Drew+Del+Toro

=**Microcystic Adnexal Carcinoma**=

A benign bump or impressive infiltrator? MAC of the upper lip
Doctor H is an otherwise healthy, 63 year old white man. He has a doctorate in epidemiology and works for the local public health department. He and his wife go to the facial plastics clinic of the ENT department after a growth on the center of his upper lip has begun to impede his favorite hobby, playing the French horn. Dr. H performs in a local orchestra and has put off getting his lip looked at for a few years in order to avoid it affecting his playing. The bump has increased in size over the past few years but only now directly impacts his ability to perform. Other than the change in size and hardness, he has not noticed any differences in the sensation or texture of the area. The lesion appears visually similar to a basal cell carcinoma. He reports that he would like the growth treated as soon as possible to get back to his playing. Dr. H has no history of cancer and reports no family history of any cancerous lesions.

His physician determines the best course of action is to surgically resect the tumor without performing a biopsy to identify it, since the tumor appears to be very slow growing and its raised surface is relatively small, at approximately 1.8 cm by 1 cm. Dr. H undergoes a Mohs surgery within the week. The Mohs technique was chosen over simple excision since the clinical margins of many head and neck cancers are hard to predict accurately and because Mohs provides the best outcomes for the reconstruction of the cosmetically (and functionally in this case) sensitive areas. According to the appropriate use criteria developed by the American Academy of Dermatology, “Mohs micrographic surgery (MMS) was appropriate 73% of scenarios involving basal cell & squamous cell carcinomas,” although the “ultimate decision regarding the appropriateness of MMS should be determined by… the physician”. The tumor is resected in stages; each section is removed, marked, cryogenically frozen, and sent to the pathologist for histological staining and examination. The pathologist can then report back to the surgeons on presence of residual tumor or unclear margins while the patient is still in surgery. After many sections of the upper lip have been removed, the pathologist reports clear margins on all sides. However, the final defect is much larger than the initial nodule. Most of Dr. H’s central upper lip is gone, the cancer had invaded the full thickness of his lip of a 1x1cm area and much of the rest of his upper lip lost some thickness. Moreover, the tumor invaded the columella (the lowest central portion of nose) and a significant section of the base of Dr. H’s nose was resected as well.

The pathologist is also able to diagnose the lesion at this time. Dr. H’s tumor is identified as a Microcystic Adnexal Carcinoma (MAC), a low grade tumor of the sweat glands. Microcystic Adnexal Carcinoma was first recognized clinically in 1982, with just over 300 known cases worldwide since then. These cancers are very frequently misdiagnosed; one study noted of its patients, “13 (27%) of the 48 cases were not diagnosed correctly at initial biopsy” .Luckily Dr. H and his wife avoided the stress that frequently comes with misdiagnoses. Causes of MACs are believed to be UV exposure and possibly exposure from radiation therapy. A majority of these cases occur in whites, but tumors have been found in “sun-protected areas” of all races. Since our patient has no history of cancer, it is likely that UV exposure on the upper lip was the cause of his tumor. Dr. H is relieved to know that MACs have very little metastatic potential but, as he has witnessed, are often very locally invasive. Only 9 cases of metastatic MACs have been reported, with local metastases being more common, “as there is often growth of the tumor along local nerve bundles”. Overall, the prognosis is very good for Dr. H. Besides the low risk of metastasis, there have only been 2 reported deaths and the recurrence rates after surgery are modest (approximately 18% for 10 years). However, there is a chance for recurrence over a very long term (up to 30 years in one case) and therefore extensive follow up observation for regrowth is recommended. Thus, Dr. H has a good chance of recovering from his tumor and living a long and healthy life, with ten year survival rates “similar to patients of similar age without MAC”.

However, the morbidity associated with this particular case (i.e. its extensive local invasion into the upper lip and nose) presents a very unfavorable outcome for Dr. H. His upper lip was reconstructed with a combination of direct closure, local flaps, and grafts while his nose received a flap of skin rotated down from the upper cheek. It will take months of healing before the transplanted skin has fully integrated and the tubes of skin can be divided and set back into place with more surgery. He will likely lose most of the sensation in his upper lip and certainly be unable to play his French horn for months if not years. Finally, the pathology report noted infiltration of the local nerve bundles and his radiologist recommends the use of adjuvant radiation therapy to avoid recurrence and local metastasis.

Dr. H thankfully has the full support of his wife during this difficult period, since he will have to take off work and stay home while the cosmetically disfiguring grafts and skin flaps heal. He could hardly believe what he saw when the bandages on his wounds were removed for the first time at the 1 week post-operative follow up and going to work with a massive bandage covering his upper lip and nose is unfeasible. More importantly, the loss of his beloved creative outlet, playing the French horn with his orchestra, for an indeterminate amount of time is emotionally difficult for Dr. H. The surgery has also left Dr. H with a condition he hadn’t anticipated going in for a removal of an upper lip mass; he can no longer breathe well out of his nose. He was left with very little structural support at at the base of his nose and plastic tubing was inserted during the surgery to his nostrils open. When they were removed to alleviate the discomfort of having a tube the size of a sharpie stuffed into his nose, the nostrils collapsed from the sides in. Dr. H and his wife wonder whether there was any way to avoid or at least alleviate the unfortunate cosmetic and functional outcomes of the surgery, and what affect Dr. H’s lifetime of horn playing may have had (if any) on this rare cancer.

Out of sight; out of mind? MAC's unclear etiology explored
Unfortunately, the rare nature of Dr. H’s Microcystic Adnexal Carcinoma (MAC) and its relatively low morbidity and mortality rates leave the direct molecular basis of the cancer largely unclear compared to more common or deadly cancers (e.g. breast cancer or lung cancer). However, a large volume of work looking at the immunohistology of the cancer is present in the literature that may provide insight into the hallmarks of cancer of MAC. Research into methods to identify the tumor and distinguish it from closely related types of skin cancer, such as squamous cell carcinomas (SCCs), basal cell carcinomas (BCCs) or desmoplastic trichoepitheliomas (dTEs), are driven by the current reliance on histological diagnosis, a nebulous prospect given the variety of cellular features within a tumor. MACs are notable for their lack of defined edges, asymmetric growth, and infiltrative nature. However, they are also very heterogeneous and vary by depth. Within the upper layer of the skin, “tadpole-shaped” cysts full of keratin appear along with basaloid cells partially differentiated into hair follicle cells. Deeper into the mass, one finds sweat duct-like structures as well as a deeply pink, sclerotic stroma. These histological features and multilayer appearance appearance of MACs point to an origin in the pluripotent keratinocytes that progresses along both hair follicle and sweat gland differentiation pathways. There has been difficulty nailing down an exact protein marker of MACs without some degree of cross reactivity with the other tumor types mentioned above. Many immunological targets have been proposed, including p75 (a neurotorphin receptor), Ber-EP4, and PHLDA1 (pleckstin homology-like domain, family A, member 1). However, the currently recommended cellular markers to identify MAC include keratins (i.e. CK15, CK AE1/AE3, and CK7), p63 (of the p53 family), epithelial membrane antigen (EMA), and carcinoembryonic antigen (CEA). p63 is responsible for maintaining the proliferative capacity of epidermal stem cells and overexpression or gain of function mutations might therefore result in the abnormal sustainment of proliferative growth found in MAC. Since the cell of origin is believed to be a stem cells, p63 probably isn’t the direct driver mutation in Dr. H’s tumor. It is usually found in the peripheral and deep parts of the tumor rather than the central mass, so it is likely not the contributing factor to the growth of the main section of the tumor but may activate its outward invasion. Epithelial membrane antigen also has a clear role in the transformation of normal epithelial stem cells to cancer cells. EMA is the product of a gene known as MUC-1, which is a membrane bound glycoprotein, whose overexpression is associated with other forms of cancer. Overexpression of MUC1 is known to prevent cell death, as it can bind to p53 and inhibit the apoptotic pathway in favor of cell cycle arrest. It can be localized to the mitochondria and prevent the activation of apoptotic mechanisms there as well. Thus, abnormalities in EMA expression might result in the cancer cell’s ability to resist cell death.

A variety of other genes have been examined for activity within MAC and other similar forms of cancers. One study found an increased production of Epidermal Growth Factor Receptor (EGFR) in 18 cases of MAC, although there was only 1 case with more than two copies of the gene; there might be other molecular factors at play in the upregulation of the gene than just gene regulation. Another study examining the histology of MAC found that 2 out of 3 tumors stained positive for GATA3. GATA3 is a member of the zinc finger family of nuclear transcription factors and binds to G-A-T-A sequences in promoters to activate or deactivate genes, and GATA3 is known to play a role in epithelial differentiation. The stain was found in the partially differentiated hair follicles of the tumor and is known to play a role in breast cancers. Another study examining the genetic basis of MACs found the anti-apoptotic Bcl-2 protein to be stained in the central tumor mass with the same pattern as CK7. The same study also noted little c-erB-2 oncoprotein expression or p53 upregulation (only 2/10 cases), but hypothesized that late p53 expression and early telomerase upregulation are both caused by UVB radiation.

One novel study looking at the cytological characteristics of a single case of MAC found that one-third of the cells sampled contained a deletion event on chromosome number six, an abnormality solely responsible for the closely related salivary gland tumors. A study examining the genetic characteristics of a similar cytological abnormality in salivary gland and benign adnexal tumors found a translocation at the same place, which creates an oncogene from two normal transcription factor genes. In the tumor types studied, the paper found it was a fusion between the MYB and NFIB genes that created an oncoprotein containing functional binding and active sites for MYB target genes. MYB controls “cell proliferation, apoptosis, and differentiation” and is “highly expressed in immature, proliferating cells” as opposed to mature, differentiated cells. The gene is normally tightly regulated by microRNAs at sites which are replaced by NFIB of the gene in the mutant. Thus, the deletion event may create a similar fusion gene between MYB and some other gene on chromosome 6 and create another oncoprotein that can sustain proliferative growth signaling and evade growth suppressors that might normally affect its expression.

Surgery or Bust? Treating with uncertainty in MAC
After learning about the various potential molecular causes of his cancer, Dr. H wonders what the standard course of treatment is for Microcystic Adnexal Carcinoma, how it compares to the course of treatment he received, and what alternatives or experimental therapies could have been used to avoid the unpleasant cosmetic and functional outcome of his surgery. Certainly, the extensive growth of the tumor that led to the large post-surgical defect and reconstruction could have been avoided with effective screening or regular dermatology checkups. Since MAC usually appears very similar to other forms of skin cancer, perhaps Dr. H would have been inclined to seek care sooner had a physician seen his lesion. However, MAC individually is not an ideal case for widespread screening due to low mortality rates, extreme rarity, and diagnostic difficulties. Additionally, a “standard of care” report is not yet available for MAC but a few studies have examined the efficacy of the three major treatment methods as well as various types of surgical procedures in particular. According to most sources of general information on the cancer, “surgery is the mainstay of treatment”. While radiotherapy reduces tumor growth and pain over the short term and reduce post-surgical recurrence in a few cases, it is also thought to be a contributing factor to the development of MAC and only recommended for primary treatment in elderly patients or inoperable cases. Physicians may be especially wary of radiotherapy because of a few cases where it resulted in recurrence, one case in particular saw the transformation of the cancer into a more extensively invasive and aggressive type. Radiation is therefore considered a secondary or adjuvant therapy, used to reduce recurrence rates for tumors with invasion along the nerve bundles even though there remain questions regarding its effect on overall survival. There is only one reported case of chemotherapeutic treatment of MAC with cisplatinum and 5-Fluorouracil, which no success after 8 months. Chemotherapy may be useful for widespread or inoperable tumors, but little information exists to demonstrate its effectiveness (the general lack of widespread invasion in MAC notwithstanding).

This seems to leave surgery unchallenged as the primary method for treating MAC, although there are a few competing methods for surgical resection. The simplest form of surgical removal of the tumor is local excision, where the physician removes the clinically apparent sections of the tumor with the patient on the table. Wide local excision is similar, but has a section of tissue removed beyond the clinically apparent margins of the tumor. Both of these methods are inferior to Mohs Micrographic surgery (MMS), however. According to a review looking at 40 MAC cases, recurrence rates between simple excision and Mohs Micrographic surgery were roughly the same. However, patients who underwent simple excision required multiple surgeries for histologically clean margins while those who underwent MMS only required one. Another study found the overall recurrence rates of MMS to be significantly lower than those for simple excision, however. As mentioned earlier, this is likely due to the microscopic extension of MAC far beyond the visually obvious tumor,a often along nerves. Beyond the usual process of MMS, some recommend the use of an additional layer of resection beyond the clean margins to avoid recurrence, yet there is no data on this practice as of yet. Finally, many studies recommend the use of a “Slow Mohs” procedure, where the final tissue section is fixed with formalin and embedded in paraffin wax rather than frozen to allow the pathologist to better interpret the margins and avoid missing small strands of tumor. This method results in a much lengthier procedure, hence the name. From Dr. H’s point of view, he underwent the surgical procedure with the best possible outcomes. His risk of recurrence is somewhere between 0-12% and while he did not undergo a “slow Mohs” procedure, the added time and potentially wider margins would have been unfavorable given his concerns about reconstruction and the location of the tumor. Although his radiologist recommended the use of adjuvant radiotherapy, there remains considerable debate regarding its effectiveness. It may help to reduce the risk of regrowth from the invasive cells hiding along his nerves, but it may not. Dr. H still wonders what the alternatives were to this “gold standard” of care and if he could have brought the tumor under control without months or years away from his horn. The genetic and molecular targets for MAC, as mentioned earlier, are not well understood, but it is reasonable to expect that at least one of the many hypothesized could be identified in Dr. H’s case. EGFR is often overexpressed in many types of cancers, and the potential effects of drugs targeting their protein products are well studied. One such study examined the potential synergistic effects of a monoclonal antibody targeting EGFR (C225) and cisplatin in patients with squamous cell carcinoma, based on evidence of increased susceptibility of C225-treated tumors to chemotherapy and radiation. The study found the treatment to be effective in 67% of their measurable patients, and further studies are underway to examine C225’s effects on radiotherapy. A more recent study looking at two FDA approved antibodies, cetuximab and pantiumumab, found that both inhibited EGFR signaling but that cetuximab triggers a stronger immune response to the targeted cells in head and neck squamous cell carcinoma. Therefore, it is likely that these two antibodies and others may be useful targets against MACs that overexpress EGFR, although the exact nature of Dr. H’s tumor is unknown.

Potential treatments against MUC-1 overexpressing tumors include more experimental attempts at cancer treatment, including photothermal ablation using gold nanorods. The authors report the use of Muc-1 antibodies attached to the surface of gold nanorods to target various cancer lines in vitro (including a squamous cell carcinoma). The antibodies bind the cancer cells, which are then exposed to a laser at a specific resonance frequency for the nanoparticles, resulting rapid heating and destruction of the tumor cells. Heating has also been shown to improve responsiveness to chemotherapy and radiation, yet the squamous cells demonstrated a reduced response to the phototherapy due to their lower expression of Muc-1. Therefore, depending on the molecular characteristics of Dr. H’s cancer, such a therapy may or may not be individually successful or have strong synergistic effects with chemotherapy or radiotherapy. Many studies note the attractiveness of p63 as a therapeutic target for cancers besides MAC, but no p63 targeted therapies exist as of yet. Even if a drug existed that targeted p63, it would only be targeting a small subset of the cancer cells within the deep sections and periphery of MACs, rather than the heart of the tumor. Finally, a few studies have similarly identified MYB as a potential target for therapeutic agents in other cancers, including similar skin cancers such as cylindromas. The study looking at Myb suppression in leukemia noted that the use of small RNA interference is being heavily researched; yet there are issues regarding clinical delivery and toxicity. The study also mentions other small RNAs to inhibit Myb transcription or targeting Myb’s interaction with other genes such as p300.

Although so many options for targeted therapies exist, there are currently no clinical trials on any of these hypothetical alternative or experimental treatments for MAC. The small number of cases and very small number of inoperable cases create low demand for novel or nonsurgical treatments. Surgical resection remains the best option for removal of the MAC and MMS provides the best protection against recurrence, even though the size of the defect and degree of reconstruction left Dr. H less than pleased. The main question Dr. H has going forward is how should he proceed post-surgically, with adjuvant radiotherapy or without? Taking into account current evidence and the clear margins from his Mohs procedure, his surgeon recommends against the use of adjuvant radiotherapy due to its uncertain efficacy. However, Dr. H agrees with his radio-oncologist and wants to do everything he can to prevent recurrence and return to his horn permanently. Dr. H decides to undergo a closely monitored course of radiation therapy and plans for yearly follow-ups with his surgeon to watch for recurrence as well.

Aperçu
Microcystic Adnexal Carcinoma is a very rare, highly locally invasive skin cancer commonly found in sun-exposed areas on the head and neck of older, white patients. Further research is required on the molecular and genetic causes of MAC, which are poorly understood due to current emphasis on histological identification, but it probably doesn't have anything to do with playing the French horn. Mohs Micrographic Surgery is the best option for treatment of this infiltrative and frequently recurring lesion while radiation remains an option for the infrequent inoperable or metastatic cases.