Appropriate use criteria in dermatopathology: Initial recommendations from the American Society of Dermatopathology.

BACKGROUND: Appropriate use criteria (AUC) provide physicians guidance in test selection, and can affect health care delivery, reimbursement policy, and physician decision-making. OBJECTIVES: The American Society of Dermatopathology, with input from the American Academy of Dermatology and the College of American Pathologists, sought to develop AUC in dermatopathology. METHODS: The RAND/UCLA appropriateness methodology, which combines evidence-based medicine, clinical experience, and expert judgment, was used to develop AUC in dermatopathology. RESULTS: With the number of ratings predetermined at 3, AUC were developed for 211 clinical scenarios involving 12 ancillary studies. Consensus was reached for 188 (89%) clinical scenarios, with 93 (44%) considered "usually appropriate" and 52 (25%) "rarely appropriate" and 43 (20%) having "uncertain appropriateness." LIMITATIONS: The methodology requires a focus on appropriateness without comparison between tests and irrespective of cost. CONCLUSIONS: The ultimate decision to order specific tests rests with the physician and is one where the expected benefit exceeds the negative consequences. This publication outlines the recommendations of appropriateness-the AUC for 12 tests used in dermatopathology. Importantly, these recommendations may change considering new evidence. Results deemed "uncertain appropriateness" and where consensus was not reached may benefit from further research.

Hypercellular Encapsulated Neuroma Imitating Desmoplastic Melanoma.

Palisaded encapsulated neuromas (PENs) are benign cutaneous nerve sheath proliferations that typically occur as flesh-colored papules solitarily on the head and neck in adults, with a slight predilection for females. Histopathologically, they are partially or completely encapsulated intradermal nodules with Schwann cells and axons in fascicles separated by clefts. Although these features are often characteristic, the hypercellular variant of PEN can pose a diagnostic challenge in distinguishing between other cellular neural and melanocytic lesions. We herein report a case of hypercellular PEN, which showed striking similarity to desmoplastic melanoma.

Panniculitis in a patient with pathologic complete response to talimogene laherparepvec treatment for recurrent, in-transit melanoma.

Talimogene laherparepvec (T-VEC) is a novel intralesional oncolytic genetically modified herpes simplex virus type 1 vector for the treatment of unresectable cutaneous, subcutaneous, and nodal melanoma. Although immunological therapies such as T-VEC offer therapeutic promise, they carry a risk of immune-related adverse events (irAEs), the full spectrum of which is incompletely understood. We report a 63-year-old previously healthy man with cutaneous melanoma of the right ankle and progressive right lower extremity in-transit metastases despite systemic therapy with immunomodulatory and molecularly targeted treatments. T-VEC treatment resulted in a complete pathologic response on scouting biopsies. Biopsy of the right lateral calf showed lobular and septal panniculitis with lymphoplasmacytic infiltrate and lipophages. Gomori methenamine silver (GMS) stain and acid-fast bacilli (AFB) stains were negative, and no polarizable foreign material was noted. T-VEC was discontinued due to complete pathologic response and, in part, concern for development of irAEs including this panniculitis and an early concomitant autoimmune colitis. This case highlights a previously unreported irAE with this novel treatment for advanced cases of melanoma.

Appropriate use criteria in dermatopathology: Initial recommendations from the American Society of Dermatopathology.

BACKGROUND: Appropriate use criteria (AUC) provide physicians guidance in test selection, and can affect health care delivery, reimbursement policy and physician decision-making. OBJECTIVES: The American Society of Dermatopathology, with input from the American Academy of Dermatology and the College of American Pathologists, sought to develop AUC in dermatopathology. METHODS: The RAND/UCLA appropriateness methodology, which combines evidence-based medicine, clinical experience and expert judgment, was used to develop AUC in dermatopathology. RESULTS: With the number of ratings predetermined at 3, AUC were developed for 211 clinical scenarios involving 12 ancillary studies. Consensus was reached for 188 (89%) clinical scenarios, with 93 (44%) considered "usually appropriate," 52 (25%) "rarely appropriate" and 43 (20%) "uncertain appropriateness." LIMITATIONS: The methodology requires a focus on appropriateness without comparison between tests and irrespective of cost. CONCLUSIONS: The ultimate decision of when to order specific test rests with the physician and is one where the expected benefit exceeds the negative consequences. This publication outlines the recommendations of appropriateness-AUC for 12 tests used in dermatopathology. Importantly, these recommendations may change considering new evidence. Results deemed "uncertain appropriateness" and where consensus was not reached may benefit from further research.

Seborrheic Keratosis With Prominent Clear Cell Changes-A Rare But Important Diagnostic Variant.

Seborrheic keratoses, although exceedingly common, occasionally have morphologic similarities to other lesions that complicate a typically straightforward diagnosis. The authors present a case of a 69-year-old man with a left shoulder lesion that displayed characteristic clinical and microscopic features of seborrheic keratosis on biopsy. However, diffuse and prominent clear cells were also noted. These stained strongly with Periodic acid-Schiff and were diastase sensitive, suggestive of glycogen accumulation and possible trichilemmal differentiation. This case is presented to demonstrate a unique and striking example of clear cell change within a seborrheic keratosis and to briefly review the published literature on this finding, which is rarely reported and demands close examination to exclude more aggressive neoplasms.

Loss of Conventional Melanocytic Markers in Malignant Melanoma and Lymph Node Metastasis; an Uncommon but Dangerous Pitfall.

Although malignant melanomas exhibit a wide range of immunophenotypes, concurrent loss of all 3 conventional melanocytic markers (S-100, Melan-A, and HMB-45) is relatively rare. We report a case of primary malignant melanoma with lymph node metastasis, both exhibiting loss of immunoreactivity for conventional melanocytic markers, while aberrantly expressing epithelial antigenicity (pancytokeratin, CAM 5.2).

Cellular Blue Nevomelanocytic Lesions: Analysis of Clinical, Histological, and Outcome Data in 37 Cases.

Cellular blue nevomelanocytic lesions (CBNLs) frequently pose diagnostic problems to pathologists, and their biological potential may be difficult to establish. In this study, the authors have analyzed the clinical, histological, and outcome data of 37 cellular blue nevomelanocytic lesions and the molecular characteristics of 4 lesions. The cohort of cases comprised 8 cellular blue nevi (CBNs), 17 atypical cellular blue nevi (ACBNs), and 12 blue-nevus-like melanomas (BNLMs) with a mean follow-up of 5 years. The average age at diagnosis was 25.9 years for patients with ACBN, versus 30.4 years for CBN, and 44.6 years for BNLM. Both CBN and ACBN occurred most frequently on the trunk or extremities, whereas BNLM primarily involved the scalp. Histologically, CBN and ACBN were characterized by a mean diameter of <1 cm, absence of necrosis, low mitotic rate (mean: 1-2 mitotic figures/mm), little or no infiltrative properties, and usually low-grade cytologic atypia. In contrast, BNLM had a mean diameter of 1.6 cm, necrosis, tissue infiltration, greater mitotic activity (mean: 6 mitotic figures/mm), and high-grade cytologic atypia. ACBNs often were larger, more densely cellular, exhibited higher mitotic counts, and were cytologically more atypical than CBN. Seven CBN cases with follow-up had a benign clinical course (average follow-up of 4.7 years). Among 6 patients with ACBN who underwent sentinel lymph node (SLN) biopsy, 3 were positive, and a single additional case had 1 positive non-SLN (this patient did not have a SLN biopsy performed). All 14 cases of ACBN with follow-up were alive and without recurrence with mean follow-up of 5 years. Of the 9 melanoma cases with follow-up, 3 patients with SLN and non-SLN involvement died from their disease (average follow-up of 4.8 years). Array comparative genomic hybridization was performed on 2 ACBNs and 1 BNLM: One of the 2 ACBNs showed chromosomal aberrations and 1 BNLM showed multiple chromosomal gains and losses. Multiplex polymerase chain reaction was performed on 1 ACBN, and no mutations were found. From these results, the authors conclude that ACBN occupy an intermediate position within the spectrum of CBN and BNLM, yet many lesions cannot be reliably distinguished from either CBN or BNLM because of overlapping histologic features. However, in general, ACBNs seem to aggregate more closely with CBN in terms of clinical, histological, molecular profile (limited data), and biological behavior.

Prior knowledge of the clinical picture does not introduce bias in the histopathologic diagnosis of melanocytic skin lesions.

A common debate among dermatopathologists is that prior knowledge of the clinical picture of melanocytic skin neoplasms may introduce a potential bias in the histopathologic examination. Histologic slides from 99 melanocytic skin neoplasms were circulated among 10 clinical dermatologists, all of them formally trained and board-certified dermatopathologists: 5 dermatopathologists had clinical images available after a 'blind' examination (Group 1); the other 5 had clinical images available before microscopic examination (Group 2). Data from the two groups were compared regarding 'consensus' (a diagnosis in agreement by ≥4 dermatopathologists/group), chance-corrected interobserver agreement (Fleiss' k) and level of diagnostic confidence (LDC: a 1-5 arbitrary scale indicating 'increasing reliability' of any given diagnosis). Compared with Group 1 dermatopathologists, Group 2 achieved a lower number of consensus (84 vs. 90) but a higher k value (0.74 vs. 0.69) and a greater mean LDC value (4.57 vs. 4.32). The same consensus was achieved by the two groups in 81/99 cases. Spitzoid neoplasms were most frequently controversial for both groups. The histopathologic interpretation of melanocytic neoplasms seems to be not biased by the knowledge of the clinical picture before histopathologic examination.

Squamous cell carcinoma with perineural and intraneural invasion associated with hyalinized tumor nodules: a diagnostic pitfall and review of the literature.

Cutaneous squamous cell carcinoma with perineural invasion (PNI) is an important inconspicuous finding. We report a case of a common tumor with an uncommon finding. A 57-year-old white man presented with paresthesias and a new lesion at the site of a previously resected squamous cell carcinoma. At the time of case review, present deep in the dermis, were large hyalinized tumor nodules. These nodules could have easily have been dismissed as sclerotic tumor nodules or fibrotic in-transit metastases. With the clinical history in mind, these nodules were further investigated by immunohistochemistry and reviewed in conjunction with the Mohs frozen section slides. These nodules were subsequently diagnosed as significant peri- and intraneural invasion. This extremely unusual presentation of PNI is a potential diagnostic pitfall that is potentially under-recognized by dermatopathologists but crucial for determining patient management.

Cutaneous epithelioid melanocytic neurofibroma arising in a patient with neurofibromatosis-1.

Tumors expressing both melanocytic and neural features can pose a diagnostic challenge to the dermatopathologist and provoke questions regarding their lineage. We report a case of a tumor arising on the right cheek of a 9-year-old boy with neurofibromatosis type 1 (NF-1). This neoplasm featured nests of non-pigmented epithelioid cells arising within a neurofibroma. The entire tumor stained strongly with S100, whereas the epithelioid population stained with MART-1, HMB-45 and MiTF. The neoplasm shows only scattered Ki-67 positivity. This tumor represents a neurofibroma with portions that have undergone melanocytic differentiation (melanocytic neurofibroma). This exceedingly rare tumor represents a distinct entity from neurotized melanocytic nevi, combined melanocytic nevi or pigmented neurofibromas and provides further evidence that melanocytes arise indirectly from ventromedial neural crest-derived Schwann cell precursors.

Cutaneous angiosarcoma clinically presenting as progressive solid facial edema in a 43-year-old male.

Cutaneous angiosarcoma of the head and neck is a rare, highly malignant neoplasm; prognosis is heavily influenced by tumor size, resectability, and stage at initial diagnosis. Most patients present with one to several erythematous to violaceous patches, plaques, or nodules. However, the clinical presentation is highly variable and leads to delayed diagnosis. We report cutaneous angiosarcoma in a 43-year-old man who presented with an 11-month history of progressive solid (non-pitting) edema involving his entire face, scalp, eyelids, and neck without characteristic clinical features of cutaneous angiosarcoma. A skin biopsy had shown non-specific findings consistent with solid facial edema or rosacea. Various etiologies were considered but there was no significant improvement after directed medical therapy. Repeat skin biopsies revealed angiosarcoma involving the dermis and sub-cutis. Computed tomography (CT) of the chest showed multiple lung nodules bilaterally and a lytic lesion in the T6 vertebra consistent with metastases. He was treated with single agent chemotherapy (paclitaxel), and had a partial response that restored his ability to open both eyes spontaneously; However, his edema has recently progressed 7 months after diagnosis. This is a rare example of cutaneous angiosarcoma presenting as progressive solid facial edema, which underscores the diverse range of clinical manifestations associated with this neoplasm.

Keratinocyte dysplasia in hematopoietic stem cell transplantation recipients in the day-28-to-84 posttransplantation period.

Severe keratinocyte dysplasia (SKD) has been reported as a common event in the early posttransplantation period of hematopoietic stem cell transplantation patients. The purpose of our study is to determine the possible causes of SKD during the intermediate posttransplantation period and to ascertain its prevalence in skin biopsies. Skin biopsy slides, obtained from hematopoietic stem cell transplantation recipients who were days 28 to 84 posttransplantation, were evaluated for SKD. Forty-four examples of SKD were identified in 467 slides, or 9%. Thirty-seven patients were evaluated as cases in a case-control design. SKD was strongly associated with a conditioning regimen containing busulfan with an odds ratio of 7.25 (P = .0002). In a multivariate-adjusted analysis, SKD was not associated with cyclophosphamide, fludarabine, total-body irradiation, or a nonmyeloablative conditioning regimen. SKD was not associated with clinical acute graft-versus-host disease. SKD histology gradually resolved, reaching a normal histology after an average of 241 days. This study finds that severe keratinocyte dysplasia in the period 28 to 84 days post-HSCT is strongly associated with a busulfan-conditioning regimen.

Histological and genetic evidence for a variant of superficial spreading melanoma composed predominantly of large nests.

Cutaneous melanomas are characterized by a range of histological appearances, and several morphological variants have been described. In this study, we report a variant of superficial spreading melanoma that is characterized by large, irregular junctional melanocytic nests. The junctional nests varied in shape and size, showed focal tendency to confluence, and were often surrounded by a cuff of epidermal keratinocytes. The melanocytes comprising the nests showed variable cytological atypia. In most of the cases, scant intraepidermal or junctional single melanocytes were seen, and other well-documented diagnostic criteria for melanoma were lacking, and as a result, histological recognition of these tumors as melanoma was difficult. Some cases were associated with an invasive dermal component or showed evidence of sun damage. To provide supporting evidence for malignancy, we analyzed these tumors for genomic aberrations. Using array comparative genomic hybridization (aCGH), we identified multiple genomic aberrations in all analyzed cases. A similar pattern of genomic aberrations was seen in a control group of bona fide superficial spreading melanomas, suggesting that these 'melanomas composed exclusively or predominantly of large nests' are indeed variants of superficial spreading melanoma. Fluorescence in-situ hybridization (FISH) was positive in 40% of the cases. However, using aCGH, the FISH-negative cases showed multiple genomic aberrations in regions that are not covered by FISH. The low sensitivity of the FISH test can be explained by the fact that FISH only evaluates four genomic loci for aberrations, whereas aCGH surveys the entire genome. In summary, we present histological and molecular genetic evidence for a morphological variant of superficial spreading melanoma. Awareness of the histological features will aid in their correct diagnosis as melanoma, and in difficult cases, judicious application of ancillary tests such as aCGH (rather than FISH) will assist accurate diagnosis.

Cutaneous and mucosal mucormycosis mimicking pancreatic panniculitis and gouty panniculitis.

BACKGROUND: Histopathologic study of lesions of cutaneous mucormycosis usually shows suppurative granulomas involving the deep dermis and subcutaneous fat. Large, broad and non-septate fungal hyphae are easily identified within the necrotic areas. OBJECTIVE: The main goal of our study is to describe the histopathologic features of 13 cases of cutaneo-mucous mucormycosis, which mimicked the findings of pancreatic and/or gouty panniculitis and discuss the histopathologic differential diagnosis among these 3 disorders. METHODS: Histopathologic examination of sections stained with hematoxylin-eosin, periodic acid-Schiff (PAS), Gomori methenamine, and Grocott stains. All sections were examined under polarized light. One case was immunohistochemically studied with anti-BCG antibody. RESULTS: Histopathologically, the most striking feature consisted of the presence of groups of necrotic adipocytes lacking nuclei and large cytoplasm with pale basophilic hue due to calcium salts deposition. In other areas, groups of necrotic adipocytes filled with radially oriented needle-shaped and slightly eosinophilic crystals were seen. These intracellular crystals were refractile under polarized light examination. Numerous thick-walled non-septate fungal hyphae scattered throughout the necrotic areas were also seen in all cases. LIMITATIONS: The study was limited to 13 cases. CONCLUSIONS: Histopathologic study of 13 cases of subcutaneous mucormycosis demonstrated features closely resembling those of pancreatic panniculitis and/or gouty panniculitis. Ghost adipocytes should be not considered as diagnostic of pancreatic panniculitis and necrotic adipocytes containing needle-shaped refractile crystals should be not interpreted as specific of gouty panniculitis.

Plexiform melanocytic schwannoma: a mimic of melanoma.

We present a unique dermal tumor for which we propose the term plexiform melanocytic schwanomma. The proliferation consisted of lobules of epithelioid and spindled cells with S100, Melan-A and HMB-45 positivity but without obvious melanin pigmentation. The nuclei were moderately pleomorphic in some areas, and in a few areas the mitotic index was elevated. Schwannian differentiation was inferred from the presence of areas with nuclear palisading resembling Verocay bodies, from plexiform architecture and from the presence of a thin rim of EMA positivity around the tumor. Array-based comparative genomic hybridization showed genomic losses that overlap with those seen in sporadic schwanomma. The differential diagnosis included melanoma, melanotic schwannoma and cutaneous melanocytoneuroma, and we compare and contrast our case with these entities.

Langerhans cell sarcoma in a patient with hairy cell leukemia: common clonal origin indicated by identical immunoglobulin gene rearrangements.

Histiocytic/dendritic cell sarcomas are rare tumors, a few of which have been reported in association with B-cell lymphoma/leukemia. Isolated reports have documented identical immunoglobulin gene rearrangements suggesting a common clonal origin for both the sarcoma and the B-cell neoplasm from individual patients. We report a case of a 75-year-old male with hairy cell leukemia who subsequently developed Langerhans cell sarcoma 1 year after his primary diagnosis of leukemia. The bone marrow biopsy containing hairy cell leukemia and skin biopsies of Langerhans cell sarcoma were evaluated by routine histology, immunohistochemistry, flow cytometric immunophenotyping and PCR-based gene rearrangement studies of the immunoglobulin heavy chain and kappa genes. The hairy cell leukemia showed characteristic morphologic, immunohistochemical and flow cytometric features. The Langerhans cell sarcoma showed pleomorphic cytology, a high mitotic rate and characteristic immunohistochemical staining for Langerin, S100 and CD1a. There was no evidence of B-cell differentiation or a background B-cell infiltrate based on the absence of immunoreactivity with antibodies to multiple B-cell markers. Identical immunoglobulin gene rearrangements were identified in both the hairy cell leukemia and Langerhans cell sarcoma specimens. Despite the phenotypic dissimilarity of the two neoplasms, identical immunoglobulin gene rearrangements indicate a common origin.

Clinicopathologic features of early lesions of primary cutaneous follicle center lymphoma, diffuse type: implications for early diagnosis and treatment.

BACKGROUND: Data on early lesions of primary cutaneous follicle center lymphoma (PCFCL), diffuse type are very limited. OBJECTIVE: We sought to elucidate the early clinicopathologic features of PCFCL, diffuse type. METHODS: Clinical, histologic, immunohistologic, molecular, and fluorescence in situ hybridization data from 24 patients with early lesions of PCFCL, diffuse type (male:female = 19:5; median age: 57 years) were determined. RESULTS: Lesions consisted mostly of solitary or clustered papules and small nodules located on the trunk (21 cases), arm (two cases), and scalp (one case). In 3 patients small papules were located at a distance from the main affected area. All biopsy specimens from early lesions showed aggregates of medium and large centrocytes admixed with small lymphocytes without formation of clear-cut lymph follicles. Staining for Bcl-2 was positive in only 7 cases, one revealing also a rearranged BCL2 signal by fluorescence in situ hybridization. Data on treatment and follow-up were available for 22 patients. At last examination 13 patients were in complete remission (median follow-up: 60 months), 6 were alive with skin disease alone (median follow-up: 60 months), two were alive with skin disease and bone-marrow or lymph node involvement, respectively, and one died of unrelated causes while in complete remission. LIMITATIONS: The retrospective study and the fact that patients were treated at different institutions are limitations. CONCLUSIONS: Early lesions of PCFCL, diffuse type present with characteristic clinicopathologic features. Dermatologists should be alert particularly to the early clinical manifestations of this lymphoma and to the presence of small, inconspicuous lesions at a distance from the main affected area in order to plan treatment properly.

Agminated cellular neurothekeoma.

Cellular neurothekeoma represents a benign, slow-growing neoplasm that typically occurs as a solitary lesion on the face, neck or arm. Reports of multiple lesions are rare. To our knowledge, multiple lesions occurring as eruptive clusters localized to a single anatomical site has not been previously reported. This report details a case of an agminated cellular neurothekeoma occurring on the nose of a 28-year-old man. Recognition of multiple localized eruptive lesions of cellular neurothekeoma is important in order to facilitate correct diagnosis and avoid unnecessary treatment.