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Malignant change in a benign eccrine spiradenoma is rare. Only 13 such cases have been previously reported. Two further cases are described herein, both of which were carcinosarcomas and arose in middle-aged women. In each case continuity was demonstrated between the benign and malignant epithelial components and the sarcomatous element. In case 1 the sarcomatous component showed osteocartilaginous and rhabdomyoblastic differentiation, whereas in case 2 only osteosarcoma was evident. To our knowledge, carcinosarcoma has not been previously described arising in eccrine spiradenoma. The literature regarding malignant eccrine spiradenoma is reviewed.

We report a rare case of apocrine neoplasm with malignant potential. The patient, a 29-year-old man, had a nodule 1 cm in diameter on his left upper eyelid which had been growing slowly for several years. It was a cystic lesion, consisting of neoplastic cells of probable apocrine gland or Moll's gland origin. This opinion was based on the histological characteristics, which included eosinophilic cytoplasm accompanied with decapitation secretion, iron granules, and granular depositions which were stained positively with periodic acid-Schiff, with and without diastase digestion. Ferritin was found in their cytoplasm, a feature that has not been reported. It was uncertain whether the neoplasm was benign or malignant, because the cells showed nuclear atypia, characterized by variation in size and hyperchromasia, but lacked the histological features of malignancy, including infiltration into the adjacent tissue and mitosis.

The presence of parathyroid hormone-related protein (PTHrP) in the apocrine adenocarcinoma tumor line (CAC-8) derived from a hypercalcemic dog was demonstrated by western and northern blot analyses. Western blots of CAC-8 tumor extracts revealed a major protein with a molecular weight of approximately 18,000 daltons that cross-reacted with antiserum to human PTHrP. Northern blots demonstrated multiple-sized messenger RNA transcripts in CAC-8 that hybridized to a full-length cDNA probe to human PTHrP. Adenocarcinomas derived from apocrine glands of the anal sac also were stained immunohistochemically for antigens that cross-react with antiserum to human PTHrP. The tumor line (CAC-8) maintained in nude mice stained positively for PTHrP in 13 of 24 tumors. Three of ten apocrine adenocarcinomas from dogs with hypercalcemia stained for PTHrP, whereas zero of ten tumors were positive from normocalcemic dogs. Normal canine epidermal keratinocytes and areas of squamous metaplasia in a perianal gland carcinoma also were positive for PTHrP. These data demonstrated that canine tissues contained a homologue to human PTHrP that likely is important in the pathogenesis of humoral hypercalcemia of malignancy.

Using a rabbit anti-human liver ferritin antibody, we examined the binding patterns of this reagent in normal skin and observed a unique binding pattern limited to the outermost layer of the eccrine duct. Examination of a variety of sweat gland neoplasms revealed 2 distinct patterns. One was the binding of this antibody to the outermost layer of cells in the epithelial cords of syringoma, producing a characteristic ring when seen in cross-section. This pattern of binding did not occur in other neoplasms known to be related to the eccrine duct such as dermal duct tumor and eccrine poroma. Only sparse sporadic binding occurred in other eccrine and apocrine neoplasms. A second characteristic binding pattern, not related to that noted in syringoma and diffuse in pattern, was seen in acrospiroma and in a number of adnexal carcinomas. Diffuse ferritin expression has been described in malignant neoplasms in tissues other than skin. Diffuse ferritin staining of certain sweat gland neoplasms may be an indication of biologic activity and potential aggressivity of these neoplasms.

Thirty benign and seven malignant adnexal tumors of the skin and one lymph node metastasis were stained for laminin and type IV collagen with rabbit antibodies against the human basement membrane (BM) proteins using the immunoperoxidase technique. Fifteen of the benign sweat gland, sebaceous gland, and hair follicle tumors showed a continuous and distinct BM around the tumor aggregates. The cylindromas and eccrine spiradenomas seemed to produce excessive amounts of BM material, part of which was seen as amorphic patches within the tumor cell clusters, whereas the trichofolliculomas, trichoepitheliomas, and pilomatrixomas showed an absence of BM from many areas. In syringomas, in addition to the tubular structures surrounded by a continuous BM, undifferentiated cell nests containing granular BM material were present. They probably represent primitive structures obtaining during early development into tubules. The seven malignant tumors and the only metastasis studied here all contained small, narrow strips of BM material extracellularly between the infiltrating tumor clusters. Only in two cases was faint staining for laminin found within the cells. The pepsin pretreatment of the formalin-fixed, paraffin-embedded samples had most probably degraded the intracytoplasmic BM material in most cases. The BM defects were found to be associated with malignancy and low differentiation of the adnexal skin tumors, as reported previously for other tumor types, but a partial loss of BM was also associated with high differentiation in some benign adnexal tumors.

The tissues from 16 cases of adenosquamous carcinoma (pseudoglandular squamous cell carcinoma or adenoacanthoma of the sweat glands of Lever) and 26 cases of invasive squamous cell carcinoma of the vulva were studied for the presence of human papillomavirus (HPV) genomes using Southern blot hybridization on fresh tissues. Types 1, 2, 3, 4, 5, 6, 16, and 18 HPV DNA probes and in situ hybridization were used on formalin-fixed paraffin sections using type 2, 6, 16, and 18 HPV DNA probes. Only one case of adenosquamous carcinoma contained an undetermined type of HPV DNA, whereas five cases of squamous cell carcinoma contained HPV DNA. Three of these five cases contained type 16, one type 6 HPV, and two an undetermined type. These results demonstrate HPV DNA associations with malignancy of the vulva that are similar to those observed elsewhere in the genital tract.

Using immunoperoxidase methods, normal sweat glands, 44 benign and 4 malignant sweat gland tumors were tested for the presence of carcinoembryonic antigen (CEA), pregnancy-specific-B1-glycoprotein (SP1) and actin (ACT). CEA and SP1 stained the secretory and duct-lining cells of normal eccrine glands. Among benign tumors, 74% were positive for CEA and 44% for SP1. The staining reaction was found mainly in luminal secretions and surrounding cells. Staining by SP1 was reduced, but not suppressed, after absorption with the purified antigen. ACT was found in myoepithelial cells of the secretory tract of normal glands and in basal cells of all cases of hidradenoma papilliferum. Only 3 sweat gland carcinomas reacted for CEA. In a malignant chondroid syringoma, no ACT-positive cells were seen in the myxochondroid stroma. The potential value of CEA, SP1 and ACT in the diagnosis of sweat gland tumors is discussed.

The identification of metastatic carcinoma of the breast may be difficult in the absence of a previous history of breast cancer. Various immunophenotypic markers have been introduced to aid in this process. A monoclonal antibody directed at a 15-kilodalton (kd) gross cystic disease fluid protein (GCDFP-15) was applied immunohistochemically to paraffin sections of 105 breast cancers and 585 nonmammary malignancies in order to assess its value in this context. In addition, GCDFP-15 was compared with another putative mammary epithelial marker, alpha-lactalbumin (ALA), with respect to sensitivity and specificity for a diagnosis of breast carcinoma. Overall, the rates of specificity and sensitivity and the predictive value of a positive result for GCDFP-15 were 95%, 74%, and 74%, respectively. Corresponding statistical parameters for ALA were 50%, 50%, and 23%. A consistent congruency between the reactivity patterns of primary and metastatic breast cancers was noted for GCDFP-15 but not for ALA. Besides mammary carcinomas, the major tumor types that expressed GCDFP-15 were carcinomas of the salivary glands, sweat glands, and prostate. Since the latter three types of lesions are unlikely to be diagnosed as metastatic breast cancer, statistical indices were recalculated after exclusion of these three tumor types. Following this exclusion, the adjusted rate of specificity of GCDFP-15 and the predictive value of a positive result for a diagnosis of metastatic carcinoma of the breast were each 99%. In contrast, predictive parameters for ALA were not altered. These results show that GCDFP-15 is a specific marker for breast cancer and is superior to ALA in this respect.

An operatively removed apocrine carcinoma of the breast from a 62-year-old Japanese lady has been observed by the ABC method, using the monoclonal antibody 115D8. The cancer cells and metaplastic epithelia exhibited similar ultrastructural findings (an apical snout, apocrine granules, etc.) as the apocrine sweat gland cells, although no evidence of apocrine secretion could be detected. The immunohistochemical testing, using monoclonal antibody, 115D8, showed an apical, linear, dot-like, staining in the supranuclear regions on the apocrine sweat gland cells and on the apocrine metaplastic cells of the mammary gland. Similar stainability also was observed in the well-differentiated area of the apocrine carcinoma, while a heterogeneity in staining, such as unstained cells and diffuse cytoplasmic-stained cells were found in the poorly-differentiated areas. These abnormal staining patterns indicate the malignant changes of the apocrine cells.

Several monoclonal antibodies (MAB) have been produced using an eccrine carcinoma cell line as an immunogen. One such MAB, SKH1, reacted with both the secretory portion and coiled duct of the eccrine and with the secretory portion of apocrine gland. SKH1, however, did not react with myoepithelial cells, intradermal ducts of both types of sweat gland, or with other components of normal axillary skin including the epidermis and follicular apparatus. The reaction was strongest if the specimen was fixed with 80% methanol, and moderate on non-fixed or acid-alcohol-fixed specimens. Only weak reaction was obtained on cold acetone-fixed specimens, and reaction was negative with formalin-fixed, paraffin-embedded tissues. SKH1 reacted positively with the cytoskeleton of the eccrine carcinoma cell line, Colo-16 and MCF-7. Applied to pathological skin specimens, SKH1 reacted with the tumor cells of clear cell hidradenoma, syringocystadenoma papilliferum, and extramammary Paget's disease. SKH1 also reacted with the tumor cells of metastatic adenocarcinomas arising from lung, breast and ovary. SKH1 did not react with the majority of tumor cells of eccrine poroma, but reacted with single-layered cells lining narrow ductal lumina. SKH1 did not react with epithelial cells lining cystic or ductal lumina of syringoma, but reacted moderately with the amorphous keratin-like substance filling the lumina. Immunoblot analysis revealed that SKH1 recognizes a 40 Kd sweat gland-associated antigen, and can be an aid to identifying tumors arising from sweat gland structures.

A 31-year-old man with multiple cystic tumors symmetrically distributed on his eyelids is presented. Histopathology and immunohistochemistry suggest the diagnosis of apocrine hidrocystomas. Apocrine hidrocystomas occur frequently on the face, but multiple and symmetrical occurrence on the eyelids has not been reported up to now.

The expression of involucrin was examined in 23 skin tumours of hair follicle origin, 17 tumours of sweat gland origin and three tumours of unknown origin, using an immunoperoxidase technique. All tumours from the hair follicle showed a positive reaction for involucrin. In particular keratoacanthoma and the squamous eddies in various tumours stained strongly. Trichofolliculoma, trichilemmoma and pilomatrixoma exhibited characteristic staining patterns which resembled those in the normal hair follicle. On the other hand the majority of the tumours of sweat gland origin did not stain, with restricted positive reactions in areas showing lumen formation or squamous metaplasia. In contrast to the lack of staining in syringoma, a positive reaction was observed in desmoplastic trichoepithelioma, which is histologically similar to syringoma. Clear cell acanthoma, the origin of which is still controversial, showed a staining pattern which indicated that its origin may not be in the sweat gland. These results suggest that testing for involucrin in skin appendage tumours may be very useful for understanding the kinetics of maturation as well as in determining the origin of the tumours.

A total of 34 cases (eccrine poroma: 2, cylindroma: 2, eccrine spiradenoma: 4, syringocystadenoma papilliferum: 1, hydroadenoma papilliferum: 1, clear cell hydroadenoma: 7, mixed tumour: 16) of sweat gland tumours of the skin were described in terms of immunohistochemical distribution of keratins using polyclonal anti-keratin antiserum (TK, detecting 41-56 KDa keratins) and monoclonal antibodies (KL1, 55-57 KDa; PKK1, 40, 45, 52.5 KDa). Keratin expression in eccrine poroma, spiradenoma and syringocystadenoma was similar to that in the ductal segment of normal sweat glands. Cylindroma showed usually slight staining for kertins. Tumour cells of hydroadenomas showed not so prominent staining for any of the keratins; however, histologically, tumour cells indicated marked variation, and the degree of keratin proteins also was different among these histological variants. Mixed tumours of the skin were strongly decorated with anti-keratin antibodies along the luminal surface cells of typical structures, while no staining occurred in outer side cells. Luminal tumour cells may be differentiated from secretory coil cells, whereas outer side cells may have a myoepithelial origin, as outer layer cells found in pleomorphic adenoma of salivary glands.

Hidroacanthoma simplex was first described in 1956, but because of its rarity there is still confusion regarding the nomenclature of this and similar entities. The histological features of fifteen cases are presented and the literature is reviewed.

Immunohistochemical distribution of human epidermal growth factor (hEGF) was described in 17 cases of mixed tumour of the skin with monoclonal antibody. In normal sweat glands, epithelial cells in the secretory portion and in the transitional area between secretory portion and duct showed prominent staining for hEGF. In the salivary pleomorphic adenoma type of mixed tumour of the skin, luminal tumour cells of tubular and duct-like structures gave a very characteristic hEGF staining reaction. The tumour cells showing strong staining for hEGF were scattered throughout the solid foci in this type of mixed tumour. Tubular epithelial cells in the clear cell adenoma type also displayed a positive hEGF reaction. And apocrine mixed tumours strong staining for hEGF occurred on the apical side of tubular and ductal tumour cells. In view of the immunohistochemical staining patterns for hEGF, the histologic origin of mixed tumours of the skin is suggested to be cells in the secretory portion and those in the transitional portion between secretory portion and duct of the sweat gland.

Eccrine syringofibroadenoma is a rare tumor considered to originate from the excretory portion of the eccrine sweat gland. A new case of this lesion, whose acrosyringeal differentiation was underlined by an immunohistological study using antibodies to keratin and involucrin, is reported herein.

Clear-cell syringoma is a histologic variant of syringoma that is otherwise clinically indistinguishable from ordinary syringoma. This variant is formed by cells that have pale or clear cytoplasm as a result of glycogen accumulation. There is a high association of clear-cell syringoma and diabetes mellitus. A case of clear-cell syringoma associated with diabetes mellitus is described. Electron microscopic examination revealed that periluminal cells showed intra- and extracytoplasmic multivesicular bodies that may be characteristic of the clear-cell variant. Immunohistochemistry for carcinoembryonic antigen (CEA) showed ordinary syringomas as in the presence of CEA within and surrounding duct-like spaces.

Sixty-four specimens of mixed tumors of the skin were studied by conventional microscopy. Sections from all 64 specimens were stained by hematoxylin and eosin, and sections from 18 of those specimens were stained by immunoperoxidase techniques for the presence of S-100 protein, carcino-embryonic antigen (CEA), keratin, actin, vimentin, epithelial membrane antigen (EMA), and gross cystic disease fluid protein-15 (GCDFP-15). Two distinctive histopathological patterns of mixed tumors of the skin became apparent, namely, apocrine and eccrine. Mixed tumors with apocrine features are by far the most common. Immunoperoxidase techniques, in our experience, do not enable differentiation between apocrine and eccrine types of mixed tumors.

A total of 78 cases of adnexal tumors of the skin were examined with the use of monoclonal antibody against epithelial membrane antigen (EMA). The EMA reaction was confined to luminal surfaces and lateral borders of sweat glands, both eccrine and apocrine, being usually absent in ductal segments. Neoplastic lesions of all the adenomatous tumours and mixed tumours of sweat glands showed specifically positive EMA staining of luminal surfaces and lateral borders of tubular, duct-like, and cystic structures. However, solid foci of those tumours were negative for EMA. Tumours of ductal origin, e.g. syringomas and poromas, exhibited positive EMA staining in their plasma membrane, although normal intact keratinocytes did not stain for EMA. Immunohistochemical distribution of EMA in skin adnexal tumours was classified into two types: one in which the luminal surfaces and lateral outer borders were positive, similar to that of the normal secretory coil, and the other in which the plasma membrane of neoplastic cells of ductal origin was positive.

The antibody against a molecular weight 15,000 protein isolated from the breast cyst fluid (GCDFP-15) was applied to tissue from cutaneous tumors, especially to sweat gland tumors. This protein was purified from the breast cyst fluid; antisera was prepared in rabbits. Ninety six cases of cutaneous tumors were stained by the PAP method. Apocrine hydrocystoma, syringocystadenoma papilliferum, so-called mixed tumor of the skin, extramammary Paget's disease, microcystic adnexal carcinoma, and mucinous carcinoma of the skin were positively stained. Eccrine poroma, eccrine spiradenoma, syringoma, eccrine hydrocystoma, papillary eccrine adenoma, adenoid type of basalioma were negative. These observations indicate that the positively stained tumors have functioning seromucous cells, which are characteristic of apocrine gland cells and eccrine dark cells in the skin.

A 16K PTH-like protein with a unique primary structure has recently been isolated from several human tumors associated with the syndrome of humoral hypercalcemia of malignancy. Certain spontaneous and transplantable animal tumors also cause this syndrome. The responsible mediator in these animal tumors is not known. We report the isolation of 16K proteins from the rat H500 Leydig cell tumor and the canine apocrine cell adenocarcinoma of the anal sac. Both proteins are potent activators of PTH receptor-coupled adenylate cyclase in bone cells. Both proteins demonstrate similarities in amino acid composition to one another and to the human PTH-like protein. Limited amino-terminal sequence information from the canine protein demonstrates homology with the human PTH-like protein. Antibodies raised to a synthetic human PTH-(1-36)-like peptide cross-react with both the rat and canine proteins in an immunoradiometric assay. These data demonstrate that by physical and immunological criteria PTH-like peptides are present in these animal tumors that appear to be closely related to the human PTH-like peptide. These data further suggest that this protein is not unique to humans, but has an evolutionary origin which extends back at least 65-80 million yr.

The staining patterns of normal sweat glands and sweat gland-derived neoplasms using 2 monoclonal antibodies to keratins (Dako-CK1, Cam 5.2) has been assessed. Based on findings in normal glands, the differentiation of these benign neoplasms is considered, with positive evidence for apocrine and eccrine differentiation, and in the latter, differentiation to ductal or secretory type epithelia. This easily applied technique (indirect immunoperoxidase) is suitable for use in routinely processed tissue and employs 2 commercially available monoclonal antibodies. The findings may be of assistance in general surgical reporting of problematic cases.

A mouse monoclonal antibody obtained after immunization of BALB/c mice with large molecular weight salivary mucins decorated an epitope in eccrine duct and acrosyringium in sections from formalin-fixed, paraffin-embedded tissues. Eccrine coil, apocrine gland and other cutaneous structures were not decorated by the monoclonal antibody. This antibody was used to study the histogenesis of a number of adnexal neoplasms.

The apocrine nevus is a rare tumor. We report a 32-year-old man with a neck nodule, histologically an apocrine nevus displaying mature and immature apocrine structures in a distinctive pattern. The carcinoembryonic antigen staining was positive intracellularly only in the smaller luminal structures. We have named this unique tumor a polymorphic apocrine nevus.

We examined 4 cases of sclerosing epithelial hamartoma for the presence of carcinoembryonic antigen (CEA) by the unlabelled antibody peroxidase-antiperoxidase method but could not detect CEA in these lesions. Because syringomas contain CEA, the detection of this antigen is a useful marker for differentiating sclerosing epithelial hamartomas from syringomas.

Apocrine hidrocystomas are often pigmented clinically. The cause of this pigmentation is not known. A case of pigmented apocrine hidrocystoma is presented with evidence of melanin as the underlying mechanism of the pigmentation. Review of an additional 150 cases suggests that this is rare. The Tyndall effect, analogous to that seen in blue dome cysts of fibrocystic disease of the breast may be the likely explanation of the pigmentation seen clinically in most cases of apocrine hidrocystomas.

The expression of two immunohistochemical markers of neural tissue and of cutaneous sweat glands (S-100 protein and Leu-7 antigen) was studied in a group of cutaneous epithelial, mostly glandular, tumors. These antigens were detected only on sweat gland neoplasms showing both types (eccrine and apocrine) of differentiation. These results suggest that antibodies to S-100 protein and to Leu-7 antigen have a limited value in the distinction between eccrine and apocrine tumours, but they may serve as a useful adjunct for the confirmation of the glandular differentiation of cutaneous epithelial tumors.

Many groups of squamoid cells arranged in whorls were found in a case of clear cell hidradenoma. These cells showed positive staining for carcinoembryonic antigen, but S-100 protein was not detected. Electron microscopic examination showed considerable amounts of tonofilaments, but neither keratohyalin granules nor multivesicular dense bodies were present in these cells. These features suggest that the constituting cells of whorls differentiated toward the eccrine ductal cells, in particular the intraepidermal ductal cells.

In an attempt to characterize the immunocytochemical attributes of eccrine sweat gland carcinoma, we studied 32 examples of this tumor with antibodies to epithelial membrane antigen (EMA), cytokeratin (CK), carcinoembryonic antigen, S100 protein, alpha-lactalbumin, salivary amylase, blood group isoantigens, beta-2-microglobulin, and Leu M1. All cases expressed EMA and CK, and 28 of 32 cases also displayed at least 2 of the 6 remaining antigens. No significant variations were noted in the immunophenotypes of histologic subtypes of eccrine carcinoma. These results provide an objective means of diagnostic separation between sweat gland carcinoma and other primary malignant cutaneous tumors. However, they do not appear to correlate with the degree of tumoral differentiation, and are of no assistance in the separation of benign and malignant sudoriferous neoplasms. The ability of immunocytochemical techniques to distinguish between primary malignant adnexal cutaneous tumors and metastases to the skin appears unlikely, but remains to be studied further. Also, the use of immunostaining panels is advised in the study of adnexal carcinomas, since no single determinant in isolation is specific for these neoplasms.

The histogenesis of hidrocystomas was examined by the use of immunostaining for S-100 protein. In normal sweat glands, S-100 protein was found exclusively in the secretory cells of eccrine glands, whereas this protein was not present in the other parts of eccrine glands or at any levels of the structure of apocrine glands. On the bases of this immunostaining pattern in normal sweat glands, we attempted to correlate the origin of 8 cases of hidrocystoma to the presence of S-100 protein-positive cells. S-100 protein was detected in the cells of one solitary eccrine hidrocystoma, but not in those of 2 cases of "classic", multiple-lesion type of eccrine hidrocystoma. This indicated that the former arose from the secretory portion of the eccrine gland and the latter from the eccrine ductal cells. Two of the 5 cases of apocrine hidrocystoma showed positive staining in a part of the lining cells of the cyst wall, while the other 3 cases were negative to this protein. This finding suggests that some of the tumors diagnosed morphologically as apocrine hidrocystoma differentiate in the direction of eccrine secretory cells. In addition to S-100 protein, we also surveyed for the presence of carcinoembryonic antigen (CEA), and all cases examined were consistently positive to this substance. The detection of S-100 protein was considered to be more helpful in classifying hidrocystomas than that of CEA.

Sixty-five cases of benign sweat gland tumors of the skin were studied for the expression and localization of gross cystic disease fluid protein-15 (GCDFP-15) by immunoperoxidase methods. There was positive staining of tumors of probable apocrine differentiation in 10 of 11 cases of apocrine hidrocystoma and five of five cases of hidradenoma papilliferum. There was no immunoreactivity for GCDFP-15 for tumors of probable eccrine differentiation, including five cases of eccrine hidrocystoma, five cases of eccrine poroma, five cases of eccrine spiradenoma, 10 cases of clear cell hidradenoma, and nine cases of syringoma. There was variable positive staining of tumors of more uncertain histogenesis, including eight of eight cases of syringocystadenoma papilliferum, one of four cases of cylindroma, and two of two cases of chondroid syringoma (mixed tumor). The above data support a functional differentiation of the expression of GCDFP-15 by eccrine compared to apocrine glandular epithelium with benign tumor development.