J. clin. Path., 1975, 28, 465-471

Inverted follicular keratosisJ. G. AZZOPARDI AND R. LAURINI

From the Department ofHistopathology, Royal Postgraduate Medical School, London

SYNOPSIS Attention is drawn to a benign skin tumour which has escaped recognition in the Britishliterature. Inverted follicular keratosis can be mistaken clinically for basal cell carcinoma and a

variety of benign skin lesions. Pathologically it is easily confused with squamous carcinoma, aserious error because this lesion occurs dominantly on the face. The lesion is thought to arise fromthe infundibulum of the hair follicle.

The purpose of this paper is to draw attention to a

lesion which has been described in the dermatologicaland ophthalmic literature but which is little knownto general pathologists. Helwig (1954) gave it thename 'inverted follicular keratosis' and describedits essential characteristics. This descripion is,however, unavailable to most pathologists. Boniukand Zimmerman (1963) reported on lesions of thistype on the eyelids. We have not been able to findany reference to it in the British literature.

Materials and Methods

We collected nine lesions, all treated by surgicalexcision. Eight were found by searching our recordsbetween 1954 and 1973 inclusive, and one was seen

Received for publication 10 December 1974.

in consultation. Haemalum eosin sections werestudied in all cases. In the eight cases from our ownmaterial, Best carmine, Masson-Fontana, Alciangreen, and periodic acid Schiff stains were alsostudied. Step sections were examined in these eightcases.

CLINICAL DATA

All lesions were single, though one patient had abasal cell carcinoma at another site in addition.As can be seen from the table, eight lesions weresituated on the face and one on the chest wall.Five lesions were situated on the cheek or upperlip. There were seven male and two female patients.All the patients were adults and, with the exceptionof a 36-year-old, aged 48 years or more. They pre-sented mostly as asymptomatic papules and allwere small lesions, measuring only a few millimetresin maximum diameter. They had a conical or dome-

Case Sex Age Site Duration Clinical Diagnosis Follow-up Original PathologicalDiagnosis

1 M 57 Lower eyelid (Clinical notes Squamous carcinoma2 F 55 Cheek 2 mth lost) Well 18 yr Squamous carcinoma

Rodent ? or keratoacanthomaKerato-acanthoma

3 M 60 Upper lip 6 mth ? Rodent Well 8 yr IFKSquamouscarcinoma

4 M 53 Cheek 6 mth - Well 10 yr IFK5 M 49 Upper lip 10 mth - Lost IFK6 M 52 Chest 'Many years' with ? 'Cutaneous Well 7j yr IFK

recent increase horn'in size

7 M 36 Cheek 2 yr - Well 6' yr IFK8 M 48 Temple 3 mth - Well 2,', yr IFK9 F 74 Nose 10 mth ? Rodent Well I yr IFK

Table Summary of clinicopathological data on cases

IFK = inverted follicular keratosis

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Fig 1 Low-power view ofmainly protuberant lesion.Note that part of lesion extends downwards into thedermis. Haematoxylin and eosin x 23

shaped elevation. They were pinkish or flesh-coloured and not obviously pigmented.

PATHOLOGYThe low-power appearance varies between a lesionthat protrudes mainly outwards to a more commonone which grows predominantly inwards into thecorium (figs 1 and 2). Even when a lesion growsdominantly outwards, part of it is inward-growingso that the entire tumour is not raised above thelevel of the surrounding skin surface (fig 1). Thesurface varies between papillomatous in the moreprotuberant, and more-or-less convex in thedominantly ingrowing lesion. There is hyperkera-tosis, parakeratosis or both superficially. The lesionis generally well demarcated, with usually sharpinversion of the epidermis on one or both edges.It may therefore have a cup-shaped structure with ageographical, though not a cytological, resemblanceto keratoacanthoma.

It has an essentially lobular configuration withblunt outlines (fig 2). There is no raggedness at theepithelial-stromal junction (fig 3). The lobulesmay he largely separate, compressing the stromabetween them, or they may merge together atvarying levels, causing apparent isolation of areasof stroma within the epithelial mass (fig 4). Hairfollicles enter the lesion on the deep aspect andlose their identity within it.The lobules contain a more-or-less central

longitudinal crypt (fig 1). This contains keratinand is lined by squamous epithelium usually with,but sometimes without, a granular layer. The cryptmay open on the surface, and its contents are thencontinuous with the keratinous scale there: in a

Fig 2 Low-power viewof mainly 'inverted'lesion. HandE x 23

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Fig 3 Sharplydemarcated laterally,the lesion is expansileand has a blunt lobularconfiguration.HandE x 45

given plane of section, the crypt may be elliptical andappear isolated from the surface. Sebaceous glandsare attached to the deep margins of the lobules inat least four of the eight cases examined by stepsectioning (fig 5). In addition, in one of the fourcases, hair shafts are present in two crypts. Thisstrongly suggests that the lobules represent a pro-

liferation of the external sheath of hair folliclesand that the infundibular portion of the follicle isprimarily involved in the process.The cytology is in part basaloid and in part

squamous. The relationship of the two cell typesconstitutes an essential and characteristic feature.Basaloid cells are more numerous at the periphery

Fig 4 Two adjacenttumour lobules withcompressed stroma,apparently isolated

fo t between them, running.|stt$ diagonally above centre.

~~~~ HandE x 110

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Fig 5 Sebaceousgland remnantsincorporated withinthe deep part of thelesion. H and E x 275

IN..... 4.or --

/ se

of the lobules, and squamous cells towards thecentre of the lobules and around the keratin-filledcrypts. While basaloid cells sometimes merge withsquamous cells indefinably, it is at the points ofjunction of these two cell types that the so-called'squamous eddy' is frequently found (figs 4 and 6).This consists of a sharply demarcated, rounded

group of larger, eosinophilic, polygonal cells setin a background of basaloid cells. The cells of theeddy have an orderly arrangement, lack pleo-morphism, and are virtually never in mitosis.Occasionally keratohyaline granules are present inthe centre of the eddy and, less commonly, a verysmall focus of keratin. A very rare cell may even

Fig 6 Numerouscharacteristic squamouseddies with uniformsquamous cells lackingcytological atypia.HandE x275

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show individual-cell keratinization. Keratohyalinegranules in a squamous eddy are sometimes num-erous and coarse, reminiscent of those seen in viralwarts, though no aetiological relationship isimplied: in such areas there is usually a prominentthick granular layer in the lining of the crypts.There is an overall organized arrangement aboutthe concentrically laminated eddies that distinguishesthem fairly easily from the epithelial pearls ofsquamous carcinoma. Squamous eddies vary innumber in different lesions and different parts of thesame lesion. They are, however, such a character-istic feature that it is very doubtful if one candiagnose this entity in their absence. They tend tobe most numerous in the centres of the epithelialmasses. Where they are very numerous, they abuton one another without becoming confluent.The basaloid cells are small, haematoxyphilic,

immature cells. Mitoses are seen in them, as many asthree per high-power field being present in someareas. This degree of proliferative activity adds tothe tendency to misdiagnose some of the lesionsas malignant. No abnormal mitoses are present.Mitoses are found only occasionally in the squamouscells (and may even be numerous in the superficialpart of the lesion) but are very rarely seen in thecells constituting the eddy.Another characteristic, but not essential, feature

is the clefting that occurs within the epithelial masses(figs 3 and 7). This is most conspicuous close to

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the surface of the lesion, around the crypts, andbetween some contiguous squamous eddies:occasionally it is seen also at the junction of theeddy and the basaloid cells. Where clefting ispronounced, microvesicles are found within theepithelium. While these clefts are doubtless in partartefact, it is unlikely that they are entirely so, sinceAlcian-green-stainable mucinous material is fre-quently present in the crevices.

Melanin pigmentation is usually conspicuousby its absence in haemalum-eosin preparations.In eight lesions no melanin is visible in haemalum-eosin sections; in one a very little melanin is visiblein stromal macrophages on very careful scrutiny.With Masson-Fontana staining, variable numbers ofmelanocytes are present in all eight lesions withavailable material. Melanocytes are patchily dis-tributed among the basaloid cells. Similarly, melaninpigment is present in some of the areas composed ofbasaloid cells.The epithelial-stromal junction is sharply defined

(figs 2 and 3). The dermis shows increased vascu-larity, with occasional telangiectatic vessels super-ficially. Inflammatory cells vary from an inconspic-uous to a moderately dense infiltrate with lympho-cytes and histiocytes the dominant cells. Plasmacells are conspicuous in only two of the nine cases,including one with a purulent scab on the surface.Eosinophils are usually scarce and neutrophilsabsent. The dermal inflammatory cells sometimes

Xi Fig 7 Cleftingbetween contiguoussquamous eddies.HandE x 275

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extend into the epithelial masses though the invasionis not usually widespread. Microabscesses are not afeature.

Discussion

Inverted follicular keratosis is almost always asolitary lesion, occurring mainly in adult life. Theaverage age in Mehregan's series (1964) was 50 years.The youngest patients in Boniuk and Zimmerman's(1963), Mehregan's (1964), and our series were17, 25, and 36 years respectively. Men are affectedabout twice as often as women. About 85 % ofthese lesions are found on the face. The cheek andupper lip are the sites of predilection, other sitesaffected being the chin, forehead, eyebrow, nose, andeyelid. Upper or lower lids may be involved, lesionshaving a predilection for the lid margins. It isimportant, in this context, to remember thatsquamous carcinoma of the lid margins is excessivelyrare. The trunk is involved uncommonly and theextremities rarely. The duration of the lesion,when known, has varied between six weeks andthree years. One patient of Duperrat and Mascaro(1963) had a seven-year history. Most of the lesionsare between 3 and 8 mm in maximumm diameter,but a few reach a size of 10 mm. They are generallyasymptomatic, firm, pinkish papules. Rarely theypresent as 'cutaneous horns'. Clinically they areoften considered to be viral warts, the remainderbeing diagnosed as basal cell carcinoma or avariety of benign lesions (Mehregan, 1964). Basalcell carcinoma was the favoured clinical diagnosisin at least three of our cases.

Pathologically, they pose very real diagnosticproblems unless one is aware of this entity. Theycan be confused with a variety of lesions, bothbenign and malignant. Our oldest case was con-sidered to be a squamous carcinoma of the eyelidand the next oldest either a squamous carcinoma ora keratoacanthoma, with the latter diagnosisfavoured. The later cases were diagnosed as invertedfollicular keratosis following Helwig's (1954)account.The most difficult differential diagnosis is from a

seborrhoeic keratosis of the variety described as'irritated'. Such a lesion, whether spontaneouslyoccurring or experimentally produced (Moralesand Hu, 1965; Mevorah and Mishima, 1965),may contain squamous eddies in abundance.Clefting has also been noted by us in irritatedseborrhoeic keratosis. We agree with Lever (1967)that the basosquamous acanthoma of Lund (1957)is a variant of seborrhoeic keratosis. However, weregard inverted follicular keratosis as a distinctentity, though not excluding the possibility of patho-

genetic kinship. Seborrhoeic keratosis usuallycontains horny invaginations, many of which areunrelated to hair follicles. Melanin pigmentationis often more prominent. But the most importantdistinction is the microanatomy: seborrhoeic kera-tosis is, and remains, raised above the level of thesurrounding skin, even when it is situated over apressure point. By contrast, inverted follicularkeratosis has a downward growing component,usually dominant but always present to a slightdegree at least. Because in the final analysis this isthe most important single distinguishing feature,the differential diagnosis may be impossible on asmall biopsy or a badly orientated specimen.Fortunately the distinction in such cases is academic.Keratoacanthoma can be distinguished with

relative ease (fig 2). Though many of the lesionshere described have a cup-like structure, they lackthe ballooned pale-staining squamous epitheliumand the infiltrative pattern of the deep edge ofkeratoacanthoma and have a lobular growth patternand characteristic squamous eddies instead.

Viral warts and other benign lesions do notconstitute a difficult problem in differential diagnosisto the pathologist, despite the clinical similarity.Squamous carcinoma is the most serious differ-

ential diagnosis, because it is not infrequentlyconsidered or made on pathological grounds inpatients with this condition. This can lead tounnecessarily drastic treatment of a benign lesion.Inverted follicular keratosis has a lobular blunt-edged architecture and lacks the frayed, jagged,infiltrative margin of squamous carcinoma. Thelateral edges are sharp, while in squamous carcinomathere is frequently a transition to abnormal epidermiswhich is not overtly malignant. The two main celltypes present have an orderly arrangement. Thesquamous eddies have a monotonous uniformitythat distinguishes them from epithelial pearls(figs 4, 6, and 7). Abnormal mitoses are not foundin inverted follicular keratosis. The nuclear andcytological pleomorphism of squamous carcinomais lacking.The pathogenesis of these lesions is debatable.

The name 'inverted follicular keratosis' has themerit of being generally descriptively accurate andand of suggesting a follicular origin. It is true thatsome of the lesions are dominantly superficial,and the designation 'inverted' is not wholly applic-able. Nevertheless, for the present, it seems desirableto retain this name. Boniuk and Zimmerman(1963) suggested the possibility of a viral aetiology.Duperrat and Mascaro (1963) were the first tosuggest origin specifically from the infundibulumof the hair follicle, and Mehregan (1964) stronglysupports this hypothesis, which has much to

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commend it. The alternative names follicular poroma(by analogy with eccrine poroma) or infundibuloma,that have been suggested, might be appropriateif this histogenetic view became generally accepted.

If one separates the irritated seborrhoeic keratosis(basosquamous acanthoma), there is no doubt thatinverted follicular keratosis is an uncommoncondition. It deserves more general recognitionespecially because of the ease with which thepathologist, unfamiliar with the condition, canmake an erroneous diagnosis of squamous car-cinoma. The seriousness of this error will beappreciated when it is remembered that about 85 %of these lesions are situated on the face. An erron-eous diagnosis of basal cell carcinoma may bemade instead, though this error is much less frequent.One of us has seen a case (not included in this series)diagnosed as basisquamous carcinoma. A diagnosisof basisquamous carcinoma is nowadays viewed withsome scepticism. The more widespread recognitionof inverted follicular keratosis as an entity will addto the legitimate doubt as to the existence of alesion that deserves to be classified as basisquamouscarcinoma.A diagnosis of inverted follicular keratosis carries

an excellent prognosis. Boniuk and Zimmerman(1963) studied 28 patients with a follow-up period offive years or more. No deaths were attributable tothe tumour. Follow-up was available in a total of46 patients: a single patient had a local recurrencefollowing cautery excision. No follow-up was possiblein two of our patients. The remaining seven are well

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without recurrence at 1, 214 , 612, 7 7, 8, 10, and

18 years respectively.

We wish to thank the surgeons, radiotherapists,and dermatologists at Hammersmith Hospital foraccess to clinical data and Dr Max Millard forthe data on case 8. We are grateful to the technicalstaff of the Department of Histopathology, and toMr W. Hinks and Miss Debbie Hawks for photo-graphic and secretarial assistance.

References

Boniuk, M. and Zimmerman L. E. (1963). Eyelid tumors withreference to lesions confused with squamous cell carcinoma.II. Inverted follicular keratosis. Arch. Ophthal., 69,698-707.

Duperrat, B. and Mascaro, J. M. (1963). Une tumeurbenigne d6velopp6e aux depens de l'acrotrichium oupartie intraepidermique du follicule pilaire: poromefolliculaire. Dermatologica. (Basel), 126, 291-310.

Helwig, E. B. (1954). Seminar on the skin: neoplasms anddermatoses. Proceedings of the 20th Seminar of the Ameri-can Society of Clinical Pathologists, International Congressof Clinical Pathology, Washington, D.C.

Lever, W. F. (1967). Histopathology of the Skin, 4th edition,p. 490. Lippincott Philadelphia: Pitman, London.

Lund, H. Z. (1957). Tumors of the Skin. (Atlas of TumorPathology, Section 1, Fascicle 2), p. 42. Armed ForcesInstitute ofPathology, Washington, D.C.

Mehregan, A. H. (1964). Inverted follicular keratosis.Arch. Derm., 89, 229-235.

Mevorah, B. and Mishima, Y. (1965). Cellular responseof seborrhoeic keratosis following croton oil irritationand surgical trauma. Dermatologica (Basel), 131, 452-464.

Morales, A. and Hu, F. (1965). Seborrhoeic verruca andintraepidermal basal cell epithelioma of Jadassohn.Arch. Derm., 91, 342-344.

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