John A. Papalas

Paget Disease of the Vulva: A Histologic Study of 56 Cases Correlating Pathologic Features and Disease Course

The Duke experience with 56 vulvar Paget disease patients was analyzed emphasizing pathologic features and controversial issues. Nearly all patients were Caucasian, and their mean age was 69 years. The average length of follow-up was 5.6 years. For each case, the following histologic features were evaluated and their association with disease course was examined: pseudo-invasion, adnexal involvement, signet-ring cells, cytologic atypia, glands formation, epidermal acantholysis, parakeratosis, hyperkeratosis, and chronic inflammation. The recurrence rate after surgical management was 32%, with epidermal acantholysis being the only statistically significant risk factor. Stromal invasion occurred in 10 patients (18%), and was not a statistically significant adverse prognostic indicator, although the single patient who died of the disease had the deepest stromal invasion. Recurrence was more common after resections with positive surgical margins, but this correlation was not statistically significant. Intraoperative frozen section analysis of the margins did not reduce recurrence rate, nor was it useful in attaining permanent free margins. The Paget cells were consistently reactive with cytokeratin-7 and carcinoembryonic antigen and unreactive with S-100 protein, HMB-45, and Mart-1. In addition, the tumor cells were usually positive for mucin stains. This profile helps distinguish vulvar Paget disease from its mimics, Pagetoid squamous cell carcinoma and malignant melanoma.

Patterns of GRP78 and MTJ1 expression in primary cutaneous malignant melanoma

Cell surface expression of glucose-regulated protein 78 (GRP78) occurs in several types of cancer; however, its role in the behavior of primary cutaneous melanoma is not well studied. The association of cell surface GRP78 with other proteins such as MTJ1 stimulates cell proliferation. In this study, we characterized the pattern of expression of GRP78 and MTJ1 in invasive primary cutaneous melanomas and analyzed the relationships between the pattern of expression and various clinicopathological parameters. We found two patterns of GRP78 expression in invasive primary cutaneous melanoma. One pattern showed a gradual fading of protein expression from superficial to deeper levels within the same tumor. The second pattern of expression showed a similar fading with an abrupt regaining of expression at the deep invasive edge of the melanoma. These two distinct patterns of GRP78 expression correlated with both patient survival and depth of tumor invasion. A moderate MTJ1 expression was found to be associated with decreased patient survival; however, no significant associations were observed between patterns of GRP78 and MTJ1 expression. Our study (1) describes two distinct patterns of GRP78 in invasive primary cutaneous melanoma, (2) inversely correlates regain of GRP78 expression with patient survival, and (3) suggests a modifying effect of MTJ1 on GRP78 in enhancing tumor aggressiveness.

Vulvar Manifestations of Crohn's Disease

Crohns disease is an inflammatory bowel disorder with several well-known extraintestinal manifestations, such as erythema nodosum, uveitis, and arthritis. Less commonly observed are vulvar manifestations, which have primarily been discussed in case reports or small case series. These cases generally highlight patients with histopathology limited to noncaseating granulomas. As these histological findings are identified in bowel biopsies from only approximately 50% of patients with gastrointestinal Crohns disease, there is likely an under-recognition and underdiagnosis of vulvar lesions as Crohns disease manifestations. We describe the largest case series to date involving patients with vulvar Crohns disease, discuss the varied clinical presentations, and describe the histopathological findings, which include noncaseating granulomas, ulcerations, lymphatic lesions, and even dysplasia and carcinoma. Our findings underscore the importance of keeping vulvar Crohns disease on the differential diagnosis when faced with a range of vulvar symptoms and suggest that regular gynecological surveillance in patients with Crohns disease may be of benefit.

Primary mucinous carcinoma of the eyelid: a clinicopathologic and immunohistochemical study of 4 cases and an update on recurrence rates.

OBJECTIVES To report 4 cases of primary mucinous carcinoma of the eyelid, demonstrate how p63 expression aids diagnosis, and review the literature regarding the local recurrence potential of these eyelid tumors. METHODS Since 1991, we have examined 4 cases of primary mucinous carcinoma of the eyelid. Histology slides were reviewed and clinical information was obtained from the medical records. Published cases of primary mucinous carcinoma involving the eyelid were identified using Ovid MEDLINE and PubMed and references within the articles. RESULTS Our average patient age was 73 years, the female:male ratio was 3:1, and patients had a painless nodular mass for 1 month to 2 years. No patient had another documented malignant tumor at the time of diagnosis. All tumors were dermis based in the upper eyelid, three-fourths invaded the orbicularis oculi muscle, and the average tumor diameter was 3.7 mm. All tumors expressed cytokeratin 7 and gross cystic disease fluid protein 15 and were negative for cytokeratin 20 expression. Tumors demonstrated p63 immunopositivity either focally in the invasive component or peripherally along the in situ component. No recurrences have been evident after an average follow-up of 52 months. Published cases occurring in the eyelid have had a 30% to 40% recurrence rate using surgery without intraoperative evaluation of surgical margins and a 7% recurrence rate after either Mohs surgery or excision with frozen section control. CONCLUSION Primary mucinous carcinoma of the eyelid is a low-grade malignant tumor with the potential for recurrence, although this may be reduced using Mohs surgery or excision with frozen section control.

Metastatic vs primary malignant neoplasms affecting the umbilicus: clinicopathologic features of 77 tumors.

Periumbilical skin is unique due to its proximity to intra-abdominal and pelvic structures. In addition to primary skin malignancies, it is a site often involved with metastatic disease. We reviewed the clinical and pathologic features of 77 umbilical malignancies occurring at our institution since 1988. Seventy-seven patients were identified (female/male ratio, 4.1:1.0) with the average age for women being 63 years and 55 years for men. Eighty-eight percent of malignancies originated outside the umbilicus and 12% were primary skin tumors. Fifty-eight (85%) patients with metastatic tumors had umbilical involvement from a known primary vs 10 (15%) with unknown primaries. Nine patients with metastatic tumors to the umbilicus would present with solitary umbilical involvement. Of these patients, 56% would not have a primary site assigned to their metastatic disease. In women, the 3 most common primary sites were the ovary, endometrium, and pancreatobiliary tree, whereas for men, it was the genitourinary tract, pancreatobiliary tree, and the gastrointestinal tract. Of the primary umbilical malignancies, 44% of patients were male and 56% female. Malignant melanoma was the most common primary umbilical malignancy. In summary, women are more likely than men to have malignant tumors affecting the umbilicus. Overall, the most likely primary site of a metastatic tumor to the umbilicus is the genitourinary tract. Rarely, patients present with metastatic tumors to the umbilicus, and most of these patients will not have a primary site of tumor origin assigned.

Acquired vulvar lymphangioma circumscriptum: a comparison of 12 cases with Crohn's associated lesions or radiation therapy induced tumors

Background: Lymphangioma circumscriptum (LC) is a benign lesion of lymphatic origin. Vulvar involvement occurs in various clinical settings.

Pyogenic variant of primary cutaneous anaplastic large-cell lymphoma: a lymphoproliferative disorder with a predilection for the immunocompromized and the young.

Cutaneous anaplastic large-cell lymphoma belongs to the class of primary cutaneous CD30-positive lymphoproliferative disorders. The pyogenic variant is marked by a neutrophil rich inflammatory background. We describe 2 cases (one which clinically presented as cellulitis, and another arising in a patient with Hodgkin lymphoma) and review the clinicopathologic features of cases reported in the literature. In all cases, the male to female ratio is 1.2:1. The average age at presentation for patients with this variant is 47 years old with 15% of patients being 25 years old or younger. Thirteen percent of patients are immunocompromized. Ten percent of patients experience extracutaneous disease progression and 18% of patients are dead at 10 months. Immunophenotypically, the anaplastic large cells demonstrate loss of pan-T cell antigens, CD2, CD3, CD5, and CD7, with 65% of cases expressing CD4 and 29% of cases expressing CD8. Epithelial membrane antigen expression is reported in over half of the cases. In the clinical context of a progressive ulcerating lesion in younger or immunocompromized patients, it is important for the pathologist when presented with a skin specimen demonstrating a neutrophil-rich inflammatory background to include the pyogenic variant of anaplastic large-cell lymphoma. We hope to increase awareness of this rare CD30-positive lymphoproliferative disorder subtype by better defining the clinical spectrum in which this entity can present.

Ossifying Dermatofibroma With Osteoclast-Like Giant Cells: Report of a Case and Literature Review

Dermatofibromas are fibrohistiocytic lesions with numerous histologic variants. Ossifying dermatofibroma with osteoclast-like giant cells is an uncommon variant that has only rarely been reported. We report another case of ossifying dermatofibroma with osteoclast-like giant cells and describe the immunohistochemical expression pattern of these rare lesions. A 72-year-old male presented with a 3.5-cm subcutaneous nodule on the posterior right shoulder of several years duration. The excision specimen showed a large, dermal-based, well-circumscribed, nonencapsulated heterogenous spindle cell proliferation. Large islands of spindled cells arranged in a storiform pattern were separated by broad fibrous bands. Collections of multinucleated giant cells were present predominantly at the periphery of the spindle cell islands. In addition, small islands of bone with osteoblastic rimming were present multifocally, concentrated in the central portion of the lesion. The spindle cells express factor XIIIA, smooth muscle actin, and CD68 on immunohistochemical stains, confirming a fibrohistiocytic origin. There was no immunohistochemical expression for S100 protein, panmel, CD57, cytokeratin, neuron-specific enolase, or CD34. A broad differential diagnosis, including variants of melanoma and osteosarcoma, should be considered when analyzing cutaneous lesions with a fibrohistiocytic component admixed with giant cells and metaplastic bone.

Recurrence Risk and Margin Status in Granular Cell Tumors of the Breast: A Clinicopathologic Study of 13 Patients

CONTEXT Granular cell tumors (GCTs) of the breast are rare neoplasms that mimic epithelial malignancy clinically and rarely occur in association with it. Granular cell tumors of the breast are not infrequently excised with positive margins. Reports describing risk of recurrence including data on margin status and follow-up are lacking. OBJECTIVE To review our series of GCTs of the breast to determine the risk of recurrence if excised with positive or close margins. DESIGN Cases of GCT of the breast were reviewed. Margin status of specimens was recorded as positive, close (<1 mm), and negative. RESULTS Thirteen female patients with GCT of the breast were identified. Mean patient age at presentation was 45 years. Seventy-seven percent of patients were African American and 23% were white. African American patients presented on average 13 years earlier than white patients. Average tumor size was 1.22 cm. Fifteen percent of lesions had positive margins on excisional biopsy or lumpectomy and 31% had tumor cells within 1 mm of the margin. One of 13 patients (8%) had coexistent invasive ductal carcinoma. Average follow-up for the entire group was 77 months. Patients with positive margins remained free of tumor progression or recurrence for 89 months and patients with close margins also remained disease free during a 64-month follow-up period. No tumors recurred out of the entire group. CONCLUSION Granular cell tumors of the breast have little long-term risk for recurrence, even when excised with positive margins. Surgical evaluation after nonexcisional biopsy may still be indicated to assess for the possible association of colocalized carcinoma.

Angiosarcoma of the Eyelid: A Clinicopathologic Comparison Between Isolated Unilateral Tumors and Tumors Demonstrating Extrapalpebral Involvement

Angiosarcomas involving the head and neck are malignant tumors which tend to involve multiple anatomical structures with an overall dismal prognosis. Reports of primary, isolated eyelid involvement are rare. We report 4 cases of angiosarcoma involving the eyelid as either an isolated tumor or as part of a more diffuse malignant process and compare the features of these 2 tumor types to cases reported in the literature. The mean age at which patients develop angiosarcoma involving the eyelid was 72. Patients with isolated tumors most often presented complaining of a discrete mass clinically resembling a stye. Patients with isolated eyelid involvement had better survival (100% at 3.2 years) compared with patients with diffuse disease (57% at 3.3 years). Those with isolated eyelid involvement have an average tumor size of 2.08 cm with no distant metastasis. Patients who have eyelid angiosarcoma with extrapalpebral involvement have tumors ranging between 5 and 10 cm on average and 21% develop metastases. True isolated angiosarcoma of the eyelid is rare. When extrapalpebral involvement is ruled out by clinical and radiographic examination, patients with isolated involvement seem to fare better compared with patients with eyelid involvement secondary to more regionally extensive tumors.