Histochemistry of Hidradenoma and Eccrine Spiradenoma

vol. 49, No. 2

Tuz JOURNAL OF IRVESTIOATIVE DERMATOLOOY

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Printed in U.S..4.

1967 by The williams & Wilkins Co.

HISTOCHEMISTRY OF HIDRADENOMA AND ECCRINE SPIRADENOMA R. K. WINKELMANN, M.D.* AND KLAUS WOLFF, M.D.** MATERIALS AND METHODS

INTRODUCTION

54-year-old white woman had Sweat gland tumors are usually described by a 5Hidredenome.—A by 5 by 6 cm, firm, bluish mass on a slight terms implying their origin or pattern of dif- pedicle that protruded below the left breast. The ferentiation. Unna (1) described syringadeno- tumor had developed during a 5-year period from

mata (sweat duet) and spiradenomata (sweat a small, red nodule. The patient's brassiere contincoil) forms. Hidradenoma can refer to syrin- ually irritated the mass, and she had been aware

the lesion since it had first appeared. For 2 to goma as in the term "hidradenoma eruptif of 3 years, a thin watery fluid, which was occasionally

(2)," to sweat gland adenoma (3), and to all blood-tinged, had drained from the mass. The pasweat gland tumors including both duct and tient always was asymptomatie. At examination, coil types (4) and including a series of iso- the tumor was sbghtly ulcerated at the tip. The le-

lated, solid, or cystic dermal tumors witb sion was not fixed to the underlying tissue, and no lymph nodes were palpable. A diagnosis glandular differentiation (5). Lund (5) in- regional of adnexal hamartoma was made, and the lesion cluded ecerine spiradenoma of Kersting and was surgically excised. On examination a sohd and

cystic tumor mass was found. Microscopically, the diagnosis of hidradenoma or tumor of sweat gland

Helwig (6) iu his concept of hidradenoma. We agree with Kersting and Heiwig that there is

was made, and tissue was frozen for histoa distinctive large-cell sweat gland tumor origin chemical examination. Six weeks passed before de-

which we call a solid and cystic hidradenoma. tailed studies were carried out. It is equivalent to the clear-cell myoepitheliEccrine Spiradenoma.—A 43-year-old white man oma but may not have clear cells.

had a 1 by 1 by 1 cm, bluish, freely movable nod-

described as containing phosphorylase and

On microscopic examination, the lesion proved to be an eccrine spiradenoma. Half of the tumor was

on the inner aspects of his right arm. The The histochemieal and electron microscopic ule nodule had started to grow slowly during the prestudies of sweat gland tumors indicate that vious 2 years. It was painful when brushed or there are some distinctive patterns of enzyme pressed lightly. No pain occurred on exposure to reactivity and ultrastrueture that may dif- an ice cube for 5 minutes. The clinical diagnosis ferentiate these tumors. Syringoma has been of glomus tumor or eccrine spiradenoma was made. possessing

the ultrastrueture of ecerine cells

frozen for histochemical studies.

Studies—Routine studies with hematoxylin and (7—9). The eccrine poroma demonstrates phosphorylase and massive glycogen content (5, 10, eosin, periodic acid-Sehiff reaction (PAS) with and diastase, and Alcian blue stains were per11). The dermal duct tumor and hydroeystoma without formed. Sections were cut on a cryostat, and procecontain phosphorylase also (12). A few foci of dures for the following enzyme were used: suephosphorylase at the periphery of an ceerine cinic-dehydrogenase (14), aminopeptidase (15), spiradenoma were observed by Hashimoto indoxyl esterase (16), naphthol AS esterase (17), and associates (13). Because phosphorylase acid phosphatase (17), nucleoside triphosphatase alkahne phosphatase (17), and diphosphoseems to characterize eeerine sweat glands (15), pyridine nucleotide (DPNH) diaphorase (19), and

and tumors of this type, we further investigated a solid and cystic hidradenoma and a

phosphorylase (20).

spiradenoma by histochemical means. This re-

REsULTs

port details these investigations which demHidrodenoma.—This tumor was composed of onstrate chemical as well as morphologic dif- solid and cystic masses of polyhedral and ferences between them. adenoidal cells and showed some evidence of clear-cell degeneration (Fig. I A). The cystic * Mayo Clinic and Mayo Foundation, Section of spaces were irregular and lined by cuboidal Dermatology. ** Mayo Graduate School of Medicine (Uni- cells. In many areas, the tumor masses proversity of Minnesota), Rochester. truded into the cystic spaces in the character ** Recipient of International Postdoctoral Research Fellowship 1F05-TW-919.

of blunt and folded papillomatous masses (Fig.

173

fl&4ci1 I

I

FIG. 1. A, Hidradenoma. The tumor masses are solid and cystic and are clearly separated by fibrous and partially hyalinized stroma. (Hematoxylin and eosin; X 17.) B, Under larger magnification, polyhedral and clear cells are seen forming the tumor lobules and protruding into the cystic spaces. Note dilated vessels in the edematous and hyalinized stroma. (Hematoxyhn and eosin; >< 65.) C, The tumor contains PAS-positive, diastaselabile material indicating glycogen (G). Some of the smaller lobules lack PAS-positive substances (arrows). The hyalinized stroma is Alcian-blue positive. (Alcian blue and PAS; X 65.) D, An intense phosphorylase reaction is present throughout the tumor. Note that the reaction of the hidradenoma is much more pronounced than that of the overlying epidermis. (Phosphorylase; X 16.) 174

HISTOCHEMISTRY OF HIDRADENOMA AND ECCRINE SPIRADENOMA

1 B). The parenehyma was clearly separated from the dermis by a thin fibrous capsule, and this tissue extended between the tumor lobes

175

reaction was comparable to that of the secretory coil of the eccrine sweat glands.

The respiratory enzymes were demonand formed the stroma. The stroma was strated as moderately to strongly reactive in edematous, and partially hyalinized, and con- the tumor. The reaction varied with the area tained dilated vessels and some inflammatory of the tumor, as the clear-cell areas had less of the enzyme, and the greatest concentrations of cells. The tumor contained IPAS-positive mate- the enzyme were in the solid-cell masses. The rial, which was identified as glycogen by its DPNH-diaphorase response was the most striklabile response to diastase (Fig. 1 C). In the ing and was obviously more intense than the clear-cell areas, small amounts of PAS-positive, epidermal reaction. Succinic dehydrogenase diastase-resistant material were found. The was a less impressive reaction, possibly be-

stroma contained Alcian blue-positive acid mucopolysaecharides.

An intensely positive phosphorylase reaction was observed throughout the tumor. The reac-

cause of the storage time in the freezer.

Hydrolase reactivity was characterized in

the tumor cells by the intense activity of

indoxyl esterase (Fig. 2 A). Blue deposits of tion was so intense that even with short in- indigo were present in the solid-cell masses cubation time there was no striking variation and were faint-to-absent in the clear-cell and from area to area of the tumor despite the degenerative areas. The tumor demonstrated variable histologic picture (Fig. 1 D). The much more activity than the normal positive •

-

•.-

• ---.... -

Fin. 2. A, Hidradenoma. An intense indoxyl esterase activity is present in most areas of the tumor but is rather faint in foci of clear-cell degeneration (errow). In order to demonstrate the high esterase content of the hidradenorna, this section was incubated only for a short time. This accounts for the minimal enzymatic activity demonstrated in the transition layer of the overlying epidermis. (Indoxyl esterase; X 25.) B, Spiradenoma. Minimal amount of iodoxyl esterase activity outlining some of the cords of tumor cells. (Indoxyl esterase; >< 100.)

176

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areas in the skin, the transitional zone of the DPNH diaphorase and suecinie dehydrogenase epidermis, or the sweat and sebaeeous glands. were readily demonstrated in the cell masses A few indoxyl esterase-positive fibroblasts (Fig. 3 D). The reaction was even from one with long cell processes were observed in the cell area to another, with the exception of some stroma. Naphthol AS esterase activity exhibited areas of suceinie dehydrogenase where the reaca similar pattern within the tumor, confirm- tion was remarkably intense. The reaction was ing the massive amounts of nonspecific esterase in the cytoplasm of the cells. in this hidradenoma. Leueine aminopeptidase We found no hydrolytic enzymes in the activity was only observed in the stroma. spiradenoma, except for a small amount of acPhosphatases revealed only negative findings tivity with the indoxyl esterase method which

in this tumor. Acid phosphatase was not outhned a few of the cell masses (Fig. 2 B).

present in the tumor cells, and alkaline phos- No leucine aminopeptidase activity or naphphatase was seen only in the stromal blood thol AS esterase activity was found. vessels. Nueleoside triphosphatase was strongly The phosphatases were absent from the cells positive in the vessels of the stroma and, al- of the spiradenoma. The vessels about the tuthough some foci of activity were present mor showed alkaline phosphatase and nueleoin the tumor masses, it was impossible to es- side triphosphatase activity. A few eholines-

tablish a clear cellular localization of this tera se-positive nerves were observed about the reaction.

tumor.

Ecerine Spiradenoma.—This tumor consisted of a solid mass of dark-stained cells when

DISCUSSION

Histoehemistry has proved to be an intereosin section (Fig. 3 A). The ecerine spi- esting and rewarding way to study tumors of observed on low power in hematoxylin and

radenomas may have more than one lobule but the skin. Neurofibromas contain eholinesterase usually they are closely compacted to form one (21); dermatofibromas contain acid phosphatumor or, as in this ease, two tumor masses tase, peptidase, and nonspecific esterase (22); and sweat gland tumors have been shown to separated by a thin strand of stroma. Under high-power microscopy, this growth have phosphorylaSe (7—12). Such modest clasconsisted of tubular, pseudotubular, and solid sifications do not exclude or include tumors

cords of darkly stained cells with a small solely on the basis of chemical content, but amount of cytoplasm (Fig. 3 B). Within the some interesting relatiouship.s become apcellular masses, some lighter stained cells were parent. By the use of a combination of ultraseen, and brightly hyaline material often ap- structural, histoehemical, and basic morphologic peared to line the adenoidal spaces centrally. evidence, new views of cutaneous pathology There was essentially no capsule and only min- become possible. imal stroma within the tumor. The PAS reacPhosphorylase is present in large concentration demonstrated essentially no cellular gly- tions only in the eeerine sweat gland coil and

eogen (Fig. 3 A). The acidophilie material duet and the apocrine duet of human skin. that lined the cellular cords and filled the Syringoma was the first sweat gland tumor to pseudolumina was PAS-positive and diastase- be studied histoehemicallar with phosphoryl-

resistant. No acid mueopolysaceharide was ase, and its content of phosphorylase is so found within the tumor, but a small amount striking that it is natural to relate this enzyme was observed in the peripheral connective tis-

with the structure from which the tumor

may be derived (7—9). Phosphorylase also is observed in eeerine poroma and the dermal duet tumor (8, 10—12). The amounts of phosphorylase in syringoeystadenoma papilliferum and hydroeystoma are consistent with Repeated studies on the same tumor confirmed their relationship to ecerine sweat gland tusue.

The phosphorylase reaction in the eeerine spiradenoma was negative at periods of incubation which readily demonstrated phosphorylase in the normal cutaneous structures. this observation. Respiratory enzymes were observed in mod-

mors (23), but of course this is not con-

clusive (Table I). The hidradenoma in our erate amounts in the spiradenoma. Both study had intense phosphorylase reactivity

Fia. 3. Spiradenoma. A, The tumor consists of a solid mass of basophilic cells separated into two lobes by a thin strand of stroma. (Hematoxylin and eosin; X 30.) B, Under higher magnification the tumor cells are small and basophilic some lighter stained cells are interspersed. They form tubular, pseudotubular, and solid cords lined by bright acidophilic material. (Hematoxylin and eosin; x 120.) C, The tumor cells are PAS-negative, but the

acidophilic material lining the cellular cords and pseudoluminal structures is strongly PAS-positive, diastase-resistant. (Alcian blue and PAS; x 30.) D, Moderate amounts of DPNH-diaphorase are present in the spiradenoma and are evenly distributed. This reaction is much less intense than normally observed in sweat glands. (DPNH-diaphorase;

x

115.) 177

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178

TABLE I Phosphorylase in benign glandular tumors of skin Tumor

Syringoma Syringocystadenoma papilliferum Hidradenoma Hidrocystoma Eccrine poroma Dermal duct tumor Eccrine spiradenoma

Present

+ + + + + —

and stroma of so many tumors (25), we do not believe it can be used as direct evidence of a functional relationship. Acid mucopolysaccharidc is similarly found in the stroma of many tumors. This type of mucin would have more importance if found within the tumor cell.

The cccrinc spiradenoma was chemically different from other swcat gland tumors because it did not contain phosphorylasc, and also lacked all hydrolytic enzymes. We observed modest respiratory enzyme activity similar to that reported by ilashimoto and as-

sociates (13). These authors found minor which associates to the group of eccrine tu- evidence for pbosphatases and did not do mors. From our histochemical study, it is pos- csterase studies of their spiradcnoma. Other sible to consider the cccrinc spiradcnoma as cccrine tumors, including the hidradenoma, an unusual sweat gland tumor, or not even a usually possess estcrasc activity. The minimal sweat gland tumor, despite the small foci of amount of indoxyl esterase activity in the phosphorylase observed in the tumor examined spiradcnoma could be related to the stroma, by Hashimoto and associates (13).

where esterases often are observed. Therefore, Our study has demonstrated that the hidrad- the spiradenoma is not only morphologically

enoma was similar to the sweat gland tu- different but also chemically different from mors in other ways. Its marked content of in-

the hidradcnoma (Table II).

doxyl esterase and naphthol AS esterase is Using the electron microscope, Mungcr and similar to the enzyme content of the sweat associates (24) found vacuoles in the cells of gland coil and to the cccrine poroma. IPcpti- the dermal cccrine cylindroma, which they dase was present in previous studies of syrin- considered similar to those seen in the dark gomas but was absent from the hidradcnoma in cells of the cccrine sweat glands. Ductlikc our study. The methods were different, but structures with central cuticular condensations this is not an adequate explanation because the of cytoplasm were interpreted as being evisweat gland coil is positive by both tech- dence of the eccrinc origin of cylindroma. niques. The dcrmal duct tumor and the syringoma have minimal nonspecific cstcrasc activity, more like the cccrinc duct than the cccrinc

Hashimoto and colleagues (9) found granules

in the cytoplasm of thc syringoma and interpreted these structures as being consistent

coil. It must be admitted that hydrolytic with dermal duct cells. In contrast, the eccrinc enzyme activity may be variable in skin spiradenoma was found by Mungcr and colstructure, and this may be due to individual leagues (26) to be without tubular structures or technical differences.

and secretory vacuoles. Collagen was found in The cccrine poroma is noted for its glyco- the pseudolumina of this tumor, indicating gen content, and the hidradcnoma in our that the contents were undoubtedly stromal in study had foci of glycogen. We would not interpret this as significant because glycogcn is TABLE II usually related to clear-cell degeneration and Enzymatic patterns of hidradenoma, spiradenoma, not necessarily to a pattern of cellular differand eccrine sweat glands entiation. Munger and colleagues (24) used the

mucin content of the dermal cccrine cylin-

Enzyme

droma to support its eccrine nature, observing that the polysaccharide was present withio the tumor cells. Diastase-resistant polysaccharidc Phosphorylasc enzymes occurred in some areas of the hidradenoma in Respiratory Esterases our study, but since it may be seen in the cells

Spiradenoma

Hidrad enoma

Ecr,ine sweat gland roil

—

---j---

---j---

+

++ +++ +++ ++

HISTOCHEMISTRY OF HIDRADENOMA AND ECCRINE SPIRADENOMA

179

origin and implying that true duets were not completely different, chemically and morpresent in the tumor studied. ilashimoto and phologically, from the hidradenoma. No chemiassociates (13) described two types of cells, cal or electron microscopic information about

indeterminate and basal cells, which sur- the mixed tumor exists, but similar studrounded lumina. They also described the infrequent presence of myocpithelial cells and secretory cells with cilia. These preliminary ultrastructural observations of sweat gland tu-

ies of this tumor may end some of the controversy about the existence of an apocrinc or cccrinc mixed tumor and its relationship to the basal cell hamartoma and the hidradcnoma.

mors indicate that it may require electron

At times, the arguments about types of

histochemical observations of many tumors to settle some questions of tumor differentiation. At present, histochcmical methods, although limited, probably provide more use-

adnexal tumors may appear a little removed

ful information.

from the major problems of biology of the skin

and may seem to be only of interest to a dermatopathologist. We would like to point out that a new type of ultrastructural and histo-

The cccrinc spiradcnoma studied was so chemical pathology is giving new insights into free from enzymes that would link it to the cc-

types of cellular proliferation and tumor

crine gland that one is tempted to survey a formation of the skin. These new data indicate broader range of skin tumors to look for two major paths of adnexal differentiation. chemical relationships. Our experience and One of these paths is the basal cell hamartoma the recent literature indicate that basal cell (basalioma). This path demonstrates an incarcinoma and hamartoma, such as trichocpi- finite variety of solid, keratotic, cystic, clear thelioma and cylindroma, also have been cell, mucinous, pigmented, fibrous, and glandufound remarkably free of chemical specificity lar forms. The second is that of the hidradc(27, 28). Cylindroma and cecrine spiradenoma noma, in the broader sense used by Pinkus have been grouped together as similar tumors

and associates (4), with glandular differentia-

by observations of Munger and co-workers tion as a primary morphologic and chemical cellular characteristic as defined by this study. In a recent paper, Mchregan and Pinkus (30) tionship between ecerine spiradenoma and observed two principal groups of tumors aristrichoepithelioma-likc structures. We have ob- ing from organoid ncvi of the skin: basal cell (24) in their discussions of the dcrmal ecerinc cylindroma. Nödl (29) discussed a similar rela-

served comparable situations in which the hamartomas and hidradcnomas. The histochemeeerine spiradcnomas and cylindromas or ical information tends to confirm these two trichocpitheliomas were present in the same patient. The present histochcmieal findings emphasize again the similarities between cccrinc spiradenoma and the eylindroma and trichoepithelioma. We suggest that clinieopathologic observations may imply that the cccrinc spiradcnoma is a glandular form of basal cell hamartoma. Chemical, light micro-

distinct lines of differentiation and suggests that adnexal tumors might be profitably considered within the context of these two cell lines of development. Thus, in our view (for all the complexities in appearance) the basic patterns of adnexal tumor development arc usually simple. The histochcmical data sup-

port such a dualistic approach to adncxal

scopic, and ultramicroscopic evidence arc com- tumors, and we would like to suggest that

patible with this view at present, with the such an hypothesis may readily be tested by exception of the observation of Hashimoto further observations. and associates (13). Such an hypothesis should provide an interesting stimulus for the future study of the relationships of these tumors.

SUMMARY

Enzyme histochemical studies were perLund (5) used the term hidradenoma in formed on a solid and cystic hidradenoma and an inclusive sense to encompass the tumor we an cccrinc spiradcnoma. The hidradenoma described histologically and histochemically displayed a striking content of phosphorylase as well as to include the mixed tumor of the and cstcrolytic enzymes that linked it histoskin and the cccrinc spiradenoma. It is readily genetically to the cccrinc secretory coil and apparent that the spiradenoma studied is other sweat gland tumors such as syringoma,

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180

Cheng, C. S., and Seligman, A. M.: Cyto-

poroma, and the dermal duct tumor. The spiradenoma was chemically similar, not to the

chemical demonstration of succinic dehydrogenase by the use of a new P-nitrophenyl substituted ditetrazole. J Histochem Cytochem,

eeerine gland, hut to the trichoepithelioma 5: 420—436,1957. and other basal cell hamartomas. UltrastrucM. M., Monis, B., Rosenblatt, D., and tural and enzymatic studies indicate two ma- 15. Nachlas, Seligman, A. M.: Improvement of the jor paths of adnexal tumor differentiation: one leads to the formation of enzymatieally basal cell hamartomas, and the other leads to hidradenomas with glandular differentiation and much distinctive enzyme activity, particularly phosphorylase and esterase.

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