Spiradenoma

Spiradenoma tumors occur in individuals of various ages but tend to develop in middle-aged and elder adults (e.g. in a study of 27 patients, the median age at diagnosis was 62 years).[2] However, cases have been reported in children as young as 2 years.[10] These tumors usually present as a solitary, sometimes painful,[11] slowly growing, 1–2 cm (i.e. centimeters), gray-to-pink nodules that lie underneath the skin's epidermis in the head, neck, trunk, arms, or legs.[12] However, these nodules have been reported to be as large as 6 cm[11] and to occur in other hair follicle-containing cutaneious sites such as the vulva,[13] breast, and breast nipple.[14] Areas of the skin that do not have hair follicles (e.g. palms of the hands and soles of feet) do not develop these nodules.[11] Less than 2% of cases present with more than one nodule; the multiple nodules in SA tend to array in a linear, blaschkoid (i.e. V-, U-, or inverted U-shaped), or zosteriform (i.e. belt- or girdle-shape tracking an area of skin served by a sensory nerve) patterns.[12] Giant vascular eccrine spiradenomas are larger (> 2 cm) and more highly vascular variants of SA that usually develop at the same cutaneous sites as SA but have also been reported to occur in the abdomen and scrotum. No malignant giant vascular SA has been described in the literature to date (2021).[12]

A recent review of 182 cases reported that spiradenocarcinomas were diagnosed in individuals 8–89 years old (mean 57.4 years). These SAC tumors developed in SA tumors that had existed for 0–720 months (mean 168.5 months); 14.4% of individuals were diagnosed with multiple carcinoma lesions. (Multiple SAC lesions may appear as a nodule associated with smaller satellite nodules.[6]) The lesions occurred on the trunk (32.3% of cases), limbs (31.3%), head or neck (30.7%), and genitalia (1.6%). These individuals presented with lesions that began to show abnormal growth (82.6% of cases), pain (47.7% of cases), and/or ulcerations (38.7% of cases).[5] In earlier studies, SAC tumors were reported to varied in size with 40% being larger than 5 cm and the majority not having metastasized; the sites to which these lesions metastasized were most commonly to lymph nodes near to the SAC or, rarely, distant tissues such as the lung, liver, brain, spinal cord, bone, skin, and breast.[6][15][16]

As determined by the microscopic histopathological appearances of their hematoxylin and eosin-stained samples, spiradenomas are non-encapsulated nodular skin lesions that extend into the dermis. The lesions consist of a relatively disorganized and dense array of proliferating basophilic cells (i.e. cells appearing blue because of their abnormally large uptake of the hematoxylin stain).[9] These cells are arranged as small cells with hyperchromatic nuclei and scant cytoplasm layered outside and larger cells with vesicular (i.e. vesicle-containing) nuclei layered inside of intertwining strips.[16] Lymphocytes commonly populate these lesions. Some lesions may merge the histopathological features of spiroadenomas with those of cylindromas.[9] Cylindromas are hair follicle tumors that consist of basal cells (i.e. small, round cells similar to those seen in the lowest layer of the skin's epidermis) which are arranged in ("jigsaw-like"[17] cylindrical patterns separated by thickened basement membranes. The cylindroma tissues may also contain disorganized, dense arrays of proliferating basophilic cells.[9]

Spiradenocarcinoma tumors almost always derive from SA tumors[18] and have areas of SA architecture abruptly transitioning to areas of SAC architecture. The SAC component of these lesions consists of cells that, along with their nuclei and cytoplasm, vary greatly in size and shape. The cells may be rapidly proliferating, have atypical mitosis figures, and may be invading nearby neural or lymphovascular structures; they do not arrange into intertwining strips of small and large cells.[16] High-grade SAC tissues show a more severely disturbed architecture, more marked variation in cell, nuclei, and cytoplasm sizes and shapes, and more rapidly proliferating cells than low-grade SAC tissues.[19] SAC tumor tissues may show various other features, e.g. they may closely resemble sarcomas.[19] In rare cases, SAC has been reported to apparently arise de novo, i.e. begin as malignant lesions.[18]

Studies indicate that a minority of SA and SAC cases have one of two potentially disease-causing mutations in their tumor cells: loss-of-function (i.e. gene-inactivating) mutations in the CYLD gene in 5 of 17 SA and 2 of 24 SAC cases or gain-of-function (i.e. gene-activating) mutations in the ALPK1 gene in 7 of 16 SA and 4 of 14 SAC cases. The two mutations are mutually exclusive, i.e. do not occur together in any individual's tumor(s).[20] Both mutations result in blocking the actions pf NF-κB.[20][17] NF-κB is a transcription factor which acts indirectly to stimulate the expression of various genes that trigger cell death by apoptosis and necroptosis[21] and also inhibit cell proliferation (see CYLD gene's mechanism of action).[22] It is proposed that the blockade of NF-κB's actions prolongs cell survival, stimulates high rates of cell growth, and perhaps has other effects which contribute to the formation and/or progression of SA and SAC tumors.[9][23]

SA and SAC tumors have been confused with leiomyoma, angiolipoma, granular cell tumor,[11] basal cell carcinoma, squamous cell carcinoma, metastatic adenocarcinoma, and adenoid cystic carcinoma tumors;[19] the giant vascular SA form of these tumors has been mistaken for a hemangioma, angiolipoma, calcifying epithelioma, neuroma, malignant melanoma, angiosarcoma, vascular malformation, and venous thrombosis.[12] CT scans, FDG-positron emission tomography, and magnetic resonance imaging to detect 1) the shape and local invasiveness of these tumors and 2) the presence of metastases[5] and 2) the clinical presentation of individuals of these tumors often suggest the correct diagnosis. However, definitive separation of SA, SAC, and giant vascular SA from the just cited lesions requires histopathological examinations.[11][17] The diagnosis of SA versus SAC tumors is often suggested by their clinical presentations, e.g. rapid enlargement or onset of pain in a long-standing SA tumor strongly suggests that it has become a SAC.[16] Findings that a known SA or undiagnosed tumor has areas of SA histology transitioning to SAC histology (see above Pathology section) is virtually diagnostic for SAC.[19]

The sporadic SA and SAC tumors reviewed here must also be distinguished from the very similar appearing SA-like and SAC-like tumors in individuals afflicted with the CYLD cutaneous syndrome. CCS is a familial disease uniformly associated with the inheritance of inactivating mutations in the CYLD gene. Individuals with CCS commonly develop an increasingly large number of skin tumors, including SA and SAC, over time. Usually, these individuals are readily distinguished from sporadic SA and SAC by their family history of the disease and the presence of large numbers of tumors. The rare cases of CCS that present with one or a few tumors are distinguished form CCS by testing for the CYLD gene: all individuals with CCS carry a mutated CYLD gene in their tumor as well as other tissues such as blood leucocytes while individuals with sporadic SA or SAC carry the mutated CYLD gene in their tumor but not other tissues (see Genetics of CCS). It is important to afford individuals with CCS and the close family members of these individuals access to in depth genetic counselling.[9]

There is no consensus on the best treatment(s) for SA and SAC tumors. Further research, including meta-analysis comparisons of different treatment regimens, is needed to define the best treatment(s) for these tumors. In all cases, however, regular follow-ups of individuals with SA and SAC are strongly recommended in order to detect as early as possible: the formation of new tumors; changes in old tumors that suggest their progression to more aggressive or malignant formss; local recurrences of surgically removed tumors; and the development of local or distant metastases.[5][11] One recommended follow-up strategy prescribes patients to have check-ups ever three months in the first year after treatment, every six months in the second year after treatment, and annually thereafter. Each check-up should incorporate the examination of the patients' regional lymph nodes and on a case-by-case basis annual chest X-rays and liver function tests.[5]

In the only meta-analysis study reported on the treatment of SA and SAC tumors to date, 35 individuals with SA tumors and no evidence of local or distant metastasis who were treated with local resection (3 of these individuals underwent additional lymph node resections after removal of their primary tumor) all 35 were disease-free with a mean follow-up period of 33 months. Among individuals with SAC tumors that had metastasized to lymph nodes but not distant tissues, 3 individuals who had surgical excisions of their tumors but not their involved lymph nodes died of metastatic disease (range 39–49 months, mean survival range 45 months); one individual was alive with disease 24 months after lymph node dissection; and 8 individuals (6 of whom had lymph node dissection) lacked evidence of recurrent disease (observation times 2 to 97 months, mean observation time 47 months).[6] In a review of 136 reported cases treated for SA or SAC: 1) 4.4% and 14.7% of individuals with SA and SAC tumors, respectively, had died (time between treatment and death was not reported); 2) patients who presented with metastasis to distant tissues had a median survival time of 16 months (11 of these patients were treated with adjuvant therapy in addition to surgery [adjuvant treatments included 5 patients treated with radiotherapy, 3 treated with chemotherapy, and 2 treated with both radiotherapy and chemotherapy]); and 3) Surgery with adjuvant therapy yielded a median survival time of 20 months (this survival time did not significantly differ from that found in individuals treated with surgery alone).[5]

• Malignant acrospiroma
• List of cutaneous conditions
• Dermal cylindroma
• Trichoepithelioma
• CYLD cutaneous syndrome
• List of cutaneous neoplasms associated with systemic syndromes