Agreement of dermatopathologists in the evaluation of clinically difficult melanocytic lesions: how golden is the 'gold standard'?

BACKGROUND: The 'gold standard' for the diagnosis of melanocytic lesions is dermatopathology. Although most of the diagnostic criteria are clearly defined, the interpretation of histopathology slides may be subject to interobserver variability. OBJECTIVES: The aim of this study was to determine the variability among dermatopathologists in the interpretation of clinically difficult melanocytic lesions. METHODS: This study used the database of MelaFind®, a computer-vision system for the diagnosis of melanoma. All lesions were surgically removed and sent for independent evaluation by four dermatopathologists. Agreement was calculated using kappa statistics. RESULTS: A total of 1,249 pigmented melanocytic lesions were included. There was a substantial agreement among expert dermatopathologists: two-category kappa was 0.80 (melanoma vs. non-melanoma) and three-category kappa was 0.62 (malignant vs. borderline vs. benign melanocytic lesions). The agreement was significantly greater for patients ≥40 years (three-category kappa = 0.67) than for younger patients (kappa = 0.49). In addition, the agreement was significantly lower for patients with atypical mole syndrome (AMS) (kappa = 0.31) than for patients without AMS (kappa = 0.76). LIMITATIONS: The data were limited by the inclusion/exclusion criteria of the MelaFind® study. This might represent a selection bias. The agreement was evaluated using kappa statistics. This is a standard method for evaluating agreement among pathologists, but might be considered controversial by some statisticians. CONCLUSIONS: Expert dermatopathologists have a high level of agreement when diagnosing clinically difficult melanocytic lesions. However, even among expert dermatopathologists, the current 'gold standard' is not perfect. Our results indicate that lesions from younger patients and patients with AMS may be more problematic for the dermatopathologists, suggesting that improved diagnostic criteria are needed for such patients.

Myxoid atypical fibroxanthoma: a previously undescribed variant.

BACKGROUND: Atypical fibroxanthomas (AFX) are dermal-based cutaneous tumors typically found in sun-damaged skin of the elderly. Histologic variants include spindle cell, clear cell, osteoid, osteoclastic, chondroid, pigmented, and granular cell. To date, myxoid change in AFX, has not been described. METHODS: Four cases were retrieved from the consultation and surgical pathology files of Knoxville Dermatopathology Laboratory, Knoxville, Tennessee during a 4-year period. The clinical and histologic findings were reviewed and Alcian blue/periodic acid-Schiff (PAS) stain and panel of immunohistochemical stains was obtained. RESULTS: All 4 lesions occurred as solitary lesions in elderly males on the head and neck (2 cases) and upper extremity (2 cases). Histologically all tumors demonstrated a well-circumscribed, cellular lesion centered in the dermis and composed of a mix of atypical pleomorphic and spindle cells in a prominent myxomatous background. A junctional component was absent and the tumors did not arise from the epidermis or adnexal structures. Subcutaneous involvement was absent in all cases. Tumor cells were negative for melanocytic and epithelial markers. Positive staining was noted with CD10 (3/4 cases) and vimentin (4/4 cases). CONCLUSION: Myxoid change in AFX is rare and previously undescribed in the English literature. Myxoid change may be a prominent finding in benign and malignant cutaneous tumors and awareness of this variant of AFX will avoid misdiagnosis.

In vivo and in vitro enhanced antitumor effects by pentoxifylline in human cancer cells treated with thiotepa.

Methylxanthines enhance lethality of alkylating agents in human cancer cells, a phenomenon attributed to the prevention of DNA repair. Pentoxifylline is a nontoxic methylxanthine, used clinically for claudication. Using human cancer cells in culture or in a mouse xenograft model, we studied combination treatments with alkylating agents and pentoxifylline or other methylxanthines. With human bladder cancer cells in culture, cytotoxicity of thiotepa was increased up to 10-fold (P less than 0.01) by posttreatment with pentoxifylline, with a major clinical metabolite of pentoxifylline, or with caffeine; the pentoxifylline concentrations required (0.4-1.0 mM) are clinically achievable in the bladder after nontoxic p.o. doses. With human bladder or breast cancer xenografts in a modified subrenal capsule assay, enhancement of thiotepa was also observed by in vivo posttreatment with pentoxifylline. In contrast, these combinations produced no increased toxicity to normal tissues in these animals, measured by weight, lethality, or histological changes of the normal bladder urothelium. These results provide evidence for a novel approach to improve the therapeutic index of thiotepa and other alkylators, used for topical therapy of bladder cancer and, possibly, systemic therapy of other malignancies.

Microphthalmia transcription factor expression in cutaneous benign, malignant melanocytic, and nonmelanocytic tumors.

The protein encoded by the microphthalmia (mi) gene is a transcription factor essential for the development and survival of melanocytes. Using a monoclonal antibody generated against human Mi transcription factor protein (Mitf) the authors previously demonstrated that Mitf expression is conserved in primary and metastatic malignant melanomas, and appears to be a highly sensitive and specific melanocytic marker. Mitf expression in various cutaneous nevi and cutaneous nonmelanocytic tumors has not been documented systematically. The authors evaluated Mitf immunostaining in 62 benign nevi, 58 primary cutaneous melanomas, and 53 nonmelanocytic tumors. Mitf immunostaining was conserved in all benign nevi, with Spitz nevi and neurotized nevi demonstrating decreased staining intensity. With the exception of desmoplastic melanomas, all primary cutaneous melanomas were immunopositive regardless of the cell type. Only one of 14 desmoplastic melanomas was Mitf positive. None of the nonmelanocytic tumors was immunopositive, including those lesions that may resemble melanoma histologically (spindle cell carcinomas, atypical fibroxanthomas, and leiomyosarcomas). The results demonstrate that Mitf antibody expression is conserved in the majority of benign and malignant melanocytic lesions, and that it may be helpful in the diagnosis of primary melanocytic skin lesions. Its use in desmoplastic melanomas is limited and is reflective of other melanocyte-associated antigens. Mitf discriminates between spindle cell nonmelanocytic tumors and melanomas with a spindle cell morphology, and is useful in a panel with other appropriate antibodies.

Anticytokeratin antibody 34 beta E12 staining in prostate carcinoma.

Anticytokeratin antibody 34 beta E12 is advocated as an immunohistochemical stain for discriminating benign and malignant lesions of the prostate. Positive staining with 34 beta E12 is said to identify benign lesions, whereas negative staining is said to help substantiate a diagnosis of carcinoma. It is further claimed that 34 beta E12 does not stain prostate carcinoma. The studies leading to these conclusions used hematoxylin-eosin-stained sections of primary prostate lesions as controls. Although the cytokeratin content of a few cell lines of metastatic prostate carcinoma has been investigated, the 34 beta E12 immunohistochemical staining of metastatic prostate carcinoma has not been evaluated. If 34 beta E12 positivity is present only in benign prostate cells, then metastatic prostate carcinoma cells should be uniformly negative with this stain. In 14 cases of moderate and high-grade prostate cancer with metastases to lymph nodes, we found 34 beta E12 positivity in 6 (43%) of 14 metastases and in 7 (54%) of 13 primary tumors. Our findings of 34 beta E12 staining in primary and metastatic moderately and poorly differentiated prostate carcinoma differ from those reported in the literature for well-differentiated prostate carcinoma. We urge caution in the use and interpretation of 34 beta E12 staining for the diagnosis of primary and metastatic prostate carcinoma.

Histopathological changes in leiomyomata treated with leuprolide acetate.

Several studies have shown a decrease in uterine and/or leiomyoma volume when treated with leuprolide acetate (LA), a widely used gonadotropin-releasing hormone agonist. The mechanism by which these changes occur is unknown. In this study, the histopathological slides of 31 women of reproductive age who underwent hysterectomy or myomectomy were blindly reviewed by a pathologist. Seventeen women underwent myomectomy. Among those, 10 were treated with LA. The tumors in all of these patients were reduced in size after therapy. Histopathologically, the LA treatment correlated with a significant reduction in cellularity. No significant change in fibrosis, edema, or mitotic activity was seen.

Anophthalmic socket pain.

We examined and treated four patients with anophthalmic socket pain. Conditions responsible for this problem in this series included scleritis after evisceration, amputation neuroma, pain from a skull-base meningioma, and chemical dependency with drug-seeking behavior. The pain associated with the scleritis after evisceration responded to removal of the scleral remnant. The pain associated with the amputation neuroma responded to removal of the orbital implant and its pseudocapsule in which the amputation neuroma was embedded. The pain associated with the meningioma was intractable. The pain associated with the chemical dependency remained a persistent problem. A careful history and physical examination are critical in the evaluation of anophthalmic socket pain. Computed tomography or magnetic resonance imaging may be helpful in some cases.

Thin melanomas.

Thin melanoma refers to that grouping of melanomas that statistically have a good prognosis and survival rate. A small but significant percentage of these lesions metastasize and cause mortality. Histologically, these lesions comprise a diverse grouping of tumors of any intraepidermal growth pattern; in the radial or vertical growth phase; or in anatomic level I, II, III, or IV. Additional histologic findings may also be variably present, such as regression, tumor infiltrating lymphocytes, and mitoses. Molecular studies suggest that thin melanomas may have different properties to thicker and metastatic melanomas. The factors governing the ability of thin melanomas to metastasize and cause mortality are not known. Certain histologic and molecular parameters, some of which have been alluded to previously, may provide clues to understanding the parameters governing the aggressive nature of some of these lesions. Further research is required to enhance our understanding of thin melanomas.

Application of immunohistochemistry in the differential diagnosis of skin tumors.

As with neoplasms in any tissue, skin tumors may be categorized as epithelial or mesenchymal, benign or malignant, and primary or metastatic. Immunoperoxidase stains are useful in elucidating the nature of the tumor cells, especially in poorly differentiated tumors. It is important to consider that tumors may exhibit staining patterns different from the typical or reported results. This may be because of intrinsic features of the neoplasm such as the aberrant expression of antigens (markers). Furthermore, the staining of the tumor may be affected by tissue preservation and fixation as well as by the selection of antibodies used for staining. For this reason, the pathologist should be vigilant in comparing the results of unknown tumors with standard controls, with results in the literature, and with his or her own experience. Unusual neoplasms may require additional tissue for analysis, study by other ancillary methods such as electron microscopy, or consultation by more experienced laboratories. These guidelines should be helpful in providing accurate diagnosis of skin tumors.

Primary cutaneous aspergillosis mimicking dermatophytosis.

We recently reviewed a skin biopsy specimen obtained from a child with acute monocytic leukemia that demonstrated abundant mycelia present within a keratin plug of a hair follicle, a granulomatous dermal inflammatory infiltrate, and focal dermal invasion by fungi. These histologic findings were suggestive of an invasive dermatophyte infection; however, Aspergillus flavus was identified by culture. This case illustrates the need for care in interpreting biopsy specimens of cutaneous fungal infection in the immunocompromised host, since proper treatment is determined by the specific agent present. The morphological features of fungi in tissue sections and histopathologic patterns of host response in the immunocompromised patient may be misleading in trying to identify fungal pathogens. At present, culture is the most reliable method for identifying pathogenic fungi and should be utilized to confirm appropriate therapy.

A comparison of paraganglioma, carcinoid tumor, and small-cell carcinoma of the larynx.

Laryngeal paraganglioma, carcinoid tumor, and small-cell carcinoma are rare. Histologically they are similar to analogous tumors in other locations but may be difficult to identify in small biopsy specimens. We compared the light microscopic, histochemical, immunohistochemical, and electron microscopic features of two laryngeal paragangliomas, one carcinoid tumor, and six small-cell carcinomas. The paraganglioma chief cells stained with Grimelius stain and for chromogranin and neuron-specific enolase. The carcinoid tumor cells stained with Grimelius stain and for chromogranin, serotonin, neuron-specific enolase, and keratin. The small-cell carcinoma cells stained for keratin and neuron-specific enolase. The patients with paragangliomas and carcinoid tumor remain healthy through 20 months of follow-up. Four of the patients with small-cell carcinomas have died. Distinction between these tumors is warranted by differing histologic appearances, staining characteristics, and biologic behavior.

Angiolymphoid hyperplasia with eosinophilia (histiocytoid hemangioma): evaluation of treatment options.

Angiolymphoid hyperplasia with eosinophilia is an uncommon benign vascular proliferative lesion of unknown cause. In this report, a case is presented of a patient who was confirmed to be positive for human immunodeficiency virus and in whom the lesion had shown rapid accelerated growth. The case is used to illustrate a variety of therapeutic techniques and to evaluate the effectiveness of the various alternatives in the treatment of this unusual clinical problem. Long-term follow-up after radical excision of the tumor mass is presented.

Primary invasive melanoma and basal cell carcinoma (collision tumor) with blue nevus-like cutaneous metastases.

The simultaneous presence of two disparate neoplasms occurring in the same specimen has been well documented, albeit uncommonly. The juxtaposition of malignant melanoma and basal cell carcinoma (BCC) has been rarely reported in case reports, with most cases describing melanoma in situ and BCC. We present two cases of invasive melanoma (Clark level IV, no microscopic satellites present) intimately associated with BCC, and in areas distinction of the two lesions was difficult. Immunohistochemical studies delineated the two cell populations. In addition, one patient presented with multiple cutaneous metastases, all simulating blue nevi. The metastases occurred in the same anatomical region as the primary tumor, and histologically consisted of pigmented dendritic melanocytes and melanophages in the superficial and mid-dermis and arranged in a blue nevus-like lesion. Histologic clues suggesting the possibility of a metastatic melanoma included a sparse lymphocytic infiltrate, the presence of an epithelioid component and atypia of the dendritic melanocytes. However, without appropriate clinical history, the lesions could be overlooked as ordinary blue nevus. Collision tumors containing invasive melanoma and BCC are rare and this is the first report of a collision tumor with blue nevus-like metastasis. Awareness of this phenomenon and pattern of metastasis, together with the clinical findings will aid in the correct classification of these lesions.

Herpesvirus infection of seborrheic keratoses.

We present three examples of patients with seborrheic keratoses complicated by necrotizing herpesvirus infection. Two patients had localized cutaneous herpetic infections, and the third patient had a generalized cutaneous herpesvirus infection. Two of the lesions were thought to be squamous cell carcinoma. The third was clinically identified as inflamed seborrheic keratosis. Herpesvirus infection was not clinically suspected in two of the patients. The histologic changes were similar in all cases. Epidermal proliferation was accompanied by hyperkeratosis and pseudo horn cyst formation. Extensive keratinocyte necrosis was present along with balloon degeneration of keratinocytes, herpetic viral inclusions, and multinucleated giant cells. Viral lesions of molluscum contagiosum and human papillomavirus have been observed in benign skin proliferations. Nevertheless, we were unable to find descriptions of herpesvirus involvement in seborrheic keratosis in a Medline search. Necrotic seborrheic keratoses should be carefully examined for the possibility of herpesvirus infection, a condition that may be improved by prompt medical intervention as demonstrated in one of our cases.

Mucinous differentiation in adnexal sweat gland tumors.

We report an eccrine acrospiroma, on the cheek of a 29-year-old female, in which the presence of abundant mucinous (goblet cell) metaplasia closely mimicked a primary mucoepidermoid carcinoma. To determine the frequency of mucinous differentiation in benign adnexal sweat gland tumors, we evaluated sixty-five cases in hematoxylin and eosin stained sections for the presence of goblet cells and sixty of these for mucicarmine positivity. Goblet cell metaplasia was seen in 3 of 12 acrospiromas, 1 of 8 mixed tumors, and in 1 of 9 cases of syringocystadenoma papilliferum. All goblet cells were positive for mucicarmine, except in one case of acrospiroma, where goblet cells were not detected on the section stained with mucicarmine. In addition, intracellular mucin, inclusive of goblet cells, was seen in 5 of 12 acrospiromas, 1 of 11 poromas, 5 of 8 mixed tumors, 3 of 13 spiradenomas, 1 of 5 cylindromas, 3 of 9 cases of syringocystadenoma papilliferum and 1 of 3 nipple adenomas. The majority of the tumors had both extracellular mucicarmine positivity (40 of 60) and luminal mucicarmine positivity (39 of 60). We conclude that mucinous differentiation in sweat gland tumors, as defined by the presence of goblet cells and/or intracellular mucicarmine positivity, is common and does not indicate aggressive behavior. Mucinous differentiation in benign sweat gland tumors should not be confused with more aggressive mucoepidermoid carcinomas of salivary gland origin or adenosquamous carcinoma.

Intravenous glomus tumor of the forearm.

An intravenous glomus tumor occurring in a forearm vein is reported. The patient had a painful subcutaneous mass which was completely excised. This mass was a neoplasm which expanded the lumen of a vein and extended throughout its wall into the surrounding subcutaneous fat. The neoplasm consisted of sheets of rounded cells with a capillary stroma. The neoplastic cells were closely apposed to the capillary vessels and were positive for vimentin, smooth muscle actin and muscle specific actin. The cells were negative for desmin, factor VIII-related antigen, epithelial membrane antigen, cytokeratins, S-100 protein and chromogranin. This is the 2nd reported case of intravenous glomus tumor of the forearm. This unusual presentation may be due to intravascular extension by a cutaneous glomus tumor. The potential for intravascular growth by glomus tumor should be recognized by surgeons, dermatologists and pathologists.

Kimura's disease and angiolymphoid hyperplasia with eosinophilia: two distinct histopathological entities.

The relationship between the disorder known in Japanese and Chinese literature as Kimura's disease and that known in Western literature as angiolymphoid hyperplasia with eosinophilia (ALHE) has been the subject of debate. Many reports have used the terms synonymously. We have reviewed the histological and clinical features of 4 cases, all occurring in Caucasians, 2 of which are typical of Kimura's disease and 2 of ALHE. Analysis of the cases indicates that the histological features of the 2 disorders are sufficiently different to warrant their recognition as 2 distinct entities. The histological and clinical features of Kimura's disease are most consistent with an allergic or autoimmune process in which blood vessels, lymphocytes and eosinophils participate. Those of ALHE suggest a primary, probably neoplastic disorder of vascular endothelium with a variable and secondary inflammatory response. Although there is some clinical overlap between patients with the 2 disorders, the histological features are distinctive, and the 2 terms should not be used synonymously.

Primary angiosarcoma of the spleen: a case report and review of the literature.

We describe a 47-year-old man with shoulder pain, multiple bony lesions, and a 1-cm lesion in the spleen. T-1 facetectomy revealed a poorly differentiated malignant neoplasm. Several months after chemotherapy, multiple splenic lesions were found by computed tomography and liver-spleen scan. A splenectomy showed a malignant spindle-cell neoplasm forming irregular vascular spaces. Tumor cells were positive for factor VIII-related antigen and vimentin. This patient died of extensive metastases from this primary angiosarcoma of the spleen. Splenic angiosarcoma is a rare neoplasm that often has a cryptic presentation and a dismal prognosis.

Biopsy specimen findings in patients with previous lower extremity cellulitis after saphenous venectomy for coronary artery bypass graft surgery.

BACKGROUND: No previous study has examined the immune and inflammatory mechanisms involved in the pathogenesis of lower extremity cellulitis after saphenous venectomy for coronary artery bypass graft surgery. OBJECTIVE: Our purpose was to determine the histopathologic, immunologic, and inflammatory findings in skin biopsy specimens from saphenous venectomy limbs of patients with previous bouts of cellulitis. METHODS: Biopsy specimens were obtained from five patients with previous episodes of cellulitis. Specimens of the contralateral lower extremity of each patient were obtained for controlled comparisons. RESULTS: Histopathologic findings did not provide evidence that could account for the tendency for cellulitis to develop. Moreover, the distribution of CD1a, HLA-DR, intercellular adhesion molecule-1, and lymphocyte function-associated antigen type 1 were similar in specimens from the postvenectomy and contralateral legs. No tumor necrosis factor-alpha expression was found in specimens from the lower extremities. CONCLUSION: The mechanisms responsible for the production of this disorder do not involve the mediators studied.