1岁猫多发性毛囊异常符合基底细胞样毛囊错构瘤

王帆

Multiple follicular abnormalities in a 1-year old cat consistent with basaloid follicular hamartomas

1岁猫多发性毛囊异常符合基底细胞样毛囊错构瘤

作者：Fabien Moog, Veronique Demorieux, Nicolas Gaide, Marie O. Semin, Jerome Abadie, Maria Zacharopoulou , Lucrecija Marinovic , Maxence Delverdier, Frederique Degorce-Rubiales  and Marie C. Cadiergues

翻译：王帆

Background–In humans, basaloid follicular hamartomas are benign follicular tumours, that can be solitary or multiple, in which case they show autosomal dominant inheritance.

Hypothesis/Objectives–This study describes clinical and histopathological findings observed in a young cat, which could be consistent with basaloid follicular hamartomas.

Case description – Multiple follicular abnormalities, consistent with cutaneous diffuse basaloid follicular hamartomas, were observed in skin samples from a one-year old neutered domestic short hair cat. Clinical signs were diffuse symmetrical alopecia with exaggerated skin markings (ventral abdomen, thorax and medial aspects of the limbs) and intense follicular-centred thickening (face and feet). Microscopic lesions were characterised by multiple proliferative follicular abnormalities in all samples. The epidermis showed a very irregular surface with the follicles filled with variably pigmented keratin.The epithelial walls of the follicles had multiple small hyperplastic basaloid cells foci. In the superficial dermis under the epidermis and around the follicles, fibroblastic spindleshaped mesenchymal cells with a homogeneous moderate density were present in the collagenous connective tissue. The interfollicular epidermis was also abnormal with multiple small proliferating trichoblastic foci originating from the basal layer. RNA scope testing for feline papillomavirus was negative.

Conclusions and clinical relevance – This case report provides the first evidence of clinical and histopathological findings of multiple follicular abnormalities, consistent with cutaneous diffuse basaloid follicular hamartomas in a cat.

背景-在人类中，基底细胞样毛囊错构瘤是良性毛囊肿瘤，可以是单发或多发，这种疾病表现为常染色体显性遗传。
假设/目的-本研究描述了在一只年轻猫上观察到的临床和组织病理学结果，这可能与基底细胞样毛囊错构瘤一致。

病例描述-在一只一岁已绝育家养短毛猫的皮肤样本中观察到多个毛囊异常，符合皮肤弥漫性基底细胞样毛囊错构瘤。临床症状为弥漫性对称型脱毛，伴皮肤斑纹明显(腹部腹侧、胸部和四肢内侧)，毛囊中心明显增厚(面部和足部)。所有样本镜下病变的特征为多发性增生性毛囊异常。表皮层表面不规则，毛囊内充满不同程度的角质。毛囊表皮细胞壁有多个小的基底细胞样增生病灶。表皮层下方浅表真皮和毛囊周围胶原结缔组织中有均匀中等密度的纺锤形成纤维间充质细胞。毛囊间表皮也异常，有多个起源于基底层的小增殖毛母细胞灶。猫乳头瘤病毒RNA评估检测为阴性。

结论和临床相关性-本病例报告提供了多发性毛囊异常的临床和组织病理学发现的首例证据，与猫皮肤弥漫性基底细胞样毛囊错构瘤一致。

Background

背景

In humans, basaloid follicular hamartomas are benign follicular tumours that can be solitary or multiple, in which latter case they show autosomal dominant inheritance. In animals, to the best of the authors’ knowledge, no cases have been reported. This study describes clinical and histopathological findings observed in a young cat, which could be consistent with basaloid follicular hamartomas.

人的基底细胞样毛囊错构瘤是良性毛囊肿瘤，可以是单发或多发，多发病例表现为常染色体显性遗传。在动物中，据作者所知没有病例报告。本研究描述了在一只年轻猫上观察到的临床和组织病理学发现，这可能与基底细胞样毛囊错构瘤一致。

Case report

病例报告

A 1-year old neutered domestic short hair cat was referred for a pruritic and alopecic diffuse dermatitis of a few weeks’ duration. Previous systemic antibiotic and glucocorticoid therapies had little to no effect. A fungal culture had returned negative.

1岁已绝育家短毛猫因持续数周的瘙痒和弥漫性脱毛皮肤病被转诊。用药史为全身抗生素和糖皮质激素几乎没有效果。真菌培养结果为阴性。

On admission, the general physical examination revealed no abnormalities apart from a depressed demeanour (Figure 1a). Diffuse symmetrical alopecia affected mainly the ventral abdomen and thorax as well as the medial aspects of all four limbs. The skin markings were exaggerated with a pronounced loss of elasticity (Figure 1b). Diffuse and mild erythema with focal hyperpigmented areas was observed (Figure 1b). The face and the feet were alopecic and severely thickened (Figure 1c). On close examination, the thickening seemed to be follicular-centred (Figure 1d,e).

入院时，全身体格检查显示除行为沉郁外，无其他异常(图1a)。弥漫性对称性脱毛主要在腹部腹侧、胸侧以及四肢内侧。皮肤皱褶明显，皮肤明显失去弹性(图1b)。观察到弥漫性轻度红斑伴局灶性色素沉着(图1b)。面部和足部脱毛并严重增厚(图1c)。仔细检查，增厚似乎以毛囊为中心(图1d,e)。

A complete serum biochemical analysis and complete blood count showed all values within normal limits. The cat tested negative for feline immunodeficiency virus/feline leukaemia virus. Microscopic lesions, in three 6 mm skin biopsy specimens from the face, were characterised by multiple proliferative follicular abnormalities in all samples. The epidermis showed a very irregular surface with the follicles filled with variably pigmented keratin (Figure 2a,b). The epithelial walls of the follicles had multiple small hyperplastic basaloid cell foci (Figure 2c). In the superficial dermis under the epidermis and around the follicles, fibroblastic spindle-shaped mesenchymal cells with a homogeneous moderate density were present in the collagenous connective tissue (Figure 2d). The interfollicular epidermis also was abnormal with multiple small proliferating trichoblastic foci originating from the basal layer. The sebaceous glands and epitrichial sweat glands were normal. RNAscope assay was assessed using a 13ZZ probe named V-FPV-E6-E72 and RNAscope 2.5 HD Assay RED according to the manufacturer’s recommendations (Bio-techne SAS; Noyal-Chatillon-surSeiche, France) with a protease incubation time of 15 min. A probe to the bacterial gene dihydrodipicolinate reductase (dapB) served as the negative control, as well as normal skin; cutaneous viral plaques/squamous cell carcinoma and mucosal papilloma on feline cases served as positive controls. In situ hybridisation tested negative for Felis catus papillomavirus 2 (FcaPV-2) E6 and E7 gene transcription (Figure 3a–e).

完整的血清生化分析和全血细胞计数显示所有值均在正常范围内。猫的猫免疫缺陷病毒/猫白血病病毒检测呈阴性。3例面部6mm皮肤活检样本的显微病变均表现为多发性增生性毛囊异常。表皮表面非常不规则，毛囊充满不同颜色的角质(图2a,b)。毛囊表皮细胞壁有多个小的基底样增生细胞病灶(图2c)。在表皮下和毛囊周围的真皮表层，胶原结缔组织中存在均匀中等密度的纺锤形间充质细胞(图2d)。毛囊间表皮细胞也异常，有多个起源于基底层的小增殖毛母细胞灶。皮脂腺和上皮汗腺正常。使用13ZZ的V-FPV-E6-E72探针和RNAscope 2.5 HD assay RED根据制造商的建议，蛋白酶孵育时间为15分钟。阴性对照为细菌基因二氢二吡啶羧酸还原酶(dapB)探针，以及正常皮肤;猫的皮肤病毒斑块/鳞状细胞癌和粘膜乳头状瘤作为阳性对照。原位杂交检测猫乳头瘤病毒2 (FcaPV-2) E6和E7基因转录阴性(图3a e)。

The cat was euthanised owing to poor quality of life. Necropsy did not reveal any gross or microscopic abnormalities of any other organs apart from strikingly thickened fascia and articular capsules of the hips and shoulders. Their microscopic examination revealed only severe fibrous hyperplasia; additional skin biopsies obtained from the head, thorax and abdomen showed similar results as before.

这只猫由于生活质量差而被安乐死。尸检没有发现任何其他器官的目测或显微镜下的异常，除了明显增厚的筋膜和髋关节和肩部关节囊。镜下仅见严重纤维增生;从头部、胸部和腹部获得的皮肤活检的结果相似。

The final clinicopathological diagnosis was cutaneous diffuse basaloid follicular hamartomas.

最终的临床病理诊断为皮肤弥漫性基底细胞样毛囊错构瘤。

Discussion

讨论

Cutaneous hamartomas (nevi) are circumscribed developmental defects of the skin, characterised by hyperplasia of one or more skin components. They are uncommon in dogs and cats and may be congenital or not. Their exact mechanism of formation is unknown.

皮肤错构瘤(痣)是局限性的皮肤发育缺陷，特点是一个或多个皮肤成分增生。它们在犬和猫中不常见，可能是先天的，也可能不是。它们的确切形成机制尚不清楚。

In humans, basaloid follicular hamartomas were previously often diagnosed as trichoepitheliomas or basal cell carcinomas. They can be hereditary, in which case they are generalised or localised, or nonhereditary with solitary, localised or multiple lesions. The generalised basaloid follicular hamartoma syndrome subtype carries an autosomal inherited pattern and affected patients show additional lesions such as milium cysts, comedones, alopecia or hypotrichosis. It is generally associated with an autoimmune disease. Multiple basaloid follicular hamartomas associated with myasthenia gravis and diffuse alopecia form the Brown–Crounse syndrome. However, some reported cases of multiple basaloid follicular hamartomas failed to demonstrate an autosomal dominance inheritance and the causative gene is unknown. The pathophysiological aetiology of the lesion has been suggested to be an abortive growth of secondary hair germs, with differentiation occurring only in the upper part of the follicle. Basaloid follicular hamartomas are morphologically similar to infundibulocystic basal cell carcinoma and immunoreactivity with cytokeratin 20 is similar, which makes some authors consider both lesions to be identical. However, the anastomoses and strands of basaloid cells are localised in the dermis opposed to the infundibulocystic basal cell carcinoma, which may involve the subcutaneous fat and skeletal muscle. In both lesions, the strands are embedded in a loose, fibrous stroma. Moreover, mitoses and single cell necrosis are rare while a high number of these are more consistent with basal cell carcinoma.

在人类，基底细胞样毛囊错构瘤以前常被诊断为毛上皮细胞瘤或基底细胞癌。它们可以是遗传性的，在这些病例中，它们是全身性或局限性的，或非遗传性的单发、局限性或多灶性病变。全身性基底细胞样毛囊错构瘤综合征亚型携带是常染色体遗传模式，患这出现其他病变，如粟粒样囊肿、粉刺、脱毛或少毛。它通常与自身免疫性疾病有关。多发性基底细胞样毛囊错构瘤伴重症肌无力和弥漫性脱毛形成Brown–Crounse综合征。然而，一些报道的多发性基底细胞样毛囊错构瘤病例没有表现出常染色体显性遗传，致病基因尚不清楚。病变的病理生理原因认为是次毛基质异常生长，伴有分化只发生在毛囊上部。基底样毛囊错构瘤在形态学上与毛囊漏斗部基底细胞癌相似，与细胞角蛋白20的免疫反应相似，这使得一些作者认为这两种病变是相同的。然而，基底样细胞的结合和排列位于真皮层，不像毛囊漏斗部基底细胞癌可能涉及皮下脂肪和骨骼肌。在这两个病变中，纤维间质嵌入疏松的纤维间质。此外，有丝分裂和单细胞坏死是罕见的，而高数量的这些与基底细胞癌更一致。

In this feline case, the main diagnostic pitfalls are papillomavirus-induced lesions (viral plaques), trichoepitheliomas and basal cell carcinomas. Recent evidence suggests that FcaPV-2 is the predominant cause of feline viral plaques/Bowenoid in situ carcinomas, although FcaPV3, FcaPV4 and FcaPV5 also may cause development of lesions. Viral plaques typically present as multiple pigmented or nonpigmented, nonpruritic lesions commonly on face, head and neck. Histologically, there is mild to moderate epidermal and infundibular hyperplasia that may progress to dysplasia and atypia in Bowenoid in situ carcinomas. The RNAscope assay used here enabled the involvement of FcaPV-2 in the lesions to be excluded. Trichoepitheliomas are thought to originate from keratinocytes differentiating toward all three segments of the hair follicle. They are polymorphic tumours as their histological appearance depends on their origin (follicular sheath or hair matrix) and degree of differentiation. Malignant transformation is uncommon and lesions tend to be solitary. Basal cell carcinomas in cats are common, solitary, well-circumscribed, firm and round small tumours that have metastasis potential. They originate from pluripotential epithelial cells in the basal layer and adnexa. Histologically, they appear as multiple basaloid cells aggregates within a stroma bed and mitotic abnormalities are common, while the mitotic activity is variable.

在猫的病例中，主要的诊断陷阱是乳头状瘤病毒引起的病变(病毒斑块)、毛上皮细胞瘤和基底细胞癌。最近的证据表明，FcaPV-2是猫病毒斑块/鲍文样原位癌的主要病因，但FcaPV3、FcaPV4和FcaPV5也可能导致发病。病毒性斑块通常表现为面部、头颈部的多处色素沉着或非色素沉着、非瘙痒性病变。组织学上，鲍文样原位癌有轻度至中度表皮层和毛囊漏斗部增生，可发展为发育异常和异型性。此处使用的RNA评估检测可以排除病变中FcaPV-2的参与。毛上皮细胞瘤被认为起源于向毛囊所有三个部分的角质形成细胞。由于其组织学表现取决于其来源(毛囊根鞘或毛基质)和分化程度，因此属于多态性肿瘤。恶性转移不常见，病变往往是孤立的。猫基底细胞癌是一种常见的、孤立的、边界清楚的、坚硬的圆形小肿瘤，具有转移可能。它们起源于基底层和附件的多能的表皮细胞。组织学上，它们表现为多个基底细胞样聚集在基质内，常见有丝分裂异常，而有丝分裂活性多变。

In humans, when not associated with a systemic disease, the prognosis of basaloid follicular hamartomas is good and the issue is mainly cosmetic provided that no suspicious changes arise. Retinoids have been used to decrease the size of lesions in generalised conditions and various excision therapies are available.

在人类，当不伴有全身性疾病时，基底细胞样毛囊错构瘤的预后良好，除影响美观外，无可疑变化。使用维甲酸来减小全身性病变的大小，以及不同程度的可以切除治疗。

In this feline case, no equivalence or specific reason for the thickened fascia and articular capsules were found and there was no evidence of another systemic disease. The fibroblastic spindle-shaped mesenchymal cells which were observed in the dermis of the cat are not reported in human cases. A potential link between the abnormalities of the dermal connective tissue and fascia/articular capsules is unclear. Information about the siblings and parents of this case was not available and no genetic testing could be done, making it impossible to hypothesise a familial/inherited condition.

在这只猫的病例中，没有发现与筋膜和关节囊增厚相关的或特定的原因，也没有发现其他全身性疾病的证据。在猫的真皮层中观察到的纺锤形间充质纤维母细胞在人类病例中没有报道。真皮结缔组织异常与筋膜/关节囊之间的潜在联系尚不清楚。无法获得有关该病例的兄弟姐妹和父母的信息，也无法进行基因检测，因此不可能假设有家族/遗传疾病。

This case report provides the first evidence of clinical and histopathological findings, including negative RNAscope testing for feline papillomavirus, of multiple follicular abnormalities, consistent with cutaneous diffuse basaloid follicular hamartomas in a cat.

本病例报告提供了临床和组织病理学发现的首例证据，包括猫乳头瘤病毒RNA评估检测阴性，多发性毛囊异常，与猫皮肤弥漫性基底细胞样毛囊错形瘤一致。

Figure 1. Clinical findings of a 1-year-old cat with basaloid follicular hamartomas. The cat had a depressed demeanour (a), extensive symmetrical alopecia on the ventral abdomen with erythema, focal hyperpigmentation and excessive skin markings with loss of elasticity (b). The face was alopecic and severely thickened (c). Close examination of the face (d) and around the footpads (e) reveals follicular-centred thickening.

图1。1岁猫基底细胞样毛囊错构瘤的临床表现。猫行为沉郁(a),大面积对称性脱毛，位于腹部腹侧红斑、局部皮肤色素沉着和皮肤皱褶明显和失去弹性(b)。面部脱毛，严重增厚(c),仔细检查面部(d)和爪垫周围(e)发现以毛囊中心增厚。

Figure 2. Histopathological findings in skin biopsy samples taken from the face of a 1-year-old cat with basaloid follicular hamartomas. (a) Hyperplastic epidermis with a very irregular surface (haematoxylin & eosin, 940). (b) Multiple small hyperplastic trichoblastic foci of basaloid cells originating from the epithelial wall of the follicles and the basal layer of epidermis; follicles filled with variably pigmented keratin (H&E, 100倍). (c) Epithelial walls of the follicles with multiple small hyperplastic basaloid cells foci (H&E, x400). (d) Homogeneous and moderate density of fibroblastic spindle-shaped mesenchymal cells in the dermis (H&E, x400).

图2。从患有基底细胞样毛囊错构瘤的1岁猫面部采样的皮肤活检样本的组织病理学发现。(a)表面不规则的表皮层增生(苏木精+伊红,40倍)。(b)起源于毛囊表皮细胞壁和表皮基底层的多灶性的毛母细胞增生灶;毛囊充满不同程度的有色素的角质(HE, 100倍)。(c)毛囊表皮细胞壁有多个基底细胞样小增生灶(HE, 400倍)。(d)真皮纤维母细胞纺锤状间充质细胞均匀、中等密度(HE, 400倍)。

Figure 3. In situ hybridisation for Felis catus papillomavirus 2 (FcaPV-2) E6 and E7. (a) Negative control – normal skin, cat, bacterial gene dihydrodipicolinate reductase (dapB) served as the negative probe control: absence of hybridisation signals. (b) Negative control – normal skin, cat: absence of hybridisation signals. (c) Positive control – cutaneous viral plaque and in situ squamous cell carcinoma, cat: strong, diffuse, hybridisation signals are evident within keratinocyte nuclei in upper layers of the epidermis. (d) Positive control – mucosal papilloma, cat: dot-like signals are evident within the cell cytoplasm. (e) Tested sample – cutaneous diffuse basaloid follicular hamartomas, cat: absence of hybridisation signals. x200.

图3。猫乳头瘤病毒2 (FcaPV-2) E6和E7的原位杂交。(a)阴性对照正常皮肤、猫、细菌基因二氢二吡啶羧酸还原酶(dapB)作为阴性探针对照:杂交信号缺失。(b)阴性对照正常皮肤，猫:无杂交信号。(c)阳性对照皮肤病毒斑块和原位鳞状细胞癌，cat:在表皮上层角质形成细胞核内明显可见强烈的、弥漫性的、杂交信号。(d)阳性对照粘膜乳头状瘤，cat:细胞质内可见明显的点样信号。(e)检测样品皮肤弥漫性基底细胞样毛囊错构瘤，猫:缺乏杂交信号。x200。

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