individuals. The tumors usually present as a nodule on the head or neck. The nuclei of the giant tumor cells are irregularly shaped, hyperchromatic, and 2 to 10 times larger than the nuclei of the surrounding cancer cells. Atypical mitoses may be present. The pathogenesis of pleomorphic basal cell carcinoma remains to be determined; however, investigations utilizing electron microscopy, immunohisto-chemistry, image analysis, and flow cytometry have provided additional insight regarding the features of the giant tumor cells and the etiology of this cancer. All of these tumors are aneuploid. Although these aneuploid tumors have alarming microscopic features, their clinical course is similar to that of basal cell carcinomas without pleomorphic giant tumor cells. Therefore, appropriate therapy to ensure adequate treatment of the tumor is recommended. Our patients' pleomorphic basal cell carcinomas were successfully treated by excision using the Mohs micrographic surgical technique.

Key Words: analysis, basal, cancer, carcinoma, cell, cytometry, electron, flow, giant, image, immunohistochemistry, malignancy, microscopy, mononucleated, monster, multinucleated, pleomorphic, skin, studies, tumor

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Basal cell carcinoma is the most common cancer of the skin. (1) The clinical morphology of this malignancy varies. (2,3) The tumor can appear as either flesh-colored papules, erythematous scaling plaques, or white sclerotic atrophic patches.

There are several histologic subtypes of basal cell carcinoma. (3-6) These include those with nonaggressive patterns of histology: follicular, nodular and superficial. They also include tumors with aggressive histologic patterns: keratinizing, infiltrating, micronodular and sclerosing.

In 1964, Okun and Blumenthal (7) first described basal cell carcinoma in which there were giant tumor cells that had nuclear atypia. Similar basal cell carcinomas with scattered, markedly enlarged, mononucleated and/or multinucleated tumor cells have subsequently been reported (7-16); the terminology used to describe these tumors is summarized in Table 1, (7-13,15-17) More recently, Garcia et al (12) introduced the nomenclature of pleomorphic basal cell carcinoma to characterize this histologic subtype of basal cell carcinoma. We describe the clinical and pathologic features of 3 patients with pleomorphic basal cell carcinoma and review the characteristics of previously reported individuals with this histologic variant of basal cell carcinoma.

Case Reports

Pleomorphic basal cell carcinoma was observed in three patients whose clinical features are summarized in Table 2. The female patient was 66 years old and the male patients were 69 and 75 years of age. All of the tumors were located on the head and neck. They ranged in diameter from 4 mm to 10 mm. The carcinomas appeared as either a flesh-colored pearly papule (Fig. 1) or plaque, or a red scaly plaque (Fig. 2).

All of the tumors were successfully treated by excision using the Mohs micrographic surgical technique; the tumors were cleared after either 1 or 2 stages of surgery. Postoperative wounds extended either to adipose or to muscle and ranged in size from 7 X 9 mm to 20 X 35 mm. The surgical defects were repaired with either a cheek advancement flap or a complex side-to-side closure. Microscopic examination of each patient's tumor is described in detail:

Patient 1. Confluent large nodular aggregates of basaloid tumor cells are present and extend deeply into the reticular dermis. Tumor giant cells can be seen on low magnification (Fig. 3a and 3b). Higher magnification reveals that the pleomorphic tumor cells are multinucleated (Fig. 4a, 4b, and 4c). The giant tumor cells had nuclei that were between 4 to 10 times larger than the surrounding tumor cells.

Patient 2. Well-defined, large nodular aggregates of basaloid tumor cells extend from the epidermis into the dermis. The giant pleomorphic tumor cells are randomly distributed throughout the tumor nests and can be noted on low magnification (Fig. 5); however, their nuclear features are more readily observed on higher magnification (Fig. 6a and 6b). The pleomorphic cells have multiple nuclei that are atypical, hyperchromatic, and irregularly shaped. Their nuclei were 2 to 4 times larger than those of the adjacent tumor cells.

Patient 3. Tumor aggregates of varying size are present in the dermis. Within the tumor nodules, large pale-staining areas of amyloid are present (Fig. 7a and 7b). Numerous mononucleated and multinucleated pleomorphic giant cells are present (Fig. 8a and 8b); their nuclei were at least twice the diameter of the other tumor cells. Some of the giant cells also contained atypical mitoses (Fig. 9).

Discussion

Pleomorphic basal cell carcinoma has been described in 52 tumors, including this report. (7-16) Retrospective studies have demonstrated the incidence of this tumor variant to range between 1% and 2.5% of basal cell carcinomas. (8,10,13) In addition, several recent textbooks now include descriptions, photomicrographs, or both, of this basal cell carcinoma subtype. (18-21)

Pleomorphic basal cell carcinoma has been observed in 48 patients: 26 men and 10 women (male: female, 2.6: 1). (7-16) The gender was not described in 12 patients. The men ranged in age from 32 to 90 years (mean = 68 yr). The women ranged in age from 41 to 87 years (mean = 70 yr). The onset age for all patients with pleomorphic basal cell carcinoma ranged from 32 to 90 years (mean = 68 yr).

Pleomorphic basal cell carcinomas were most commonly located on the head and neck (32 of the 52 tumors, 61.5%) (7-9,12,13,15) (also current report). Less often, they were found on the trunk, the arms, and the buttocks. The tumors usually appeared as a nodule (19 tumors) (7,11-13,15,16) (also current report). However, the clinical morphology was variable and also included either pearly papules or scaly and erythematous plaques.

Microscopic examination of these tumors at low magnification frequently showed pathologic features characteristic for basal cell carcinoma. Often, the histologic findings are those of a nodular basal cell carcinoma and include nodular aggregates of basaloid tumor cells with palisading of the peripheral tumor cell and retraction of the surrounding dermal stroma from the tumor. Even at low magnification, the pleomorphic tumor cells can be visualized. They tend to be randomly distributed throughout the tumor nests.

At higher magnification, several histologic characteristics of the giant tumor cells can be observed (Table 3) (7-16) (also current report). All of the pleomorphic basal cell carcinomas had giant mononucleated tumor cells; in addition, many of the pleomorphic tumor cells were multinucleated. In some tumors, the pleomorphic giant cells were observed in areas of squamous differentiation. (13,17,22) The size of the nucleus in these giant cells ranged between 2 to 10 times larger than the nuclei of the surrounding cancer cells. The nuclear features found in all of the tumors included atypia, hyperchromaticity, and irregular shape: several of the pleomorphic basal cell carcinomas had giant tumor cells containing atypical mitoses.

Pathologic variants of pleomorphic basal cell carcinoma have been observed. Val-Bernal et al (16) described pleomorphic basal cell carcinoma in a patient whose tumor had clinical and pathologic features of a fibroepithelioma of Pinkus. Meehan et al (15) reported a patient whose basal cell carcinoma had tumor epithelial and stromal giant cells; although the patient's cancer shared some pathologic features similar to those of carcinosarcoma of the skin (biphasic sarcomatoid basal cell carcinoma), (23,24) the authors considered their patient's tumor to be a variant of pleomorphic basal cell carcinoma.

Several researchers have sought to further elucidate the nature of the giant tumor cells of pleomorphic basal cell carcinomas. Additional investigations of these tumors have included electron microscopy, immunohistochemical studies, image analysis, and flow cytometry. These studies have provided additional insight into the characterization of these tumors.

Electron microscopy of pleomorphic basal cell carcinoma has been performed by Ono et al (9) and Ochai et al (10) Except for large convoluted nuclei, ultrastructural studies revealed that giant tumor cells were not different from ordinary tumor cells. In addition, autophagocytosis (demonstrated by the presence of autophagic vacuoles) and macrophagocytosis (phagocytized, degenerated tumor cells which have previously been described as Councilman bodies and are now referred to as apoptotic bodies) were noted in the giant tumor cells with multiple nuclei. (9,10)

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Immunohistochemical studies have yielded contrasting results. Cultan and Maluf (13) showed increased expression of the proliferating cell nuclear antigen (PCNA) and Ki-67; both the small and giant tumor cells showed increased expression of bcl-2 antigen. These results suggest that the giant tumor cells are cycling and capable of cell division. Meehan et al (15) also observed moderate bcl-2 staining of the epithelial tumor giant cells. However, in contrast to Cultan and Maluf, (13) both Meehan et al (15) and Val-Bernal et al (16) observed low Ki-67 expression by the tumor giant cells and Val Bernal et al (16) noted that both the small and giant tumor cells showed negativity for bel-2. Hence, their results indicate that the epithelial giant tumor cells were not cycling and that these cellular changes may represent a senescent event.

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Image analysis and flow cytometry studies have confirmed that these tumors are aneuploid; hence, they contain incomplete or excessive amounts of chromosomal material. (25) Garcia et al (12) used image cytometry to evaluate the DNA content of the nuclei of the giant tumor cells. (26) They demonstrated that the nuclear area was proportional to the DNA content in the giant tumor cells. However, the pleomorphic basal cell carcinomas were not polyploid; therefore, their genome did not contain a multiple of the normal amount of chromosomal material. (25) Val-Bernal et al (16) used DNA flow cytometric analysis and observed that the tumor showed a hypodiploid DNA.

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The treatment of pleomorphic basal cell carcinoma has not frequently been reported. The clinical behavior of these tumors appears to be similar to those of basal cell carcinomas with similar pathologic patterns but without the presence of giant tumor cells. (7, 10, 12) We elected to excise our patient's cancers using the Mohs micrographic surgical technique. The tumors were completely removed after either one or two stages of excision and were repaired with either a complex side-to-side closure or cheek advancement flap.

Conclusion

Pleomorphic basal cell carcinoma is an uncommonly described pathologic variant of basal cell carcinoma. Including our patients, 52 pleomorphic basal cell carcinomas have been described in 48 individuals. The tumor is most commonly present as a nodule on the head and neck region. Microscopic examination frequently reveals pathologic features of a nodular basal cell carcinoma; in addition, giant tumor cells are readily apparent on low magnification viewing. The giant tumor cell nuclei are 2 to 10 times larger than the adjacent cancer cells. The nuclei are characteristically irregular in shape, atypical, and hyperchromatic. Several of these cells have atypical mitoses. All of the pleomorphic basal cell carcinomas have mononucleated giant tumor cells; several also contain giant cells that are multinucleated. Electron microscopy, immunohis-tochemistry studies, image analysis, and flow cytometry have been performed attempting to further categorize the features of the giant tumor cells and the pathogenesis of pleomorphic basal cell carcinoma. All of these tumors have been shown to be aneuploid and to demonstrate clinical behavior similar to that of basal cell carcinoma of the same pathologic subtype without giant tumor cells. Appropriate therapy to ensure adequate treatment of the tumor is recommended. We successfully treated our patient's pleomorphic basal cell carcinoma by excision using the Mohs micrographic surgical technique.

References

1. Cohen PR. Basal cell carcinoma. Gt Houston Dent Soc 1995;67(1):20-21.

2. Chopra, KF, Cohen PR. Linear basal cell carcinomas: report of multiple sequential tumors localized to a radiotherapy port and review of the literature. Tex Med 1997;93(7):57-59.

3. Johnson TM, Tschen J, Ho C, et al. Unusual basal cell carcinomas. Cutis 1994:54:85-92.

4. Cohen PR, Schulze KE, Nelson BR. Cutaneous carcinoma with mixed histology: a potential etiology for skin cancer recurrence and an indication of Mohs microscopically controlled surgical excision. South Med J 2005;98:740-747.

5. Cohen PR, Schulze KE, Nelson BR. Basal cell carcinoma with mixed histology: a possible pathogenesis for recurrent skin cancer. Dermatol Surg, in press.

6. Eliezri YD, Cohen PR. Cancer recurrence following Mohs micrographic surgery: a mechanism of tumor persistence. Plast Reconstr Surg 1992; 90:121-125.

7. Okun MR, Blumental G. Basal cell epithelioma with giant cells and nuclear atypicality. Arch Dermatol 1964;89:598-600.

8. Rupec M, Vakilzadeh F, Korb G. [The presence of giant cells with multiple nuclei in basalioma]. Arch Klin Exp Dermatol 1969;235:198-202.

9. Ono T, Egawa K, Higo G, et al. Basal cell epithelioma with giant tumor cells. J Dermatol 1985;12:344-348.

10. Ochai T, Suzuki H, Morioka S. Basal cell epithelioma with giant tumor cells: light and electron microscopic study. J Cutan Pathol 1987;14:242-247.

11. Elston DM, Bergfeld WF, Petroff N. Basal cell carcinoma with monster cells. J Cutan Pathol 1993;20:70-73.

12. Garcia JA, Cohen PR, Herzberg AJ, et al. Pleomorphic basal cell carcinoma. J Am Acad Dermatol 1995;32:740-746.

13. Cultan RT, Maluf HM. Immunohistochemical characterization of pleomorphic giant cells in basal cell carcinoma. J Cutan Pathol 1999;26:353-356.

14. Meehan SA, Egbert BM, Rouse RV. Basal cell carcinoma with epithelial and stromal giant cells [Abstracts of papers presented at the 35th Annual Meeting of the American Society of Dermatopathology]. J Cutan Pathol 1998;25:505.

15. Meehan SA, Egbert BM, Rouse RV. Basal cell carcinoma with tumor epithelial and stromal giant cells: a variant of pleomorphic basal cell carcinoma. Am J Dermatopathol 1992;21:473-478.

16. Val-Bernal JF, Gomez-Ortega JM, Fernandez-Llaca H, et al. Fibroepithelioma of pinkus with tumor giant cells. Am J Dermatopathol 2002; 24:336-339.

17. Okun MR. Pleomorphic giant cells in basal cell carcinoma [letter]. J Cutan Pathol 2000;27:99.

18. Okun M, Edelstein L, Fisher B. Gross and Microscopic Pathology of the skin. Boston: Dermatopathology Foundation Press, 1988:812.

19. Mehregan AH, Hashimoto K, Mehregan DA, et al. Basal cell epithelioma. In: A Guide to Dermatohistopathology, 6th ed. Norwalk, Appleton & Lange, 1995, pp 629-647.

20. Walter JB, Talbot IC. Walter and Israel General Pathology, 7th ed. New York, Churchill Livingstone, 1996 as cited by Val-Bernal JF, Gomez-Ortega JM, Fernandez-Llaca H, Gomez-Roman JJ: Fibroepithelioma of pinkus with tumor giant cells. Am J Dermatopathol 2002;24:336-339.

21. Maize JC, Burgdorf WHC, Hurt MA, et al. Tumors of the epidermis In: Cutaneous Pathology. Philadelphia, Churchill Livingstone, 1998, pp 439-478.

22. Cutlan RT, Maluf HM. Pleomorphic giant cells in basal cell carcinoma. Reply [letter]. J Cutan Pathol 2000;27:99.

23. Bigby SM, Charlton A, Miller MV, et al. Biphasic sarcomatoid basal cell carcinoma (carcinosarcoma): four cases with immunohistochemistry and review of the literature. J Cutan Pathol 2005;32:141-147.

24. Tschen JA, Goldberg LH, McGavran MH. Carcinosarcoma of the skin. J Cutan Pathol 1988;15:31-35.

25. Siegel DH, Sybert VP. Understanding aneuploidy. Pediatr Dermatol 2005;22:270-275.

26. Herzberg AJ, Garcia JA, Kerns BJ, et al. DNA ploidy of basal cell carcinoma determined by image cytometry of fresh smears. J Cutan Pathol 1993;20:216-222.</p> <pre> Man is still the greatest problem on this earth. David Sarnoff </pre> <p>Juan P. Tschen, Philip R. Cohen, MD, Keith E. Schulze, MD, Jaime A. Tschen, MD, and Bruce R. Nelson, MD

From St. Thomas University, St. Joseph Dermpath, Dermatologic Surgery Center of Houston, Department of Dermatology, University of Texas Houston Medical School, and Department of Dermatology, Baylor College of Medicine, Houston, TX.

Reprint requests to Bruce R. Nelson, MD, Dermatologic Surgery Center of Houston, 6655 Travis, Suite 840, Houston, TX 77030.

None of the authors received funding for this paper or have a commercial association that might pose a conflict of interest in connection with the submitted article.

Accepted December 1, 2005.

RELATED ARTICLE: Key Points

* Pleomorphic basal cell carcinoma is a pathologic variant of basal cell carcinoma characterized by the presence of atypical-appearing, mononuclear or multinucleated cells.

* Pleomorphic basal cell carcinomas are aneuploid tumors which have alarming microscopic features: the nuclei of the giant tumor cells are irregularly shaped, hyperchromatic, and 2 to 10 times larger than the nuclei of the surrounding cancer cells.

* Pleomorphic basal cell carcinoma usually presents as a nodule on the head or neck.

* The pathogenesis of pleomorphic basal cell carcinoma remains to be determined; however, additional insight regarding the features of the giant tumor cells and the etiology of this cancer have been elucidated from investigations which utilize electron microscopy, immunohistochemistry, image analysis, and flow cytometry.

* The clinical behavior of pleomorphic basal cell carcinoma is similar to that of basal cell carcinomas of the same pathologic subtype without giant tumor cells; therefore, appropriate therapy to ensure adequate treatment of the tumor is recommended.

Table 1. Synonyms for pleomorphic basal cell carcinoma

Synonyms                                                    Reference

Basal cell epithelioma with monster cells                   11
Basal cell carcinoma with pleomorphic giant cells           13,17
Basal cell epithelioma with giant cells and nuclear atypia   7
Basal cell epithelioma with giant tumor cells                9,10,15,16
Basalioma with the presence of giant cells with multiple     8
  nuclei
Pleomorphic basal cell carcinoma                            12,15

Table 2. Summary of clinical features of reported patients

Case  A/R/S   Location                   Size        Morphology

1     66/W/F  L nasal sidewall            4 X 4 mm   Pearly papule
2     69/W/M  L post auricular           10 X 10 mm  Scaly erythematous
                                                       plaque
3     75/W/M  Rt base of posterior neck  10 X 10 mm  Pearly plaque

Case  NOS  Depth    PO Size     Repair

1     1    Adipose   7 X 9 mm   Cheek advancement flap
2     1    Adipose  13 X 15 mm  Complex closure
3     2    Muscle   20 X 35 mm  Complex closure

A, age; F, female; L, left; M, male, NOS, number of stages (of Mohs
surgical excision); PO, postoperative; R, race; Rt, right; S, sex; W,
white.

Table 3. Histologic characteristics of giant tumor cells in pleomorphic
basal cell carcinomas (a)

Case (b)   Mononucleated  Multinucleated  Nuclear size (c)

 1-5       +              +               2-4 x (d)
 6-12      +              +               2-4 x (d)
13-14      +              +               3-5 x
15         ND             +               2-4 x
16         +              - (e)           [less than or equal to] 8 x
17-35 (f)  +              +               [less than or equal to] 7 x
36-47      +              - (g)           3-10 x
48         +              +               3-5 x (d)
49         +              +               >2 x
50-52      +              +               2-10 x

Case (b)   Atypical mitoses  Additional studies  Reference

 1-5       +                 None                 7
 6-12      -                 None                 8
13-14      -                 EM                   9
15         -                 EM                  10
16         -                 None                11
17-35 (f)  +                 IA                  12
36-47      +                 IHC                 13,14
48         +                 IHC                 15
49         -                 FC, IHC             16
50-52      +                 None                CR

(a) All of the tumors had giant cells that had the following nuclear
features: atypia, hyperchromaticity, and irregular morphology.
(b) Number of tumors
(c) The nuclear size of the giant tumor cells as compared to the nuclei
of the average surrounding tumor cells.
(d) Estimates based on figures from the original articles.
(e) Although the author's comment that "the most striking feature in our
case, however, was the presence of cells with a single huge nucleus,
rather than multinucleate cells," some of the giant cells pictured in
their article suggest multinucleation. (12)
(f) This study described 19 tumors in 15 patients.
(g) According to the authors, "the nuclei had irregular nuclear
contours and were frequently multilobulated, but no true multinucleation
was observed." CR, current report; EM, electron microscopy; FC, flow
cytometry; IA, image analysis; IHC, immunohistochemical studies; ND, not
described; +, present; -, absent.