Spiradenoma

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Eccrine spiradenoma

Spiradenoma

Spiradenoma also called eccrine spiradenoma is a rare, benign sweat glands tumor that originates in the skin 1. Spiradenomas or eccrine spiradenomas arise from the eccrine sweat glands that form small, solitary nodules that can grow to several centimeters in size (0.3 to 5 cm) 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12. Usually, there is no connection to the overlying epidermis 13. However, some authors indicate spiradenoma arising from apocrine gland origin 14, 15.

Eccrine spiradenomas form firm nodules that show up on your scalp, neck and upper body, but can also occur in other areas like the breast. Although rare, multiple eccrine spiradenomas on the trunk and extremities have been described 16, 17. Typically, eccrine spiradenomas are often blue or flesh-colored, but may also be grey, pink, purple, red or yellow slow growing and solitary nodule on the head or upper trunk in adult patients and can be very painful 18, 19, 20, 21, 22. Spiradenoma skin tumors range from under 1 cm to several centimeters. Spiradenomas are sometimes painful.

Eccrine spiradenoma can occur at any age, but most often affects young adults in the 2nd to 4th decades of life with no difference between males or females 23, 24, 25, 18.

While eccrine spiradenomas are usually benign, long-standing lesions can sometimes develop into malignant spiradenocarcinomas, especially in people over 50 26, 27, 28, 29, 30, 31. Spiradenocarcinomas (malignant spiradenomas) are aggressive and have high metastasis rates and low survival rates.

Ultrasound evaluation of the tumor generally reveals a smooth, lobulated mass in the superficial subcutaneous tissue 32. The mass appears hypoechoic and often has increased vascularity. The classic MRI appearance is a T1-hypointense, T2-hyperintense mass, with homogeneous enhancement after contrast administration 33.

Clinically, it is difficult to differentiate eccrine spiradenoma from other skin tumors, therefore biopsy is vital for accurate diagnosis. It is important to find out epithelial cells, myoepithelial cells and lymphocytes along with void spaces between blood vessels under the microscopes for diagnostic confirmations 6. Characteristic histological findings on hematoxylin and eosin (H&E) staining are two distinct cell types: a basaloid cell population with hyperchromatic nuclei and scant cytoplasm and a larger cell type with abundant, pale cytoplasm 34, 13. The cells are arranged into sheets, cords, or trabeculae, with cells with large nucleus and pale cytoplasm are located in the center and cells with smaller dense nucleus are located in the periphery 6. The lumen of this contains an acidic substance which is being arranged around a smaller lumen. Some tumors are markedly vascular with cystic dilation of their vascular channels, likely accounting for their increased vascularity seen on ultrasound 32, 13.

Eccrine spiradenoma may accompany similar tumors of apocrine origin, such as trichoblastoma and cylindroma. Histologically, the eccrine glands have relatively clear cytoplasm and occasionally squamous epithelium whereas the apocrine glands have eosinophilic cytoplasm and nuclei located at the base bottom (off centered) 35.

The standard treatment for spiradenoma is surgical excision, but with no clear consensus regarding the width of surgical margins 36. Imaging techniques like CT scans, MRIs, and ultrasounds can also be used to help with treatment.

Figure 1. Eccrine sweat glands

Eccrine sweat glands

Figure 2. Eccrine spiradenoma

Eccrine spiradenoma

Footnotes: A 49-year-old woman presented with a solitary deep mass of 10-year duration on the right upper arm. The lesion was asymptomatic, firm, and 2.5×2.5 cm in size, with a bluish color in the overlying intact skin (arrow) on her right upper arm.

[Source 37 ]

Figure 3. Spiradenoma scalp

eccrine spiradenoma scalp
[Source 38 ]

Figure 4. Giant vascular eccrine spiradenoma

Giant vascular eccrine spiradenoma

Footnotes: A 47-year-old woman with a 5-year history of a right shin lump. It has been enlarging gradually and has been asymptomatic at rest. However, it has become exquisitely tender to light touch in the preceding months. She was otherwise well, with a history of bipolar affective disorder. She did not have a history of varicose veins or any skin lesions. On examination, there was a tender 3- × 4-cm ovoid mass on the anteromedial aspect of the right leg with surrounding pink discoloration. It was firm to palpation with a rubbery consistency. It was mobile over the anterior surface of the tibia. She did not have any other skin lesions or varicosities. Cardiovascular examination findings were otherwise unremarkable. Surgical excision was performed through a longitudinal incision directly over the mass. A 3- × 2-cm rubbery gray-blue mass was identified in the subcutaneous tissue with multiple feeding veins. The mass was dissected from the surrounding tissue, and the feeding veins were ligated. Histologic examination of the mass confirmed features consistent with a vascular eccrine spiradenoma, including multinodular structure with focal cystic change, intracystic altered blood, pericystic cholesterol clefts, and hemosiderin. Giant vascular eccrine spiradenoma is a rare variant of eccrine spiradenoma first described by Cotton et al. in 1986 39. They reported two cases of large eccrine spiradenoma with a marked degree of vascularity. The giant vascular variant is different from eccrine spiradenoma by its larger size (diameter of > 2 cm) and high vascularity. Bleeding and internal hemorrhage are common presentations and give rise to the frequent misdiagnosis of giant vascular eccrine spiradenoma as angiomatous lesions 40, 41.

[Source 42 ]

Figure 5. Spiradenoma pathology

Spiradenoma

Footnotes: Bland basaloid cells admixed with lymphocytes and droplets of basal membrane material. Focal ductal differentiation can be recognized.

[Source 43 ]

Figure 6. Eccrine spiradenoma pathology

Eccrine spiradenoma pathology

Footnotes: High-powered view demonstrating small, dark, basaloid cells with hyperchromatic nuclei, larger cells with pale nuclei in the center of the clusters, and numerous scattered lymphocytes seen throughout (H&E, magnification 100x)

[Source 14 ]

Spiradenoma causes

The exact cause of eccrine spiradenoma is still unknown and remains controversial. Some authors found spiradenoma arising from eccrine sweat glands in the dermis and superficial subcutaneous tissue. However, some authors indicate spiradenoma arising from apocrine gland origin 14, 15. Multiple spiradenomas may be a sign of a familial spiradenoma syndrome or Brooke-Spiegler syndrome. To diagnose Brooke-Spiegler syndrome, in addition to spiradenomas, trichoepitheliomas and cylindromas must be present. Brooke-Spiegler syndrome is an uncommon autosomal dominant disorder characterized by a high affinity to form multiple skin tumors, especially trichoepitheliomas, cylindromas, and spiradenomas 44. The mutations in the CYLD gene on chromosome 16q12 have been described in families with cylindromas, trichoepitheliomas, and spiradenomas 45. Recently, the CYLD gene has been recognized as an important tumor suppressor gene with a prominent role in the regulation of nuclear factor kappa-beta (NF-κβ), a transcription factor that promotes cell survival and oncogenesis 46, 47. Thus, defective tumor suppression genes seem to be important in the development of spiradenomas 14. The CYLD gene provides instructions for making CYLD enzyme called CYLD lysine 63 deubiquitinase that helps regulate numerous signaling pathways, many of which are involved in cell growth 48. These pathways include nuclear factor-kappa-B (NF-KB), Wnt, c-Jun N-terminal kinase (JNK), transforming growth factor beta-1 (TGFB1), and Notch signaling pathways 48. By regulating these signaling pathways, the CYLD lysine 63 deubiquitinase enzyme helps cells respond properly to signals that promote cell growth and division (proliferation) or self-destruction (apoptosis), as necessary. By regulating signals that control cell growth, the CYLD lysine 63 deubiquitinase (CYLD) enzyme acts as a tumor suppressor, which means that it helps prevent cells from growing and dividing too fast or in an uncontrolled way.

Spiradenoma signs and symptoms

Eccrine spiradenoma is a rare, benign sweat glands tumor that originates in the skin. Eccrine spiradenomas arise from the eccrine sweat glands that form small, solitary nodules that can grow to several centimeters in size (0.3 to 5 cm) 2, 3, 4, 5, 6, 7, 8, 9, 10. However, some reviews indicate spiradenoma from apocrine gland origin 14, 15. Usually, there is no connection to the overlying epidermis 13. A large majority of patients present with pain or tenderness associated with the lesion, as was seen in 91% of the patients first described by Kersting and Helwig in 1956 34.

Eccrine glands are simple sweat glands that open directly onto your skin’s surface. Eccrine sweat glands occur over most of your body and are made up of coiled ducts and a secretory coil deep in the dermis. Eccrine sweat glands are found in most of your body and help regulate body temperature. Eccrine glands release sweat to the skin’s surface when the body temperature rises. The sweat evaporates, cooling the skin and blood.

Eccrine spiradenomas form firm nodules that show up on your scalp, neck and upper body, but can also occur in other areas like the breast. Although rare, multiple eccrine spiradenomas on the trunk and extremities have been described 16, 17. Typically, eccrine spiradenomas are often blue or flesh-colored, but may also be grey, pink, purple, red or yellow slow growing and solitary nodule on the head or upper trunk in adult patients and can be very painful 18, 19, 20, 21, 22. Spiradenoma skin tumors range from under 1 cm to several centimeters. Spiradenomas are sometimes painful.

Eccrine spiradenoma can occur at any age, but most often affects young adults in the 2nd to 4th decades of life with no difference between males or females 23, 24, 25, 18.

Spiradenoma diagnosis

Ultrasound evaluation of the tumor generally reveals a smooth, lobulated mass in the superficial subcutaneous tissue 32. The mass appears hypoechoic and often has increased vascularity. The classic MRI appearance is a T1-hypointense, T2-hyperintense mass, with homogeneous enhancement after contrast administration 33.

Clinically, it is difficult to differentiate eccrine spiradenoma from other skin tumors, therefore the definitive diagnosis of eccrine spiradenoma consists of a skin biopsy; however, fine needle cytology has also been reported 49.

Spiradenoma pathology

Eccrine spiradenoma comprises large, sharply circumscribed, basophilic nodules (“cannon balls” or “blue balls”) arranged in intertwining cords, islands, or sheets in the dermis or subcutaneous tissue that are surrounded by a fibrous capsule 50. It is important to find out epithelial cells, myoepithelial cells and lymphocytes along with void spaces between blood vessels under the microscopes for diagnostic confirmations 6. Characteristic histological findings on H&E staining are two distinct cell types: a basaloid cell population with hyperchromatic nuclei and scant cytoplasm and a larger cell type with abundant, pale cytoplasm 34, 13. The cells are arranged into sheets, cords, or trabeculae, with cells with large nucleus and pale cytoplasm are located in the center and cells with smaller dense nucleus are located in the periphery 6. The lumen of this contains an acidic substance which is being arranged around a smaller lumen. Some tumors are markedly vascular with cystic dilation of their vascular channels, likely accounting for their increased vascularity seen on ultrasound 32, 13.

Duct-like structures can be present at the center of the lesions, which often have scattered lymphocytes 18. Strands of cells are positive for cytokeratin and the lumina are positive for carcinoembryonic antigen 51. Eccrine spiradenoma may accompany similar tumors of apocrine origin, such as trichoblastoma and cylindroma. Histologically, the eccrine glands have relatively clear cytoplasm and occasionally squamous epithelium whereas the apocrine glands have eosinophilic cytoplasm and nuclei located at the base bottom (off centered) 35. S-100 staining has been noted in eccrine spiradenoma and cylindromas attributed to eccrine differentiation. In cases where eccrine spiradenoma has co-expression of cytokeratin and smooth muscle actin, authors have suggested differentiation toward myoepithelial cells 52.

Malignant eccrine spiradenoma is suspected in patients with rapid enlargement, an increase in number, change in color, or with the development of symptoms, such as pain, ulceration, or pruritus. Histological findings may include atypical cells, elevated mitotic counts, loss of the typical lobular pattern and dual cell population, rare foci of necrosis, and enlarged cells of one cell type on histological evaluation 24, 53. Additionally, tumor cells extending through the capsule into adjacent stroma are also suggestive 54.

Immunohistochemistry can be useful in evaluating for malignant cases of eccrine spiradenoma. In a case of malignant eccrine spiradenoma of the breast, typical histological features were noted along with areas of adenocarcinoma, squamous cell carcinoma, and sarcoma with staining positive for the p53 protein 55. Others have demonstrated that cells may express cytokeratins, epithelial membrane antigen, and p53 56.

Eccrine spiradenoma differential diagnosis

Eccrine spiradenoma should be considered in the differential diagnosis of skin tumors.

  • Cylindroma — In cylindroma the low power view shows discrete polygonal tumor islands. There is frequently a more prominent population of S100 positive dendritic cells while in eccrine spiradenoma there is a lymphocytic infiltrate 7, 57, 58. Dermal cyclindroma can be differentiated histologically from eccrine spiradenoma. Comprised of cords of cells, surrounded by a prominent basement membrane, that exhibit a mosaic pattern, cyclindromas lack pseudoglandular structures and a true capsule, have more hyaline material and are more superficial with a tendency to approach the epidermis which bay be flattened or atrophic 59.
  • Spiradenocylindroma — some tumors features of both cylindroma and eccrine spiradenoma can be seen and are designated as overlap tumors 58.
  • Cutaneous lymphadenoma — in this tumor there is a lobular tumor of basaloid cells which may show peripheral palisading, and a dense mixed inflammatory cell infiltrate though predominantly lymphocytic 58.

Spiradenoma treatment

Because of eccrine spiradenoma potential for local recurrence or malignant transformation, complete surgical excision is the preferred treatment method but with no clear consensus regarding the width of surgical margins and this tumor does not seem to recur if complete resection had been pursued 36. Although most cases of spiradenoma are benign, they can recur locally with incomplete excision. Imaging techniques like CT scans, MRIs, and ultrasounds can also be used to help with treatment. Routine follow-up to screen for local recurrence or malignant degeneration is also important 60.

Other treatment options may include radiotherapy, carbon dioxide laser ablation, or chemotherapy, are reserved for cases in multiplicity or that are malignant 14. Due to the potential for malignant transformation, wide surgical excision or Mohs micrographic surgery offers the most conservative treatment choice, and lesions treated tend not to recur 14. One author suggests a combination of surgical management (staged surgical resections with reconstruction using complex linear closures and random-pattern cutaneous flaps) and medical management (carbon dioxide laser) for good cosmetic results 61.

For the treatment of eccrine spiradenocarcinoma (malignant eccrine spiradenoma), no treatment has been routinely established as paramount 14. Resection with wide margins (1–3cm) down to the fascia with lymph node dissection has been described as the most accepted treatment 56, 62, 63. Radiation and chemotherapy have also been proposed, but no conclusive studies have substantiated optimal practice 11, 64, 62. Hyperthermic limb perfusion chemotherapy has been tried as some believe that alterations of temperature may target treatment to tumor cells over healthy ones 65. A meta-analysis of eccrine spiradenocarcinoma demonstrated that patients with no metastasis who underwent surgical excision had a disease-free survival rate of 100 percent at 33 months 62. In contrast, patients with distant metastases treated with either surgery alone or surgery and adjuvant chemotherapy had a median survival of 12 and 20 months, respectively. Despite the difference in median survival rates between the two groups, the results were not statistically significant. Resection of lymph node metastasis resulted in patients who were disease free at the final follow-up evaluation (mean 47 months) suggesting that, in the case of positive lymph nodes, surgical resection is certainly warranted. The authors concluded that aggressive surgical removal is necessary in cases of malignant eccrine spiradenoma with or without metastasis 62.

In cases of malignant eccrine spiradenoma, close clinical follow up every three months the first year after resection, every six months the second year after resection, and annually thereafter is important given the possibility of recurrences 14. Due to the high rate of metastasis to the liver and lung, annual chest radiographs, liver function tests, liver ultrasound, chest and abdomen CT, and/or MRI may be useful 53. But again, no consensus has validated these practices. Genetic counseling for cases of familial eccrine spiradenoma is also advised 61.

Spiradenoma prognosis

Eccrine spiradenoma is a rare, benign sweat glands tumor that originates in the skin. Very rarely malignant changes into eccrine spiradenocarcinoma may occur if the eccrine spiradenoma lasts long enough, typical history was one of rapid enlargement of a cutaneous nodule of long standing 66, 29, 56. Malignant transformation occurs more often in cases of multiple benign eccrine spiradenoma than in solitary cases 11. There are just over 100 cases reported of malignant transformation 67. Malignant transformation of eccrine spiradenoma generally occurs 20 to 30 years after initial lesion detection 11. Malignant spiradenomas nearly always arise from a long-standing benign lesion, although they can rarely arise as de novo malignancies 67. Malignant spiradenomas tend to be diagnosed in older patients. They can present with rapid growth, erythema, ulceration, and bleeding and may resemble melanoma 67.

Many mechanisms have been proposed, such as trauma, but none are substantiated in the literature 68, 64, 53. In these rare cases of malignant potential, p53 may be increased even in the presence of a benign-appearing histology 69, 70. Malignant eccrine spiradenoma are aggressive tumors that spread both hematogenously and lymphogenously and have been reported to have a mortality of 39 percent if left untreated 64, 53. Since the rate of metastasis is close to 50 percent and can result in death, these patients must be followed closely. Currently, no guidelines have been developed for surveillance in patients with multiple eccrine spiradenoma, although it seems reasonable that patients with larger-sized, multiple, and/or symptomatic lesions be monitored regularly.

Malignant transformation of eccrine spiradenoma shares many clinical and pathologic features with malignant transformation of dermal cylindroma. Pathology shows anaplastic basaloid cells with areas of highly pleomorphic cells and numerous mitotic figures 60.

In 2000, Granter et al 71, 72 divided malignant eccrine spiradenoma into 2 groups (high and low grade) based on clinical and histological features. High-grade malignant eccrine spiradenoma has more obvious features of malignancy with pleomorphism and increased mitoses (4–32/hpf) 71, 53. Low-grade malignant eccrine spiradenoma has less obvious features of malignancy, such as loss of the typical ductal cells, mild-to-moderate pleomorphism, and lower mitotic rates (2–10/hpf) 71, 53. Malignant eccrine spiradenoma tends to have a high rate of metastasis to regional lymph nodes, lungs, brain, and liver; therefore, radiological studies, such as x-ray, computed tomography (CT), or magnetic resonance imaging (MRI), are useful in assessing for metastatic foci.

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