Canine Noninflammatory Alopecia: A Comprehensive Evaluation of Common and Distinguishing Histological Characteristics
Canine Noninflammatory Alopecia: A Comprehensive Evaluation of Common and Distinguishing Histological Characteristics
Canine Noninflammatory Alopecia: A Comprehensive Evaluation of Common and Distinguishing Histological Characteristics
Background – Noninflammatory alopecia is a frequent problem in dogs, and the pathogenesis is still unclear.
Objective – The objective of this study was a comparative histological description of skin biopsies from dogs
with different alopecic disorders and control dogs matched for coat type, season and disease duration.
Animals – Twenty-one cases of alopecia X in plush-coated dogs, 12 cases of recurrent flank alopecia, three
cases of hyperestrogenism, 15 cases of hyperadrenocorticism, 12 cases of hypothyroidism and 12 cases of pri-
mary alopecic disorders of unknown cause were evaluated. The controls were biopsies from 38 dogs of different
coat types.
Methods – We evaluated five serial sections of each biopsy histologically and immunohistologically to compare
the histological findings within the disease groups and with the control.
Results – All the dogs with hair cycle disorders had a significant increase in the number of hairless hair follicles,
which we assigned to kenogen. In addition, dogs with alopecia X had the lowest percentage of anagen follicles
and the highest percentage of telogen follicles.
Conclusions – The marked increase in kenogen follicles is a strong indication that the induction of the new ana-
gen phase is impaired in hair cycle disorders. The findings in dogs with alopecia X further suggest that premature
catagen is also involved in the pathogenesis. Further work to investigate the stem cell compartment and possible
initiating factors for the different cycle phases is required to elucidate the exact pathogenesis.
Table 1. (Continued)
Case Coat Age Season Duration since
number Disease Breed type (years) Sex of biopsy onset of alopecia
68 Hypothyroidism Border collie 1 6 FS 3 1
69 Hypothyroidism American Staffordshire terrier 2 4 M 4 1
70 Hypothyroidism Rhodesian ridgeback 2 7 FS 1 2
71 Hypothyroidism Bergamasco shepherd 6 11.5 M 2 1
72 Hypothyroidism Pyrenean shepherd 6 8 M 4 4
73 Hypothyroidism Poodle 7 4 MC 2 4
74 Hypothyroidism Doberman 2 4 FS 2 —
75 Hypothyroidism Bearded collie 6 13 FS 2 —
76 Hypothyroidism Labrador retriever 1 10 M 3 1
Abbreviations: F, female; FS, female spayed; M, male; MC, male castrated; and RFA, recurrent flank alopecia. Coat types: 1, normal; 2, short fine;
3, long fine; 4, plush coated; 5, wire haired; 6, long, dense undercoat; and 7, anagen dominated. Duration since onset of alopecia: 1, up to
3 months; 2, 3–6 months; 3, 6–12 months; and 4, over 12 months. Season of biopsy: 1, spring (March–May); 2, summer (June–August); 3,
autumn (September–November); and 4, winter (December–February).
*Cases of alopecia X in plush-coated dogs that were previously characterized.15
†Case provided by Joan Rest (Focus – Veterinary Histopathology International).
compared with control dogs. The number of telogen folli- nization, follicular atrophy or follicular dystrophy was sig-
cles did not differ between control and alopecic dogs. The nificantly increased in alopecic dogs. In both control dogs
number of hair follicles with excessive trichilemmal kerati- (94.5%) and alopecic dogs (99.3%), the majority of the
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Müntener et al.
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2
3
1
2
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Figure 2. Representative photomicrographs of hair cycle stages. (a) Telogen follicle containing a hair shaft (thick arrow). Note the position of the
dermal papilla (arrow 1) directly adjacent to the club hair without trailing connective tissue sheath cells and situated at the border of subcutaneous
fat and dermis. The club hair is anchored in trichilemmal keratin, and no inner root sheath is present. (b) Multiple kenogen follicles (thick arrows).
These are also located in the dermis but do not contain hair shafts. (c) Two hair follicles in early anagen (thick arrows). While the right one is in ana-
gen I, with a thickened and prolonged keratinocyte strand between the dermal papilla and the club hair, the left one is in anagen II, characterized
by the partial enclosure of the dermal papilla by matrical cells. Arrow 1 indicates a secondary follicle in telogen. Note that the two early anagen folli-
cles still contain their old club hairs (arrow 2). (d) Several hair follicles in late anagen in which their dermal papillae have reached the deepest posi-
tion in the subcutaneous fat tissue and the hair shaft is well developed (thick arrows). (e) Example of a hair follicle in early catagen (thick arrow).
The follicle is still located deep in the subcutaneous fat tissue. Its dermal papilla is wide and has almost achieved the typical onion-shape of cat-
agen III (arrow 1). Note also the papillary stalk of fibroblasts between the dermal papilla and the connective tissue sheath (arrow 2). The neighbour-
ing follicle is in late anagen (arrow 3). (f) A hair follicle in late catagen (thick arrow). The hair shaft has developed into a club hair (arrow 1) and the
epithelial strand is well developed (arrow 2). Even though the follicle is still surrounded by subcutaneous fat tissue, its upward movement is obvi-
ous by the trailing connective tissue sheath cells (arrow 3). (g) Examples of tangential follicular sections, where it cannot be determined whether
they are in late anagen or early catagen (thick arrows). They are completely surrounded by subcutaneous fat tissue and contain a well-developed
hair shaft. (h) Examples of follicles for which the cycle stage was not determined (thick arrows). They are located in the dermis and thus cannot be
assigned to either anagen or catagen. In addition, tangential sections of telogen follicles, which can be recognized by the trichilemmal keratin sur-
rounding the hair shaft, can be seen (arrows 1). They could also be in late catagen, but as catagen is of short duration, the likelihood that they are
in telogen is much higher. Thus, they were counted as telogen with hair shaft. Also visible in this image are epithelial structures of kenogen follicles
(arrows 2). They are high up in the dermis and have no hair shaft. Haematoxylin and eosin stain; scale bars represent 100 lm.
atrophic follicles were in kenogen, with the remainder in disorder is presented in Table 5. As only three dogs with
telogen. hyperestrogenism were available, they were not included
Epidermal hyperkeratosis did not differentiate control in the statistical analyses. In dogs with alopecia X, the
dogs from dogs with hair cycle disorders. In contrast, number of telogen follicles with a hair was significantly
infundibular hyperkeratosis and follicular casts were sig- higher than in the control dogs and in dogs with other
nificantly more frequent in alopecic dogs. Epidermal alopecic disorders (although it was similar in the three dogs
pigmentation also differed between control and alopecic with hyperestrogenism). The percentage of anagen folli-
dogs. While multifocal mild epidermal pigmentation was cles was highest in dogs with recurrent flank alopecia or
significantly more common in control dogs, multifocal hypothyroidism, although it was significantly lower in
marked or diffuse hyperpigmentation was significantly alopecic dogs than in the control animals. The proportion of
more common in alopecic dogs. hair follicles with excessive trichilemmal keratinization in
dogs with hyperadrenocorticism was at least double that
Comparison between control dogs and dogs with in other alopecic dogs. Severe infundibular hyperkeratosis
specific alopecic disorders was most obvious in dogs with recurrent flank alopecia.
The comparison of the histological parameters between Epidermal pigmentation was significantly increased in
the control dogs and dogs assigned to a specific alopecic all alopecic disorders, but was most pronounced in
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Histology of canine noninflammatory alopecia
1 2
Figure 3. Representative photomicrographs of hair follicles displaying excessive trichilemmal keratinization, follicular atrophy or follicular dystro-
phy. (a) Example of a telogen follicle containing an excessive amount of trichilemmal keratin, which protrudes, flame like, into the outer root sheath
(thick arrow). Additionally, this follicle is dystrophic, with an abnormal shape and a thickened connective tissue sheath. Note also the extremely
large and misshapen dermal papilla (arrow 1). (b) Three examples of kenogen follicles with an excessive amount of trichilemmal keratin that pro-
trudes, flame like, into the outer root sheath (thick arrows). They have no hair shaft and are assigned to kenogen by the position of their dermal
papilla (border pf subcutis and dermis) as well as the absence of trailing connective tissue sheath cells, which would categorize them as catagen.
Arrow 1 indicates a telogen follicle that contains a hair shaft. (c) Examples of atrophic kenogen follicles, at most two cell layers across (thick
arrows). (d) Cross-sections of atrophic telogen follicles (thick arrows). Note the adjacent kenogen follicles of normal size, characterized by the pres-
ence of trichilemmal keratin but no hair (arrows 1). (e) Atrophic kenogen follicles (arrows 1) as well as a mildly dystrophic kenogen follicle with
abnormal shape and a thickened connective tissue sheath (arrows 2). The absence of a hair shaft was confirmed by serial sections. (f) Example of
a dystrophic kenogen follicle displaying a bizarre shape and a thickened connective tissue sheath (thick arrow). Haematoxylin and eosin stain. Scale
bars represent 100 lm.
dogs with recurrent flank alopecia and in the three parameters and the dermal thickness (Table 6). There
dogs with hyperestrogenism. Epidermal thickness, der- were few histological differences that discriminated
mal thickness and size of the sebaceous glands were between the different diseases. Dogs with alopecia X
not significantly decreased in dogs with hyperadreno- had significantly fewer anagen follicles (early and late
corticism in comparison to the other alopecic condi- anagen) and significantly more telogen follicles contain-
tions. However, the dermis was significantly thinner in ing a hair than dogs with other hair cycle disorders.
dogs with alopecia X and significantly thicker in dogs Another consistent finding was that dogs with hypo-
with hypothyroidism. More dogs with hypothyroidism thyroidism had a significantly thicker dermis. Dogs with
had dermal inflammation, but the difference was not recurrent flank alopecia had a significantly lower num-
significant. ber of telogen follicles containing a hair than dogs with
alopecic disorders of unknown cause, hyperadreno-
Comparison between the specific alopecic disorders corticism and hypothyroidism. Excessive trichilemmal
When comparing the specific hair cycle disorders, we keratinization was significantly less common in dogs
statistically evaluated only the hair cycle-specific with hypothyroidism than in dogs with alopecia X or
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Figure 4. Photomicrographs of follicles with variable infundibular hyperkeratosis. (a) Normal follicular infundibulum, which is not dilated and con-
tains a normal amount of infundibular keratin (thick arrow). (b) Mild infundibular hyperkeratosis (thick arrows). (c) Moderate infundibular hyperkera-
tosis (thick arrows). (d) Severe infundibular hyperkeratosis (thick arrow). (e) Example of a follicular infundibulum typically seen in cases of
recurrent flank alopecia (thick arrow). In addition to the severe infundibular hyperkeratosis, the infundibulum is pear shaped (wider at the bottom
than at the top) and the infundibular keratin extends into the lumina of the secondary hair follicles (arrows 1). (f) Comedone, characterized by an
extremely dilated infundibulum filled with keratin (thick arrow). Haematoxylin and eosin stain. Scale bars represent 100 lm.
hyperadrenocorticism. Dogs with alopecic disorders of alopecia showed significantly more (P < 0.05) multifocal
unknown cause and hyperadrenocorticism had a signi- marked or diffuse hyperpigmentation than dogs with
ficantly increased percentage of atrophic follicles in alopecia X.
comparison to dogs with recurrent flank alopecia or There were no significant differences in epidermal
hypothyroidism. thickness between dogs with the alopecic disorders and
Plush-coated dogs with alopecia X had significantly control dogs. However, the category of three or more
greater density of hair follicles (10 follicles ⁄ mm; P < 0.05) epidermal layers was significantly more common
than all the other disease groups except hypothyroidism. (P < 0.05) in dogs with recurrent flank alopecia and
The other disease groups consisted predominantly of hypothyroidism than in dogs with alopecia X, and it was
dogs with other coat types and had on average 4.2– also significantly more common in dogs with hypo-
5.8 follicles ⁄ mm of epidermal width, which is a similar thyroidism than in those with hyperadrenocorticism
density to the control dogs. (P < 0.05).
Dogs with alopecia X showed significantly more
(P < 0.05) multifocal mild epidermal pigmentation than Comparison of hair cycle parameters between
dogs with recurrent flank alopecia and hypothyroidism, control dogs of different coat types
and dogs with hyperadrenocorticism had more than those We were not able to compare data from plush-coated
with recurrent flank alopecia. Dogs with recurrent flank dogs, long-haired dogs and dogs with anagen-dominated
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(a)
(b)
(a) (b)
(c) (d)
Figure 7. Photomicrographs showing the grading applied to sebaceous glands. (a) and (b) The variability in sebaceous gland size in the control
dogs. Even though they may be small and inconspicuous, they are usually present with every follicular complex (thick arrows). (c) Examples of
atrophic sebaceous glands (thick arrows). In addition to being very small and inconspicuous, they are missing from most follicular complexes (see
the follicular complex on the right side of the picture). (d) Example of hyperplastic sebaceous glands in a dog with recurrent flank alopecia showing
a marked increase of follicular lobuli dispersed around the follicular complex (thick arrows). Haematoxylin and eosin stain. Scale bars represent
100 lm.
yield any clear trends, except for dogs with cyclical flank winter had significantly fewer anagen (specifically late
alopecia, in which the percentage of telogen follicles anagen) follicles, but there were no other significant
decreased and the percentage of anagen follicles findings.
increased with disease duration.
Comparison of hair cycle stages and histological
Comparison of hair cycle stages and histological parameters with age and sex
parameters with time of sampling In dogs with alopecia X, neutered female dogs had signi-
Analysis was only possible between biopsies taken ficantly fewer telogen follicles and significantly more
in the autumn (September–November) and winter kenogen and atrophic follicles than male dogs. No other
(December–February) because too few dogs were significant findings were observed in the alopecic or
sampled at other times of the year. Biopsies taken in control groups.
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Histology of canine noninflammatory alopecia
Table 3. Percentage distribution of different hair cycle stages and other histological parameters and their statistical significance in alopecic disor-
ders
Alopecia Recurrent
Control All alopecic X-like flank Hyperoestro- Hyperadreno- Hypo-
dogs cases Alopecia disease alopecia genism corticism thyroidism
(n = 38) (n = 76) X (n = 21) (n = 13) (n = 12) (n = 3) (n = 15) (n = 12)
Dermis (mm)† 1.09 0.99 0.65** 0.92 1.12 0.87 1 1.55**
ND total (%) 27.22 17.54** 23.54 18.35* 12.43** 19.72 10.14** 19.97*
ND with hair (%) 25.73 12.33** 14.55** 14.55* 7.77** 17.18 7.71** 15.14*
ND without hair (%) 1.49 5.2* 8.94* 3.8* 4.66* 2.53 2.44 4.83*
Tel with hair (%) 16.54 18.65 31.23** 16.47 4.2** 31.5 15.27 14.45
Kenogen (%) 14.01 54.2** 42.59** 54.73** 66.23** 43.35 64.98** 51.17**
Ana total (%) 39.85 5.79** 0.81** 4.56** 12.61** 2.55 6.08** 9.48**
Ana ND (%) 0.1 0.1 0.08 0 0.48 0 0 0.03
Ana early (%) 8.59 3.08** 0.28** 2.49** 6.78 1.12 2.69** 5.93*
Ana late (%) 31.16 2.61** 0.45** 2.07** 5.35** 1.43 3.4** 3.52**
Ana-Cat (%) 0 3.5** 1.8** 5.52** 4.16** 2.87 3.21** 4.15**
Cat total (%) 2.37 0.33** 0.07** 0.38* 0.37** 0 0.31** 0.78*
Cat early (%) 0.77 0.1** 0** 0.08* 0.22* 0 0* 0.32
Cat late (%) 1.63 0.23** 0.07** 0.3* 0.15* 0 0.31* 0.46*
ETK (%) 0.6 8.57** 9.3** 6.56* 4.47* 7.17 17.49** 2.79
FA (%) 5.31 20.02** 19.05* 27.24** 12.42 10.7 28.24** 13.49
DF (%) 0.33 10.18** 6.96** 12.72** 5.74** 10.2 16** 9.94**
Abbreviations: Ana, anagen; Ana-Cat, not determinable if late anagen or early catagen; Cat, catagen; DF, dystrophic follicles (the given percentage
applies to the total number of assessed hair follicles); ETK, excessive trichilemmal keratinization (the given percentage applies to the total number
of assessed hair follicles); FA, follicular atrophy (the given percentage applies to telogen without hair follicles); ND, not determinable; and Tel, telo-
gen. No statistical significance is indicated for cases of hyperestrogenism due to the small group size (three dogs).
*P < 0.05, **P < 0.001, statistically significant difference from control group.
†The values given are mean values of the dermis thickness of all dogs in the respective group.
C A C A C A C A C A C A C A
(n = 8) (n = 6) (n = 8) (n = 13) (n = 13) (n = 10) (n = 1) (n = 23) (n = 8) (n = 8) (n = 0) (n = 10) (n = 0) (n = 5)
Dermis (mm)‡‡ 1.31§ 1.36 1.25** 1.3 1.05†† 0.75† 1.11 0.64 0.76§**†† 1.1† — 1.28 — 1.04
ND total (%) 24.93 15.89 26.84 14.85† 25.5 18.19 25.85 22.31 32.86 9.82* — 16 — 20.02
ND with hair (%) 23.46 11.86† 25.36 8.97† 23.83 13.79† 24.95 13.86 31.56 8.04* — 14.15 — 15.1
ND without hair (%) 1.46 4.03† 1.48 5.88 1.67 4.4† 0.9 8.4 1.31 1.78 — 1.85 — 4.92
Tel with hair (%) 20.73‡§ 16.67 24.14 14.47 11.9‡ 12.37 11.6 30.14 12.93§ 12.42 — 17.6 — 7.34
Kenogen (%) 12.15 49.6* 12.68 60.14* 15.91 59.83* 31.25 44.51 11.98 65.99* — 55.96 — 51.18
Ana total (%) 40.02 13.31† 33.3 7.5* 45.43 5.7* 29.5 1.13 38.45 8.14* — 6.75 — 7.65
Ana ND (%) 0.46 0.05 0 0.28 0 0 0 0.07 0 0.25 — 0 — 0
Ana early (%) 8.46 7.05 12.58¶ 5.88† 6.38¶ 1.97† 8.05 0.26 8.4 4.7 — 3.27 — 2.47
Ana late (%) 31.11 6.2† 20.72¶ 1.33† 39.05¶ 3.73* 21.45 0.8 30.05 3.19* — 3.48 — 5.18
Ana-Cat (%) 0 3.24† 0 2.64† 0 3.8† 0 1.8 0 3.64† — 3.49 — 12.68
Cat total (%) 2.18 1.3 3.04 0.39† 1.25†† 0.11† 1.8 0.14 3.79†† 0* — 0.2 — 1.12
Cat early (%) 0.69 0.28 0.33** 0.08 0.35†† 0.11 0.9 0 1.96**†† 0† — 0.2 — 0.34
Cat late (%) 1.49 1.03 2.72 0.31† 0.98 0† 0.9 0.14 1.83 0† — 0 — 0.78
ETK (%) 0.89 3.13 0 5.53* 0.85 8.67† 0.9 11.46 0.46 8.33† — 10.84 — 7.09
FA (%) 3.89 16.61 3.13 13.86 8.45 30.82* 8.95 18.95 3.34 15.5 — 23.82 — 20.71
DF (%) 0.46 7.45† 0 8.93* 0.35 14.3* 0.9 8.32 0.44 11.32† — 15.71 — 5.42
Abbreviations: A, alopecic; Ana, anagen; Ana-Cat, not determinable if late anagen or early catagen; Cat, catagen; C, Controls; DF, dystrophic follicles (the given percentage applies to the total number of assessed hair
follicles); ETK, excessive trichilemmal keratinization (the given percentage applies to the total number of assessed hair follicles); FA, follicular atrophy (the given percentage applies to telogen without hair follicles); ND,
not determinable; and Tel, telogen. Examples of coat types: normal, German shepherd; short, fine, boxer; long, fine, Bernese mountain dog; plush coated, Pomeranian; wire haired, Airedale terrier; long, dense under-
coat, Bergamasco shepherd; and anagen dominated, poodle.
*Statistically significant difference from control group of same coat type, P < 0.001.
†Statistically significant difference from control group of same coat type, P < 0.05.
‡Statistically significant difference between coat type normal versus long, fine, P < 0.05.
§Statistically significant difference between coat type normal versus wire-haired, P < 0.05.
¶Statistically significant difference between coat type short, fine versus long, fine, P < 0.05.
**Statistically significant difference between coat type short, fine versus wire-haired, P < 0.05.
††Statistically significant difference between coat type long, fine versus wire-haired, P < 0.05.
For the plush-coated breeds, no statistical significance is indicated owing to the small number of control dogs (n = 1). For the breeds with long hair and dense undercoat and the anagen-dominated dogs, no statistical
significance can be indicated owing to the absence of controls.
‡‡The given values are mean values of the dermis thickness of all dogs in the respective group.
217
Histology of canine noninflammatory alopecia
218
Table 6. Statistical comparison of different hair cycle disorders in regard to different hair cycle stages and other histological parameters
Alopecia
Alopecia X versus Alopecia Alopecia Alopecia X-like Alopecia X-like Recurrent flank Hyperadreno-
Müntener et al.
X versus recurrent X versus X versus disease versus disease versus Alopecia X-like alopecia versus Recurrent flank corticism
Alopecia X-like flank hyperadre- hypo- recurrent flank hyperadreno- disease versus hyperadreno- alopecia versus versus hypo-
disease alopecia nocorticism thyroidism alopecia corticism hypothyroidism corticism hypothyroidism thyroidism
Dermis (mm)† n.s. S** (0.7 S* (0.7 S** (0.7 n.s. n.s. S* (0.9 versus 1.6) n.s. S* (1.1 S* (1 versus 1.6)
versus 1.1) versus 1) versus 1.55) versus 1.6)
ND total (%) n.s. S* (23.5 S** (23.5 n.s. n.s. S* (18.4 versus 10.1) n.s. n.s. S* (12.4 S* (10.1 versus 20)
versus 12.4) versus 10.1) versus 20)
ND with hair (%) n.s. S* (14.6 S* (14.6 n.s. n.s. S* (14.6 versus 7.7) n.s. n.s. S* (7.8 S* (7.7 versus 15.1)
versus 7.8) versus 7.7) versus 15.1)
ND without hair (%) n.s. n.s. S* (8.9 n.s. n.s. n.s. n.s. n.s. n.s. n.s.
versus 2.44)
Tel with hair (%) S* (31.2 S** (31.2 S* (31.2 S* (31.2 S* (16.5 n.s. n.s. S* (4.2 versus S* (4.2 n.s.
versus 16.5) versus 4.2) versus 15.3) versus 15.4) versus 4.2) 15.3) versus 14.5)
Kenogen (%) n.s. S** (42.6 S** (42.6 n.s. n.s. n.s. n.s. n.s. n.s. n.s.
versus 66.2) versus 65)
Ana total (%) S** (0.8 S* (0.8 S** (0.8 S** (0.8 n.s. n.s. n.s. n.s. n.s. n.s.
versus 4.6) versus 12.6) versus 6.1) versus 9.5)
Ana ND (%) n.s. n.s. n.s. n.s. n.s. — n.s. n.s. n.s. n.s.
Ana early (%) S* (0.3 S* (0.3 S* (0.3 S** (0.3 n.s. n.s. n.s. n.s. n.s. n.s.
versus 2.5) versus 6.8) versus 2.7) versus 5.9)
Ana late (%) S** (0.5 S* (0.5 S* (0.5 S* (0.5 n.s. n.s. n.s. n.s. n.s. n.s.
versus 2) versus 5.4) versus 3.4) versus 3.5)
Ana-Cat (%) n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s.
Cat total (%) n.s. n.s. n.s. S* (0.1 n.s. n.s. n.s. n.s. n.s. n.s.
versus 0.8)
Cat early (%) n.s. n.s. n.s. S* (0 n.s. n.s. n.s. n.s. n.s. S* (0 versus 0.3)
versus 0.3)
Cat late (%) n.s. n.s. n.s. S* (0.1 n.s. n.s. n.s. n.s. n.s. n.s.
versus 0.5)
ETK (%) n.s. n.s. n.s. S* (9.3 n.s. n.s. n.s. n.s. n.s. S* (17.5 versus 2.8)
versus 2.8)
FA (%) n.s. n.s. n.s. n.s. S* (27.2 n.s. S* (27.2 S* (12.4 versus 28.2) n.s. S* (28.2 versus 13.5)
versus 12.4) versus 13.5)
DF (%) n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s.
Abbreviations: alopecia X like, alopecia of unknown cause in nonplush-coated breeds; Ana, anagen; Ana-Cat, not determinable if late anagen or early catagen; Cat, catagen; DF, dystrophic follicles (the given percent-
age applies to the total number of assessed hair follicles); ETK, excessive trichilemmal keratinization (the given percentage applies to the total number of assessed hair follicles); FA, follicular atrophy (the given per-
centage applies to telogen without hair follicles); ND, not determinable; n.s., no statistically significant difference; S, statistically significant difference; and Tel, telogen. No statistical significance is indicated for cases
of hyperestrogenism owing to the small group size (three dogs).
*P < 0.05, **P < 0.001.
†The given values are mean values of the dermis thickness of all dogs in the respective group.
Table 7. Percentage distribution of different hair cycle stages and larity between dogs with alopecia X and hyperestroge-
other histological parameters and their statistical significance in nism may involve the estrogen receptor, which inhibits
alopecic dogs in regard to disease duration
anagen and has been investigated in alopecia X.4,25,26
Duration Duration Duration Duration Our findings in alopecia X in plush-coated breeds
up to 3–6 6–12 over were similar to those previously reported, and included
3 months months months 12 months
hyperkeratosis, follicular keratosis, excessive trichilem-
(n = 14) (n = 11) (n = 12) (n = 20)
mal keratinization, epidermal atrophy, few small anagen
Dermis (mm)‡ 1.22* 1.11 0.77* 0.88 bulbs, epidermal hyperpigmentation, melanin aggregates
ND total (%) 17.3 16.62 19.48 22.15
within follicular keratin, follicular atrophy and more telo-
ND with hair (%) 12.67 11.03 14.08 14.18
ND without hair (%) 4.63 5.59 5.4 7.92
gen follicles, with most telogen follicles retaining their
Tel with hair (%) 18.1 19.18 24.43 21.69 hair shaft.1,15,16 We also found a thinner dermis, but this
Kenogen (%) 57.66 54.31 52.39 45.08 should be interpreted with caution because the apparent
Ana total (%) 4.66* 5.8 1.78* 6.11 thickness of the dermis depends on how vertically the
Ana ND (%) 0.02 0.34 0 0.09 biopsy is cut.
Ana early (%) 2.14 3.56 0.96 2.57 Dogs with hypothyroidism had a significantly thicker
Ana late (%) 2.51 1.9 0.82† 3.45†
epidermis and dermis than the control animals and other
Ana-Cat (%) 1.77 3.59 1.77 4.77
Cat total (%) 0.5 0.5 0.16 0.25
disease groups, and fewer atrophic follicles than the
Cat early (%) 0.2 0.1 0 0.1 other disease groups. Thus, even accounting for variation
Cat late (%) 0.3 0.4 0.16 0.15 in dermal thickness by biopsy location or orientation,
ETK (%) 11.89 6.66 12.22† 7.02† these criteria could help differentiate hypothyroidism. It
FA (%) 20.01 16.56 18.92 17.45 has been reported that telogen follicles, often hairless,
DF (%) 13.28 8.44 7.56 6.76 predominate in hypothyroidism,8,23 whereas we found
Abbreviations: Ana, anagen; Ana-Cat, not determinable if late anagen that kenogen rather than telogen follicles were most fre-
or early catagen; Cat, catagen; DF, dystrophic follicles (the given per- quently associated with all the alopecic disorders. Thyroid
centage applies to the total number of assessed hair follicles); ETK, hormones prolong anagen duration in humans,27 and
excessive trichilemmal keratinization (the given percentage applies
dermal papilla fibroblasts are a direct target of thyroid-
to the total number of assessed hair follicles); FA, follicular atrophy
(the given percentage applies to telogen without hair follicles); ND, stimulating hormone.28 Experimentally, hypothyroid bea-
not determinable; and Tel, telogen. There are no statistically signifi- gles exhibit fewer hair shafts in the follicles and a failure
cant differences between duration groups ‘up to 3 months’ and to initiate anagen, which was corrected by thyroid hor-
‘3–6 months’, as well as between groups ‘up to 3 months’ and ‘over mone replacement therapy.8
12 months’, ‘3–6 months’ and ‘6–12 months’, and ‘3–6 months’ and Recurrent flank alopecia has been associated with the
‘over 12 months’.
following characteristics: follicular atrophy and infundibu-
*Statistically significant difference between duration groups ‘up to
3 months’ and ‘6–12 months’, P < 0.05.
lar hyperkeratosis, with keratin extending into the opening
†Statistically significant difference between duration groups ‘6–12’ of primary and secondary follicles; occasional distorted
and ‘over 12 months’, P < 0.05. follicles; telogen follicles narrowed to a thin cord of cells;
‡The values given are mean values of the dermis thickness of all pigmentation of the epidermis, outer root sheath and
dogs in the respective group. sebaceous glands; and pigmentary incontinence around
the deep hair follicle.6,29 In our cases, recurrent flank alo-
trichilemmal keratin at the level of the sebaceous glands pecia was mainly distinguished by marked infundibular
or above, rather than catagen. Serial sections were very hyperkeratosis, rare telogen follicles, frequent kenogen
helpful for the allocation of the stages, as reported else- and atrophic follicles, and epidermal hyperplasia and pig-
where.16 Moreover, our finding that telogen follicles were mentation. Pear-shaped severe infundibular hyperkerato-
no more frequent in alopecic dogs than in control dogs, sis, with keratin extending into the openings follicle of the
with the exception of alopecia X and hyperestrogenism, secondary follicles (Figure 4e), appeared to be character-
supports our criteria. Otherwise, an increased number of istic of recurrent flank alopecia and was rare in other alo-
catagen follicles should result in an increased number of pecic conditions. The number of anagen follicles was
telogen follicles, because catagen inevitably progresses higher than in the other alopecic diseases, which is possi-
into telogen. bly associated with the recurrent nature of the disease,
We could not reliably distinguish histologically between although the frequency of the different follicular stages
the different alopecic disorders. Alopecia X was associ- may differ when the alopecia is developing or resolving.
ated with fewer anagen and kenogen follicles (although Hyperadrenocorticism is reported to have predomi-
they were still three times more frequent than in the nance of hairless, atrophic telogen follicles,1 with atrophic
control dogs) and more telogen follicles than the other sebaceous glands, epidermis and infundibular epithe-
conditions. A similar picture was seen in dogs with hyper- lium.23 Comedones and calcinosis cutis are not always
estrogenism, but more dogs need to be studied to con- present but are typical.1,4 We saw the hairless (kenogen)
firm this. These and other findings suggest that catagen follicles, which were often atrophic, as well as a moder-
is induced prematurely,14 resulting in fewer anagen and ate to severe infundibular hyperkeratosis, but atrophy of
more telogen follicles. We did not see more catagen folli- the epidermis, dermis and sebaceous glands was not
cles, but this might be due to the short duration of cat- clearly reflected in our cases. Most of the dogs we evalu-
agen. It is also possible that these findings are normal for ated, with the exception of those with hyperestrogenism
plush-coated breeds, because a comparison with healthy or hypothyroidism, had a thin epidermis, but we could not
plush-coated dogs was not performed. The possible simi- easily differentiate sebaceous glands in affected dogs
ª 2012 The Authors. Veterinary Dermatology
ª 2012 ESVD and ACVD, Veterinary Dermatology, 23, 206–e44. 219
Müntener et al.
from those in the control dogs. We assessed the seba- 4. Frank LA. Comparative dermatology – canine endocrine derma-
ceous glands as normal if they were present with most toses. Clin Dermatol 2006; 24: 317–325.
5. Scott-Moncrieff JCR, Guptill-Yoran L. Hypothyroidism. In:
follicular complexes, even if small and inconspicuous. We
Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal
regarded them as atrophic if they were missing from Medicine, 6th edn. St Louis, MO: Elsevier-Saunders, 2005;
most complexes, with the remaining ones small and 1535–1544.
inconspicuous. This strict definition may reflect the differ- 6. Gross TL, Ihrke PJ, Walder EJ et al. Dysplastic diseases of the
ences from the reported findings. Glucocorticoids induce adnexa. In: Skin Diseases of the Dog and Cat. Clinical and Histo-
catagen in mice.30 In addition, human hair follicles display pathologic Diagnosis, 2nd edn. Oxford: Blackwell, 2005; 518–
a functional equivalent of the hypothalamic–pituitary– 536.
7. Daminet S, Paradis M. Evaluation of thyroid function in dogs suf-
adrenal axis and synthesize cortisol upon stimulation
fering from recurrent flank alopecia. Can Vet J 2000; 41: 699–
by adrenocorticotrophic hormone and corticotrophin- 703.
releasing hormone.31 Corticotrophin-releasing hormone 8. Credille KM, Slater MR, Moriello KA et al. The effects of thyroid
inhibits hair shaft elongation and hair keratinocyte prolifer- hormones on the skin of beagle dogs. J Vet Intern Med 2001;
ation, and stimulates catagen induction and hair keratino- 15: 539–546.
cyte apoptosis.31 The number of catagen follicles was 9. Rothstein E, Scott DW, Miller WH Jr et al. A retrospective study
not, however, increased compared with biopsies from of dysplastic hair follicles and abnormal melanization in dogs with
follicular dysplasia syndromes or endocrine skin diseases. Vet
control dogss or from dogs with other alopecic disorders,
Dermatol 1998; 9: 235–241.
and the effects of cortisol, adrenocorticotrophic hormone 10. Milner Y, Sudnik J, Filippi M et al. Exogen, shedding phase of
and corticotrophin-releasing hormone in dogs need fur- the hair growth cycle: characterization of a mouse model. J In-
ther study. vestig Dermatol 2002; 119: 639–644.
The control dogs with a normal coat had significantly 11. Stenn K. Exogen is an active, separately controlled phase of the
more telogen follicles than dogs with long and fine or hair growth cycle. J Am Acad Dermatol 2005; 52: 374–375.
12. Higgins CA, Westgate GE, Jahoda CAB. From telogen to exo-
wire-haired coats. In addition, dogs with long, fine hair
gen: mechanisms underlying formation and subsequent loss of
had more follicles in late anagen. As late anagen is the the hair club fiber. J Investig Dermatol 2009; 129: 2100–2108.
phase of continued hair growth, this seems to reflect the 13. Rebora A, Guarrera M. Kenogen, a new phase of the hair cycle?
coat type. In winter, irrespective of the coat type, dogs Dermatology 2002; 205: 108–110.
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cles in comparison to biopsies taken in the autumn. This non-inflammatory alopecia in dogs. Proceedings of the 22nd
finding reflects the longer coat during winter and the need Annual Congress of ESVD-ECVD, Mainz, 2007; 25–32.
15. Frank LA, Donnell RL, Kania SA. Oestrogen receptor evaluation
to save energy at this time of the year.
in Pomeranian dogs with hair cycle arrest (alopecia X) on melato-
In summary, all the hair cycle disorders in this study nin supplementation. Vet Dermatol 2006; 17: 252–258.
were associated with an increase in the prevalence of 16. Müntener T, Doherr MG, Guscetti F et al. The canine hair cycle –
kenogen follicles, which were often atrophic. This indi- a guide for the assessment of morphological and immunohisto-
cates that induction of new anagen growth is impaired. chemical criteria. Vet Dermatol 2011; 22: 383–395.
Only dogs with alopecia X or hyperestrogenism differed; 17. Sinclair R. Male pattern alopecia. BMJ 1998; 317: 865–869.
they showed the lowest percentage of anagen follicles 18. Rebora A, Guarrera M. Teloptosis and kenogen: two new con-
cepts in human trichology. Arch Dermatol 2004; 140: 619–
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21. Kobayashi T, Shimizu A, Nishifuji K et al. Canine hair-follicle
Acknowledgements keratinocytes enriched with bulge cells have the highly prolifera-
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We thank all the submitting veterinarians for the addi- 346.
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Résumé
Contexte – L’alopécie non-inflammatoire chez le chien est un problème fréquent dont la pathogénie reste
obscure.
Objectif – L’objectif de cette étude est de réaliser une description histopathologique comparative de biop-
sies cutanées de chiens atteints de différentes alopécies et de chiens contrôles associés en fonction du
type de leur pelage, de la saison et de la durée de la maladie.
Animaux – Vingt et un cas d’alopécie X chez des chiens à pelage pelucheux, 12 cas d’alopécie récidivante
des flancs, 3 cas d’hyperoestrogénisme, 15 cas d’hyperadrénocorticisme, 12 cas d’hypothyroı̈die et 12 cas
d’alopécies primaires de cause inconnue ont été évalués. Les contrôles étaient des biopsies de 38 chiens
de différents types de pelage.
Méthodes – Nous avons évalués cinq séries de chaque biopsie d’un point de vue histopathologique et
immunohistologique afin de comparer les résultats histologiques entre les groupes de maladie et les con-
trôles.
Résultats – Tous les chiens atteints de troubles du cycle pilaire avaient une augmentation significative du
nombre de follicule pileux sans poils, que nous avons identifié comme kénogène. De plus, les chiens
atteints d’alopécie X avaient un pourcentage plus faible de follicules anagènes et le pourcentage le plus
élevé de follicules en phase télogène.
Conclusions – L’augmentation marquée des follicules kénogènes constitue une forte indication que
l’induction de la nouvelle phase anagène est altérée dans les troubles du cycle pilaire. Les résultats obte-
nus chez les chiens atteints d’alopécie X suggèrent en outre que la phase catagène prématurée est égale-
ment impliquée dans la pathogénie. Un approfondissement des études sur le compartiment des cellules
souches et les possibles facteurs responsables pour les différentes phases du cycle est nécessaire afin
d’en élucider la pathogénie exacte.
Resumen
Introducción – la alopecia no-inflamatoria es un problema frecuente en perros y la patogenia sigue siendo
confusa.
Objetivo – El objetivo de este estudio era una descripción histológica comparativa de las biopsias de piel
de perros con diversos desórdenes alopécicos y perros control apareados por capa similar, por muestras
en la misma estación y por duración de la enfermedad.
Animales – Se evaluaron veintiún casos de alopecia X en perros con capa de pelo densa, 12 casos de alo-
pecia recurrente del flanco, 3 casos de hiperestrogenismo, 15 casos de hiperadrenocorticismo, 12 casos
de hipotiroidismo, y 12 casos de desórdenes alopécicos primarios de causa desconocida. Los controles
fueron biopsias tomadas de 38 perros con diversos tipos de capa.
Métodos – Evaluamos cinco secciones seriadas de cada biopsia por histologı́a e inmunohistologı́a para
comparar los resultados histológicos dentro de los grupos de enfermedad y control.
Resultados – Todos los perros con desórdenes del ciclo del pelo tenı́an un aumento significativo en el
número de folı́culos pilosos sin pelo, que asignamos a la fase quenógena. Además, los perros con la alope-
cia X tenı́an el porcentaje más bajo de folı́culos pilosos en fase anágena y el porcentaje más alto de los folı́-
culos en fase telógena.
Conclusiones – El aumento marcado en folı́culos en fase quenógena es indicativo de que la inducción de
la nueva fase anágena en el pelo está deteriorada en desórdenes del ciclo folicular. Los resultados en per-
ros con la alopecia X sugieren además que una fase catágena prematura está implicada en la patogénesis.
Para aclarar la patogenia de estos desordenes se necesitan nuevos estudios que investiguen el comparti-
mento de células madre y los factores que inician las diversas fases del ciclo folicular.
Zusammenfassung
Hintergrund – Eine nicht entzündliche Alopezie ist ein häufiges Problem bei Hunden, wobei die Pathoge-
nese noch immer unklar ist.
Ziele – Das Ziel dieser Studie war eine vergleichende histologische Beschreibung von Hautbiopsien von
Hunden mit unterschiedlichen alopezischen Erkrankungen und Kontrollhunden, die bezüglich Felltyp,
Jahreszeit und Dauer der Erkrankung mit den Patienten abgestimmt waren.
Tiere – Einundzwanzig Fälle von Alopezia X bei Hunden mit einem Plüschfell, 12 Fälle von wiederkehrender
Flankenalopezie, 3 Fälle von Hyperöstrogenismus, 15 Fälle von Hyperadrenocortizismus, 12 Fälle einer
Hypothyreose und 12 Fälle einer primären alopezischen Erkrankung unbekannter Ursache wurden eva-
luiert. Die Kontrollproben kamen von 38 Hunden mit unterschiedlichen Haarkleidtypen.
Methoden – Wir untersuchten fünf aufeinander folgende Schnitte einer jeden Biopsie histologisch und
immunhistologisch, um die histologischen Befunde innerhalb der Gruppen mit unterschiedlichem Kran-
kheitsbild und den Kontrollen zu vergleichen.
Ergebnisse – Alle Hunde mit Erkrankungen des Wachstumszyklus der Haare zeigten eine signifikante
Zunahme der Anzahl der haarlosen Haarfollikel, was wir als kenogen bezeichneten. Zusätzlich hatten
Hunde mit Alopezia X den niedrigsten Prozentsatz an anagenen Haarfollikeln und den höchsten Prozent-
satz an telogenen Follikeln.
Schlussfolgerung – Die deutliche Zunahme an kenogenen Follikeln ist ein deutlicher Hinweis darauf, dass
die Induktion der neuen anagenen Phase bei Fehlsteuerungen des Haarzyklus beeinträchtigt ist. Die Ergeb-
nisse bei Hunden mit Alopezia X weisen weiters darauf hin, dass eine frühzeitige Katagen-Phase in der
Pathogenese ebenfalls eine Rolle spielt. Weitere Studien sollten Stammzellen und mögliche Auslösefakto-
ren für die verschiedenen Zyklusphasen untersuchen, um die genaue Pathogenese aufzuklären.