Pathologic Patterns of the Sebaceous Gland*

Pathologic Patterns of the Sebaceous Gland*

PATHOLOGIC PATTERNS OF THE SEBACEOUS GLAND* JOHN S. STRAUSS, M.D.t AND ALBERT M. KLIGMAN, M.D. By studying the way in which a structure cells which s...

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PATHOLOGIC PATTERNS OF THE SEBACEOUS GLAND* JOHN S. STRAUSS, M.D.t AND ALBERT M. KLIGMAN, M.D.

By studying the way in which a structure cells which subsequently rupture in the fundus reacts to an imposed experimental stress, one can often better understand the changes exhibited in spontaneous dlsease. Much has been learned about the potentialities of the eccrine

of the gland. Fragments of the thin eosinophilie cell wall, which morphologically resemble keratin, persist in the sebum; occasionally the entire cell walls survive as ghosts. Furthermore, the inand apocrine sweat units in this fashion (1—12). dividual oil droplets are separated by keratinPrevious study of the response to injury in the like trabeculae. A dual potentiality is exhibited sebaceous gland has been restricted mainly to the by sebaceous cells in their capacity to produce changes that occur in the sebaceous duct per se fat predominantly and keratin to a minor de(13). In this study we have followed the reac- gree. Epidermal cells have this bipotentiality tion of the sebaceous gland itself to a variety of with keratin as the major product. cutaneous insults and have correlated the findings MA.TERIALS AND METRODS with those which occur in disease states. The scalp and cheek of post-puberal individuals

MOBPOLOGY AND FUNCTION OF

TRN SEACEOUS GLAND 1. Morphology: The glands of the glabrous skin are not free but are associated with hair follicles, a combination recognized as the pilosebaceous unit. In terminal hair follicles which bear coarse hairs, as on the scalp and beard, the gland is the

minor component of the unit, actually an appendage of the follicle. By contrast, the sebaceous

glands of vellus hair follicles are proportionally

larger. Indeed, the vellus hair follicles of the glabrous skin of the face are truly sebaceous follicles in which the hair has been reduced to an inconspicuous appendage of an extraordinarily large sebaceous gland. These differences must be

were selected for study because the glands here are among the largest and most numerous. Biopsy specimens were obtained before the experimental stresses as well as at varying intervals afterwards. All specimens were serially sectioned and stained with hematoxylin and eosin. The experimental stresses were as follows: 1. Contact dermatitis: (a) A moderate primary irritant dermatitis was produced by painting the cheek daily with benzene for one month. (b) Severe allergic contact dermatitis of the cheek was produced by applying 0.25 ml. of 0.1% acetone solutions of dinitrochlorobenzene and pentadecyl catechol to sensitive skins. inch 2. Occlusion with adhesive tape: A

pointed out because this study has focused square area of the cheek was kept constantly primarily upon the sebaceous follicles of the face. covered with plastic adhesive tape for six to 2. Function: (14) The sebaceous gland is a eight weeks. 3. Plucking: All of the scalp hairs within a holocrine organ. Sebum is excreted through the steady casting off of cells, a process of continuous half inch area were epilated manually with a growth. The division of relatively undifferentiated basal cells is followed by progressive trans-

forceps; only those individuals in whom complete extraction was possible were used.

formation into mature fat-ladened sebaceous

4. Puncture: In the scalp and on the cheek, multiple punctures through the follicular wall,

* From the Department of Dermatology (Donald M. Pillsbury, M.D., Director), University of and probably through the gland itself, were made Pennsylvania School of Medicine, Philadelphia 4, by introducing a fine needle into the long axis Pennsylvania, and The Department of Dermatol- of the follicle and plunging it up and down in ogy (Herbert Mescon M.D., Professor), Boston various directions. University School of Medicine, 80 East Concord 5. Dermabrasion: After freezing with ethyl Street, Boston 18, Massachusetts. This work was supported by a grant from The chloride, the cheek was abraded to a depth of National Institutes of Health, PHS E-1589. t Formerly Public Health Service Research approximately 1 to 2 mm. with a revolving Fellow of the National Institutes of Health. wire brush. Presented at the Eighteenth Annual Meeting 6. Derinal inflammation: Nodular inflammaof The Society for Investigative Dermatology, tory reactions of varying degrees of severity were Inc., New York, N. Y. June 1, 1957. 51

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produced by intradermal injections of the following substances: (a) sebum (ether extracted from hair), concentrated, and in dilutions up to 1 :100; (b) comedones (ground up and sus-

fail to undergo the normal sebaceous transformation. In its complete form the entire lobule may be occupied by these undifferentiated epithelial cells. The replacement of the gland by undifferpended in saline); (c) fatty acids of varying chain entiated epithelial cells may be incomplete with lengths suspended in olive oil; (d) cholesterol varying percentages of cells showing the presence suspended in olive oil; (e) squalene suspended in of varying amounts of fat. Those cells which are olive oil; (f) turpentine suspended in olive oil; in varying stages of sebaceous transformation at (g) croton oil suspended in olive oil; and (h) the time of injury may fail to mature in the nor-

mal way and instead show apparent excessive 7. Galvanic injury: The ostia of sebaceous keratinization of the cell walls and retention of

olive oil alone.

follicles on the face were lightly coagulated with

a fine needle activated by a low amperage gal-

thick eosinophilic, keratin-like cytoplasmic trabeculae. These excessively keratinized cells are

vanic current. This superficial injury did not hardier, do not rupture, and persist as ghosts clogging up the fundus of the gland. directly involve the sebaceous gland. 4. Proliferation: Tongues and cords of indiffer8. Thallium: 0.25cc of a 0.1% thallium acetate solution in saline was injected intradermally ent epitheial cells may grow out of the undifferentiated lobules into the dermis. into the scalp. 5. Keratinous metaplasia: The periphery of the 9. Cotchicine: 0.25 cc of a 0.1% coichicine solution was injected intradermally into the scalp. gland may be transformed into a stratified

10. Methylcholanthrene: A 0.6% solution of squamous epithelium similar to the epidermis. 20-methyicholanthrene in benzene was painted Keratinized squamae fill the cavity formerly on the cheek daily for one month. The opposite occupied solidly by sebaceous cells. control cheek was painted with benzene (see B. Detailed Observations

number la).

11. Acne: Biopsy specimens of experimental The experimental stresses divide themselves chloracne as well as acne vulgaris have been into four groups:

examined.

RESULTS

A. General Patterns of Response

Several patterns of response were discernible. 1. Destruction: Severe stress destroys the gland

totally. The terminal hair follicle is far more resistant to destruction. 2. Atrophy: Following certain stresses, not quite severe enough to destroy the gland, involution of varying degrees may occur. 3. Failure of 8ebcweous maturation: This change will be emphasized because it is so characteristic.

1) Superficial surface injuries (contact dermatitis, adhesive tape).

2) Localized damage to the pilosebaceous unit (galvanic injury, plucking, puncture, dermabrasion, and dermal inflammation).

3) Cellular inhibitors (colehicine, thallium acetate). 4) Carcinogens (methyicholanthrene). 1. Superficial surface injuries

There were no important changes in the sebaceous glands in four biopsy specimens taken at varying intervals (1—4 weeks) after the

The sebaceous cells may become replaced to production of allergic or primary irritant type varying degrees by undifferentiated epithelial contact dermatitis. Similarly, there were no cells. The mature sebaceous cells are cast off and changes in the sebaceous glands in three speciare replaced from the basal layer by cells which mens taken 6 to 9 weeks after the continuous application of adhesive tape. The deep location

The use of the word "sebum" throughout this article is not technically correct, for in reality the ether extracted material was "surface lipid" consisting of sebum from the sebaceous glands plus the ether soluble products of keratinization. Nevertheless, because the collections were made from the scalp where relatively great amounts of sebum are rapidly produced from large sebaceous glands,

it is probable that the material was mostly sebaceous in origin.

of the glands protects them from superficial injury. Minor changes in the fofficular ostia were not reflected in the morphology of the gland. 2. Localized damage to the pilosebaceous unit

a. Plucking: (Figure 1A, 1B) Fourteen biopsy specimens removed immediately and one to four

Fin. 2. Check, one week after repeated puncture of the pilosebaceous apparatus. (A) (X50). On a smaller scale the changes are like those which follow plucking: follicular hvperkeratosis, some glandular atrophy and partial replacement of the sehaceous gland with undifferentiated cells. (B) Sehaceous acinus from the same follicle as shown in 2A (deeper cut) (X102). The periphery of the gland is mostly undifferentiated except for small sebaceous nests. The fuuclns is packed with cell ghosts which have not undergoue the usual fragmentation because of thicker cell walls.

FIG. 1. Scalp—18 clays after plucking. (A)

(X66). The upper portion of the follicle is dilated and filled with keratin. Below this the sebaceous

glands are atrophic and have been replaced almost completely by cells of the undifferentiated type. The changes mimic comcdo formation. (B) Sehaceous glands from 1A (X206). Except for a few nests of sehaceous cells, the shrunken gland is occupied by undifferentiated epithelial cells.

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FIG. 3. Cheek 9 days after dermahrasion (XlO5. This is the prototypical example of replacement of the gland hy primitive undifferentiated epithelial cells.

weeks after plucking of the scalp hairs were not observed. The infundibulum becomes gradstndied. Plucking damages the follicle exten- ually dilated by a tremendous mass of horny cells sively. Except for cellular remnants in the base of

(hyperkeratosis). This extensive horny accumula-

the bulb, the matrix is largely removed. The tion is due principally to the failure of the follicle internal root sheath is almost completely ex- to be "swept" clean by the growing hair. Pretirpated, and the lower one-third of the external sumably there is an increased rate of keratinizaroot sheath is often ripped away. There is no tion also, despite the fact that this particular site direct injury to the gland. At five days, an occa- is not directly involved by the original injury. sional gland shows a reduced accumulation of These changes are inconstant and variable in fat in the cells, a partial lack of maturation. At degree. Within the period of one to three weeks, this time there is some distention of the follicular the lower portion of the follicle gradually forms infundibulum with keratinized squamae produced an undifferentiated epithelial strand as in normal by the upper portion of the external root sheath. telogea, accompanied by great thickening of the By two weeks some of the glands are largely re- hyaline membrane. In the changes which follow plucking, there is placed by undifferentiated cells and are no longer making sebum; within the next two weeks the evidence of a dynamic inter-relationship between undifferentiated lobules may shrink considerably. the components of the pilosebaceous unit. Though Unfortunately no biopsy specimens were taken the gland was not directly injured, both undifferafter a month and thus final reconstitution was entiation and atrophy occurred secondary to

PATHOLOGIC PATTERNS OF THE SEBACEOSTS GLANDS

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Fin. 4. Dermal inflammation: Scalp 2 weeks after the intradermal injection of 0.03cc of sehum (X22). Each of the glands (SG) at the top right of the two follicles shown have not oniy become undifferentiated hut have undergone keratinous mataplasia. Each lobule is a stratified squamous epithelium producing a comedo-like mass of keratinized squamae.

changes in the follicle, particularly tbc distcution of the infundibulum by horny cells. The pilose-

basal-type cells. This process reaches its most complete stage after dermabrasion. Restoration

baccous unit is a functionally integrated structure. b. Puncture: (Figure 2A, 213) In three biopsy specimens examined one week after puncture, there was partial undifferentiation of the peripheral cells of the gland accompanied by follicular and some perifollicular infiltration with lymphocytes. The fundus of the gland was filled with

to normal is complete in three weeks. d. Dermal infiammotion: (Figure 4, 5A, SB)

Inflammatory changes in the dermis were of course dominant after the injection of sebum,

eroton oil, squalene, fatty acids, etc. This varied in degree and quality with the different chemicals and substances. The sebaceous glands, however, tended to show a patterned response. With mild keratinized ghosts of cells which had been caught inflammation, as after the injection of olive oil, in a stage of partial sehaccous differentiation at the changes in the sebaceous gland were inconsethe time of injury. quential. Infiamniation, severe enough to cause c. Derinabrasion: (Figure 3) The changes at disorganization or rupture of the follicle, usually varying intervals after dermabrasion have been results in failure of sebaceous maturation and the described elsewhere (15). The conspicuous evcnt formation of undifferentiated lobules. Accomis almost total lack of scbaccous maturation; panying the marked granulomatous inflammatory the glands are completely occupied by immature infiltrate associated with severe injury as distinct

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Fjo. 5. Dermal inflammation; Scalp with proliferative changes after the injection of 0.1 cc of 0.1% croton oil in olive oil. (A) (X33). There is marked acanthosis suggesting pseudoepitheliomatous hyperplasia overlying the dense polymorphous infiltrate nnd fibroblastic proliferation in the dennis. In some foci the basal layer is not definitely identifiable where the inflammatory infiltrate and edema is extremely dense and penetrates the overlying epithelium. No mature sehaceous glands are visible. (B) (X40). This is a deeper section in the same block of tissue and the lohulations of the hyperplastic epithelium suggests their origin not only from the follicular external root sheath but also from the sebaceous gland. There is one solitary focus of mature sebaceous cells (SC) at the right.

from ulceration and suppurativc necrosis, the undifferentiated glands may proliferate in a disordcrly fashion forming lobulated tongucs and

ogist is accustomed to calling pseudoepitheliomatous hyperplasia. The ruptured follicular epithelium also tends to form proliferating sheets.

shects of epithelial cells. These proliferating It is possible that the histopathologist has overmasses of indifferent epithelial cells are most looked these sources in the genesis of pseudoconspicuous at the edge of markedly inflammed epitheliomatous hyperplasia. Occasionally there tissue and mimic closely what the histopathol- are varying degrees of keratinous metaplasia of

PATHOLOGIC PATTERNS OF THE SEBACEOUS GLANDS

aS :t

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ic

Fin. 6. Cheek, one week after electrodesiceation of the follicular orifice (Xl04). Undifferentiated cells occupy the periphery and at one site there is keratinous metaplasia (1(M). The fundus of the gland is filled with the keratinous remnants of cells which at the time of injury were probably undergoing sobaceous differentiation.

the gland with active production of keratin acquired keratohyaline granules, and finally resulting in the accumulation of kcratinized produced thin squamae. By two weeks these squamae in the himcn. The general pattern changes were completely reversed and the glands described above is rather non-specific and can he elicited with a number of agents which do not necessarily act in the same way. Of course, the

were restored to a near normal condition.

3. Cell Inhibition

extent and quality of the change will be dea. Thallium: (Figure 7A) In three specimens pendent on the intensity of the stimulus, its taken at one and two weeks after injection of dnration in tissue, and the peculiarities of the thallium acetate, the sebaceous glands were defense reactions. We have not studied these replaced by undifferentiated cells. This was most items in detail. c. Galvanic current: (Figure 6) In six subjects biopsy specimens were examined immediately after injury, and one and two weeks later. Immediately afterwards, there was localized coagulation necrosis of the upper follicular epithelium

prominent at one week; in addition there were

marked atrophy nd bizarre distortion of the gland. By two weeks these changes had already

started to regress. It is interesting that the effect was restricted to the gland. The hair follicle was not influenced.

without damage to the gland. At six days, the b. Colchicine: (Figure 7B) In eight specimens central portions of the sebaceous glands which taken one to three weeks after the injection of were formerly filled with cells in the process of eolehieine, there were varying degrees of undiffersebaceous differentiation were replaced by keratinized cell remnants. The peripheral cell layers were mostly undifferentiated, but in a few areas

there was distinct keratinous metaplasia. Here

entiation of the gland, and the follicle underwent

telogen formation. Furthermore, the glands

underwent involution and shrank considerably in size. It may he noted that the effect of eolehi-

the cells flattened as they moved upwards, cine on the hair bulb and sebaeeons gland is

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Fie. 7. (A) Scalp, one week after the injection of 0.1% thallium (X72). There is marked atrophy and undifferentiation of the sebaceons glands. With this dosage of thallium, no changes were seen in the hair. (B) Scalp, one week after the injection of 0.1% colehicine (X53). The glands (SO) have practically disappeared. Only small nests of undifferentiated cells remain.

cholanthrene induced destruction of the sebaceous glands in mice. Some increased follicular tinized hair cells nor sebaceous cells are pro- hyperkeratinization was noted as compared to the control benzene applications. None of the duced. analogous; multiplication does not cease, but the new cells remain undifferentiated. Neither kera-

4. Superficial Carcinogens

There were no important changes in the

precancerous changes, induced by methyleholanthrene ill animal skin, were observed.

Chlorecne: (Figure SA, SB) sebaceous glands in two specimens after daily application of 20-methylcholanthrene for one The changes in ehlornaphthelene (halowax) month. This is in striking contrast to the methyl- induced acne have been described elsewhere

PATHOLOGIC PATTERNS OF THE SEBACEOUS GLANDS

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I

FIG 8. Comedo formation in chloracne and acne vulgaris. (A) Comedo formation in Halowax-induced acne of the back (XSO). The gland is atrophic and mostly undifferentiated. (B) Atrophic sebaceous gland shown in SA (X218). Most of the cells are of the undifferentiated type. A few mature sebaceous cells are present in the central portion of the gland. (C) Early comedo in acne vulgaris (cheek) (X45). The sebaceous glands are markedly atrophic for the cheek and have been replaced for the most part by undifferentiated cells. (D) Late comedo formation in acne vulgaris on the cheek (X42). The changes shown in 8C are more advanced.

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(16, 17). Suffice it to say here that the most the stereotyped defense of both the gland and the conspicuous change is massive hyperkeratosis of hair is temporary cessation of synthesis of special-

the infundibulum and adjacent portion of the ized cell products, sebum and keratin respecfollicle, leading to eomedo formation. As the tively, with regression to undifferentiated epithehyperkeratosis develops the glandular appendage hal cells of the primitive type. Redifferentiation gradually atrophies and disappears, a change into specialized cell types readily occurs when which is once again evidence of the integrated the inhibiting force is removed. In this connecresponse of the pilosebaeeous unit. The gradual regression of the gland is preceded by varying

tion, we even have observed the partial redifferentiation of sebaeeous glands in follicles from

degrees of undifferentiation of the sebaeeous

which comedones have been expressed. In general

cells.

return to the undifferentiated state takes place more readily in the gland than the hair. The capacity to undergo keratinous meta-

Acne Vulqaris: (Figure SC, SD) The material available for study consisted of more than fifty facial biopsy specimens of acne patients. Here, we will restrict our attention to the more characteristic changes in the gland. It will be instructive to relate these changes to those occurring after experimental injury. As the eomedo forms a variable degree of tindifferentiation develops. Paralleling this, there is

gradual atrophy of the gland. It may disappear altogether or be a mere remnant in the clinically conspicuous "whitehead" or "blackhead." The primary pathologic event in acne vulgaris is not in the sebaeeous gland. Glandular atrophy is

plasia with the production of keratinized squamae

rather than sebaceous cells is another inherent potentiality of the gland. It does not take place directly, but ensues after the appearance of un-

differentiated cells. The pluripotentiality of epithelial cells in the epidermis and its appendages is again demonstrated by this behavior. The pilosebaceous apparatus is an integrated unit. Primary disturbances in the follicle may be reflected by secondary changes in the gland. The

commonest example of this is the glandular atrophy which invariably follows distention of the upper follicle (infundibulum) by keratinized

secondary to eomedo formation. As after squamae, as in acne vulgaris, chloracne and

plucking, the atrophy and undifferentiation after plucking. In contrast to primary atrophy appear to be a sequelae of follieular hyperkera- from a direct effect on the gland, this is an tosis. The gland is inevitably influenced by any marked follieular disturbance, especially horny distention of the orifice. DISCUsSION

example of secondary atrophy following changes to other portions of the pilosebaeeous apparatus. It cannot be assumed that atrophy is due simply to the back pressure caused by an obstruction to flow of sebum. Some sebaceous differentiation

In interpreting the various responses to a may continue against similar pressure in sebadiversity of stresses, we have sought particularly

ceous cysts.

In clinical dermatology there are no inflamto discern characteristic patterns. Most important of these is failure of sebaceous maturation matory diseases which localize primarily, or with variable replacement by undifferentiated uniquely, in the sebaceous gland; however, epithelial cells. This change is often transient this appendage, like any other cutaneous epitheand may be a stage in the ultimate atrophy of the hal structure may be the source of neoplastic or gland. It is readily missed, especially when cystic changes. In the present experiments, propartial, and has received practically no notice liferative growths of undifferentiated cells budded from dermatopathologists. The corresponding out of the glands only when there was considerprocess takes place regularly in the hair follicle able disorganization of the follicle and marked at the end of each cycle (telogen). The matrix inflammation. This may contribute to pseudocells do not keratinize but form a column of un- epithehiomatous hyperplasia. The development differentiated epithelial cells. It is significant of tumors and cysts was not observed following that this telogen-like pattern is a more or less these acute experimental stresses. standard response of the follicle to a score of Finally, as regards the sebaeeous duet, its insults of sufficient magnitude to damage the cells have properties of both the keratinizing matrix, viz., x-ray, eolehieine, thallium, fever, epithehium and the sebaeeous gland. Its responses local inflammation, etc. It would appear that follow those which might be expected from its

PATHOLOGIC PATTERNS OF THE SEBACEOUS GLANDS

bipotential characteristics and do not require separate discussion. SUMMARY

1. The patterns of pathologic response of the sebaceous gland following a variety of acute

stresses include 1. destruction, 2. atrophy, 3. replacement by undifferentiated epithelial cells, 4. proliferation, and 5. squamous thetaplasia. 2. While atrophy, destruction, and proliferation are common to many tissues following in-

jury, the failure of sebaceous maturation with the replacement of the glands by undifferentiated cells and squamous metaplasia are rather characteristic of this structure. 3. The pilosebaceous apparatus responds as a

unit. Injuries to the infundibulum or piliary

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DISCUSSION DR. FRANCIS A. ELLIS (Baltimore, Md.): I enjoyed the paper very much. I wish to bring up

DR. JoHN S. STRAUSS (in closing): I want to

thank Dr. Effis for his comments. In reference the use of the term of "undifferentiated cells." to the undifferentiated cells, these are epithelial cells which do not show any tendency towards In cancer one uses the term undifferentiated either sebaceous or keratinous maturation. Uncells to designate a very anaplastic cell. Certainly differentiated cells are seen most commonly, this is not the connotation which authors mean and to the greatest degree, after dermabrasion, when they use the term undifferentiated cells. but they also appear following other injuries to the pilosebaceous apparatus. When actual The speaker said that the cells were "undifferkeratin formation is present, I call the changes entiated" stratified epithelium cells and I would keratinous metaplasia rather than undifferentianot consider them exactly as undifferentiated tion. Probably undifferentiation is a stage in the ultimate development of keratinous metaplasia. cells in the way this term is usually used.

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