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.

A 13-Year Retrospective Study of Basal Cell Carcinoma in a Canadian Dermatology Practice: A Comparison Between Anatomical Location and Histopathologic Subtypes.

BACKGROUND: It is unknown whether the histologic subtypes of basal cell carcinoma (BCC) arise from a common progenitor cell or whether other factors play a role in their development. OBJECTIVE: To investigate the relationship between the different BCC histopathologic subtypes and anatomical distribution of BCCs in a Canadian dermatology practice. METHODS: The charts of all patients diagnosed with BCC between 1993 and 2005 from a single private dermatology practice in Vancouver, Canada, were reviewed. Descriptive data analysis was undertaken to look at the distribution of histologic subtypes based on age, gender, and anatomical location. RESULTS: Nodular BCCs accounted for 58% of all tumors. Sixty-six percent of these were situated on the head/neck (odds ratio [OR] = 3.0, 95% confidence interval [CI] = 2.1-4.3, P < .0001). Infiltrative (OR = 2.4, 95% CI = 1.5-4.1, P = .0003) and superficial BCCs were more common in women (OR = 3.7, 95% CI = 2.5-5.7, P < .0001), affected the trunk (OR = 3.2, 95% CI = 2.1-4.9, P < .0001), and appeared in younger individuals (OR = 1.8, 95% CI = 1.2-2.7, P = .004). CONCLUSION: Our results show a preference of distinct BCC subtypes for certain anatomical locations.

Molecular abnormalities in ovarian carcinoma: clinical, morphological and therapeutic correlates.

The histopathological classification of ovarian surface epithelial carcinomas (referred to hereafter as 'ovarian carcinoma') has shifted over the past 10 years to reflect more clearly our understanding of molecular events during carcinogenesis. Ovarian carcinoma is no longer viewed as a single entity but as multiple disease processes, with each having different molecular pathways altered during oncogenesis, resulting in differences in clinical and pathological features, such as biomarker expression, pattern of spread and response to chemotherapy. There are five subtypes of ovarian carcinoma that are sufficiently distinct and well-characterized that they should be considered to be different diseases, i.e. high-grade serous, clear cell, endometrioid, mucinous and low-grade serous, from most to least common, respectively. This review summarizes the molecular abnormalities of these five ovarian carcinoma subtypes, relating them to clinical and pathological features.

High prevalence of angiotropism in congenital melanocytic nevi: an analysis of 53 cases.

The mechanisms responsible for the development of congenital melanocytic nevi (CMN) have yet to be elucidated. A potential clue to their origin is the observation of angiotropism of nevus cells in CMN. Interestingly, neural crest stem cells (NCSCs), the precursors of melanocytes, demonstrate angiotropism in the embryo. There is accumulating evidence that NCSCs migrate along the external surfaces of vessels during a portion of their journey to the skin. Comparable angiotropism and migration of melanoma cells have been described as extravascular migratory metastasis in melanoma. In this report, we systematically examined for the first time, the frequency of angiotropism in 53 CMN. The lesions originated from 27 females and 26 males with an average age of 9.81 years (range 0.42-28 years). The mean nevus size was 7.43 cm (range 0.3-40 cm). Twenty-seven (50.9%) of the 53 lesions were less than 1.5 cm in diameter. Sixteen nevi (30.2%) were medium sized (1.5-19.9 cm), and 10 CMN (18.9%) were large/giant (>20 cm in diameter). The trunk was the most common location (23/53) followed by the head and neck (17/53). Thirty-eight (71.7%) of the 53 lesions were compound melanocytic nevi, and 15 (28.3%) of the 53 lesions were dermal nevi. In summary, angiotropism was observed in 50 (94.3%) of 53 cases. Consequently, such angiotropism may potentially explain the origin of the precursor cells giving rise to CMN. Further explanations concerning dysregulated growth are clearly needed for the actual appearance of CMN and their physical characteristics.

Angiotropism in primary cutaneous melanoma with brain metastasis: a study of 20 cases.

Previous clinical and experimental studies suggested that invasion of the brain by metastatic melanoma may follow the external surfaces of vascular channels, that is, angiotropic extravascular migratory metastasis. Such angiotropic invasion seemss analogous to that of neoplastic glial invasion of the nervous system. We, therefore, have retrospectively investigated 20 primary melanoma cases and their respective metastatic brain lesions. The following parameters were analyzed in each primary melanoma: presence of angiotropism, Breslow thickness, Clark level, mitotic rate, sentinel lymph node (SLN) status, and time interval between the primary lesion and the metastasis. The metastatic brain lesions were examined for the presence of angiotropism. Of the 20 cases, 14 showed angiotropism in the primary lesion. The angiotropic group had a significantly deeper Breslow thickness (median 4.4 mm vs. 1.4 mm, P < 0.01) and was more mitotically active (median 11 vs. 4.7 mitoses/mm, P = 0.04). Interestingly, the angiotropic group had an average time lapse of 33 months from the primary lesion to the brain metastasis, whereas the nonangiotropic group had a 57-month time interval. Although the Kaplan-Meier analysis failed to show a survival difference in this small cohort (P = 0.235), there was a trend toward significance. Seven of 20 brain metastases showed angiotropism; however, no significant correlation between angiotropism in the primary melanomas and the corresponding metastatic lesions could be demonstrated. Indeed, angiotropism in the brain metastases was difficult to assess because the available material were generally small partial biopsy samplings and many showed conspicuous necrosis. Ten melanoma patients underwent SLN biopsy. The 3 of 6 positive cases in the angiotropic group had an average time lapse of 32 months from the primary lesion to the brain metastasis, whereas the 4 positive SLN biopsies in the nonangiotropic group had an average of 63 months. This preliminary study of angiotropism in primary melanomas and their corresponding brain metastasis shows a striking trend suggesting that angiotropism in primary melanomas may predict the rapid development of brain metastases. This study also has demonstrated the difficulty in studying angiotropism in melanoma brain metastases because of small sample sizes and abundance of necrotic tissue. The authors are in the process of collecting larger and more representative numbers of melanoma brain metastases for further investigations.

Trichoblastic sarcoma with osteosarcomatous differentiation: evolution of one lesion with 3 histologic appearances over a 3-year period.

Only one description of trichoblastic sarcoma exists in the literature. Here, we present the first case of trichoblastic sarcoma with heterologous osteosarcomatous differentiation. Biospy 1 demonstrated an intermediate-grade trichoblastic sarcoma with pleomorphic cells and atypical mitotic figures observed only in the stroma. The epithelium contained no malignant cells. The histologic morphology was reminiscent of an intermediate-grade phyllodes tumor of the breast. Biopsy 2, an excisional biopsy taken 7 months later, showed a high-grade sarcoma with osteosarcomatous differentiation. Immunohistochemistry performed on both specimens showed positive CD10 and bcl-2 staining in the sarcomatous component; p63 was positive in the benign epithelium only. p53 was negative in both the benign epithelium and the malignant stroma. Ki-67 labeling was approximately 10% in both components. Specimen 3, a complete rhinectomy performed 3 months later, showed a poorly differentiated sarcoma. Six months following his rhinectomy procedure, multiple pulmonary nodules consistent with metastatic disease were detected on chest computed tomography. This is the first case report documenting the evolution of an intermediate-grade trichoblastic sarcoma to a high-grade lesion with osteosarcomatous differentiation, to a poorly differentiated sarcoma. The tumor morphologically resembles malignant phyllodes tumor of the breast. Our case is the first to show negative p53 and positive bcl-2 staining in a trichoblastic sarcoma. We propose that cutaneous trichoblastic sarcoma is pathogenetically analogous to phyllodes tumors of the breast, adenosarcoma of the uterus, or ameloblastoma of the oral cavity.

Cutaneous ciliated cyst on the finger: a cutaneous mullerian cyst.

As previously recognized by various authors, "cutaneous ciliated cyst" is a confusing term. Typically, the term refers to rare cystic lesions, commonly found on the lower limbs of women in their reproductive years. To date, 40 cases diagnosed as "cutaneous ciliated cyst" have been reported in the literature. Histologically, the cysts are composed of a simple layer of ciliated columnar cells along with nonciliated columnar cells, cuboidal cells, and round "peg-like" cells, resembling fallopian tube epithelium. This histology has been described in cysts found in males and females and in locations other than the lower limbs. Controversy has thus arisen over the etiology of these lesions, with some believing that the cysts arise from heterotopic Mullerian rests and others advocating for ciliated metaplasia of eccrine glands. We herein describe the first case of cutaneous ciliated cyst of Mullerian origin occurring on the dorsal thumb of a 16-year-old female. A review of literature shows that 2 groups of cysts are covered under the umbrella term "cutaneous ciliated cysts." We thus propose the abandonment of the confusing term "cutaneous ciliated cyst" and the adoption of "cutaneous Mullerian cysts" for estrogen receptor/progesterone receptor-positive lesions resembling simple fallopian tube epithelium and "Cutaneous ciliated eccrine cyst" for estrogen receptor/progesterone receptor-negative lesions usually occurring in males, which are immunohistochemically compatible with an eccrine origin.

Diagnostic challenge of aleukemic leukemia cutis preceding acute myelogenous leukemia: A case report.

Aleukemic leukemia cutis is a rare condition in which malignant white cells invade the skin before they appear in the peripheral blood or bone marrow. It is often associated with a poor prognosis. The condition presents a diagnostic challenge as its manifestations are quite variable terms of lesion type. It can manifest as papules, nodules, and/or plaques, and in rare cases erythematous macules, blisters, and ulcers. The most commonly affected areas of the body are the lower extremities, followed by the upper extremities, back, trunk, and face. Due to the non-specific presentation of the disease, skin biopsy and comprehensive immunohistochemical testing can be extremely helpful in the diagnostic work-up. We describe a case of leukemia cutis presenting prior to acute myelogenous leukemia that was initially misdiagnosed as hyper-IgG4 disease.

Cutaneous HPV16 and p16 Positive Basaloid Squamous Cell Carcinoma with Brain Metastasis: A Case Report.

Basaloid squamous cell carcinoma is an infiltrative and aggressive variant of squamous cell carcinoma with basaloid features. Primary skin-derived basaloid squamous cell carcinoma is rare. Basaloid squamous cell carcinoma is commonly observed in the oropharyngeal and anogenital regions and is associated with high-risk human papillomavirus. We report a case of primary basaloid squamous cell carcinoma overlying the right scapula with metastasis to the regional lymph nodes and brain despite surgical resection and adjuvant chemoradiation. Histopathologic investigations of high-risk cutaneous squamous cell carcinoma do not routinely involve human papillomavirus testing. In contrast, oncogenic human papillomavirus and p16 are screened in head and neck squamous cell carcinoma for prognostication. Since the patient presented with an aggressive variant of squamous cell carcinoma and distal metastasis despite standard therapies, human papillomavirus testing was performed. P16, a surrogate marker for human papillomavirus infection and specifically HPV16 was identified in the tumor. This is a unique report of HPV16 in primary cutaneous basaloid squamous cell carcinoma with distal brain metastasis.

The characterization of paclitaxel-loaded microspheres manufactured from blends of poly(lactic-co-glycolic acid) (PLGA) and low molecular weight diblock copolymers.

Paclitaxel-loaded biodegradable drug delivery systems manufactured from poly(lactic-co-glycolic acid) (PLGA) are known to release the drug at extremely slow rates. The objective of this study was to characterize paclitaxel-loaded microspheres composed of blends of PLGA with low molecular weight ampipathic diblock copolymers. The encapsulation and release of a series of poly(epsilon-caprolactone) (PCL)- or poly(D,L-lactic acid) (PDLLA)-co-methoxypolyethylene glycol (MePEG) diblock copolymers was measured using quantitative gel permeation chromatography. Polymeric miscibility was determined by glass transition temperature measurements using differential scanning calorimetry and paclitaxel release was measured using HPLC methods. The PCL- and PDLLA-based diblock copolymers encapsulated at high efficiency and were miscible in PLGA microspheres (30-120m microm size range). The burst phase of paclitaxel release was increased up to 20-fold by the inclusion of diblock copolymers in PLGA microspheres. Approximately 10% of the more hydrophobic PCL-based copolymers released from the microspheres in a short burst over 3 days followed by very slow release over the following 10 weeks. Only the PDLLA-based copolymer released from the PLGA microspheres in a controlled manner over 10 weeks. All microspheres containing PEG were found to have more hydrophilic surfaces (as measured by contact angle) with improved biocompatibility (reduced neutrophil activation) compared to PLGA only microspheres. These results indicate that low molecular weight polyester-based diblock copolymers may be effectively encapsulated in PLGA microspheres to increase paclitaxel release (probably through a micellization process) and improve biocompatibility.

The plexiform spindle cell nevus nevi and atypical variants: report of 128 cases.

The plexiform spindle cell nevus (PLXSCN) is a distinct melanocytic lesion that often provokes concern for melanoma. We describe the features of 119 typical PLXSCNs and 9 atypical/high-grade lesions. Histologically, all cases had a fascicular plexiform architecture and were composed of predominately spindled cells. The 6 atypical plexiform spindle cell tumors (PLXSCTs) exhibited features such as greater mitotic activity, increased cellularity/nodular confluence, and more concerning cytological atypia. Three high-grade tumors (perhaps evolving plexiform spindle cell melanomas) had additional alarming clinical or histologic characteristics, such as patient age greater than 40 years, greater degree of cellularity, higher degree of cytological atypia, mitotic rate greater than 3/mm(2), regional lymph node metastases, and greater than 1 positive sentinel lymph node. Follow-up data were available for 18 typical PLXSCNs: all patients were without tumor recurrence or death in a mean follow-up period of 3.9 years (range, 1 month to 10 years). One atypical PLXSCT and 3 high-grade lesions had follow-up information: the atypical PLXSCT had sentinel lymph node involvement, and the patient was alive without recurrent disease at 1-year follow-up; 2 of the 3 high-grade lesions were positive for lymph node involvement, and all 3 patients were alive with 2-, 4-, and 0.8-year follow-up periods. All PLXSCTs should be completely excised with clear margins, and high-grade or potentially malignant lesions may require management as melanoma.

Degree of histologic inflammation in lupus erythematosus and direct immunofluorescence results: red and inflamed lesions do not increase the chances of getting a bright band.

BACKGROUND: In the diagnostic work-up of lupus erythematosus (LE), direct immunofluorescence (DIF) examination could be helpful. Classically, clinically red lesions are targeted by clinicians in the hope of yielding an informative DIF result. However, the investigative correlation between the degree of inflammation and DIF positivity has never been published in the literature. OBJECTIVE: In this study, we sought to discover if histologically inflamed lesions correlated with DIF positivity results. METHOD: We studied 112 lesions histologically consistent with LE and correlated the degree of histologic inflammation on the DIF hematoxylin and eosin-stained biopsy with DIF positivity. The degree and location of the inflammation, as well as the involvement of the dermoepidermal interface, were documented. RESULTS: A positive lupus band test was defined as the presence of either (1) granular IgG alone ± other immunoglobulins and/or C3 or (2) granular IgM or Ig A plus other immunoglobulins ± C3. Fifty-four of 112 (48%) cases had positive DIF (DIF+) results, 26 of 112 (23%) had negative DIF (DIF-) results, and 32 of 112 (29%) had nonspecific DIF patterns. Of the DIF+ cases, 41 of 54 (76%) showed some degree of inflammation, whereas 25 of 26 (96%) DIF- cases had inflammation (p  =  .60). Most of the biopsies in the study (85%) were inflamed, but the degree and location of the inflammation had no influence on DIF+ results. The intensity of the DIF+ band further failed to show any relationship with the degree of inflammation. CONCLUSION: The level of inflammatory activity in a clinical lesion fails to correlate with DIF positivity. Furthermore, other common histopathologic findings of LE are not predictive of DIF results.

Sentinel lymph node metastasis is not predictive of poor outcome in patients with problematic spitzoid melanocytic tumors.

The diagnosis and clinical management of spitzoid melanocytic tumors with atypical features remain problematic and controversial. In the past decade, sentinel lymph node mapping has been advocated as a diagnostic test in this setting to discriminate melanoma from benign tumors. Recent studies, however, consistently show that despite the presence of lymph node metastases these patients almost always fare well. We investigated the outcome of patients with atypical Spitz tumors and spitzoid melanoma who received sentinel lymph node mapping to clarify current recommendations in managing patients with these diagnostically challenging tumors. A search of the electronic files of the Massachusetts General Hospital Pathology Service identified 41 patients treated with sentinel lymph node biopsy for atypical Spitz tumor or spitzoid melanoma from 1998 to 2008. These patients included 23 patients with atypical Spitz tumors and 17 patients with spitzoid melanoma. Sentinel lymph nodes were positive in 26% of patients with atypical Spitz tumors (6/23) and 35% with spitzoid melanomas (6/17). One patient with spitzoid melanoma developed in-transit metastasis; 0 of 40 patients developed metastases beyond the regional lymph node basin with a mean follow-up of 57 months. Sentinel lymph node biopsy may not be a reliable prognostic discriminatory test in patients with atypical Spitz tumors. Patients with spitzoid melanomas and positive sentinel lymph nodes have a more indolent course than those with bona fide conventional melanoma and positive sentinel nodes.

Residency choices by graduating medical students: why not pathology?

Pathology is an unpopular residency choice for medical students worldwide. In some countries, this has contributed to a crisis in pathologist human resources that has affected the quality of clinical laboratories. Several previous studies have used information from junior medical students and from residents to suggest ways of improving pathology recruitment. There are, however, no published studies of pathology residency choice that focus on the senior medical students who must be recruited. This study uses focus groups of senior medical students to explore both general and pathology-specific influences on residency choice. Several general influences are identified, including students' expectations for their future clinical practices, their own clinical rotation experiences, influences from other people including mentors, and their choice to reject certain fields. Several specific antipathology influences are also revealed, including negative stereotypes about pathologists, a perceived incompatibility of personality between most medical students (extroverted) and pathologists (introverted), and perceptions of pathologists as being in some ways nonmedical. The most important antipathology influence was that, from the students' perspective, pathology was utterly invisible in clinical practice. Most students did not consider and then reject a pathology residency: instead, pathology was completely ignored. Given the importance of clerkship electives in influencing medical student career choice, promoting clerkship experiences in pathology may improve recruitment. However, departments of pathology must first make pathology visible to students and teach them how pathologists contribute to clinical care.

Kingella kingae endocarditis: A rare case of mitral valve perforation.

Kingella kingae, a HACEK (Haemophilus parainfluenzae, Aggregatibacter actinomycetemcomitans, Aggregatibacter aphrophilus, Cardiobacterium hominis, Eikenella corrodens, Kingella kingae) organism, is a common resident of the upper airway in children; it has been associated with endocarditis in children with pre-existing heart conditions. This case report describes K. kingae endocarditis leading to valvular damage in a previously healthy 18-month-old child. Our patient developed a K. kingae bacteremia that was later complicated by meningitis, septic embolic stroke, and endocarditis of the mitral valve, leading to perforation of the posterolateral leaflet. The patient was initially treated conservatively with cefotaxime but, subsequently, required a mitral valve repair with a pericardial patch and annuloplasty. This report draws attention to the need for clinicians to be aware of the potentially serious complications of K. kingae infection in young children. If K. kingae infection is suspected then therapy should be initiated promptly with a ß-lactam, followed by early echocardiographic assessment. This case also highlights the lack of specific guidelines available for K. kingae endocarditis.

Fomepizole fails to prevent progression of acidosis in 2-butoxyethanol and ethanol coingestion.

INTRODUCTION: 2-butoxyethanol (2BE) is a solvent commonly incorporated into household and industrial cleaning products. Its ingestion causes rapid central nervous system depression, hypotension, and metabolic acidosis attributable to metabolism of the parent compound to butoxyacetic acid (BAA) by alcohol dehydrogenase. Lactic acidosis is also reported to develop in some cases. Published treatment strategies include the use of ethanol infusion, ethanol with concomitant dialysis, dialysis alone, and fomepizole. CASE REPORT: We present an unusual case of a coingestion of ethanol and 150-250 mL of pure 2BE, which resulted in rapid obtundation, severe airway edema, hypotension, and prolonged acidosis despite the coingestion of ethanol and the administration of a loading dose of fomepizole. Continuous veno-venous hemodialysis was employed to treat the acidosis. Ingestion was confirmed by gas chromatography and mass spectrometric determinaiton of 2BE and BAA. The patient recovered without sequelae. CONCLUSION: Alcohol dehydrogenase inhibitors may not be adequate to prevent acidosis in significant ingestions to 2BE and extracorporeal treatments may be necessary.

Improved breast cancer biomarker detection through a simple, high frequency, low cost external proficiency testing program.

AIMS: We describe a simple, low cost, high frequency immunohistochemistry external proficiency testing program, and show how its use can lead to improved breast cancer biomarker detection. METHODS: Over a 30 month period in British Columbia, Canada, we used tissue microarray slides to follow the performance of twelve clinical laboratories in nine separate external proficiency testing runs. Sensitivity for detection of oestrogen receptor (ER), progesterone receptor (PR), and HER2 were calculated for each laboratory, biomarker, and run. RESULTS: Mean sensitivities for detection of ER, PR, and HER2 were 97.1%, 84.8%, and 90.7%, respectively. HER2 sensitivity improved over time, from 87.0% to 92.9% (p=0.04), with a trend towards improvement seen for PR (81.9-88.1%, p=0.13). ER sensitivities were high throughout the test period. Improvements occurred without mandating any specific laboratory changes. CONCLUSIONS: This simple, low cost, high frequency external proficiency testing program is highly sustainable and can be implemented in any multi-institutional group or region.

Surgical repair of left internal jugular phlebectasia.

Jugular vein phlebectasia, a fusiform dilatation of a vein without tortuosity, is a rare cause of cervical neck swelling in children. It commonly presents as a soft cystic mass in the neck that transiently appears during straining. Because of its rarity, jugular vein phlebectasia cases have frequently been misdiagnosed or have been managed inappropriately. This report describes the case of a left-sided internal jugular phlebectasia in a 4-year-old child that was surgically treated with a resection and an end-to-end repair.