p63 and smooth muscle actin expression in low‐grade spiradenocarcinomas in a case of CYLD cutaneous syndrome

Low‐grade spiradenocarcinoma is a rare skin tumor, with fewer than six reported cases, arising in the context of CYLD cutaneous syndrome (CCS; syn: Brooke‐Spiegler syndrome [BSS]). We report two independent cases of spiradenocarcinoma arising in a 50‐year‐old man with CCS. The tumors grew rapidly, prompting clinical excision. The histologic features in our cases corresponded to the salivary gland type basal cell adenocarcinoma‐like pattern, low grade (BCAC‐LG), that has been previously recognized as a recurrent finding in CCS. We performed genetic testing of the patient and found a novel mutation in CYLD. Recognition of low‐grade spiradenocarcinoma can be difficult for the pathologist as the features can be subtle, especially in those cases where the transition from benign to malignant tumor is gradual. We examined p63 and smooth muscle actin (SMA) expression patterns in BCAC‐LG and compared it with the expression pattern in the precursor spiradenoma. Our report provides information on two rare tumors in the context of CCS and suggests that the pattern of p63 and SMA staining may aid pathological detection of the BCAC‐LG subtype of spiradenocarcinoma.     

Association between EGFR gene polymorphisms,skin rash and response to anti‐EGFR therapy in metastatic colorectal cancer patients

Cetuximab and panitumumab are epidermal growth factor receptor (EGFR) inhibitors used in metastatic colorectal cancer (mCRC). Most patients develop a papulopustular rash that may predict tumor response to treatment. EGFR gene polymorphisms may also determine tumor response and appearance of skin rash. We hypothesized an association between EGFR gene polymorphisms, papulopustular rash and response to anticancer treatment. Four EGFR polymorphisms (?216, ?191, CA‐SSR, R521K) were analysed in 51 patients with mCRC receiving anti‐EGFR. Severity of cutaneous rash and tumor response was measured following standard scales. We report an association between SNP‐216 and tumor response (P = 0.003): no tumor progression occurred in TT genotype. Moreover, 92.3% of the responder patients developed skin rash, 62.9% of them presenting a grade ≥2 (P = 0.015). Thus, although underpowered, our preliminary data suggest that SNP‐216 polymorphism of the EGFR gene could be useful in predicting tumor response and the appearance of severe skin rash might also be associated.     

Primary cutaneous CD4+ small‐ to medium‐sized pleomorphic T‐cell lymphoproliferative disorder in a pediatric patient successfully treated with low‐dose radiation

Primary cutaneous CD4+ small‐ to medium‐sized pleomorphic T‐cell lymphoproliferative disorder (PCSM‐LPD) is a rare and low‐grade form of cutaneous T‐cell proliferation with the average age of diagnosis of 54 years. Because of its rarity, the etiology or exact clinicopathology of PCSM‐LPD remains unclear, with < 10 pediatric cases reported. A 13‐year‐old boy presented to our clinic with a raised tumor with PCSM‐LPD histology and was successfully treated with ultra‐low‐dose radiation therapy. While no standard of care has been established for pediatric PCSM‐LPD, this report represents an example of achieving remission in a pediatric tumor with minimal potential for therapy‐related long‐term toxicity.     

Retroperitoneal undifferentiated pleomorphic sarcoma having microsatellite instability associated with Muir‐Torre syndrome: case report and review of literature

Muir‐Torre syndrome represents a rare autosomal dominant familial cancer predisposition disorder defined by the occurrence of cutaneous sebaceous tumors and an internal malignancy, most commonly gastrointestinal carcinoma. Most examples of hereditary non‐polyposis cancer syndrome (Lynch syndrome), including the Muir‐Torre syndrome, are associated with microsatellite instability (MSI) and germline mutations in mismatch repair genes—most commonly MLH1 or MSH2. We present a 58‐year‐old man with Muir‐Torre syndrome and a large retroperitoneal mass (14.3 cm in greatest dimension) encompassing the left adrenal gland. Sections showed a cellular malignant tumor composed of spindle cells with a high mitotic index and lacking morphologic evidence of adipocytic differentiation. It was weakly reactive for smooth muscle actin (SMA) and negative for desmin, CD117, CD31, CD34, S100 protein and pan‐cytokeratin. Further immunohistochemical analysis revealed intact expression of MLH1 but loss of MSH2 in tumor nuclei. Compared to non‐neoplastic tissue, the tumor showed MSI in five of seven dinucleotide markers. Fluorescence in situ hybridization (FISH) failed to reveal 12q15 amplification, effectively excluding dedifferentiated liposarcoma as a diagnostic consideration. This is a rare case of a patient with Muir‐Torre syndrome who developed a related high‐grade undifferentiated pleomorphic sarcoma as the associated internal malignancy.     

CK7 expression in primary cutaneous squamous cell carcinoma

Aim: To evaluate cytokeratin 7 (CK7) immunoreactivity in invasive primary cutaneous squamous cell carcinomas (SCCs). Methods: Twenty‐seven primary cutaneous SCCs from 25 patients were evaluated for tumor grade using hematoxylin and eosin‐stained slides and for percentage and intensity of immunoreactivity for CK7. All cases exhibited features of SCC with an in situ component. No glandular or tubular differentiation was present. Staining intensity was graded on a scale of 0–3, with 0 indicating no reaction. Of immunoreactive cases, percentage of tumor staining and distribution of immunoreactivity was documented. Results: Six of 27 SCCs (22%) exhibited immunostaining for CK7. Of those cases, three were poorly differentiated, exhibiting 2 to 3+ intensity in 5–15% of cells. Two were poorly differentiated, with 2 to 3+ intensity in 30–60% of cells. The remaining immunoreactive tumor was moderately differentiated, with 1+ intensity and 5% staining in an area of microinvasion. Conclusion: A subset of cutaneous SCCs, in particular, poorly differentiated tumors, may show focal‐to‐partial immunoreactivity for CK7. This is important to bear in mind when immunohistochemistry is used to distinguish SCC from simulants, such as porocarcinoma, or other adnexal carcinomas with squamous metaplasia. Pulitzer M, Desman G, Busam KJ. CK7 expression in primary cutaneous squamous cell carcinoma.     

Vergleich und Bewertung der aktuellen Staging‐Systeme des Karzinoms der Haut

Background: Recently the “Union for International Cancer Control” (UICC) and the “American Joint Committee on Cancer” (AJCC) changed their TNM (tumor, node, metastasis) classification of cutaneous carcinomas. Methods: We compared these classifications, tested their practicability with 615 prospectively collected, unselected, primary cutaneous squamous cell carcinomas, and introduced additional classification criteria. Results: Neither classification contains information about prognosis. Non‐metastasizing types of cutaneous carcinoma should be excluded. The vermilion border of the lower lip and the eyelids should be included. Both systems have been improved, but in part they are irreproducible. The AJCC has introduced six “high‐risk features” to differentiate between T1 and T2. However, this does not seem reasonable. Only rare cases are classified as T4. Both systems have different N classifications. A clinical cT classification based on tumor size 2 cm seems reasonable but not sufficient. It should be complemented by a postoperative p (pathologic) T classification based on tumor thickness: “no risk”≤ 2 mm thickness (0% risk of metastasis), “low risk” > 2 mm to 6 mm thickness (4% risk of metastasis), and “high risk” > 6 mm thickness (16% risk of metastasis). Immune suppression, poor differentiation/desmoplasia, and the ear as tumor site are additional risk factors for metastasis, currently not evaluable. Conclusions: The classifications are unsuitable for a realistic estimate of the risk of metastasis which is possible using a combination of tumor size and thickness. The N staging system should consider histopathologic findings.     

Familiäres Auftreten einer segmentalen Typ‐2‐Manifestation der kutanen Leiomyomatose

Background: There are several malignant or benign skin diseases which can be explained by the phenomenon of mosaicism or segmental manifestation, e. g. segmental neurofibromatosis 1 or cutaneous leiomyomatosis. Loss of heterozygosity is a crucial element for segmental manifestations. Two types of segmental manifestations can be defined in autosomal dominant skin diseases such as cutaneous leiomyomatosis. Type 1 is caused by a novel postzygotic segmental mutation; type 2 reflects an additional postzygotic loss of heterozygosity of the gene locus responsible for cutaneous leiomyomatosis in a initially heterozygous embryo. Loss of heterozygosity is a genetic process when a heterozygous cell becomes homozygous or hemizygous by loosing the corresponding wild‐type allele. This phenomenon can be regarded as a precondition for tumor growth. In type‐2 cases, the segmental manifestation is more distinctive with additional disseminated disease because of a germline mutation with heterozygosity of all somatic cells outside the strongly affected area. Patients and Methods: A 74‐year‐old female patient and her 52‐year‐old son presented with segmental leiomyomas following the lines of Blaschko as well as disseminated skin tumors. The woman has undergone hysterectomy at the age of 29 because of multiple uterine leiomyomas, as had her mother and grandmother. Results: Based on their typical clinical appearance, these cases represent the rare familial occurrence of type‐2 manifestation of leiomyomas which indicates a postzygotic loss of the wild‐type allele. Conclusion: Very unusual is the familial occurrence in mother and son of this type‐2 manifestation of cutaneous leiomyomatosis. Apparently the gene locus is prone to a postzygotic loss of heterozygosity.     

BRCA1‐associated protein (BAP1)‐inactivated melanocytic tumors

Although discussed using variable terminology, cutaneous BRCA1‐associated protein (BAP1)‐inactivated melanocytic tumor (BIMT) has been considered a discrete diagnostic entity since 2011. Here, we review the initial genomic studies that identified these distinct melanocytic tumors and the clinical and histopathological features that define these tumors. These epithelioid, predominantly dermal, and melanocytic tumors present as erythematous nodules and histopathologically have features that may overlap with Spitz nevi and nevoid melanoma. There is no sex predilection, and cutaneous BIMTs can appear at any age; however, in most familial (germline mutant) cases patients have multiple cutaneous tumors with a first diagnosis in the second or third decade of life; ocular melanoma and other tumors are increasingly identified in these kindreds with germline BAP1 mutation. These tumors have been described with a myriad of terms including: Wiesner nevus, nevoid melanoma‐like melanocytic proliferation (NEMMP), BAP1 mutant Spitz nevus, BAP1 mutant nevoid melanoma, cutaneous BAPoma, and most recently cutaneous BIMT.     

Inverse correlation between microtubule‐associated protein 1A/1B‐light chain 3 and p62/sequestosome‐1 expression in the progression of cutaneous squamous cell carcinoma

The expression of autophagy‐related markers has occasionally been reported to correlate with the clinical stage of disease in patients with solid cancer, indicating autophagy activation. However, there have been no such reports for cutaneous squamous cell carcinoma. In this study, we investigated the expression levels of two autophagy‐related markers, microtubule‐associated protein IA/IB light chain 3 (LC3) and p62/sequestosome‐1 (p62), in cutaneous squamous cell carcinoma specimens and assessed their correlation to clinicopathological factors in patients with this type of cancer. As a marker of the autophagosome, LC3 expression increases with autophagosome formation/accumulation, whereas p62 expression decreases due to selective degradation via autophagy. We performed immunostaining for LC3 and p62 in 50 cutaneous squamous cell carcinoma specimens obtained from patients treated by surgical resection, counted the number of cells that showed positive staining, and calculated the percentage of positive cells per low‐power microscopic field. We next investigated the correlations between the expression levels of these markers and various clinicopathological factors. The results indicated that LC3 expression increased significantly with advanced clinical stage (P < 0.001) and increased tumor diameter (P = 0.046). By contrast, the expression of p62 decreased significantly with advanced clinical stage (P < 0.001) and increased tumor diameter (P = 0.001). These results suggest that autophagy becomes activated during disease progression in patients with cutaneous squamous cell carcinoma.     

Endocrine mucin‐producing sweat gland carcinoma occurring on extra‐facial site: a case report

Cutaneous endocrine mucin‐producing sweat gland carcinoma (EMPSGC) is a very rare low‐grade malignant neoplasm analogous to the mammary solid‐papillary carcinoma. It frequently expresses neuroendocrine markers and may show mucinous differentiation. Although the nodules are circumscribed, myoepithelial cells cannot be showed in most cases and about half of the cases are associated with invasive mucinous carcinoma. Hence, it has been suggested to be invasive and the precursor lesion of some primary cutaneous mucinous carcinomas. After being recognized as a distinct entity, all cases reported to date occurred either in the periocular region or on the cheek. Two thirds of the patients were female. Herein we present an unusual case of in situ EMPSGC on the chest wall skin of a middle‐aged man.     

Cartilage hair hypoplasia with cutaneous lymphomatoid granulomatosis

Cartilage–hair hypoplasia (CHH) is an autosomal recessive chondrodysplasia characterized by short‐stature, sparse hair and impaired cellular immunity. We describe a young girl who was diagnosed with CHH based on the findings of recurrent infections, short stature with metaphyseal chondrodysplasia, and a confirmed bi‐allelic RMRP gene mutation. At 13 years, the patient developed an Epstein–Barr virus (EBV)‐driven lymphoproliferative disorder involving the lung, which responded partially to chemotherapy. Simultaneously, she developed multiple indurated plaques involving her face, which had histological findings of granulomatous inflammation and EBV‐associated low‐grade lymphomatoid granulomatosis. The patient received a matched unrelated peripheral blood stem cell transplant at 15 years of age, and her immunological parameters and skin lesions improved. Lymphomatoid forms of granulomatosis and cutaneous EBV‐associated malignancies have not been described previously in CHH. This case highlights the possibility of EBV‐associated cutaneous malignancy in CHH.     

Histopathologic and Ultrasound Characteristics of Cutaneous Capillary Malformations in a Patient with Capillary Malformation–Arteriovenous Malformation Syndrome

Capillary malformation–arteriovenous malformation (CM‐AVM) syndrome is an autosomal dominant disorder caused by mutations in RASA1. Multifocal, small, round‐to‐oval, pinkish‐to‐red cutaneous capillary malformations are seen in more than 90% of people with RASA1 mutations. These RASA1‐associated cutaneous capillary malformations (CMs) can accompany internal or cutaneous arteriovenous malformation (AVM) or arteriovenous fistula to constitute CM‐AVM syndrome. The cutaneous capillary malformations in CM‐AVM syndrome are unusual in that some lesions have high‐flow characteristics (according to Doppler or a white halo). We describe the histopathologic and corresponding ultrasound and Doppler findings in a CM from a patient with clinical CM‐AVM syndrome and show that an arterial component is not present in the dermis or the most superficial portions of the subcutaneous fat but that there is ultrasound evidence that an AVM resides in the underlying adipose tissue.     

Lymph node location of a clear cell hidradenoma: report of a patient and review of literature

Cutaneous clear cell hidradenoma is an uncommon benign adnexal tumor which is not supposed to metastasize, contrary to its rare malignant counterpart, hidradenocarcinoma. We report the case of a 49‐year‐old man, who had had a stable inguinal lymph node enlargement for 6 years. An excision was performed and revealed an intra‐nodal tumor, made of large clear cells with abundant cytoplasm and round nuclei without atypia or mitosis. The immunohistochemical staining showed diffuse positivity for keratin AE1/AE3, keratin 5/6 and p63, and focal staining with keratin 7, epithelial membrane antigen (EMA) and carcinous epithelial antigen (CEA), which underlined some ductular structures. Tumor cells were negative for renal markers PAX8 and CD10. Ki67 stained less than 1% of tumor cells. A translocation involving MAML2 gene was evidenced by fluorescence in situ hybridization (FISH) analysis. No primary cutaneous tumor was found after extensive examination. Altogether, these results are in favor of an isolated nodal hidradenoma, for which we discuss two hypothesis: a primary nodal lesion, or a ‘benign metastasis’ of a cutaneous tumor. Cases of morphologically benign hidradenoma with lymph node involvement are exceptional. Our case, similar to every other reported case, was associated with an excellent prognosis, supporting the idea that these patients should not be overtreated.     

Cutaneous Epithelioid Hemangioendothelioma on the Sole of a Child

Epithelioid hemangioendothelioma (EHE) has been considered to be a low‐grade malignant vascular neoplasm, although follow‐up of recent series has demonstrated that EHE involving the skin and soft tissues should be better regarded as a fully malignant vascular tumor since it has more metastatic potential than previously thought. We report a case of an EHE involving the left sole of 6‐year‐old boy, the youngest patient with cutaneous EHE described to date. Immunohistochemical studies demonstrated a lymphatic endothelial line of differentiation for neoplastic cells. Cutaneous EHE is rare in childhood, with only five previously described cases.     

Cutaneous nodular fasciitis with genetic analysis: a case series

Nodular fasciitis is a benign self‐limited myofibroblastic neoplasm, which usually involves the upper extremities and trunk of young patients. These tumors have been shown to harbor a translocation involving the MYH9 and USP6 genes, leading to overexpression of the latter. We report seven cases of nodular fasciitis with cutaneous presentations. All cases involved the dermis, with six involving the superficial subcutis, and one auricular tumor extending into cartilage. All cases showed USP6 rearrangement by fluorescence in situ hybridization; in two of three cases, the characteristic MYH9‐USP6 fusion was shown by RT‐PCR. All patients underwent conservative resection. Nodular fasciitis is an uncommon mesenchymal neoplasm that can occasionally present in superficial locations and is sometimes mistaken for a malignant process. Molecular testing can be useful to distinguish this entity from other cutaneous spindle cell tumors.     

Epithelial deletion of podoplanin is dispensable for re‐epithelialization of skin wounds

The mucin‐like transmembrane protein podoplanin (PDPN) is prominently represented in tumor‐associated gene expression signatures of numerous types of cancer including squamous cell carcinoma, and gain‐of‐function and knockdown approaches in tissue culture strongly suggested an important role of PDPN in cell proliferation, migration and adhesion. PDPN is absent during epidermal homeostasis but is highly expressed in basal keratinocytes during cutaneous wound healing. Enhanced motility of immortalized keratinocytes upon ectopic PDPN overexpression argues for wound healing defects upon podoplanin deficiency in keratinocytes; however, in vivo data that unequivocally define the impact of PDPN by functional studies in a physiologically relevant system are still missing. Here, we have applied an in vivo loss‐of‐function approach by generating a novel transgenic mouse line with keratinocyte‐specific podoplanin deficiency. Performing cutaneous full‐thickness excisional wounds to examine re‐epithelialization capacity, unexpectedly, no defects were observed in wound healing properties of mutant mice. Similarly, PDPN‐deficient primary keratinocytes showed no impairment in migration, adhesion or proliferation. Thus, PDPN function is not rate‐limiting for re‐epithelialization but may be functionally compensated by an as yet unknown protein. Our data also call for in vivo functional studies on PDPN in settings of skin tumor development and progression to clarify PDPN's role in skin pathology.     

Epidermal growth factor receptor gene numerical aberrations are frequent events in actinic keratoses and invasive cutaneous squamous cell carcinomas

Please cite this paper as: Epidermal growth factor receptor gene numerical aberrations are frequent events in actinic keratoses and invasive cutaneous squamous cell carcinomas. Experimental Dermatology 2010; 19: 151–153. Abstract: Epidermal growth factor receptor (EGFR) gene amplification and protein overexpression are common in several cancers. EGFR status has seldom been studied in cutaneous squamous carcinomas (SCCs), or their precursors, actinic keratoses (AKs). We evaluated the presence of EGFR genomic aberrations and EGFR protein overexpression in 25 AKs and 35 invasive SCCs by means of fluorescence in situ hybridization (FISH) and immunohistochemistry. EGFR numerical aberrations were detected in 52% of AKs and 77.1% of SCCs (P = 0.042). EGFR amplification was identified in 12% of AKs and 20% of SCCs. No differences regarding EGFR numerical aberrations were observed when AKs with high‐grade dysplasia were compared with SCCs. A good correlation was observed between EGFR numerical aberrations and EGFR overexpression. Our results suggest that EGFR numerical aberrations occur in the early stages of epithelial carcinogenesis in skin, not playing a role in the progression from low‐grade SCCs into more aggressive phenotypes.     

Lymphomatoid papulosis: is a second lymphoma commoner among East Asians?

Background. Lymphomatoid papulosis (LyP) is a low‐grade cutaneous lymphoma, which lies within the spectrum of primary cutaneous CD30‐positive lymphoproliferative disorders. Around 10–20% of LyP cases are associated with a second lymphoma. Aim. To analyse a cohort of Asian patients with LyP, diagnosed from 1987 to 2007 at the National Skin Centre (NSC), Singapore, in terms of epidemiology, treatment and association with a second lymphoma. Methods. Patients were identified through the NSC clinical and histological databases. Results. During this period, 13 patients were diagnosed with LyP based on clinicopathological criteria. The mean age at diagnosis was 41 years, the male : female ratio was 2.3 : 1, and 92% of the patients were Chinese. Recurrent papulonecrotic lesions were present for a mean of 3 years before diagnosis. Treatment of LyP comprised monotherapy (n = 4) or combination therapy (n = 9) using corticosteroids, oral antibiotics, methotrexate and/or phototherapy. Mean duration of follow‐up was 6.4 years. Eight patients (61.5%) were diagnosed with a second lymphoma, either before (n = 2), concurrently with (n = 1) or after (n = 5) the diagnosis of LyP. Mycosis fungoides (MF) was the commonest lymphoma (78%, n = 7), followed by primary cutaneous anaplastic large‐cell lymphoma (12%, n = 2). There was one death (mortality rate 7.7%), which occurred in a patient who had developed stage IIA MF after LyP, which subsequently progressed to systemic T‐cell lymphoma. Conclusions. LyP is a chronic, relapsing disease with considerable morbidity, but an overall good prognosis. A strikingly large proportion of our Asian patients (61.5%) had a second lymphoma, compared with previous studies. This emphasizes the importance of regular lifetime surveillance for associated lymphomas in all patients with LyP.