High-fidelity detection, subtyping, and localization of five skin neoplasms using supervised and semi-supervised learning.

Background: Skin cancers are the most common malignancies diagnosed worldwide. While the early detection and treatment of pre-cancerous and cancerous skin lesions can dramatically improve outcomes, factors such as a global shortage of pathologists, increased workloads, and high rates of diagnostic discordance underscore the need for techniques that improve pathology workflows. Although AI models are now being used to classify lesions from whole slide images (WSIs), diagnostic performance rarely surpasses that of expert pathologists. Objectives: The objective of the present study was to create an AI model to detect and classify skin lesions with a higher degree of sensitivity than previously demonstrated, with potential to match and eventually surpass expert pathologists to improve clinical workflows. Methods: We combined supervised learning (SL) with semi-supervised learning (SSL) to produce an end-to-end multi-level skin detection system that not only detects 5 main types of skin lesions with high sensitivity and specificity, but also subtypes, localizes, and provides margin status to evaluate the proximity of the lesion to non-epidermal margins. The Supervised Training Subset consisted of 2188 random WSIs collected by the PathologyWatch (PW) laboratory between 2013 and 2018, while the Weakly Supervised Subset consisted of 5161 WSIs from daily case specimens. The Validation Set consisted of 250 curated daily case WSIs obtained from the PW tissue archives and included 50 "mimickers". The Testing Set (3821 WSIs) was composed of non-curated daily case specimens collected from July 20, 2021 to August 20, 2021 from PW laboratories. Results: The performance characteristics of our AI model (i.e., Mihm) were assessed retrospectively by running the Testing Set through the Mihm Evaluation Pipeline. Our results show that the sensitivity of Mihm in classifying melanocytic lesions, basal cell carcinoma, and atypical squamous lesions, verruca vulgaris, and seborrheic keratosis was 98.91% (95% CI: 98.27%, 99.55%), 97.24% (95% CI: 96.15%, 98.33%), 95.26% (95% CI: 93.79%, 96.73%), 93.50% (95% CI: 89.14%, 97.86%), and 86.91% (95% CI: 82.13%, 91.69%), respectively. Additionally, our multi-level (i.e., patch-level, ROI-level, and WSI-level) detection algorithm includes a qualitative feature that subtypes lesions, an AI overlay in the front-end digital display that localizes diagnostic ROIs, and reports on margin status by detecting overlap between lesions and non-epidermal tissue margins. Conclusions: Our AI model, developed in collaboration with dermatopathologists, detects 5 skin lesion types with higher sensitivity than previously published AI models, and provides end users with information such as subtyping, localization, and margin status in a front-end digital display. Our end-to-end system has the potential to improve pathology workflows by increasing diagnostic accuracy, expediting the course of patient care, and ultimately improving patient outcomes.

The dichotomy in carcinogenesis of the distal esophagus and esophagogastric junction: intestinal-type vs cardiac-type mucosa-associated adenocarcinoma.

Adenocarcinoma of the distal esophagus and esophagogastric junction continues to rise in incidence. An intestinal metaplasia (Barrett esophagus)-dysplasia-carcinoma sequence induced by gastroesophageal reflux disease is well established. However, a significant number of adenocarcinomas in the vicinity of the esophagogastric junction are seen in the background of gastric/cardiac-type mucosa without intestinal metaplasia. Thus, the aim of this study was to investigate the role of Barrett esophagus (intestinal-type mucosa) in the classification and prognosis of tumors of the distal esophagus and esophagogastric junction. Clinicopathological and molecular characteristics were examined in 157 consecutively resected adenocarcinomas of the distal esophagus and esophagogastric junction and were compared between tumors arising in association with intestinal-type and cardiac-type mucosa. Intestinal-type mucosa-associated adenocarcinomas were more likely to be associated with younger age (P=0.0057), reflux symptoms (P<0.0001), proximal location (P=0.0009), lower T stage (P<0.0001), fewer nodal metastases (P=0.0001), absence of lymphatic (P<0.0001), venous (P=0.0060) or perineural (P<0.0001) invasion. Histologically, intestinal-type mucosa-associated tumors were more likely to be low-grade glandular tumors (P=0.0095) of intestinal or mixed immunophenotype (P=0.015) and express nuclear ß-catenin (P=0.0080), whereas tumors arising in a background of cardiac-type mucosa were more frequently associated with EGFR amplification (P=0.0051). Five-year overall survival rate was significantly higher in patients with intestinal-type mucosa-associated tumors (28 vs 9%, P=0.0015), although no survival benefit was seen after adjusting for potential confounders. Our findings support the theory that multiple distinct pathways of tumorigenesis exist in the vicinity of the esophagogastric junction, including one in which tumors arise from dysplastic intestinal metaplasia (intestinal pathway), and one potentially involving dysplasia of the cardiac-type mucosa (non-intestinal pathway). Additional studies are warranted to further clarify their pathogenesis and the molecular mechanisms involved.

Quantitative assessment of dermal cellularity in nephrogenic systemic fibrosis: a diagnostic aid.

BACKGROUND: Nephrogenic systemic fibrosis (NSF) affects patients with impaired renal function who have received gadolinium-containing contrast agents (GCCAs). Increased dermal cellularity is a key diagnostic feature of NSF, however, the histologic findings can be subtle. OBJECTIVE: We sought to determine whether dermal cellularity in skin biopsy specimens from NSF cases: (1) differs significantly from that of controls; and (2) correlates with duration of the skin lesions, level of plasma creatinine, GCCA dose, or a combination of these. METHODS: Seventeen NSF skin biopsy specimens and age-, sex-, and site-matched controls were retrieved from the dermatopathology files of the Massachusetts General Hospital in Boston. Dermal cellularity was manually quantified on hematoxylin-eosin-stained sections and patient medical records were reviewed for demographic and clinical data. RESULTS: NSF cases showed a mean dermal cellularity of 70.8/high-power field (control mean: 14.4/high-power field, P < .001) and a cut-off range of 19 to 26/high-power field was established. No significant correlation was identified between dermal cellularity and demographic and clinical data. LIMITATIONS: In this retrospective analysis, duration of skin lesion was defined as the interval from most recent prior GCCA study, rather than the actual clinical onset, to time of skin biopsy, and the cumulative GCCA dose may reflect a minimum if GCCA was received at an outside institution. CONCLUSION: Enumeration of dermal cellularity on hematoxylin-eosin-stained sections can aid in the histologic diagnosis of NSF in the setting of chronic kidney disease and GCCA exposure and is independent of patient age, sex, plasma creatinine, time from last GCCA exposure, and GCCA dose.

Clinicopathologic and molecular profiles of microsatellite unstable Barrett Esophagus-associated adenocarcinoma.

Microsatellite instability (MSI) has been reported in various tumors, with colon cancer as the prototype. However, little is known about MSI in Barrett esophagus (BE)-associated adenocarcinoma. Thus, the aim of this study was to compare the clinicopathologic and molecular features of BE-associated adenocarcinomas with and without MSI. The study cohort consisted of 76 patients with BE-associated adenocarcinomas (66 male, 10 female), with a mean age of 65.1 years. Immunohistochemistry (IHC) for MLH1, MSH2, MSH6, PMS2, and CD3 and in situ hybridization for Epstein-Barr virus-encoded RNA were performed. MLH1 and PMS2 expression was lost by IHC in 5 cases (6.6%); of these, 5 showed high-level MSI (MSI-H) by polymerase chain reaction assay, and 4 showed hMLH1 promoter methylation. Histologically, tumors with MSI-H were heterogenous and included conventional adenocarcinomas with tumor-infiltrating lymphocytes (n=1), medullary carcinoma (n=2), signet ring cells (n=1), and signet ring cell and mucinous components (n=1). Compared with tumors negative for MSI by IHC, BE-associated adenocarcinomas with MSI-H were associated with older patient age (P=0.0060), lymphovascular invasion (P=0.027), and significantly larger numbers of tumor-infiltrating lymphocytes (P<0.0001). However, there was no statistical difference in overall survival between the 2 groups (P=0.285). In conclusion, MSI-H is uncommon in BE-associated adenocarcinomas, but is associated with clinicopathologic features fairly similar to sporadic microsatellite unstable colorectal cancers. Given the growing evidence that indicates lack of benefits from adjuvant therapy with fluorouracil in the colonic counterpart, it may be important to identify MSI-H in BE-associated adenocarcinomas.

Pachydermodactyly.

A 16-year-old boy presented to the Pediatric Dermatology Clinic at the Charles C. Harris Skin and Cancer Pavilion with a two-year history of asymptomatic swelling of fingers on both hands. His condition had remained undiagnosed after previous evaluation by several dermatologists and hand specialists. He initially had noticed increased fullness of his proximal left fourth digit. Several months later, he noted swelling of his left fifth digit and right second through fourth digits. The patient reported no pain, pruritus, restriction of movement, morning stiffness, or trauma. He also denied repetitive hand-rubbing movements although his mother stated that he had this habit as a child. Past medical history included allergic rhinitis and asthma. Similar hand findings were not present in any other members of his family.

Poikilodermatous mycosis fungoides.

Poikilodermatous mycosis fungoides is a rare form of cutaneous T-cell lymphoma that is characterized clinically by localized or diffuse patches, which consist of telangiectases, mottled hyper- and hypopigmentation, and atrophy. The immunophenotype of neoplastic cells is similar to that observed in classic mycosis fungoides. Therapeutic options used in poikilodermatous and classic mycosis fungoides include both skin-directed and systemic treatments. We present a case of poikilodermatous mycosis fungoides in a 53-year-old woman, who initially presented with erythroderma and who has failed multiple treatment modalities.

Glomangioma.

A 22-year-old man presented with a 9-year history of multiple blue nodules on the medial aspect of his right arm. A biopsy specimen showed a cystic space with a cuboidal cellular lining that stained positive for α-smooth-muscle actin; these findings were consistent with multiple glomangiomas. We review the clinical and histopathologic characteristics of this rare entity.

Epidermal nevus.

A healthy 25-year-old man presented with a widespread, non-organoid, non-epidermolytic epidermal nevus. In addition to extensive hyperpigented patches and thin plaques following Blaschko lines, there were superimposed psoriasiform plaques on the elbows and warty plaques on the upper trunk. Striate palmar keraoderma also was evident. We review the clinical morphologies, sites of involvement, histopathologic findings (presence or absence of epidermolytic hyperkeratosis), and syndromal associations of non-organoid EN with underlying mutations in different genes.

Giant multi-loculated apocrine hidrocystomas.

Giant, multi-loculated hidrocystomas represent a rare variant of the common, benign hidrocystoma. Hidrocystomas are generally 1-3 mm and rarely exceed 10 mm. We describe a case of giant multi-loculated hidrocystomas 1-2 cm in size that were located near both upper and lower eyelids. Multiple modalities have been used to treat hidrocystomas, including excision, pulsed-dye laser, electrodesiccation, curettage, tricholoracetic acid, botulinum toxin, and anticholinergics.

Erythema dyschromicum perstans.

A 39-year-old Hispanic man presented with widespread, symmetric, hyperpigmented, brown-gray-blue, oval-to-circular, discrete and coalescing patches on the upper extremities, trunk, neck and face, many with an associated annular erythematous border. Histopathologic features showed an interface dermatitis, thin lichenoid and superficial perivascular infiltrates, and dermal melanophages. These changes were consistent with a diagnosis of erythema dyschromicum perstans (EDP). The etiology of EDP is unknown, but many associations have been described. The rim of erythema that appears during the inflammatory phase of the disorder distinguishes it from other disorders of hyperpigmentation. There is no consistently effective treatment for EDP. We highlight the use of narrow-band UV B phototherapy in the treatment of this disorder, which has shown good success in our patient thus far.

Behçet syndrome.

We present a 34-year-old man with a two-year history of aphthous stomatitis, who later developed painful, erythematous nodules on his lower extremities. A pathergy test was positive, and the diagnosis of Behçet syndrome (BS) was made. It is important for the dermatologist to recognize the wide variety of cutaneous manifestations of this disorder. A pathergy test is a simple diagnostic tool that may assist in making a diagnosis. Case reports of other unusual skin manifestations in BS also are reviewed.

Sarcoidal tattoo granuloma.

A 41-year-old man presented for evaluation of a widespread eruption. The eruption started six months beforehand as bumps within pre-existing black tattoos over his trunk and arms. One month later, the patient developed eye pain and the diagnosis of a uveitis was made. A different eruption soon followed, which the patient described as patches of rough skin. Finally, the patient developed discrete patches of hair thinning. The clinical examination, history, skin biopsy findings, and elevated angiotensin-1 converting enzyme and immunoglobulin levels supported the diagnosis of systemic sarcoidosis, which manifested as a sarcoidal tattoo granuloma, perifollicular cutaneous sarcoidosis, and uveitis.

Disseminated superficial porokeratosis.

A 62-year-old woman with psoriasis and psoriatic arthritis presented for evaluation and treatment of a one-week history of pruritic, pink spots on her trunk and extremities. Several weeks prior, therapy with certolizumab pegol and methotrexate was started for her psoriatic arthritis. A biopsy specimen was consistent with the diagnosis of porokeratosis. Owing to the setting of immunosuppression and presence of symmetric pruritic lesions on non-sun exposed areas, the diagnosis of disseminated superficial porokeratosis was made.

Porokeratosis plantaris, palmaris, et disseminata.

We describe a 73-year-old woman with a long-standing history of annular, hyperkeratotic papules that began on the palms and soles and gradually spread to her trunk, extremities, and face. The clinical presentation and biopsy findings were consistent with PPPD, which is a rare subtype of porokeratosis that begins on the palms and soles and gradually spreads to the trunk and extremities. Owing to the risk of malignant degeneration in porokeratosis, patients should be closely monitored with total body skin examinations. There is no definitive treatment for PPPD. Oral retinoids are sometimes helpful although relapses are common after discontinuation of therapy.

Melanocytic lesions of the conjunctiva.

CONTEXT: Melanocytic proliferations are among the most common neoplasms of the conjunctiva. They often represent challenging lesions for pathologists unfamiliar with unique histologic features of melanocytic proliferations in this location and with nomenclature used by ophthalmologists. OBJECTIVE: To comprehensively review clinical aspects, pathologic features, and management of melanocytic proliferations of the conjunctiva. DATA SOURCES: Review of the literature and personal experience of the authors. CONCLUSIONS: Classification, state of the art, and practical aspects of pathology of melanocytic proliferations of the conjunctiva are discussed.

Nephrogenic systemic fibrosis: a pathologic study of autopsy cases.

CONTEXT: -Nephrogenic systemic fibrosis (NSF) is a rare but serious disorder initially described as a purely dermatologic process. Isolated autopsy reports have described multiorgan involvement by this disease. OBJECTIVE: -To further illustrate the varied and systemic involvement of NSF by describing the autopsy experience at the Massachusetts General Hospital. DESIGN: -We describe the findings in a series of 4 autopsy cases of patients diagnosed with NSF. This report describes the history of renal dysfunction, exposure to gadolinium-containing contrast agents, specific laboratory parameters, and the extent of systemic involvement identified by postmortem examination. RESULTS: -Causes of death included systemic thromboembolic disease (n = 3) and pneumonia (n = 1). Laboratory parameters and type, dose, or timing of gadolinium-containing contrast-agent exposure did not correlate with clinical findings and outcomes. All patients demonstrated cutaneous manifestations of the disease and nephrocalcinosis, with some exhibiting calcification and fibrosis of the dura, thyroid, and heart including the cardiac conduction system, on postmortem examination. Soft tissue calcification was associated with concurrent hyperparathyroidism or high serum parathyroid hormone levels. CONCLUSIONS: -Thromboembolic disease can be a significant clinical complication of NSF. Patients with NSF may also develop characteristic histologic features of fibrosis and calcification in multiple organs, with significant morbidity and mortality. This autopsy series highlights the variability of systemic manifestations of NSF.

Pigmented epithelioid melanocytoma: favorable outcome after 5-year follow-up.

Pigmented epithelioid melanocytoma (PEM) is a recently described entity encompassing epithelioid blue nevus (of Carney complex) and most tumors earlier considered as so-called "animal-type melanoma". Loss of expression of a Carney complex gene, cyclic adenosine 3',5' monophosphate-dependent protein kinase regulatory subunit 1alpha, is observed in the majority of PEMs. Initial reports with short-term follow-up have suggested that although PEMs frequently metastasize to lymph nodes, they have a more favorable outcome than conventional melanomas. In this report, we present the results of long-term follow-up in 26 patients with PEMs from North America and Australia. There were 9 males and 17 females, with a median age of 20 years. The tumors involved the trunk (6 cases), extremities (12 cases), genitalia (1 case), and the head and neck region (7 cases) had a median Breslow thickness of 2.2 mm (range 0.80 to 10.0 mm) and a median Clark level of 4. Eight of the patients developed lymph node metastases. After a median follow-up period of 67 months (range 39 to 216 mo), all patients are alive and free of disease. These findings provide further evidence that PEM is a unique low-grade melanocytic tumor with limited metastatic potential (to lymph nodes), but a favorable long-term clinical course.

Infiltrating intramuscular spindle cell lipoma of the face.

Spindle cell lipoma is a benign lipomatous tumor, which usually arises on the back of the neck, shoulder or upper back of males in the third to seventh decade of life. We report herein an unusual infiltrating intramuscular spindle cell lipoma arising in the nose of a 53-year-old man. The patient presented with a 0.5-cm 'cyst' of the nose, just above the right alar crease, which was removed. Four years later, the lesion recurred and was re-excised. Histologically, a proliferation of mature adipocytes, ropey collagen fibers and spindle cells within a myxoid stroma was present in the subcutaneous tissue and infiltrated between skeletal muscle fibers. Nine cases of intramuscular spindle cell lipoma with histological examination have previously been reported and have involved the oral cavity and muscles of the extremities. To our knowledge, this is the first report of an infiltrating intramuscular spindle cell lipoma arising on the face.

Effect of tumor characteristics and duplication of the muscularis mucosae on the endoscopic staging of superficial Barrett esophagus-related neoplasia.

Endoscopic mucosal resection (EMR) is being advocated as a diagnostic, staging, and therapeutic technique for the management of Barrett esophagus (BE)-related neoplasia. With the emergence of new endoluminal therapy including EMR for the treatment of BE-related superficial adenocarcinomas, accurate staging has become crucial to select patients for different treatment arms. Intramucosal adenocarcinomas can be successfully treated by endoluminal techniques, whereas submucosal invasive tumors with a greater risk of lymph node metastasis are likely candidates for esophagectomy. Endoscopic ultrasound (EUS) is used to stage superficial BE-related neoplasms, yet endoscopic staging can be incongruent to that obtained after pathologic examination. In this study, we sought to determine morphologic factors, which may influence EUS staging in 35 cases with intramucosal adenocarcinoma diagnosed by subsequent EMR, focusing on tumor characteristics and structural changes associated with BE. Among the latter duplication of the muscularis mucosae, either fragmented or well-organized, was seen in 64% of 11 cases that were overstaged as having submucosal invasion by EUS, compared with 38% of those accurately staged. A greater vertical thickness of the tumor was also associated with overstaging by EUS (1.61+/-0.75 mm in the discordant vs. 1.16+/-0.67 mm in the concordant groups, P=0.028). The results illustrate how morphologic factors may affect EUS staging of superficial esophageal adenocarcinomas. EUS alone is not sufficient for staging these neoplasms precisely, and to accurately stratify patients into different treatment arms, EMR should play a role as a complementary staging modality.

Organizing pneumonia and pulmonary lymphatic architecture in diffuse alveolar damage.

Diffuse alveolar damage represents the pathologic basis of most cases of the acute respiratory distress syndrome. Diffuse alveolar damage reflects injury to the pulmonary alveolar wall and microvasculature, leading to the exudation of water and plasma proteins that can overwhelm the local lymphatic drainage. Organizing pneumonia is a prominent histopathologic feature in some cases of diffuse alveolar damage. We examined whether diffuse alveolar damage-organizing pneumonia and changes in lymphatic architecture might be indicators of clinical outcome in acute respiratory distress syndrome. Formalin-fixed lung sections (n = 26) from thoracoscopic lung biopsies of patients with diffuse alveolar damage in the fibroproliferative phase, with or without organizing pneumonia, were immunostained with anti-CD31 and anti-D240, markers of vascular and lymphatic endothelium, respectively, and examined by morphometric analysis. Positively staining vessels were enumerated and maximal luminal diameters recorded in randomly selected low-power fields. Patients with diffuse alveolar damage-organizing pneumonia showed greater survival than those with diffuse alveolar damage (67% versus 33%, P = .03). The maximal luminal diameter of D240+ lymphatic vessels was larger for diffuse alveolar damage-organizing pneumonia than diffuse alveolar damage (28 +/- 4 versus 59 +/- 16 microm, P = .02). In addition, larger lymphatic luminal diameters (28 +/- 4 versus 47 +/- 11 microm) were associated with increased survival (P = .12). We conclude that lung biopsy histopathology and pulmonary lymphatic morphology may predict survival in acute respiratory distress syndrome.