Granulomatous and lichenoid dermatitis after IgG4 anti-PD-1 monoclonal antibody therapy for advanced cancer.

Nivolumab is a fully human IgG4 monoclonal antibody directed against programmed cell death protein 1 (PD-1). PD-1 inhibition allows T-cell activation and recruitment to destroy cancer cells. Checkpoint inhibitors have shown significant survival advantage and relatively low side-effects in comparison with conventional chemotherapy in several types of advanced cancer. Granulomatous cutaneous reactions have been reported showing sarcoidal and panniculitic morphology. Here we present a case of drug-induced lichenoid and granulomatous dermatitis after checkpoint inhibitor therapy observed in a 63-year-old male treated with nivolumab for advanced glioblastoma. This morphology has not been previously reported. We documented a high number of CD8+ T-cells within the lesions. Additionally, we review the side-effects observed with the use of checkpoint inhibitors, with special focus on cutaneous manifestations.

Clinicopathologic findings in (anti-FcepsilonR1alpha) autoimmune-related chronic urticaria.

BACKGROUND: One cause of chronic urticaria is autoreactivity which is diagnosed by detecting autoantibodies against the IgE receptor alpha subunit (anti-Fc R1alpha). OBJECTIVE: To compare the histopathologic features of chronic urticaria patients testing positive for anti-IgE receptor antibody (Ab) to those testing negative. METHODS: Totally, 438 patients with a clinical presentation of chronic urticaria (2011-2013) had anti-IgE receptor Ab tested and 37 of those patients had skin biopsy. We evaluated microscopic features including: spongiosis, dermal edema, presence of mast cells, density of lymphocytic infiltration, predomination of eosinophils/neutrophils; intravascular neutrophils and presence of vasculitis. The aforementioned features were compared between negative and positive anti-IgE receptor Ab groups. RESULTS: Of 37 patients , 69% were women and 31% were men. 49% had positive anti-IgE receptor Ab and 51% had negative anti-IgE receptor Ab. In the positive anti-IgE receptor Ab group, 83% showed intravascular neutrophils. Eosinophil predominance was identified in 72% and neutrophil predominance was identified in 28%. In the negative anti-IgE receptor Ab group, 89% showed intravascular neutrophils. Eosinophil predominance was identified in 53% and neutrophil predominance was identified in 47%. There was no evidence of vasculitis in either group. CONCLUSION: There were no significant histopathologic differences between the anti-IgE receptor Ab positive and negative cases. Therefore, serum testing for anti-IgE receptor Ab is required to identify this subgroup of chronic urticaria patients.

Cutaneous meningioma: a potential diagnostic pitfall in p63 positive cutaneous neoplasms.

Cutaneous meningiomas are divided into three groups. Type I lesions present at birth and are derived from ectopic arachnoid cells. Type II lesions usually present in adults and are derived from arachnoid cells surrounding nerve bundles. Type III lesions are due to direct extension or metastasis from dural-based neoplasms. Dural-based meningiomas are known to express p63. The aim of our study is to examine the expression of p63 in type II and type III meningioma. Two cases of cutaneous meningioma (type II and type III) were evaluated for the expression of p63, EMA, CK 5/6, S100 and CD31. The cells of interest were spindled to epithelioid and arranged in a whorling pattern. Immunohistochemical staining showed expression of EMA and p63 in both cases, while stains for CK 5/6, S100 and CD31 were negative. Among cutaneous tumors, p63 is considered a marker of epithelial derivation, as it is positive in epidermal and adnexal neoplasms. It is important to be aware of p63 expression in the context of cutaneous meningioma to avoid misinterpretation as an epithelial tumor. On the basis of our small study, it is unlikely that p63 expression would be helpful in distinguishing between type II and type III meningioma, as both may be p63-positive.

Bilateral areolar leiomyomas in a patient undergoing BRAF inhibition therapy for melanoma.

BRAF inhibition therapy, used to treat melanomas with BRAF mutations, is associated with both neoplastic and non-neoplastic cutaneous side effects including squamous cell carcinomas, warty dyskeratomas, verrucous keratoses, photosensitivity and widespread eruptions that present histopathologically as acantholytic dyskeratosis. We report a case of a patient undergoing BRAF inhibition therapy for disseminated melanoma with a V600E mutation who developed bilateral areolar leiomyomas, one of which was biopsied and the other of which resolved after discontinuation of vemurafenib therapy. To our knowledge, this is the first reported case of a mesenchymal neoplasm developing in association with BRAF inhibition therapy.

Penile Myointimoma: A Clinicopathologic Study of 4 Tumors.

Penile myointimoma is a rare, benign tumor occurring within the corpus spongiosum vasculature of the glans penis. Thus far, there have been twenty-three reported tumors in the literature. We present four additional tumors of this unique myointimal proliferation. Patients ranged in age from 20 to 68 years and presented with a firm mass on the glans penis. All four tumors displayed distinctive morphologic features consisting of a myointimal proliferation with plexiform architecture of bland myofibroblastic cells in a myxoid background in the corpus spongiosum vasculature. Characteristic cytoplasmic immunoreactivity of lesional cells with smooth muscle actin in addition to a desmin positive collarette of native vessel smooth muscle was seen in all four tumors. No disease was reported in any of the patients at last clinical follow-up (9 months to 15 years) after biopsy or excision. Myointimoma is part of a rare group of mesenchymal tumors that has been recently classified by its distinctive location, morphology, and immunohistochemical reactivity. For any nodular, spindle cell lesion of the corpus spongiosum, myointimoma should be included in the differential diagnosis given its unique characteristics and favorable clinical outcome.

Dermal hypersensitivity reaction: a PCR-confirmed pattern of herpetic dermatitis.

BACKGROUND: Herpetic dermatitis due to herpes simplex virus (HSV) and varicella zoster virus (VZV) can present with similar clinical and histopathologic features. Further confounding matters, viral cytopathic changes are not always observed in biopsy specimens. Therefore, use of polymerase chain reaction (PCR) analysis can play an integral role in the definitive diagnosis of herpetic dermatitis and in the distinction of HSV-1/HSV-2 from VZV. METHODS: Forty patients with skin biopsies (2004-2011) had PCR analysis performed to detect HSV-1/2 or VZV. Patient demographics, clinical impression and histopathologic characteristics were reviewed and correlated with PCR findings. RESULTS: Overall, there was complete correlation between clinical impression, histopathology and PCR results in 21 of 40 cases. In 19 cases, clinical impression and histopathology were discrepant and in 15 of these cases PCR confirmed HSV or VZV infection. We also describe 3 cases of herpetic dermatitis without viral change that histopathologically demonstrate the pattern of a dermal hypersensitivity reaction. CONCLUSIONS: The results of this study suggest that routine use of PCR for definitive diagnosis of herpetic dermatitis should be considered when there is a clinical suspicion of herpes virus infection, even when there is a lack of specific histopathologic findings. Additionally, a dermal hypersensitivity reaction should be recognized as one histopathologic manifestation of herpes incognito.

An audit of dermatopathology requisitions: hand written vs. electronic medical record data entry accuracy.

BACKGROUND: At our institution, dermatopathology case requisitions are received in hand written form or via electronic medical record (EMR). Categories for requisition data entry include patient demographics, physician name and procedure site/date. Systematic data entry problems potentially cause considerable documentation error, propagate inaccurate patient information and potentially delay billing/revenue collection. METHOD: We compared dermatopathology data entry errors on hand written requisitions to data entry errors using the EMR. A total of 11,475 requisitions (8545 hand written and 2930 EMR) were included in the study (the time frame was 4/1/2011-9/30/2011). RESULTS: For hand written requisitions, there were 258 data entry errors on 8545 specimens (3.0%). For requisitions entered via EMR, there were 113 errors on 2930 specimens (3.9%). Container labeling, which is a hand written process with both requisition methods, was the most common source of error. CONCLUSIONS: Currently, even with an EMR, containers are at least partially hand labeled and 96% of EMR errors occurred during this process. Other EMR data entry errors are extremely uncommon (4/2930 cases). This suggests introduction of a labeling process entirely linked to EMR data entry could nearly eliminate data entry errors. Although this study focused solely on dermatopathology cases, the findings can be extrapolated to all types of specimens.

Expression of MiTF may be helpful in differentiating cellular neurothekeoma from plexiform fibrohistiocytic tumor (histiocytoid predominant) in a partial biopsy specimen.

BACKGROUND: Overlapping histopathologic features of cellular neurothekeoma (CNT) and plexiform fibrohistiocytic tumor (PFHT), when both are predominantly composed of histiocytoid cells, make distinction between these entities challenging. Some have suggested that CNT and PFHT are related entities. No prior study has demonstrated a reliable immunohistochemical panel to differentiate these entities. METHODS: Skin biopsies diagnosed as CNT and PFHT, from 2004 to 2010 were retrieved with accompanying pathology reports. Each case was reviewed by at least 2 dermatopathologists and 2 soft tissue pathologists for confirmation of diagnosis. All cases were then evaluated for immunohistochemical expression of PAX2, NKIC3, CD10, and microphthalmia transcription factor (MiTF). RESULTS: Histopathologically, the histiocytoid areas of each tumor shared similar architecture, demonstrating nests and fascicles of histiocytoid to spindled cells, with some separation of nests by collagen bands. Both CNT and PFHT were uniformly positive for NKIC3 and CD10, and both were frequently PAX2 positive. MiTF was strongly and diffusely positive in CNT and was consistently negative in the PFHT. CONCLUSIONS: CNT and PFHT share many histopathologic features and immunohistochemical staining patterns. Of the stains we evaluated, we found that expression of MiTF may be a reliable marker for distinguishing CNT from histiocytoid-predominant PFHT, especially in instances where only a small part of the tumor is sampled for evaluation.

Cystic fibrosis transmembrane conductance regulator is helpful in the distinction of extra-mammary Paget's disease from squamous cell carcinoma in situ (Bowen's disease).

Cystic fibrosis transmembrane conductance regulator (CFTR) represents a cAMP-dependent channel found in normal apocrine glands. The classification and histogenesis of extra-mammary Paget's disease (EMPD) remains controversial, but it is generally accepted that primary EMPD exhibits apocrine differentiation. Therefore, we examined the utility of CFTR in the differential diagnosis of EMPD and squamous cell carcinoma in situ (SCCIS). Twenty-five cases of SCCIS and 14 cases of EMPD were evaluated for immunohistochemical expression of CFTR. Expression was scored as 0 (<5% of cells positive), 1+ (5-75% of cells positive) or 2+ (>75% cells positive). Twenty-three of 25 cases of SCCIS showed no reactivity for CFTR, and the remaining 2 cases showed 1+ staining. Thirteen of 14 cases of EMPD showed 2+ staining, while 1 case showed 1+ staining. We recognize that the pathological appearance along with clinical history and site of occurrence are sufficient to distinguish EMPD and SCCIS in most instances. However, distinction between the two can become more challenging when the location and histopathology are not characteristic. We conclude that when an immunohistochemical panel is diagnostically necessary, the expression of CFTR favors a diagnosis of EMPD over SCCIS.

Cellular neurothekeoma with fascicular growth features mimicking cellular dermatofibroma.

BACKGROUND: Cellular neurothekeoma (CNT) is a benign cutaneous mesenchymal neoplasm. Most demonstrate a lobulated to micronodular architecture. Rarely, CNT demonstrates a predominantly fascicular growth pattern, without prominent sclerosis and thus can mimic cellular dermatofibroma (DF). METHODS: Three CNT with a predominantly fascicular pattern were obtained. The clinicopathologic features and accompanying immunohistochemical stains were evaluated. RESULTS: All cases demonstrated a moderately cellular proliferation of epithelioid to spindle cells with pale to eosinophilic slightly granular cytoplasm, vesicular nuclei, and a single nucleolus arranged in a fascicular pattern with thick collagen bundles at the periphery (collagen trapping). One case had prominent epidermal hyperplasia. The neoplastic cells expressed NKI-C3, CD10, and micropthalmia transcription factor and lacked expression of factor XIIIa, S-100, epithelial membrane antigen, and CD34. CONCLUSIONS: Our cases showed an unusual pattern of CNT with a predominantly fascicular growth pattern, thickened collagen bundles at the periphery, and occasionally epidermal hyperplasia. The overlap with cellular DF is striking. The presence of plump to epithelioid cytomorphology with abundant cytoplasm, with focally prominent nucleoli; the presence of focal lobulated to micronodular growth pattern along with micropthalmia transcription factor positivity; and lack of factor XIIIa expression are helpful in distinguishing fascicular CNT from cellular DFs.

Sarcomatoid renal cell carcinoma presenting in the oropharynx.

Metastasis stemming from a distant malignancy is far less common than an oropharyngeal primary and represents only 1% of all oral neoplasms. The difficulty in diagnosing a metastasis in the oropharynx may be compounded if the lesion is poorly differentiated and bears little resemblance to the primary tumor. We present the case of synchronous metastatic renal cell carcinoma of the mandibular gingiva in a woman with sarcomatoid clear cell renal cell carcinoma. The metastatic lesion was poorly differentiated and lacked expression of the renal cell carcinoma (RCC) antigen. In contrast, PAX-8 staining was strongly positive. This case serves to highlight the diagnostic difficulty posed by poorly differentiated lesions in the oropharynx and reinforces the sensitivity of the cell lineage-specific transcription factor PAX-8 in poorly differentiated RCC.

Epithelioid hemangioma (angiolymphoid hyperplasia with eosinophilia) arising on the extremities.

BACKGROUND: Epithelioid hemangioma (EH) is a benign vascular proliferation usually accompanied by a mixed inflammatory infiltrate. METHODS: Skin biopsy specimens from four patients with EH on the extremities were studied. Architecture, extent of vascular proliferation and the presence of epithelioid endothelial cells were evaluated. The features of the inflammatory infiltrate were also assessed, including the distribution, depth, predominant cell type, presence of germinal centers, and distribution and number of CD30+ cells. RESULTS: All cases showed the typical lobular pattern of small vessels centered about a 'feeder' vessel. Larger vessels were lined by epithelioid endothelial cells. The mixed inflammatory infiltrate was nodular, perivascular and periadnexal. Germinal centers were seen in two cases. Large activated CD30+ lymphocytes were seen in all cases. CONCLUSIONS: EH can lead to diagnostic confusion with cutaneous lymphoma and other entities, especially when its mixed inflammatory infiltrate predominates over its vascular component and contains large activated CD30+ lymphocytes. Awareness that the presence of CD30+ activated lymphocytes is not specific for lymphoma and recognition of the vascular component is critical for proper diagnosis of EH.

Extra-acral cutaneous/soft tissue sclerosing perineurioma: an under-recognized entity in the differential of CD34-positive cutaneous neoplasms.

BACKGROUND: Perineuriomas are an uncommon group of tumors composed of perineurial cells of peripheral nerve sheath lineage. Variants include soft tissue (extraneural), intraneural, sclerosing, reticular and plexiform forms. Sclerosing perineuriomas have been reported to occur almost exclusively on the hands of young men. Herein, we report three extra-acral cutaneous/soft tissue perineuriomas that show significant associated sclerosis. METHODS: Skin biopsy specimens from three patients were evaluated for cytomorphology and degree of associated sclerosis, which was classified as either focal or diffuse. Immunohistochemical expression of epithelial membrane antigen (EMA), CD34 and S-100 was also assessed to facilitate further classification. RESULTS: Histopathologically, the tumors showed both focal and diffuse sclerosis, and lesional cells were generally spindled in shape. Immunohistochemical staining showed diffuse positivity for CD34 and focal or diffuse positivity for EMA. The cells uniformly lacked expression of S-100 protein. CONCLUSIONS: Sclerosing perineuriomas can occur in extra-acral locations and should be considered in the differential of EMA-positive cutaneous spindle-cell proliferations. It is also important to recognize that perineuriomas can express CD34 and should be considered in the differential diagnosis of CD34-positive cutaneous neoplasms.

Syphilis: A Contemporary Clinicopathologic Assessment.

Syphilis is a sexually transmitted disease caused by the spirochetal bacterium Treponema pallidum that has been of public health concern for centuries. In the United States, it is currently a reportable disease and one which is recently generating increasing case numbers especially in at risk populations of immune deficiency and men who have sex with men. The present series examines biopsies from 13 patients collected over a 12-year period from a general hospital network in north suburban Cook County, Illinois. There were 13 patients (11 male: 2 female) with varied presentations, including primary ulcerated anogenital chancres, mucosal lesions, peculiar rashes, and alopecia. The reason(s) for biopsy were not clear from the clinical record, as a clinical consideration of syphilis was recorded in only 3 cases. Histologic examination of the mucocutaneous lesions encompassed a spectrum of findings including ulceration, psoriasiform hyperplasia, intense mixed band-like inflammation at the dermal-epidermal junction with a prominent plasma cell component. The contemporary availability of an effective immunostain is a valuable diagnostic adjunct. The organisms generally parallel the intensity of the inflammatory infiltrate but the distribution may vary and rarely, organisms may be absent despite serologic confirmation. Previous corkscrew morphology of the organism described ultrastructurally is reflected in the immunostained representation. Although the diagnosis of syphilis remains a clinical one in most cases, some patients will have unusual presentations and biopsies will be done. The awareness of the pathologist will facilitate prompt and effective treatment.

Brooke-Spiegler Syndrome With Cervical Spine Lesion.

Brooke-Spiegler syndrome (BSS) is a rare hereditary autosomal dominant disorder with variable phenotypic expressivity that results in a variety of benign cutaneous face, scalp, and neck tumors with a histology profile of cylindroma, spiradenoma and trichoepithelioma. Reports of lymph node and distant metastasis are scarce. We present the first case of Brooke-Spiegler syndrome with metastasis to the cervical spine. An 86-year-old female with Brooke-Spiegler syndrome presented to the clinic with a finding of cervical spine lesion involving vertebral body, prevertebral, paraspinal, foraminal, and epidural spaces. The histopathology of the lesion showed benign cylindroma. Considering the location of the lesion and local invasion of neural structures, the malignant transformation of existing tumors could not be excluded. Brooke-Spiegler syndrome rarely presents with malignant transformation and distant metastatic spread. It is important to be aware of these rare cases while monitoring the disease and addressing clinical symptoms. This is to our knowledge the first case of metastatic spread of the cylindroma to the cervical spine resulting in local bone destruction and neural elements compromise. Physicians should be aware of this rare possibility.

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.

Cutaneous Leishmaniasis: Contribution of Routine Histopathology in Unexpected Encounters.

The ulcerated papules of cutaneous leishmaniasis represent an unusual form of granulomatous dermatitis caused by Leishmania species, a protozoan transmitted by sandfly bites. As the disease is not native to North America, clinical suspicion is partially based on a compatible travel history and may result in a biopsy. The key role of standard morphology is the identification of Leishmania organisms, supplemented by Giemsa and/or CD1a immunostaining. Histologically, the organism may be confused with Histoplasma species, which is resolved by staining with methenamine silver or PAS. Four cases of cutaneous leishmaniasis are presented for which organisms were present in 3; polymerase chain reaction and DNA sequencing for speciation done by the Center for Disease Control and Prevention (CDC) was confirmatory in 3 cases, including the one case without histologically identifiable organisms. Rare unexplained cases of cutaneous leishmaniasis without a travel history have been reported outside endemic areas. The present cases emphasize the importance of diagnostic awareness of unusual infections such as this in the context of political unrest, ease of international travel, climate change and the possible expansion of geographic vector distribution. In the morphologic absence of organisms, the diagnosis may require molecular techniques, currently available on a referral basis to pathologists without charge from CDC.

Myeloid leukemia cutis: a histologic and immunohistochemical review.

BACKGROUND: The histologic diagnosis of myeloid leukemia cutis (LC) can be difficult, requiring confirmatory immunohistochemical stains. OBJECTIVE: We reviewed 21 biopsy-proven cases of LC with emphasis on the use of immunohistochemistry in the diagnosis. MATERIALS AND METHODS: Clinical and histologic features were reviewed on 21 cases of biopsy proven LC. Immunohistochemical stains for CD4, CD34, CD56, CD68, CD117, CD123, TdT, lysozyme and myeloperoxidase were performed on 12 with available tissue blocks. RESULTS: Ages ranged from 24 to 88 years (mean = 57), with 12 men: 9 women. Primary hematologic diagnoses included acute myeloid leukemia (n = 14), myelodysplastic syndrome (n = 3), essential thrombocythemia (n = 1) and myeloid leukemia, NOS (n = 3). Monocytic myeloid LC was most common (35%). There was 100% positivity with CD68 and lysozyme. Myeloperoxidase, CD117 and CD34 immunostains were less sensitive in myeloid LC (58%, 33% and 17%, respectively). CD4 was positive in 67%. CD56 was positive in 33%. CONCLUSION: Myeloid leukemia with monocytic differentiation more commonly involves the skin than other types of myeloid leukemia. CD68 and lysozyme immunostains, although not lineage specific for monocytes/macrophages, are the most sensitive immunostains in the detection of myeloid LC. Myeloperoxidase immunostains are useful, but immunostains for CD117 and CD34 are insufficiently sensitive. CD4 expression is common, but CD56 expression is not.