J. clin. Path., 1970, 23, 464-471

Differentiating neoplasms of hair germ'

J. T. HEADINGTONFrom the Department ofPathology, The University of Michigan, Ann Arbor, Michigan, USA

SYNOPSIS Differentiating neoplasms of hair germ are benign epithelial-mesenchymaltumours of skin in which hair follicle development may be partly or completely recapitulated.The epithelial component is equivalent to the hair germ. The mesenchymal component isequivalent to the dermal papilla. Epithelial-mesenchymal interaction results in the morpho-genesis of hair follicles. In neoplasms showing stromal induction, there is centrifugal organiz-ations: hair bulbs are found at the periphery of tumour lobules and hairs are projected centrallyto lie within small keratinizing cysts. Neoplasms of hair germ without advanced morpho-differentiation are termed 'trichoblastomas', and those neoplasms in which hair follicledevelopment is advanced are called 'trichogenic trichoblastomas'.

This report describes a small group of unusualcutaneous neoplasms, probably derived from hairgerm, which (1) recapitulate the development ofthe hair follicle; (2) illustrate an inductiverelationship between epithelial and mesenchymalcomponents analogous to that between hair bulband dermal papilla; (3) demonstrate a topo-graphical organization similar to that seen in theskin; and (4) do not correspond to neoplasmspreviously described.

Material

Two of the three neoplasms (cases 1 and 2) were

obtained from the files of the Department ofPathology in The University of Michigan; thethird was acquired through the courtesy ofProfessor Tawan Virayakul, Faculty of Medicine,Chiang Mai University, Chiang Mai, Thailand.Pertinent clinical details are given in the Table.

Received for publication 9 February 1970.

'Presented in part at the annual meeting of the International

Academy of Pathology, on 11 March, 1968, San Francisco,California.

Methods

Sections stained with haematoxylin and eosinwere available from case 1 and 2; the paraffinblocks were also available from case 1. In case 3the entire neoplasm, fixed in 10% neutral bufferedformalin and embedded in paraffin, was available.Special stains for reticulin (Wilders), elastic fibres(Verhoeff's), glycogen (PAS with and withoutmalt diastase digestion), hyaluronic acid (alcianblue with and without bovine testicular hyaluron-idase digestion), and acid mucopolysaccharide(colloidal iron technique of Hale as modified byRhinehart and Abdul-Haj) were used on thematerial from cases 1 and 3. In case 3 serialsections to depict topographical relationshipswere cut and stained from selected blocks.

Case No. Age Sex Site Coniment

l 31 F Scalp No recurrence, 4 yr2 25 F Buttock Onset at puberty3 51 M Groin Asymptomatic progressive

growth, 1 yr

Table Clinical data on cases of neoplasm of hairgerm

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Differentiating neoplasms of hair germ

Clinical and Gross Findings

CASE 1

A raised, broadly pedunculated hairless mass,1-7 x 1'5 x 0-5 cm, was present in the scalp. Smallcystic areas were noted in the substance of theneoplasm after it was sectioned.

CASE 2

The lesion consisted of focal thickening and smallyellow prominences in the skin overlying asubcutaneous lobular mass. The largest of thelobules was within the subcutaneous panniculusand did not appear to be directly attached to thedermis. The colour and consistence of thisneoplasm were not recorded. It exceeded 1 0 cm indiameter.

CASE 3The neoplasm was 5 0 x 3 0 x 2-0 cm.There was noattached skin or subcutaneous tissue. The surfacewas grey-white, firm, and slightly bosselated; afew delicate strands of connective tissue adheredto it. The cut surface was white, hard, andvaguely convoluted. There were no areas ofsoftening and no cysts.

Significant gross features of these neoplasms arethat all are longer than 1 0 cm in the greatest di-mension; all are found within the dermis or atthe junction of dermis and subcutaneous tissue;and two of three tumours were removed as dis-crete lobular masses.

Microscopic Findings

CASE 1

The lesion was well circumscribed and entirelyintradermal. The expansile growth of the mainmass had displaced sweat glands and pilo-sebaceous units and caused thinning of overlyingepidermis. Most of the neoplasm was formed bydiscrete and confluent nodules of epithelial cellscontained within a loose-textured fibroblasticstroma (Fig. 1). Two general configurations ofepithelial elements were found: (a) well defined,circumscribed anastomosing masses of epithelialcells, frequently arranged in double-celled strandsand closely associated with collagen-formingstroma (Fig. 2), and (b) nodular aggregates of

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Fig. 1 Case 1. Trichoblastoma. Low-power view Fig. 2 Case 1. Trichoblastoma. Higher-power viewshows solid islands of uniform epithelial cells and of the tumour shown in Figure 1. A uniform ball ofcontrasting anastomosing strands of epithelial cells, smallpolygonal cells showing a distinct peripheralsome organized in a distinct double row. Stroma is pallisade is in continuity with double-cell epithelialmore dense in association with epithelial strands. strands. The pattern closely resembles a hair bulbH&E, x 75. without a dermal papilla. H& E. x 125.

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Fig. 3 Case 1. Trichoblastoma, the structuresimulating hair bulb. Note uniformity of matrix-likecells and dark masses of melanin pigment. In contrastto areas anastomosing cell cords, stroma is notprominent. H & E, x 275

small, uniform polygonal epithelial cells oftencontaining abundant melanin pigment (Fig. 3).These epithelial cell cords and nodular masseswere occasionally in continuity with each other.Some of the largest epithelial nodules had under-gone central liquefactive necrosis with microcystformation.The anastomosing epithelial strands closely

resembled hair germ of the catagen follicle (Fig. 1),and the solid masses of small polygonal cellshair matrix (Figs. 2 and 3). There was, however,no evidence of hair follicle morphogenesis orincomplete organization of 'matrices'.A paraepithelial fibroblastic stroma was present

between some anastomosing epithelial cords butdid not increase in density around nodularepithelial masses. Compared with normal dermis,the interstitial acid mucopolysaccharide contentwas slightly increased in the fibroblastic areas.The stromal-epithelial masses appeared randomlydistributed without any suggestion of topo-graphical organization or lobular configuration.

This lesion (trichoblastoma) was considered tobe an example of a neoplasm of hair germ inwhich stromal induction had resulted in the

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Fig. 4 Case 2. Trichogenic trichoblastoma. Low-power view shows a lobular pattern, dense cellularstroma, and central epidermal microcyst. Note thatepithelial strands are confined by a thick stromalenvelope. H & E, x 40.

formation and organization of matrix-like cells,but in which hair follicles had not developed.

CASE 2The general configuration was that of a wellcircumscribed nodular mass surrounded by adelicate collagenous envelope. Lobules werecomposed of anastomosing strands of epithelialcells, often in a double row, enclosed by amoderately cellular fibroblastic stroma withvariable collagenization. Epithelial elements werenot observed at the periphery of the neoplasm; theoutermost zone was always composed of colla-genous stroma. In the peripheral zone, epithelialcords usually paralleled the margin of the lobule(Fig. 4).

Within some lobules, islands of matrix cellsshowed various degrees of organization, frequentlyforming abortive hair follicles containing centralkeratohyaline masses (Fig. 5). When such follicle-like structures developed, the peripheral epithelialcells also showed differentiation and organizationto simulate the outer hair sheath (Fig. 5). Onesuch abortive follicle clearly duplicated a dermal

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Fig. 5 Case 2. Trichogenic trichoblastoma.Components ofan abortive hair follicle are present,including focal development of the clear cells of theouter sheath. Note continuity with anastomosingepithelial strands and cellular paraepithelialcollagenous stroma. H & E, x 125.

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Fig. 7 Case 2. Trichogenic trichoblastoma. A smallepidermal cyst consistent with ectatic hair sheathcontains wellformed hairs. H & E, x 140.

*; Lf,'> --X-4'# >- i< = f-txFig. 6 Case 2. Trichogenic trichoblastoma. Note awellformed bifid hair bulb and double papilla. Clearcells of the outer sheath are in continuity with thebulb. H & E, x 140.

papilla with a bifid bulb (Fig. 6). Within a fewlobules small cysts lined by keratinizing squamousepithelium contained well formed hair shafts(Fig. 7).

Topographical organization of the lobules wasmanifested by (1) epithelial components oflobules always circumscribed by more peripheralstromal elements; (2) hair follicle morphogenesistending to occur toward the periphery of thelobules where almost all well formed follicles werefound; (3) hair shafts, when formed, alwaysprojecting towards the centre of the lobule. Suchhair shafts were always enclosed within epith-elium; none were found outside the collagenousenvelope of the neoplasm and no foreign bodyreaction to hair shafts was seen within theneoplasm.

This lesion (trichogenic trichoblastoma) wasinterpreted as a neoplasm of hair germ withadvanced stromal induction, in which both truefollicles and follicle-like structures were formed.

CASE 3This neoplasm consisted of anastomosing lobulessimilar in configuration to case 2. Stromal-epithelial masses were surrounded by looselyorganized vascular connective tissue which

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Fig. 8 Case 3. Trichogenic trichoblastoma. Low-power view shows a dense peripheral stromal mantleand cross-cut hair follicles at various levels.Anastomosing epithelial cords are found within iHdefined lobules. Note blood vessels within aninterlobular system at the arrow. H& E, x 40.

Fig. 10 Case 3. Trichogenic trichoblastoma. Higher-power view of the epithelial area seen in Figure 8.The cellular paraepiihelial stroma is rich in AMPand contains numerous mast cells. H& E, x 120.

Fig. 9 Case 3. Trichogenic trichoblastoma. A smallhair follicle with its base toward the periphery ofalobule is in continuity with epithelial cords. Note thedelicate reticulin pattern adjacent to epithelium.Reticulin, x 80.

penetrated between the lobules (Fig. 8). Largethin-walled blood vessels formed an interlobularplexus, while smaller vessels penetrated thelobules.The intralobular connective tissue was more

dense and collagenized toward the periphery ofthe lesion; adjacent to epithelial cords it wasloose-textured and more cellular. This para-epithelial zone was rich in hyaluronic acid andcontained moderate numbers of mast cells, incontrast to small numbers in the dense peripheralstroma.

Delicate reticulin fibres were found in thegreatest number in the paraepithelial zones, andincreased in number where epithelial cellspallisaded to replicate outer hair sheath. Thereticulin adjacent to epithelial cords also showeda tendency to orientate perpendicular to epithelialbasement membranes. Small numbers of elasticfibres, without any special pattern or relationship,were found within interlobular stroma.Although well developed hair follicles were

found in several lobules (Figs. 8 and 9), most ofthe neoplasm contained only interconnectingepithelial cords similar to those described in case 2(Fig. 10).Topographical organization of this neoplasm,

although subtle, was definite and precise. Thepattern was similar to that described for case 2.Most follicles were orientated with their dermalpapillas to the periphery and their apices towardthe centre of the lobules. Hair shafts sheathed by

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A'1Fig. 12 Case 3. Trichogenic trichoblastoma. Areas ofsebaceous differentiation ofepithelium in continuitywith a cyst wall similar to that shown in Figure 11.H&E, x 275.

Fig. 11 Case 3. Trichogenic trichoblastoma. Low-power view shows a small epidermal cyst containingdense adherent keratin masses. The cyst is incontinuity with epithelial strands. In serial sections,hairs were projected into such cysts. H& E, x 30.

epithelium projected within small cysts lined byketatinizing squamous epithelium (Fig. 11).Several areas of the epithelium adjacent to andcontinuous with the epithelium of small cystsreceiving projected hairs showed unmistakablesebaceous differentiation (Fig. 12).

This lesion (trichogenic trichoblastoma) wasinterpreted as a benign neoplasm of hair germshowing advanced focal morphogenesis as well astopographical organization.The complete microscopic features of tumours

showing advanced stromal induction are sum-marized as follows:-

1 Sharply circumscribed stromal-epithelialmasses form interconnecting lobules.

2 The peripheral margin of a lobule is invari-ably stromal. The stroma becomes more cellularand increases in the interstitial acid mucopolysac-charide content adjacent to epithelium.

3 The undifferentiated epithelial componentconsists of anastomosing epithelial cords whichfrequently line up in a two-cell column or row.

4 Differentiating hair follicles are found incontinuity with epithelial cords.

5 When hair follicles are formed, there is atendency for hair bulbs to be orientated to theperiphery and for hairs to be projected towardsthe centre of the lobule.

6 Hairs originating from completely developedfollicles are usually contained within epithelialsheaths until they project into small cysts lined bykeratinizing squamous epithelium.

7 Focal sebaceous differentiation may bepresent.

Discussion

During catagen of the normal cycle of hair lossand regrowth the definitive hair germ is a cord ofundifferentiated epithelial cells which extendsfrom the remnants of the outer sheath to thedermal papilla (Montagna and Van Scott, 1958).During anagen, hair germ organizes and differ-entiates into hair matrix which then forms hairshaft, hair cuticle, and the various layers of theinner sheath. Because the hair bulb is lost with theonset of catagen, the germinative source of each

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new generation of hair follicles must originatefrom the epithelial extension of the outer sheathto dermal papilla, the hair germ.

In this study, while there is not direct morpho-logical evidence that the epithelial cords found ineach of the neoplasms described is actually hairgerm, there is good circumstantial evidence in theform of developing hair follicles in continuity withundifferentiated epithelial cords which closelysimulate hair germ, and in the intimate associationof epithelium with mesenchyme.

In normal anagen hair follicles the dermalpapillae contain abundant metachromatic muco-polysaccharide (Oliver, 1968; Braun-Falco, 1958).The large amounts of acid mucopolysaccharide inthe paraepithelial zone of the intralobular con-nective tissue in these hair germ tumours (case 3)are regarded, therefore, as additional evidence thatthis mesenchymal zone is analagous to activedermal papillae. The many small capillariesobserved within the mucopolysaccharide-richintralobular connective tissue of the neoplasmsare also similar to the highly vascular state of thedermal papilla during the growth phase of thehair follicle.

It is generally regarded that during catagen clubhair formation with loss of hair bulb and lowersheath is discontinued distal to the sebaceousgland. The sebaceous gland is not lost andregenerated in cyclic fashion (Montagna and VanScott, 1958). However, the regeneration ofsebaceous glands from ce11s -of the outer sheathhas been demonstrated experimentally (Montagnaand Chase, 1950), and sebaceous differentiation ofepidermal cells has also been noted. The differenti-ation in one of these neoplasms (case 3) suggeststhat hair germ neoplasms may, in certain foci, becapable of differentiation as an entire pilo-sebaceous unit.

Experimental evidence now supports thepostulate that the dermal papilla induces hairformation (Oliver, 1968). Additional investigativework has provided evidence for the inductibleeffects of mesenchyme in the morphogenesis offeathers (Wang, 1943) and teeth (Pindborg andClausen, 1958). It is therefore central to theconcept of differentiating neoplasms of hair germthat the mesenchymal component is essential forthe induction of hair follicles from hair germepithelium. Differentiating neoplasms of hairgerm are, therefore, not exclusively epithelialtumours, but are in fact heterogeneous biologicalsystems of epithelial-mesenchymal interaction.The two hair germ neoplasms in which hair

follicles were well developed displayed an unusualdegree of topographical organization. If eachneoplastic lobule were considered to be a sphere,the bulbs of almost all of the observed hairfollicles are in a centrifugal position. Furthermore,these follicles are orientated perpendicular to thesurface of the lobule and extend toward thecentre. Hair shafts in these lesions do not growhaphazardly into connective tissue; they remain

within epithelial sheaths and project into smallcysts lined by keratinizing squamous epitheliumwhich tend to be located toward the centre of thelobules. Thus the natural projection of hairtoward an epithelial surface is maintained in thehighly differentiated hair germ neoplasms. Thistendency for normal cutaneous relationships isalso seen in the epithelial areas of benign cysticteratomas of ovary as well as in so-called dermoidcysts in other sites.

In view of the enormous numbers of normalhair follicles within man and beast in which thereare many cycles of hair growth, and in view of theintense mitotic activity and biological sensitivityof proliferating matrix cells, it is astonishing thatneoplastic aberrations of the hair cycles are notmore common. Differentiating neoplasms of hairgerm are in fact extremely rare. A survey of allcutaneous adnexal tumours received in theDepartment of Pathology in the University ofMichigan since 1896 has yielded only twoexamples. A search of the world's literature hasrevealed no reports, with the exception of case 2which was previously described in a survey ofprimary neoplasms of the hair follicle (Headingtonand French, 1962). At that time this neoplasmwas erroneously considered as arising from hairmatrix, not hair germ, although the suggestion ofits stromal induction was briefly discussed and theobvious relationships and similarities to certainodontogenic neoplasms were commented on.Two well recognized and commoner lesions

deserve comparative comment. The first, tricho-epithelioma (Gray and Helwig, 1963) (epithel-ioma adenoides cysticum), is a usually benign,well circumscribed epithelial proliferation,occasionally transmitted as an irregular auto-somal dominant trait, in which small keratinizingcysts simulating effete hair follicles may be found.Hair, hair matrix cells, and stromal aggregatesconsistent with dermal papillas are not present.The second lesion, trichofolliculoma (Gray andHelwig, 1962), microscopically has a character-istic pattern ofsmall and frequently well developedfollicular structures radiating from a centralkeratinizing cystic space which is usually incontinuity with the epidermis. Well formed dermalpapillas and hairs often give the characteristicclinical finding of a tangled tuft of small hairsemerging from the skin surface. The small size,central cystic space, constantintradermal location,and continuity with epidermis serve to distinguishthis lesion from the trichogenic trichoblastoma.The trichomatrioma (Hulett, 1958) (the pilo-

matrixoma, calcifying epithelioma, of Forbis andHelwig, 1961) is composed of hair matrix cellswithout evidence of stromal induction.The description of this small group of differ-

entiating neoplasms of hair germ suggests that anumber of interesting morphological variants ispossible, and, although rare, they can be separ-ated with confidence from other neoplasms ofcutaneous adnexae.

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References

Braun-Falco, 0. (1958). The Histochemistry of the hair follicle.In The Biology of Hair Growth, edited by W. Montagnaand R. A. Ellis, pp. 65-90. Academic Press, New York.

Forbis, R., Jr.. and Helwig, E. B. (1961). Pilomatrixoma (calcifyingepithelioma). Arch. Derm., 83,606-618.

Gray, H. R., and Helwig, E. B. (1962). Trichofolliculoma. Arch.Derm., 86, 619-625.

Gray, H. R., and Helwig, E. B. (1963). Epithelioma adenoidescysticum and solitary trichoepithelioma. Arch. Derm., 87,102-114.

Headington, J. T., and French, A. J. (1962). Primary neoplasms ofthe hair follicle. Arch. Derm., 86, 430-441.

Hulett, R. M. (1958). Trichomatrioma: a clinicopathologic entityseparable from calcifying epithelioma of Malherbe. Arch.Derm., 77, 285-296.

Montagna, W., and Chase, H. B. (1950). Redifferentiation ofsebaceous glands in the mouse after total extirpation withmethylcholanthrene. Anat. Rec., 107, 83-91.

Montagna, W., and Van Scott, E. J. (1958). The Anatomy of thehair follicle. In The Biology of Hair Growth, edited byW. Montagna and R. A. Ellis, pp. 39-64. Academic Press,New York.

Oliver, R. F. (1968). The regeneration of vibrissae-a model forthe study of dermal-epidermal interactions. In EpithelialMesenchymal Interactions, edited by R. Fleischmajer andR. E. Billingham, pp. 267-279. Williams and Wilkins,Baltimore.

Pindborg, J. J., and Clausen, F. (1958). Classification of odonto-genic tumours. Acta odont. scand., 16, 293-301.

Wang, H. (1943). Morphogenetic functions of the epidermal anddermal components of the papilla in feather regeneration.Physiol. Zool., 16, 325-349.

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