Multiple Hereditary Infundibulocystic Basal Cell Carcinomas a Genodermatosis Different from Nevoid Basal Cell Carcinoma Syndrome

OBSERVATION Multiple Hereditary Infundibulocystic Basal Cell Carcinomas A Genodermatosis Different From Nevoid Basal Cell Carcinoma Syndrome

Luis Requena, MD; Maria del Carmen Farin˜a, MD; Mercedes Robledo, MD; Omar P. Sangueza, MD; Evaristo Sanchez Yus, MD; Aurora Villanueva, MD; Amparo Marquina, MD; Roser Tamarit, MD

Background: Infundibulocystic basal cell carcinoma is 2 was performed using polymorphic markers (D9S196, a recently described distinctive clinicopathologic vari- D9S280, D9S287, and D9S180), and the affected mem- ant of basal cell carcinoma. Histopathologic differential bers shared the same haplotype. Loss of heterozygosity diagnosis among infundibulocystic basal cell carci- analysis was performed in 2 affected members of this fam- noma, trichoepithelioma, and basaloid follicular hamar- ily from whom tumoral DNA was available, and al- toma has generated controversy in the literature. though these individuals were constitutively heterozygous for D9S196, they did not show loss of heterozygosity Observations: Members of 2 families with multiple in- for this marker in their neoplasms. fundibulocystic basal cell carcinomas are described. Each patient showed multiple papular lesions, mostly located Conclusions: Multiple hereditary infundibulocystic basal on the face. No patient showed palmar pits or jaw cysts. cell carcinomas represent a distinctive genodermatosis Forty-two cutaneous lesions from 5 patients were stud- different from multiple hereditary trichoepitheliomas and ied histopathologically. Thirty-nine lesions were infun- nevoid basal cell carcinoma syndrome. We propose clini- dibulocystic basal cell carcinomas. This clinicopatho- cal and histopathologic criteria to distinguish infundibu- logic variant of basal cell carcinoma consists of a relatively locystic basal cell carcinoma from trichoepithelioma, ba- well-circumscribed basaloid neoplasm composed of buds saloid follicular hamartoma, and folliculocentric basaloid and cords of neoplastic cells arranged in anastomosing proliferation. fashion and with scant stroma. Some of the neoplastic cords contain tiny infundibular cysts filled by cornified cells with abundant melanin. Linkage analysis in family Arch Dermatol. 1999;135:1227-1235

N 1987, TOZAWA and Ackerman1 We herein describe 2 families in described a new clinicopatho- which several members have multiple in- logic variant of basal cell carci- fundibulocystic basal cell carcinomas. noma that they named basal cell None of the patients had palmar pits or jaw carcinoma with follicular differen- cysts. Furthermore, results of linkage Itiation. Their report generated consider- analysis demonstrated that the affected From the Departments of able controversy in the literature, mainly members shared the same haplotype, but Dermatology (Drs Requena and concerning the difference between this loss of heterozygosity (LOH) for D9S196 Farinã) and Genetics basal cell carcinoma with follicular differ- could not be demonstrated in 2 patients (Dr Robledo), Fundacioń entiation and trichoepithelioma.2-9 Later, from whom tumoral DNA was available. Jimeńez Dıáz, Universidad 10 Autońoma, and the Department in 1990, Walsh and Ackerman pro- Therefore, a diagnosis of nevoid basal cell of Dermatology, Hospital posed a new name for this variant of basal carcinoma syndrome could be elimi- Clıńico San Carlos, cell carcinoma, ie, infundibulocystic basal nated. We believe that multiple heredi- Universidad Complutense cell carcinoma, on the basis of the main his- tary infundibulocystic basal cell carcino- (Dr Yus), Madrid, Spain; the topathologic characteristics of the neo- mas represent a distinctive genodermatosis Departments of Dermatology plasm. These authors stated that infun- different from nevoid basal cell carci- and Pathology, Medical College dibulocystic basal cell carcinoma was found noma syndrome. We discuss the histo- of Georgia, Augusta (Dr frequently in patients with nevoid basal cell pathologic differential diagnosis with that Sangueza); and the carcinoma syndrome (Gorlin syn- of lesions that look like infundibulocys- Departments of Pathology (Dr Villanueva) and drome). More recently, debate has ensued tic basal cell carcinoma, namely follicu- Dermatology (Drs Marquina again as to whether this infundibulocys- locentric basaloid proliferation, basaloid and Tamarit), Hospital tic basal cell carcinoma and basaloid fol- follicular hamartoma, and trichoepithe- Universitario Dr Peset, licular hamartoma are the same or differ- lioma. We review the literature about the Valencia, Spain. ent entities.11-13 subject, giving our interpretation for each

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 Figure 1. Multiple pearly, small papules involving the face, mostly the nasolabial folds.

Figure 3. Pearly papules on the anterior aspect of the legs.

Figure 2. Papules involving the labia majora of the vulva. Figure 4. A pedunculated lesion with eroded surface on the left shoulder.

one of the previously described cases on the basis of the cised from the face and neck, mostly for cosmetic rea- histopathologic illustrations provided in the reports and sons. All lesions showed histopathologic features of in- the histopathologic criteria that we propose herein. fundibulocystic basal cell carcinoma.

REPORT OF CASES Patient 2

FAMILY 1 A 45-year-old sister of patient 1 was seen with multiple small papules scattered over the back and the anterior Patient 1 aspect of the legs (Figure 3) that had been present for many years. A larger lesion with pedunculated shape and A 50-year-old woman presented with multiple pearly, eroded surface was present on the left shoulder small papules involving the face (Figure 1), scalp, neck, (Figure 4). There were no facial lesions. The eroded le- chest, and vulva (Figure 2) that had been present for sion on the left shoulder was excised, and it showed his- several years, but had increased in number and size dur- topathologic features of nodular basal cell carcinoma with ing the last few years. During physical examination, more areas of infundibulocystic basal cell carcinoma. Three small than 100 lesions were counted. Clinical diagnosis was papules excised from the back were stereotypical ex- multiple trichoepitheliomas, and 28 lesions were examples of infundibulocystic basal cell carcinoma.

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 Figure 5. Pearly papules, some of them with annular shapes, on the upper Figure 6. A papular lesion with eroded surface was seen in the left external lip and chin. The scar of the nose tip resulted from a lesion previously auditory canal. excised in another center.

lesion from the right nasolabial fold showed histo- Other Family Members pathologic features of infundibulocystic basal cell carcinoma. In accord with these siblings, a younger sister showed the same facial lesions as patient 1, but this third patient Other Family Members could not be examined by us because she lives in another country. The parents of the 3 siblings had died of Patient 1’s father had died of unrelated causes, but ac- unrelated causes, but according to both patients, they had cording to both siblings seen by us, their father had mul- no cutaneous lesions. tiple pearly small papules scattered over the face. Two brothers and 2 sons of patient 1 were examined in our FAMILY 2 department, and they showed no cutaneous lesions. In the 5 patients examined by us, no palmar or plan- Patient 1 tar pits were seen, and results of the radiographic sur- vey demonstrated that jaw cysts or other bone anoma- A 51-year-old woman presented with multiple pearly pap- lies were not present. ules scattered over the face, mostly located on the upper lip, nasolabial folds, and chin (Figure 5). Some of the RESULTS lesions showed an annular shape, with delled centers and raised borders. A papular lesion with identical shape was HISTOPATHOLOGIC CHARACTERISTICS present in the left external auditory canal (Figure 6), OF INFUNDIBULOCYSTIC and another lesion had been excised previously (in an- BASAL CELL CARCINOMAS other center) from the tip of the nose and interpreted as trichoepithelioma. Four lesions from the face and the le- Forty-two specimens from the 5 patients were studied sion from the left external auditory canal were excised histopathologically. Except for a nodular basal cell car- for histopathologic study. One lesion showed features of cinoma in patient 1, family 2, and 2 superficial basal nodular basal cell carcinoma; the other 4 lesions exhib- cell carcinomas in patient 2, family 2, the remaining 39 ited characteristic findings of infundibulocystic basal cell specimens showed essentially the same histopathologic carcinoma. features, ie, relatively well-circumscribed basaloid neoplasms. Some neoplasms were superficial with no Patient 2 involvement of the deep reticular dermis, whereas in other specimens, neoplastic aggregations of basaloid A 54-year-old sister of patient 1 was seen with multiple cells extended throughout the full thickness of the der- translucent papules on the face and back. The lesions were mis and involved the skeletal muscle to the base of the predominantly located on the upper lip and nasolabial folds. specimen (Figure 7). Neoplastic aggregations con- Two lesions on the back were eroded and covered by crusts. sisted of buds and cords of basaloid and squamoid cells Two facial lesions and both eroded lesions on the back were arranged in radial and anastomosing fashion. Some neo- excised for histopathologic study. The facial lesions were plastic aggregations showed peripheral palisading, and infundibulocystic basal cell carcinomas, whereas the back others, areas of necrosis en masse. Tiny infundibular lesions were superficial basal cell carcinomas. cysts containing cornified cells with abundant melanin were seen within some aggregations of neoplastic cells. Patient 3 The stroma of the neoplasms was scant and consisted of wiry bundles of collagen in lamellated or compact A 22-year-old daughter of patient 1 was seen with sev- arrangement. In some specimens, clefts separated neo- eral pearly papules on the nasolabial folds. An excised plastic stroma from adjacent dermis (Figure 8),

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 Figure 7. Histopathologic characteristics of infundibulocystic basal cell Figure 9. Combined features of conventional nodular basal cell carcinoma and carcinoma. Neoplastic aggregations of basaloid cells involved the deeper infundibulocystic basal cell carcinoma. Scanning magnification showed a reticular dermis and even below it, extending into skeletal muscle neoplasm that ulcerated the epidermis and involved the full thickness of the (hematoxylin-eosin, original magnification ϫ10). dermis. Areas of infundibulocystic basal cell carcinoma may be seen in both lateral margins of the neoplasm (hematoxylin-eosin, original magnification ϫ5).

0.037 MBq ␣-phosphorus 32–labeled deoxycytidine triphosphate (Amersham Life Science Ltd, Buckingham- shire, England); 1 U Taq polymerase (Boerhinger, Mann- heim, Germany); and 1 ϫ PCR buffer (Boerhinger) (50- mmol/L calcium chloride; 10-mmol/L Tris [pH, 8.3] (Serva Electrophoresis, Heidelberg, Germany); and 1.5- mmol/L magnesium chloride). The PCR analysis was performed in a 2400 thermocycler (Perkin-Elmer Applied Biosystem Division, Foster City, Calif) with the following conditions for 30 cycles: 94°C for 45 seconds, 55°C for 40 seconds, and a final extension of 5 minutes at 72°C. The PCR products were analyzed on denaturing 8% polyacrylamide gels and exposed at −70°C with com- mercially available film (Kodak X-OMATIC S film; East- Figure 8. Histopathologic characteristics of infundibulocystic basal cell carcinoma. This specimen consisted of a relatively well-circumscribed man Kodak, Rochester, NY). The primer sequences are neoplasm with clefts separating neoplastic stroma from adjacent dermis. available from Genome Database (available at http:// Tiny infundibular cysts were seen within some neoplastic cords of basaloid gdbwww.gdb.org). The order of the polymorphic mark- cells (hematoxylin-eosin, original magnification ϫ10). ers was derived from genetic linkage data.14,15 For LOH analysis, tumoral DNA from patients 1 and whereas in others, no clefts were seen. In a specimen of 3 of family 2 was obtained. The PCR conditions were the patient 2, family 1, features of nodular basal cell carci- same described above, except the number of cycles was noma and infundibulocystic basal cell carcinoma were reduced to 23. combined, with gradual transition between the 2 pat- To determine whether the infundibulocystic basal terns (Figure 9). cell carcinomas in family 2 could be attributable to a nevoid basal cell carcinoma syndrome, linkage and GENETIC STUDIES LOH studies were performed using 4 polymorphic markers (D9S196, D9S280, D9S287, and D9S180) We obtained DNA using standard procedures from pe- flanking the PTC gene. The linkage analysis showed ripheral blood samples of all available members of fam- that the affected members I.1, II.2, II.3, and III.1, and ily 2, and tumoral DNA was obtained from paraffin- the healthy 23-year-old male III.2 shared the same embedded tissue of infundibulocystic basal carcinomas haplotype (Figure 10). Studies of LOH were per- from patients 1 and 3 of this family. formed in patients 1 and 3 of this family. Both patients Linkage analysis was performed using 4 polymor- were constitutively heterozygous for D9S196, but they phic markers, D9S196, D9S280, D9S287, and D9S180, did not show LOH for this marker in their cutaneous that map to chromosome 9q22.3 flanking the neoplasms. PATCHED (PTC) gene. Polymerase chain reaction (PCR) analysis was performed in 20-µL volumes con- COMMENT taining 100 ng of template DNA; 200-µmol/L deoxy- adenosine triphosphate, deoxyguanosine triphosphate, We herein describe 2 families with several members af- and deoxythymidine triphosphate each; 10-µmol/L fected by multiple infundibulocystic basal cell carcino- deoxycytidine triphosphate; 15 pmol of each primer; mas. In our opinion, these patients have a genoderma-

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1 3 1 2 1 2 II 3 2 2 2 2 2 1 1 1 1 1 1 1 2 3 1 1 3 3 3 3

III 1 2 3 1 3 1 1 12 2 2 2 3 32 1 1 1 1 11 3 1 3 1 13

• D9S196 • D9S280 • D9S287 • D9S180

Figure 10. Pedigree and linkage analysis in family 2.

Figure 11. Basaloid follicular hamartoma, lesion present since birth. Multiple tosis different from multiple hereditary trichoepitheliomas small papules are grouped into an erythematous plaque on the left side of and nevoid basal cell carcinoma syndrome. Clinically, the the neck. cutaneous lesions were similar to those of multiple hereditary trichoepitheliomas, because the patients showed indubitable examples of infundibulocystic basal cell multiple small pearly papules scattered over the face, with carcinomas of our series ulcerated the epidermis and lesions predominantly located on nasolabial folds. How- involved subcutaneous fat and skeletal muscle at the ever, they also showed additional lesions on the scalp, base of the specimens, and neoplastic aggregations neck, back, chest, and extremities. In contrast to nevoid destroyed preexisting adnexal structures of the dermis, basal cell carcinoma syndrome, our patients with mul- all architectural features of malignant neoplasms. Fur- tiple hereditary infundibulocystic basal cell carcinomas thermore, 1 specimen from patient 2, family 1, showed had no palmar pits, jaw cysts, or other bone anomalies, combined features of a large nodular basal cell carci- which are necessary to establish the diagnosis of Gorlin noma, which ulcerated the epidermis, and infundibulo- syndrome.16 Furthermore, genetic studies of linkage analy- cystic basal cell carcinoma. The main controversial sis and LOH using polymorphic markers demonstrated point of infundibulocystic basal cell carcinoma is its dif- that the affected members shared the same haplotype. Two ferential diagnosis with trichoepithelioma,2-9 basaloid members of family 2 were constitutively heterozygous follicular hamartoma,11-13 and folliculocentric basaloid for D9S196, but they did not show LOH for this marker proliferation.20,21 Ackerman4,6,8 and Walsh and Acker- in their neoplasms. Although LOH has not been re- man10 have established clear-cut histopathologic criteria ported in 100% of patients with nevoid basal cell carci- for differential diagnosis between infundibulocystic noma syndrome,17-19 the haplotype and LOH data sug- basal cell carcinoma and trichoepithelioma. Briefly, gested that this family did not have nevoid basal cell trichoepithelioma is a benign neoplasm with follicular carcinoma syndrome. Hereditary transmission of mul- differentiation that appears as a relatively symmetric tiple infundibulocystic basal cell carcinoma seems to be and well-circumscribed neoplasm in which stroma pre- autosomal dominant, although a striking feature in our dominates over the epithelial component. This abun- 2 families was that all patients examined by us were dant stroma is highly fibrocytic, closely resembling fol- female. licular papillae and the perifollicular connective tissue The biological behavior of infundibulocystic basal sheath. In neoplastic aggregations of trichoepithelioma cell carcinoma, however, seems to be less aggressive follicular papillae and bulbs are readily recognizable. than that of other clinicopathologic variants of basal cell Usually, at scanning magnification, a histopathologic carcinoma, because most of the lesions remain small for differential diagnosis between trichoepithelioma and a long time and show little tendency to ulcerate the epi- infundibulocystic basal cell carcinoma may be estab- dermis. In our experience, this biological behavior is lished with confidence on the basis of the abundant and similar to that of most of the facial lesions in patients highly fibrocytic stroma in trichoepithelioma and the with nevoid basal cell carcinoma syndrome, which scant stroma with a paucity of fibrocytes in infundibu- remain small in size, without ulceration for a long time. locystic basal cell carcinoma. In this syndrome, only a few lesions become large and Infundibulocystic basal cell carcinoma also should ulcerated basal cell carcinomas. Nevertheless, some be differentiated from basaloid follicular hamartoma.

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 Table 1. Literature Review of the Reported Cases of Basaloid Follicular Hamartoma, Multiple Trichoepitheliomas With Alopecia and Myasthenia Gravis, and Infundibulocystic Basal Cell Carcinoma*

Age of Source, y Patient/Sex Clinical Appearance Associated Anomalies Published Diagnosis Our Interpretation Brown et al,22 1969 32 y/F Multiple papules on the face Alopecia, Hair follicle hamartoma Basaloid follicular and axilla aminoaciduria, hamartoma myasthenia gravis Mehregan and 23 y/F Multiple papules on the face, Scarring alopecia, Follicular hamartoma Trichilemmal cysts Hardin,42 1973 palms, and soles palmar pits Keough et al,31 1977 26 y/F Solitary plaque on the ND Basaloid follicular Basaloid follicular abdomen hamartoma hamartoma Delacretaz and 40 y/F Small cystic lesions on the ND Follicular harmatoma Basaloid follicular Balsiger,26 1979 face and vulva hamartoma Ridley and Smith,23 32 y/F Multiple papules on the face Alopecia, myasthenia Hair follicle hamartoma Basaloid follicular 1981 gravis hamartoma and trichoepitheliomas Mehregan and 53 y/F Multiple papules on the arm, Graves disease Basaloid follicular Basaloid follicular Baker,27 1985 back, chest, and abdomen hamartoma hamartoma 32 y/F Solitary plaque on the scalp ND Basaloid follicular Basaloid follicular hamartoma harmatoma 47 y/M Solitary plaque on the scalp ND Basaloid follicular Infundibulocystic basal harmatoma cell carcinoma Starink et al,43 1986 51 y/F Multiple papules on the face Alopecia, myasthenia Trichoepitheliomas Trichoepitheliomas and neck gravis Geffner et al,40 1986 10 y/F Multiple linear papules on the ND Trichoepitheliomas Basaloid follicular trunk hamartoma Tozawa and 53-84 y/ Solitary papule on the face ND Basal cell carcinoma Infundibulocystic basal Ackerman,1 1987 8M, 7F with follicular cell carcinoma differentiation Weltfriend et al,24 29 y/F Infiltrated plaques on the face Alopecia, myasthenia Hair follicle hamartoma Basaloid follicular 1987 gravis hamartoma Morton et al,32 1988 33 y/F Perioral indurated plaque Alopecia, systemic Basaloid follicular Basaloid follicular lupus erythematous hamartoma hamartoma Miyakawa et al,41 52 y/F Multiple papules on the face Alopecia, myasthenia Trichoepitheliomas Basaloid follicular 1988 gravis hamartoma Gartmann et al,39 14 y/F Multiple papules on the face Nevoid basal cell Basaloid follicular Infundibulocystic basal 1989 20 y/M and upper back carcinoma syndrome hamartoma cell carcinoma

Walsh and ND Localized and generalized Nevoid basal cell Infundibulocystic basal Infundibulocystic basal Ackerman,10 1990 lesions carcinoma cell carcinoma cell carcinoma Mayou et al,35 1991 33 y/F Multiple papules on the face Alopecia, Hair follicle hamartoma Trichoepitheliomas anti–acethylcholine receptor antibodies Kato et al,38 1992 39 y/F Multiple papules on the ND Basaloid follicular Basal cell carcinoma, retroauricular fold hamartoma Pinkus fibroepithelioma type Brownstein,11 1992† 57 y/F Multiple papules on the face 53 y/M Multiple papules on the face 55 y/F Multiple papules on the face Basaloid follicular Infundibulocystic basal 27 y/M Multiple papules on the face ND hamartoma cell carcinoma 22-88 y/ Solitary papules on the face, 60% F, scalp, back, chest, 40% M shoulder, and calf Broberg and 18 y/F Multiple papules on the face ND Basaloid follicular Trichoepitheliomas Gisslen,36 1992 hamartoma Jimenez-Acosta et 36 y/F Linear plaque on shoulder and ND Basaloid follicular Basaloid follicular al,28 1992 arm hamartoma hamartoma Alessi and Azzolini,30 4 y/M Plaque on the face ND Hair follicle hamartoma Basaloid follicular 1993 hamartoma Kato and Ueno,44 56 y/F Papule on the nose ND Infundibulocystic basal Infundibulocystic basal 1993 cell carcinoma cell carcinoma Nelson et al,29 1993 34 y/M Multiple papules on the neck ND Basaloid follicular Basaloid follicular 60 y/F Multiple papules on the face ND hamartoma hamartoma Mascaró et al,25 2 y/M Atrophic follicular macules on Cystic fibrosis, 1995 subaxillary areas hypotrichosis, hypohidrosis 6 y/M Milia-like papules on the face Cystic fibrosis, Basaloid follicular Follicular hamartoma hypotrichosis, hamartoma hypohidrosis 3 mo/F No cutaneous lesions Cystic fibrosis, hypotrichosis

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Age of Source, y Patient/Sex Clinical Appearance Associated Anomalies Published Diagnosis Our Interpretation de Eusebio et al,45 69 y/M Papule on the neck ND Infundibulocystic Infundibulocystic basal 1996 basaloid neoplasm cell carcinoma 50 y/F Papule on the nose ND Infundibulocystic Micronodular basal cell basaloid neoplasm carcinoma Akasaka et al,37 22 y/F Multiple papules on the Alopecia, systemic Basaloid cell Trichoepitheliomas 1996 forehead lupus erythematosus harmatoma Benzarti et al,33 22 y/F Multiple papules on sacral ND Basaloid follicular Basaloid follicular 1996 area hamartoma hamartoma Toyoda et al,34 55 y/M Papule on the nose ND Basaloid follicular Basaloid follicular 1998 hamartoma hamartoma

*ND indicates not described. †Describes 4 familial cases (listed individually) and 56 sporadic cases (grouped).

Basaloid follicular hamartoma is a rare follicular malfor- 5 6 4 mation with distinctive histopathologic features. It was 7 originally described by Brown et al22 in 1969 as multiple papules in nasolabial folds associated with myasthenia 3 gravis and diffuse alopecia. Since then, several cases have 8 been reported, and now it is evident that basaloid follicular hamartoma may assume the following 5 different 2 clinical forms: (1) an acquired generalized type, associated with myasthenia gravis and diffuse alopecia22-24; 9 (2) a congenital generalized type, associated with diffuse alopecia and cystic fibrosis25; (3) a generalized familial 1 type, without any apparent associated disease26; (4) a localized linear and unilateral type27-29 (Figure 11); and (5) a localized and solitary type that mimics a plaque of alopecia on the scalp27 or appears as an indurated papular plaque.30-34 In our opinion, some of the cases reported as basaloid follicular hamartoma are better interpreted as trichoepitheliomas,35-37 basal cell carcinoma of fibroepithelioma (Pinkus) type,38 or infundibulocystic basal cell carcinomas.11,39 Conversely, some cases reported as trichoepitheliomas are in our opinion examples of basaloid follicular hamartomas.40,41 Finally, some patients with myasthenia gravis seem to have multiple trichoepitheliomas and basaloid follicular hamartomas,23 support- ing the notion that multiple follicular neoplasms and Figure 12. Histopathologic characteristics of basaloid follicular hamartoma. hamartomas may be cutaneous markers of a more com- Top, Scanning view shows vellus hair follicles (arrows 1 to 9) replaced by plex familial syndrome. Table 1 summarizes the litera- cords and strands of basaloid cells arranged in anastomosing fashion. This folliclular malformation only involves vellus follicles of superficial dermis, ture review and our interpretation of the reported cases and no proliferation of basaloid cords is seen in interfollicular and deeper of basaloid follicular hamartoma, multiple trichoepithe- dermis (hematoxylin-eosin, original magnification ϫ10). Bottom, Higher liomas associated with alopecia and myasthenia gravis, magnification of the vellus follicle marked by arrow 9 shows a malformed and infundibulocystic basal carcinoma. From the histo- follicle that is replaced by cords of basaloid cells surrounding a tiny infundibular cyst (hematoxylin-eosin, original magnification ϫ100). pathologic point of view, basaloid follicular hamartoma is characteristic, and the lesion consists of malformed and distorted hair follicles composed of cords and present, with no proliferations of basaloid neoplastic ag- strands of basaloid cells arranged in radial and anasto- gregations in interfollicular dermis and no involvement mosing fashion (Figure 12). In contrast to trichoepi- of deeper reticular dermis. In brief, basaloid follicular thelioma, the stroma of basaloid follicular hamartoma is hamartoma consists of malformed hair follicles, whereas scant or absent, and when present it consists of eosino- infundibulocystic basal cell carcinoma is a malignant philic compact collagen bundles with no fibrocytes. No neoplasm composed of aggregations of neoplastic cells follicular bulbs and papillae are seen in basaloid follicu- that involve and destroy preexisting hair follicles and in- lar hamartoma. Unlike infundibulocystic basal cell carci- terfollicular dermis, and sometimes infiltrate deeper der- noma, basaloid follicular hamartoma is a superficial mal- mis, subcutaneous fat, and skeletal muscle. formation of hair follicles, and basaloid cords and strands Finally, infundibulocystic basal cell carcinoma should are seen only at the sites where normal follicles should be also be differentiated from the so-called folliculocentric ba-

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 Table 2. Differential Diagnosis Among Basaloid Follicular Hamartoma, Folliculocentric Basaloid Proliferation, Trichoepithelioma, and Infundibulocystic Basal Cell Carcinoma

Basaloid Follicular Folliculocentric Basaloid Infundibulocystic Basal Hamartoma Proliferation Trichoepithelioma Cell Carcinoma Nature Malformation Reactive, probably Benign neoplasm Malignant neoplasm hyperplastic Clinical variants Solitary variant; linear None, histopathologic Solitary variant; multiple Solitary variant; multiple variant; congenital finding only variant variant generalized; acquired generalized Inheritance Autosomal dominant ND Autosomal dominant Autosomal dominant Associated anomalies Alopecia; myasthenia ND Alopecia; myasthenia gravis None* gravis; cystic fibrosis Histopathologic features Epithelial component Malformed follicles Folliculocentric proliferation Architecture of benign Basaloid cords and composed of with vertical and axial neoplasm of germinative strands involving basaloid cords and arrangement; prominent follicular cells preexisting follicles strands basement membrane and interfollicular surrounding basaloid dermis aggregations Stroma Scant or none None Abundant and highly Scant fibrocytic Follicular bulbs and None None Frequent None papillae Deeper dermis and No involvement; no No involvement In classic trichoepithelioma, Neoplastic basaloid subcutaneous fat involvement of only superficial dermis aggregations interfollicular involved; in sometimes involve dermis trichoblastoma, deeper subcutaneous fat and dermis and subcutaneous skeletal muscle fat may be also involved

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