Basal cell carcinoma with ductal and glandular differentiation: a clinicopathological and immunohistochemical study of 10 cases

ARTICLE

Auteur(s) : Noriyuki MISAGO¹, Toshimi SATOH², Yutaka NARISAWA¹

¹ Division of Dermatology, Department of Internal Medicine 
² Department of Pathology, Faculty of Medicine, Saga University, Nabeshima 5-1-1, Saga 849-8501, Japan

Article accepted on 30/7/2004

In 1969, Freeman and Winkelmann [1] reported cases of eccrine epithelioma in a study entitled, “Basal Cell Tumor with Eccrine Differentiation (Eccrine Epithelioma)”. Following their original report, several other studies [1-5] documented other cases that are now generally accepted as cases of syringomatous carcinoma or cutaneous adenoid cystic carcinoma [6, 7]. These cases are unrelated to BCC and lack its features [6, 7]. So-called adenoid (cystic) BCC, which has been documented as devoid of histochemical reactions indicating apocrine or eccrine differentiation [8], are considered to simulate tubular structures due to mucin deposition within BCC aggregations, thus resulting in a cribriform appearance [9]. 
However, there have been some reports concerning the finding of authentic tubular structures within BCCs [10-14]. Nevertheless, excluding the textbooks of Requena and Ackerman et al. [7, 9], there are few extensive histopathological studies concerning tubular structures in BCC, and no previous detailed clinicopathological and immunohistochemical studies of BCC with tubular structures have been found. Herein we report the detailed clinicopathological and immunohistochemical features of 10 cases of BCC with tubular structures, which are presumed to show apocrine differentiation.

Materials and methods

From the careful examination of 600 BCC specimens treated in our institution over the last 10 years, we selected 10 cases that showed distinct tubular structures. Our criteria for authentic tubular differentiation within BCC were as follows: 1) considerable or numerous tubular structures often with an eosinophilic cuticular border within at least three aggregations of BCCs that could not be explained as either entrapped normal eccrine or apocrine ducts, and 2) luminal cells or cytoplasmic vacuoles that were immunohistochemical positive for carcinoembryonic antigen (CEA) (monoclonal, II-7, Dako, dilution 1:100) and epithelial membrane antigen (EMA) (E29, Dako, dilution 1:100). Even specimens with cytoplasmic vacuoles or abnormally appearing tubular structures with positive staining for CEA and EMA, which are assumed not to be entrapped normal eccrine or apocrine ducts, were excluded from the study when these structures were only focally (one or two aggregations) observed. Rare and diagnostically confusing cases as to whether the specimens were BCC or trichoblastoma [15], were also excluded from this study.

Immunohistochemistry was also performed on deparaffinized sections from these ten cases using the following antibodies against cytokeratins (CKs): CK1 (34βB4, Enzo, ready-to-use), CK10 (DE-K10, Dako, dilution 1:50), CK14 (LL002, Novocastra, dilution 1:20), CK7 (Ks7.18, Progen, ready-to-use), and CK8/18 (CAM5.2, Becton Dickinson, ready-to-use). Immunohistochemistry was conducted using the avidin-biotin method with an alkaline phosphatase detection system according the manufacturer’s instructions. Normal positive controls consisted of normal apocrine units from two normal adult axillary samples as well as normal eccrine units without inflammatory cells located some distance from the ten BCC lesions. For some antibodies, the staining process included trypsinization by proteinase K (Dako) (for 34βB4, Ks7.18 and CAM5.2) or microwave oven treatment in target retrieval solution (Dako) (for II-7 and LL002).

Results

Clinical features

The clinical information for the ten selected cases is summarized in Table I. BCC with tubular structures affected women more than men (3 men and 7 women) with an age range of 60 to 85 years (mean 73.6). All 10 BCCs with tubular structures were located on the face and scalp, and four were situated on the eyelid. The clinicopathological subtype of BCC in each of the 10 cases was of the nodular type (including two cases of nodular-infiltrative type).

Table I. Summary of clinical findings in 10 cases of BCC with tubular structures

Histopathological features

The tubular structures in these 10 cases could be largely grouped into two categories: ductal structures and glandular (secretory) structures. Ductal structures were observed in all 10 cases and glandular structures were seen in two cases (cases 9, 10). The ductal structures were characterized by immature, flattened or small cuboidal luminal cells, which often had an eosinophilic cuticular border. The luminal cells were usually associated with one or two layers of flattened outer cells. Squamous cells sometimes surrounded these layered ductal structures. The basic and common form of these ductal structures was small to medium-sized (Figure 1A, B), and this common form was observed in all cases except one (case 7). Tiny ductal structures were seen in two cases (cases 2, 3) (Figure 1C, D), and dilated ductal structures were observed in four cases (cases 4-6, case 10) (Figure 1E, F). In two cases (cases 7, 9), well-differentiated and normal-appearing luminal cells were seen, that had small cuboidal luminal cells with clear cuticular borders and prominent eosinophylic cytoplasm (Figure 1G, H). Ductal structures that demonstrated differentiation toward acrosyringium, characterized by the presence of keratohyaline granules, were seen in two cases (cases 8, 10) (Figure 1I). The cytoplasmic vacuoles, resembling those in embryonic apocrine and eccrine units, were usually associated with the ductal structures and were observed in seven cases (except for cases 2, 3, and 10). The cytoplasmic vacuoles were usually grouped in an alveolar pattern (Figure 1J), and grouped cytoplasmic vacuoles forming a ductal structure were seen (Figure 1K).
The glandular structures were characterized by large cuboidal or columnar luminal cells with abundant eosinophilic cytoplasm and large round nuclei. In two cases (cases 9, 10), the characteristic luminal cells of glandular structures were observed (Figure 2A-C), and one of the two cases (case 10) showed the features of luminal cells with decapitation secretion, suggesting evidence of apocrine differentiation (Figure 2D, E).
One case (case 4) was associated with follicular differentiation in the form of an infundibular cystic structure. One case (case 8) concomitantly showed sebaceous differentiation, and this case was reported elsewhere [16].

Immunohistochemical features

The results of immunohistochemical staining in normal apocrine and eccrine units are summarized in Table II. There were no differences in the staining patterns for the CKs used in this study as well as for CEA and EMA between normal apocrine and eccrine units.
The results of immunohistochemistry for the tubular structures in the 10 cases of BCC are summarized in Table III. All tubular structures were positive for CEA and EMA on the luminal surface of the tubular structures and cuticular debris within the cavities of the tubes in all ten BCCs. The positive staining for CEA/EMA highlighted the tubular structures in BCC (Figure 3A), and provided a clear distinction between the authentic tubular structures and pseudo adenoid structures caused by mucin depositions within the aggregations of BCC (Figure 3B). The cytoplasmic vacuoles were also positive for CEA/EMA in their cuticular borders (Figure 3C)

Table II. The results of immunohistochemical staining in normal apocrine and eccrine units

Table III. The results of CK staining patterns in tubular structures in BCCs

We attempted to use CKs 1 and 10 as markers for intermediate cells of the ductal portion, CK14 as a marker for the ductal portion, and CK7 and CK8/18 for the glandular portion.
In four cases (cases 1, 3, 4, 5), CK1 and CK10 were positive for the outer cells and surrounding squamous cells in approximately 25% (average, range 20-30%) of the ductal structures within the BCCs (Figure 3D). In all 10 cases, CK14 was positive for luminal, outer, and surrounding cells in approximately 60% (average, range 30-70%) of the ductal structures (Figure 3E, F). CK7 and CK8/18 showed no positive reaction for any ductal structures in all 10 cases. In two cases (cases 9, 10), which exhibited glandular structures, CK7 and CK8/18 were positive for all of the glandular structures (Figure 3G, H, I). The glandular structures in case 9 were also positive for CK14, but the structures with decapitation secretion in case 10 were negative for CK14.

Discussion

Among the selected 10 BCCs with tubular structures from the examined 600 BCCs, there were 3 men and 7 women (M/F ratio, 0.43), and the mean age was 73.6 years. All 10 BCCs (8 nodular type, 2 nodular-infiltrative type) were located on the face and scalp, and four were situated on the eyelid. A more recent investigation that studied a large series of BCCs showed that an M/F ratio of 1.02 and a mean age of 66.3 years in nodular BCCs [17]. Another study showed that the orbital region harbors 12.6% of all facial BCCs [18]. Thus, it can be said that our selected BCCs with tubular structures affected women more than men, had an older mean age and the favored location was the eyelid, as compared with conventional nodular BCCs.
Organized histopathological studies concerning tubular structures in BCCs can only be found in an article by Heenan et al. [13] and in the textbook by Requena et al. [7]. Both authors described and documented two types of tubular structures: ductal structures with luminal cells with cuticular borders, and cytoplasmic vacuoles [7, 13]. Requena et al. [7] suggested that glandular structures with decapitation secretion are extremely rare and that there are usually no signs of specific differentiation within the tubular structures in BCCs. Besides the documentation in their textbook [7], reported cases with glandular structures with decapitation secretion in BCC are scarce and were found in only two reports [10, 11].
Although the results of our histopathological study of tubular structures in BCC were generally similar to the descriptions by both authors [7, 13], we showed more detailed histopathological features of the ductal structures and demonstrated the highly rare glandular structures in BCC. The ductal structures represented various types and forms, small to medium-sized (the most common form), tiny, dilated, well-differentiated or acrosyringeal types. The cytoplasmic vacuoles, resembling those in embryonic apocrine and eccrine units, were often associated with the ductal structures. The cytoplasmic vacuoles were usually grouped in an alveolar pattern. In this study, we demonstrated grouped cytoplasmic vacuoles forming a ductal structure, which was taken as evidence that ductal structures are created by coalescence of cytoplasmic vacuoles. The glandular structures were characterized by large cuboidal or columnar luminal cells with abundant eosinophilic cytoplasm and large round nuclei. Only one case demonstrated the features of luminal cells with decapitation secretion.
No previous detailed immunohistochemical studies of tubular structures in BCC, distinguishing between ductal and glandular structures, have been reported thus far. The results of this immunohistochemical study using CKs supported our definition of histopathological distinction between ductal and glandular structures in tubular structures in BCCs. CK7 and CK8/18 (a marker for the glandular portion) clearly showed a positive reaction for all the glandular structures and a negative reaction for all the ductal structures in the BCCs examined. In the 10 BCC specimens studied, CK14 (a marker for the ductal portion) was positive in approximately 60% of the ductal structures, and in one case of glandular structure without decapitation secretion.
The negative staining of CK14 in approximately 40% of the ductal structures in the 10 BCCs examined, and the positivity of CK14 for glandular structures in the one glandular case may be explained by incomplete and abnormal differentiation of these tubular structures in BCC. However, the occasional positive staining results for CK1 and CK10 in some outer and surrounding cells in ductal structures suggests that differentiation toward the intermediate cells may occur in the ductal structures within BCC as in poromas [19]. In any event, this histopathological and immunohistochemical study demonstrated that the tubular structures in BCC differentiate toward either ductal or glandular structures.
It has not yet been elucidated whether the tubular structures in BCC are apocrine or eccrine in nature. Based on this study of 10 BCC cases with tubular structures, we concur with Requena et al. [7], who assumed that the tubular structures in BCC show apocrine differentiation, on the following points: 1) one case clearly demonstrated a glandular structure with decapitation secretion, 2) one case demonstrated an associated feature with follicular differentiation in the form of an infundibular cystic structure, 3) one case demonstrated an associated feature with sebaceous differentiation [16], and 4) the concept that BCC is a malignant neoplasm of abnormal folliculosebaceous-apocrine germinative cells [9]. It was interesting that four of the 10 BCCs were situated on the eyelid where modified apocrine units, namely Moll’s glands, exist. Nevertheless, the possibility that a malignant neoplasm of follicular germinative cells can show eccrine differentiation or that BCC includes a malignant neoplasm of abnormal eccrine germinative cells [20] cannot be completely excluded.
There is a scarcity of reports on BCC with tubular structures although BCC is one of the most common malignant cutaneous neoplasms. We found 10 BCCs with tubular structures out of 600 BCCs examined. Additionally, in this study, cases with cytoplasmic vacuoles or tubular structures with positive staining for CEA/EMA were excluded when these structures were determined to be focally located only. The frequency of tubular structures found within BCCs should be higher than presented here [13]. n

References

1. Freeman RG, Winkelmann RK. Basal cell tumor with eccrine differentiation (eccrine epithelioma). Arch Dermatol 1969; 100: 234-42.

2. Sánchez NP, Winkelmann RK. Basal cell tumor with eccrine differentiation (eccrine epithelioma). J Am Acad Dermatol 1982; 6: 514-8.

3. Serrano G, Aliaga A, Bonillo J, Pelufo C, Otero D. Basal cell tumor with eccrine differentiation (eccrine epithelioma). J Cutan Pathol 1984; 11: 553-7.

4. Hanke CW, Temofeew RK. Basal cell carcinoma with eccrine differentiation (eccrine epithelioma). J Dermatol Surg Oncol 1986; 12: 820-4.

5. Sequeira J, Wright S, Baker H. Basal cell carcinoma with eccrine differentiation (eccrine epithelioma) -a histochemical and immunocytochemical analysis of a case. Clin Exp Dermatol 1987; 12: 58-60.

6. McKee PH, Fletcher CD, Rasbridge SA. The enigmatic eccrine epithelioma (eccrine syringomatous carcinoma). Am J Dermatopathol 1990; 12: 552-61.

7. Requena L, Kiryu H, Ackerman AB. Basal-cell carcinoma with apocrine differentiation. In: Requena L, Kiryu H, Ackerman AB eds: Neoplasms with apocrine differentiation, Philadelphia, Lippincott Raven, 1998: 1021-41.

8. Kirkham N. Tumors and cysts of the epidermis. In: Elder D, Elenitsas R, Jaworsky C, et al. eds: Lever’s histopathology of the skin, 8^th ed. Philadelphia, Lippincott Raven, 1997: 685-746.

9. Ackerman AB, Reddy VB, Soyer HP. Trichoblastic carcinoma. In: Ackerman AB, Reddy VB, Soyer HP eds: Neoplasms with follicular differentiation, New York, Ardor Scribendi, 2001: 625-1005.

10. Wood MR, Pranich K, Beerman H. Investigation of possible apocrine gland component in basal cell epithelioma. J Invest Dermatol 1958; 30: 273-81.

11. Sakamoto F, Ito M, Sato S, Sato Y. Basal cell tumor with apocrine differentiation: apocrine epithelioma. J Am Acad Dermatol 1985; 13: 355-63.

12. Kidd MK, Tschen JA, Rosen T, Altman AR, Golgberg L. Carcinoembryonic antigen in basal cell neoplasms in black patients: an immunohistochemical study. J Am Acad Dermatol 1989; 21: 1007-10.

13. Heenan PJ, Bogle MS. Eccrine differentiation in basal cell carcinoma. J Invest Dermatol 1993; 100: 295S-9S

14. Chang YT, Liu HN, Wong CK. Penile basal cell carcinoma with eccrine differentiation. Clin Exp Dermatol 1995; 20: 487-9.

15. Grosshans E, Misago N, Sánchez Yus E, Soyer HP, Requena L. A basaloid neoplasm with ductal differentiation. Am J Dermatopathol 2003; 25: 77-80.

16. Misago N, Suse T, Uemura T, Narisawa Y. Basal cell carcinoma with sebaceous differentiation. Am J Dermatopathol 2004; 26: 298-303.

17. Scrivener Y, Grosshans E, Cribier B. Variations of basal cell carcinomas according to gender, age, location and histopathological subtype. Br J Dermatol 2002; 147: 41-7.

18. Heckmann M, Zogelmeier F, Konz B. Frequency of facial basal cell carcinoma does not correlate with site-specific UV exposure. Arch Dermatol 2002; 138: 1494-7.

19. Ban M, Yoneda K, Kitajima Y. Differentiation of eccrine poroma cells to cytokeratin 1- and 10-expression cells, the intermediate layer cells of eccrine sweat duct, in the tumor cell nests. J Cutan Pathol 1997; 24: 246-8.

20. Hyman AB, Barsky AJ. Basal cell epithelioma of the palm. Arch Dermatol 1965; 92: 571-3.