Pilomatrix carcinoma: 13 new cases and review of the literature with emphasis on predictors of metastasis.

BACKGROUND: Pilomatrix carcinoma is a rare cutaneous tumor derived from follicular matrix cells with few cases documented in the literature. OBJECTIVE: We sought to better characterize this tumor by analyzing its epidemiologic, clinical, and histopathologic features in 13 new cases and by reviewing the literature. METHODS: All cases of pilomatrix carcinoma from a large regional dermatopathology practice were identified and analyzed by chart review for clinical and histopathologic characteristics. Similar characteristics were compiled from an additional 123 cases in the English-language literature. Cox proportional hazards regression models were used to determine risk factors associated with the development of metastasis for all identified metastatic tumors. RESULTS: Our 13 tumors were most common in middle-aged to older white men and presented mostly on the head/neck. Histopathologically, tumors were asymmetric, were poorly circumscribed, were composed of basaloid and "ghost" cells, had frequent atypical mitoses, and had infrequent lymphovascular invasion. Wide excision was considered the most definitive treatment modality, but local recurrence was common. When analyzing all reported cases of metastasis using statistics, metastasis was significantly associated (hazard ratio 3.45, P < .0413) with local tumor recurrence. LIMITATIONS: The retrospective, single-center design and the reliance on electronic medical records are limitations. CONCLUSIONS: This study helps better characterize pilomatrix carcinoma and identifies potential predictors of metastasis.

Topical formulation engendered alteration in p53 and cyclobutane pyrimidine dimer expression in chronic photodamaged patients.

While the clinical attributes of photoaging are well characterized in the literature, the pathogenic mechanisms that underlie these changes are incompletely elucidated. At the molecular level, p53 tumor-suppressor gene product mediated excision repair of ultraviolet (UV)-induced DNA damage is a critical effector in xeroderma pigmentosum (XP) and potentially in conventional photoaging. We examined p53 activity and measured UV-induced DNA damage via cyclobutane pyrimidine dimers (CPDs) quantitatively in 20 volunteers before and after an 8-week, open-label prospective topical application of a proprietary DNA recovery serum (Celfix). There was a statistically significant decrease in immunohistochemically determined p53 and CPD levels. While these data are preliminary, the findings lend support to the theoretical possibility of a topical agent reversing the effects of photodamage at the molecular level and, potentially, an ameliorative outcome clinically.

Synergistic and antagonistic interactions of oxybenzone and ocean acidification: new insight into vulnerable cellular processes in non-calcifying anthozoans.

Cnidarians face significant threats from ocean acidification (OA) and anthropogenic pollutants such as oxybenzone (BP-3). The convergence of threats from multiple stressors is an important area to investigate because of potential significant synergistic or antagonistic interactions. Real-time quantitative PCR was performed to characterize the expression profiles of twenty-two genes of interest (GOI) in sea anemones (Exaiptasia diaphana) exposed to one of four treatments: 1) 96 h of OA conditions followed by a 4 h exposure to 20 ppb BP-3; 2) Exposure to 4 h 20 ppb BP-3 without 96 h of OA; 3) Exposure to 96 h of OA alone; or 4) laboratory conditions with no exposure to BP-3 and/or OA. These 22 GOIs represent cellular processes associated with proton-dependent transport, sodium-dependent transport, metal cation binding/transport, extracellular matrix, amino acid metabolism/transport, immunity, and/or steroidogenesis. These 22 GOIs provide new insight into vulnerable cellular processes in non-calcifying anthozoans exposed to OA and BP-3. Expression profiles were categorized as synergistic, antagonistic, or additive of BP-3 in the presence of OA. Two GOIs were synergistic. Fifteen GOIs were antagonistic and the remaining five GOIs were additive in response to BP-3 in acidified seawater. A subset of these GOIs appear to be candidate biomarkers for future in situ investigations. In human health, proton-dependent monocarboxylate transporters (MCTs) are promising pharmacological targets and recognized as potential biomarkers. By comparison, these same MCTs appear to be targets of xenobiotic chemical pollutants in cnidarian physiology. In the presence of BP-3, a network of collagen synthesis genes are upregulated and antagonistic in their expression profiles. Cytochrome b561 is a critical protein required for collagen synthesis and in silico modeling demonstrates BP-3 binds in the pocket of cytochrome b561. Understanding the underlying molecular mechanisms of "drug-like" compounds such as BP-3 may lead to a more comprehensive interpretation of transcriptional expression profiles. The collective antagonistic responses of GOIs associated with collagen synthesis strongly suggests these GOIs should be considered candidate biomarkers of effect. GOIs with synergistic and additive responses represent candidate biomarkers of exposure. Results show the effects of OA and BP-3 are interactive with respect to their impact on cnidarians. This investigation offers mechanistic data that supports the expression profiles and underpins higher order physiological responses.

Neutrophilic dermatosis revisited: an initial presentation of lupus?

BACKGROUND: We report 7 patients with a distinct and unusual eruption consisting of a neutrophilic dermatosis in conjunction with lupus erythematosus (LE). The significance of these findings and their relevance to LE are discussed. OBJECTIVE: We aimed to evaluate the significance of eruptive neutrophilic dermatosis in conjunction with LE. METHODS: Seven original cases were collected during 10 years at a tertiary referral center, and were reviewed by a single board-certified dermatopathologist. All patient demographics were tabulated and analyzed. Eleven articles reporting 15 similar cases were obtained from a literature review. RESULTS: Of a total of 7 adult patients, 14% (1 of 7) had a history of LE, whereas 86% (6 of 7) exhibited synchronous initial presentation of neutrophilic dermatosis with LE. Of note, 100% (7 of 7) of the patients exhibited cutaneous lesions on sun-exposed sites. LIMITATIONS: Only 7 of 400,000 cases showed this phenomenon, giving rise to the idea this may be just by chance. CONCLUSIONS: Our data and literature review suggest the existence of a neutrophilic dermatosis distinct from conventional Sweet syndrome that may herald conventional signs and symptoms or represent an initial presentation of cutaneous LE. This neutrophilic dermatosis may share a similar pathogenic mechanism related to ultraviolet exposure.

Permanent Makeup Procedure Heralds the Development of Systemic Sarcoidosis.

Permanent cosmetic procedures including tattooing are determined as risk factors that prompt the development of cutaneous granulomatous conditions. Scar sarcoidosis is an uncommon manifestation of a systemic granulomatous disease with a few cases reported in the literature worldwide. Although the incidence rates of sarcoid lesions at sites of pigment deposition are low, granuloma formation can provoke a severe systemic inflammatory response. We report a 48-year-old Hispanic female with a new onset of scar sarcoidosis that progressed to a systemic condition. Erythematous maculopapular eruptions arose on her left eyebrow area at the sites of scars from cosmetic tattooing, prior to exacerbation of the small airway disease. Histopathologic examination revealed typical findings of cutaneous sarcoidosis, including non-caseating epithelioid granulomas. This case highlights the importance of early detection of cutaneous sarcoidosis in long-standing scars due to the associated risks of systemic sarcoidosis.

Intravascular schwannoma.

Schwannoma is defined as a benign nerve sheath neoplasm of Schwann cell origin. Cutaneous schwannoma typically manifests along the course of peripheral nerves as a solitary, well-defined, skin-colored nodule within the deep dermis or subcutis of the flexor aspects of the extremities. Schwannoma enlarges slowly and typically follows a benign course, with local recurrence and malignant transformation being exceedingly rare. Although involvement of the vasculature by neurofibroma has been rarely reported, intravascular schwannoma has not been documented to date. We present a unique case of cutaneous schwannoma, as confirmed by histological morphology and immunohistochemistry, within the dermal venous system. Presentation of this case is followed by a discussion of the differential diagnoses of schwannoma, the possible etiologies of the extension of this lesion into the vasculature, and the significance of such a phenomenon.

Sea Anemones Responding to Sex Hormones, Oxybenzone, and Benzyl Butyl Phthalate: Transcriptional Profiling and in Silico Modelling Provide Clues to Decipher Endocrine Disruption in Cnidarians.

Endocrine disruption is suspected in cnidarians, but questions remain how occurs. Steroid sex hormones are detected in corals and sea anemones even though these animals do not have estrogen receptors and their repertoire of steroidogenic enzymes appears to be incomplete. Pathways associated with sex hormone biosynthesis and sterol signaling are an understudied area in cnidarian biology. The objective of this study was to identify a suite of genes that can be linked to exposure of endocrine disruptors. Exaiptasia diaphana were exposed to nominal 20ppb concentrations of estradiol (E2), testosterone (T), cholesterol, oxybenzone (BP-3), or benzyl butyl phthalate (BBP) for 4 h. Eleven genes of interest (GOIs) were chosen from a previously generated EST library. The GOIs are 17ß-hydroxysteroid dehydrogenases type 14 (17ß HSD14) and type 12 (17ß HSD12), Niemann-Pick C type 2 (NPC2), Equistatin (EI), Complement component C3 (C3), Cathepsin L (CTSL), Patched domain-containing protein 3 (PTCH3), Smoothened (SMO), Desert Hedgehog (DHH), Zinc finger protein GLI2 (GLI2), and Vitellogenin (VTG). These GOIs were selected because of functional associations with steroid hormone biosynthesis; cholesterol binding/transport; immunity; phagocytosis; or Hedgehog signaling. Quantitative Real-Time PCR quantified expression of GOIs. In silico modelling utilized protein structures from Protein Data Bank as well as creating protein structures with SWISS-MODEL. Results show transcription of steroidogenic enzymes, and cholesterol binding/transport proteins have similar transcription profiles for E2, T, and cholesterol treatments, but different profiles when BP-3 or BBP is present. C3 expression can differentiate between exposures to BP-3 versus BBP as well as exposure to cholesterol versus sex hormones. In silico modelling revealed all ligands (E2, T, cholesterol, BBP, and BP-3) have favorable binding affinities with 17ß HSD14, 17ß HSD12, NPC2, SMO, and PTCH proteins. VTG expression was down-regulated in the sterol treatments but up-regulated in BP-3 and BBP treatments. In summary, these eleven GOIs collectively generate unique transcriptional profiles capable of discriminating between the five chemical exposures used in this investigation. This suite of GOIs are candidate biomarkers for detecting transcriptional changes in steroidogenesis, gametogenesis, sterol transport, and Hedgehog signaling. Detection of disruptions in these pathways offers new insight into endocrine disruption in cnidarians.

Perineural invasion progressing to leptomeningeal carcinomatosis: is the absence of peripheral nerves an important sign?

BACKGROUND: Leptomeningeal carcinomatosis (LMC) is a rare, frequently fatal complication of cranial nerve invasion by a primary cutaneous carcinoma. OBJECTIVE: Complete absence of nerve tissue was observed in retrospect in a Mohs surgery case that had subsequently proceeded to LMC. We theorized that the cancer invaded the perineural space and spread contiguously until meeting a point of resistance, in this case the mental foramen. Pressure on the nerve resulted in Wallerian degeneration of the peripheral nerve, causing progressive anesthesia and obscuring the presence of perineural invasion (PNI). Our objective was to find out if this was an isolated phenomenon or an important sign of PNI progressing to LMC. METHODS: We report and describe a case and review similar case reports in the literature. RESULTS: Twenty-two case reports fit our criteria. In only two cases was carcinomatous PNI reported in initial surgical specimens. LIMITATIONS: There are relatively few similar case reports in the literature. In many reports, histopathologic findings are not detailed enough to be helpful. Absence of peripheral nerves, although inferred, is not specifically stated in any other case report. CONCLUSION: The absence of nerve tissue in a Mohs surgery specimen, coupled with signs of cranial nerve involvement, could be important early indicators of PNI progressing to LMC.

Expression of alpha-methylacyl-CoA racemase (P504S) in sebaceous neoplasms.

BACKGROUND: Alpha-methylacyl-CoA racemase (AMACR), also known as P504S, is a protein that plays an important role in mitochondrial and peroxisomal beta-oxidation of branched-chain fatty acid and bile acid intermediates. AMACR has been established as a valuable diagnostic marker for prostate cancer and has recently been shown to be useful in the diagnosis of colorectal carcinoma. Despite the importance of lipid metabolism in sebum production by sebaceous glands of the skin, there are no studies evaluating the expression of AMACR in sebaceous neoplasms. METHODS: Five samples of normal sebaceous glands as well as five cases each of sebaceous hyperplasia (SH), sebaceous adenoma (SA), basal cell carcinoma (BCC) with sebaceous differentiation and extraocular sebaceous carcinoma (SC) were evaluated for immunohistochemical (IHC) expression of AMACR. Each case was reviewed by a single dermatopathologist and graded using a semi-objective grading schema. RESULTS: Normal sebaceous glands showed strong (4+) expression of AMACR. Among sebaceous neoplasms, SH showed the highest expression (4+), SA and BCC with sebaceous differentiation showed varied expression (2+ and 1+, respectively), and extraocular SC showed no expression of AMACR. CONCLUSIONS: The expression of AMACR is increased in benign sebaceous glands and SH; with decreasing AMACR expression in tumors with less sebaceous differentiation (i.e. SA and SC). These findings provide insight into the potential pathogenesis of sebaceous neoplasms while assisting in the microscopic distinction of SA from SC.

Amyloid light chain deposition associated with dermatofibroma: serendipity or association?

Primary cutaneous amyloidosis, also known as nodular amyloidosis, is defined as deposition of amyloid light chain in the skin in the absence of a systemic cause of amyloidosis. Such amyloid is produced by a localized aggregate of clonal plasma cells. In contrast, secondary cutaneous amyloidosis is related to lesions such as squamous cell carcinoma, Bowen disease, basal cell carcinoma, and discoid lupus erythematosus, and has been shown in most cases to be derived from keratin epithelial elements. Herein, we present a unique case of nodular amyloidosis occurring in association with a cellular dermatofibroma.

Bif-1 and Bax expression in cutaneous Merkel cell carcinoma.

BACKGROUND: Bax-interacting factor-1 (Bif-1) binds to Bax, which in turn activates this proapoptotic protein. In the absence of Bif-1, the ability to induce apoptosis through the intrinsic pathway is greatly reduced. Merkel cell carcinoma (MCC) classically shows an aggressive behavior and lack of response to chemotherapy, which remains unexplained. Previous studies have documented the presence of Bax in MCC, but Bif-1 expression has not been evaluated. Herein, the expression of Bif-1 and Bax in cutaneous MCC is examined. MATERIALS AND METHODS: The immunohistochemical expression of Bif-1 and Bax protein was examined in nine cases of MCC. Both positive and negative controls were conducted. All the cases were reviewed by a single dermatopathologist. RESULTS: Bif-1 was detected in nine cases (100%), and Bax was expressed in six cases (66%). The percent positive cells for Bif-1 in MCC ranged from 85% to 98% positive (mean 93.9%). At the same time, decreased Bax expression was shown with 0-8% positive cells (mean 3.45%). CONCLUSION: The increased expression of Bif-1 in MCC is associated with low levels of Bax staining. These findings suggest that the upregulation of Bif-1 could in part be responsible for tumorigenesis in cutaneous MCC. As shown, Bax and Bif-1 expression are not exclusively antithetical; therefore, future studies evaluating the expression of both proteins should be conducted.

Histologic mimics of perineural invasion.

BACKGROUND: Perineural invasion (PNI) by primary cutaneous cancers is an important adverse risk factor. Certain benign conditions may mimic microscopic PNI. Mohs surgery is being performed more frequently on smaller primary cutaneous malignancies. While PNI may be present in these cases, it is likely to be microscopic and asymptomatic, affecting as little as one cutaneous nerve branch. METHODS: Review of the literature base regarding PNI as well as contribution of original findings. RESULTS: Four benign entities that could easily be confused with microscopic PNI are presented. CONCLUSION: At least four benign mimics of microscopic PNI exist, important in the differential diagnosis of microscopic PNI. Knowledge of these entities should help dermatopathologists to correctly distinguish them from PNI and avoid unnecessary additional treatment.

Utility of p63 in the differential diagnosis of atypical fibroxanthoma and spindle cell squamous cell carcinoma.

Atypical fibroxanthoma (AFX), spindle cell squamous cell carcinoma (SCSCC) and spindle cell melanoma are the primary entities in the differential diagnosis of a cytologically atypical spindle cell tumor arising on sun-damaged skin. AFX is generally regarded as a diagnosis of exclusion in this context: in the absence of S100 or keratin reactivity, a diagnosis of AFX is favored. However, keratin reactivity may be focal or even absent in SCSCC, and although numerous positive markers of AFX have been proposed, none has shown sufficient sensitivity and specificity for routine diagnostic use. We evaluated 20 AFX and 10 SCSCC with a panel of cytokeratins and p63 to assess the utility of the latter antibody in this differential diagnosis. All 10 SCSCC showed strong expression of p63, whereas all 20 AFX were p63 negative. Two additional cases (excluded from the study) were negative for keratins and S100 on initial shave biopsies, resulting in a favored diagnosis of AFX, but p63 stains performed retrospectively were positive. However, review of the excision specimens in both cases revealed deep subcutaneous extension, excluding AFX. p63 reactivity argues against the diagnosis of AFX and is therefore a useful addition to the standard immunohistochemical panel for cutaneous spindle cell neoplasms.

Perineural invasion: identification, significance, and a standardized definition.

BACKGROUND: Mohs surgeons have expanded the range of cancers treated using the Mohs technique. Mohs surgeons today are expected to diagnose perineural invasion (PNI) when as little as one nerve is involved. OBJECTIVE: To address the issue of identification and significance of perineural invasion from the perspective of the Mohs surgeon. The experience of other medical specialties dealing with the same issue are reviewed and applied. METHODS AND MATERIALS: This article is based on a review of the entire medical literature regarding PNI. RESULTS: PNI is a significant complication of cancers, regardless of the organ of origin. The most common complication of PNI is recurrence of the cancer. Leptomeningeal carcinomatosis occurs in neglected or aggressive cancers. The process is indolent and contiguous, lending itself well to treatment with Mohs surgery. There are diagnostic mimics of PNI. Variation of reported incidences and cure rates suggest that diagnostic criteria for PNI may not be consistent from study to study. CONCLUSION: We propose the following definition for the minimum histopathologic criteria required to make a diagnosis of PNI: "In the presence of a malignancy, PNI may be diagnosed according to the observation of cytologically malignant cells in the perineural space of nerves. In equivocal cases, the observation of total or near-total circumferential involvement is supportive, as is the presence of perineural tracking in tangential sections and intraneural involvement."

Pedunculated hemangiopericytoma-like tumor: peculiar fibroepithelial polyp or fibrous histiocytoma variant.

Pathologists are continually challenged with the difficult task of discriminating between innocuous disease processes and potentially malignant entities. Apropos of this concern, we present a series of three cutaneous polypoid lesions that simulated fibroepithelial polyp, yet upon close scrutiny yielded histologic features of solitary fibrous tumor (SFT) or hemangiopericytoma. These pedunculated lesions showed a storiform pattern of spindled cells with interspersed gaping vascular channels reminiscent of SFT or hemangiopericytoma. Interestingly, the immunohistochemical staining profile of these lesions was negative for CD34 and positive for bcl-2 and factor XIIIa. These findings were discordant with SFT and suggest a relationship with fibrous histiocytoma. We propose that this entity represents a hitherto described variant of fibrous histiocytoma known as pedunculated hemangiopericytoma-like fibrous histiocytoma.

Malignant perivascular epithelioid cell tumor ('PEComa'): a case report and literature review of cutaneous/subcutaneous presentations.

Perivascular epithelioid cell (PEC) tumors, also called 'PEComas,' are distinct tumors showing PEC differentiation with characteristic histologic and immunophenotypic features. PEComas are rare tumors documented in the literature presenting in numerous anatomic sites including the thorax, abdomen, pelvis, soft tissue and skin. Criteria for malignancy does not exist for the subset of PEComas that pursue an aggressive clinical course. Herein, we present an unusual case of a malignant PEC tumor presenting as a scalp nodule in a patient with a prior diagnosis of 'melanoma' based upon the immunophenotypic profile of an excised enlarged cervical lymph node. The purpose of this case presentation is to further describe the rare clinical manifestations of a subcutaneous PEC tumor, emphasize the malignant potential of this entity, and review the literature focusing upon clinicopathologic features of cutaneous/subcutaneous PEComas.

Bcl-2, CD34 and CD10 expression in basaloid follicular hamartoma, vellus hair hamartoma and neurofollicular hamartoma demonstrate full follicular differentiation.

Generalized basaloid follicular hamartoma syndrome (GBFHS) is a rare, recently-described, autosomal-dominantly inherited disorder that presents with disseminated milia, palmoplantar pitting, hypotrichosis and basaloid follicular hamartomas (BFH). BFH is a benign adnexal tumor that resembles basal cell carcinoma (BCC). In this study, we report two cases of GBFHS and stain BFH, a vellus hair hamartoma (VHH) and a neurofollicular hamartoma (NH) with CD34, bcl-2 and CD10 to characterize and compare the staining patterns of these follicular tumors. Standard immunohistochemistry labeling with CD34, bcl-2 and CD10 was performed on paraffin-embedded, formalin-fixed tissue sections of five BFH (four for CD10), one VHH and one NH. CD34 stromal staining was observed in all specimens. Bcl-2 stained the outermost cell layers of the basaloid nests in all specimens. CD10 stained the peritumoral stroma of all specimens. The BFH, NFH and the VHH showed CD10 staining of matrical cells. CD34 and CD10 stain peritumoral stroma of BFH, VHH and NH. Bcl-2 stains the outermost cell layer of these tumors. CD10 was also observed to stain matrical cells. These results show the similarities in differentiation between these benign follicular neoplasms and trichoepithelioma.

Immunohistochemical distinction of cutaneous spindle cell carcinoma.

Cutaneous spindle cell squamous carcinoma is an uncommon variant of squamous cell carcinoma in which keratinocytes infiltrate the dermis as single cells with elongated nuclei rather than as cohesive nests or islands, and signs of keratinization of conventional squamous cell carcinoma are insubstantial or nonexistent. Spindle cell carcinoma must be distinguished from spindle cell/desmoplastic melanoma, cutaneous leiomyosarcoma, atypical fibroxanthoma (AFX), and scar. In instances when there is no definitive evidence of squamous differentiation, immunohistochemical studies may confer diagnostic discrimination. Twenty-four cases consisting of 12 spindle cell squamous cell carcinomas, 3 AFXs, 3 leiomyosarcomas, 3 desmoplastic melanomas, and 3 scars were evaluated with a battery of immunohistochemical stains, with the specificity and sensitivity of each marker calculated. The immunohistochemical battery consisted of S-100, desmin, CD68, and smooth muscle actin and cytokeratins P KER (keratins predominantly of molecular weight 56 and 69 kd) and low-molecular weight keratin (CAM 5.2), AE1/AE3, p63, and 34 beta E12 (CK903). Spindle cell squamous carcinomas were negative for S-100, CD68, smooth muscle actin, and desmin with the exception of 2 cases with weak staining for smooth muscle actin. 34 beta E12 provided positive results for each spindle cell squamous carcinoma. The other cytokeratin stains were less sensitive for spindle cell squamous carcinoma than 34 beta E12. The final immunohistochemical results were as follows: 34 beta E12 (12/12, 100%), p63 (10/12, 80%), AE1/AE3 (8/12, 67%), low-molecular weight keratin (7/12, 58%), and P KER (4/12, 33%). The 3 AFXs were positive for CD68 and negative for all other stains, whereas the 3 leiomyosarcomas stained positively for desmin and smooth muscle actin and negatively for all other stains. The 3 melanomas stained positively for S-100 and negatively for all other immunohistochemistry. The scars were negative for all stains. In conclusion, our study of 34 beta E12 proved most promising in distinguishing spindle cell squamous carcinoma from the histologic mimickers, AFX, spindle cell melanoma, scar, and leiomyosarcoma.

Acetylcholine receptor expression in Merkel cell carcinoma.

Neurocrest-derived tissues express muscarinic and nicotinic acetylcholine receptors (mAChR and nAChR respectively). These receptors are critical for migration of neurocrest-derived cells to their corresponding tissues during development. Recent reports demonstrate neurocrest-derived melanoma and numerous non-Merkel cell neuroendocrine tumors express both muscarinic and nicotinic receptors. In light of the controversy surrounding the origin and pathogenesis of Merkel cell carcinoma (MCC), we investigated the immunohistochemical expression of both mAChR and nAChR in MCC. Fifteen cases of primary non-metastatic cutaneous MCC archived at a large veterans' hospital and tertiary referral dermatopathology service were retrieved by computer-assisted search. Immunohistochemistry was utilized to evaluate the presence of M3, M5 and beta 2 nAChR expression. All the cases were confirmed prior to study by a single board certified dermatopathologist (MBM). Fifteen cases of primary cutaneous MCC were diffusely positive for M3 and M5 mAChR staining. All cases lacked immunohistochemical staining for the beta 2 nAChR. Despite the limited number of cases, MCC appears to uniformly express M3 and M5 receptors. These receptors have been linked to cell proliferation and migration which may confer a potential therapeutic target.