Julio Alexander Díaz Pérez

The proliferation of recognized neoplasms related to related to rearrangements involving kinase genes, arising in diverse somatic tissue lineages, poses an increasing challenge in surgical pathology. For instance, ALK rearrangements have been observed in diverse neoplasms of epithelial, connective tissue, and hematolymphoid lineages, many of which are associated with overexpression of ALK by immunohistochemistry as a useful biomarker. An even higher order challenge and pitfall would be the scenario where a tumor without an ALK rearrangement nonetheless overexpresses the protein, thereby simulating an ALK-defined neoplasm. Herein, we present this exact scenario, where an angiomatoid fibrous histiocytoma, exhibiting the recently-described phenomenon of its overexpression of ALK, clinically, histologically, and immunophenotypically simulated ALK-positive histiocytosis.

The accurate diagnosis of giant cell-rich tumors of bone is challenging, especially in limited tissue samples. This diverse group of neoplasms have similar and often ambiguous clinical presentations, radiologic features, and morphologic characteristics. During the last decade, the discovery of pathogenic recurrent genetic alterations has allowed the development of immunohistochemical surrogate markers and FISH assays that can help differentiate the entities of this broad group from one another. The correct diagnosis of these neoplasms is essential in the management of the affected patients.

Bone matrix-forming tumors are a group of neoplasms that exhibit differentiation toward any stage of osteoblast development. Their clinicopathologic features can resemble one another, yet their clinical management may vary significantly. Therefore, appropriate treatment requires accurate diagnosis, which can be challenging, especially with limited biopsy specimens. Recently, the driver genetic alterations underlying these neoplasms have been discovered, and their protein products can be targeted for diagnosis and therapy. Herein, we summarize the recent advances in our understanding of bone matrix-forming tumors and emphasize the integration of molecular genetics into their conventional clinicopathologic evaluation.

Cartilage-forming tumors are a broad and diverse group of neoplasms frequently affecting the skeleton. Distinguishing between the members of this group is important because of significant differences in treatment and prognosis. Accurate diagnosis can be challenging because of similarities in their clinical, radiographic, and pathologic features. Immunohistochemistry and molecular tools are helpful in select instances. Therefore, careful evaluation and correlation of these features are essential in arriving at the correct diagnosis and appropriate patient management. This review provides an overview of the current literature, emphasizing helpful features in diagnosis.

Discoid lupus erythematosus (DLE) is the most common type of cutaneous lupus and is clinically characterized by alopecia, depigmentation, and scars on sun-exposed skin. Squamous cell carcinoma is a potential long-term complication. The most important risk factor for squamous cell carcinoma development in people with dark skin is chronic scarring and inflammation, such as those seen in long-standing discoid plaques. African Americans who develop squamous cell carcinoma in the setting of chronic scarring and inflammation have a greater risk of metastasis and recurrence compared to sun-induced squamous cell carcinoma seen in whites. Despite this, the pathogenesis of squamous cell carcinoma development in chronic DLE is not fully understood. Herein, we describe a case of an African American patient who developed squamous cell carcinoma on a long-standing discoid plaque. Analysis of the lesion revealed a null type pattern of p53 protein expression and abundant CD123(+) plasmacytoid dendritic cells, as potential drivers of oncogenesis and inflammation, respectively. Dermatologists should be aware of the increased risk of squamous cell carcinoma development within long-standing discoid plaques for a prompt early diagnosis and active long-term surveillance.

Desmoplastic small round cell tumor (DSRCT) is a rare malignant tumor that occurs mainly in the retroperitoneum of children and young adults. In its prototypical form, DSCRT displays characteristic morphology with nested primitive small round cells in a desmoplastic stroma and a distinctive immunophenotype with polyphenotypic differentiation. However, DSCRT can also exhibit a broader clinical, histologic and immunohistochemical spectrum and, therefore, cause diagnostic difficulties. Given that DSCRT is an aggressive and nearly universally fatal disease, making the correct diagnosis is critically important. Herein, we report three patients with DSRCT and unusual clinical, morphologic or immunohistochemical characteristics, in order to highlight its remarkable diversity and increase awareness of this unusual, distinctive neoplasm.

Objectives: Amputation due to gangrene and arthroplasty for degenerative joint disease are common orthopedic procedures and are expected to increase as populations age. Histopathologic examination of these specimens can identify unsuspected diseases. Methods: We reviewed gangrenous amputations and large joint arthroplasty specimens for diagnosis of unexpected lymphoma, January 2014 to January 2020. Pathology and medical records were reviewed to determine diagnosis, treatment, and outcome. Results: Five cases (0.08%) of unexpected primary extranodal marginal zone lymphoma (MZL) centered in bone were identified in 1,624 amputations for gangrene and 4,163 arthroplasty specimens. The female-to-male distribution was 3:2. Median age was 71 years (range, 62-87). The 3 cases arising in the setting of gangrene involved the first toe phalanges and metatarsals, and the femoral head was involved in all cases of joint disease (2 cases). The bone showed variable (10%-80%) infiltration by dense populations of small lymphoid cells with MZL immunophenotype. One patient died from sepsis 18.5 months after diagnosis; all others are alive with a median follow-up of 27.45 months. Conclusions: Histopathologic examination of nonneoplastic orthopedic specimens identifies unexpected primary bone extranodal MZL in a small percentage of cases. This neoplasm may be the result of chronic antigenic stimulation in some circumstances.

Aims: Simple bone cysts are benign intramedullary tumours primarily involving the long bones in skeletally immature individuals. Several mechanisms have been proposed for their pathogenesis. Although the diagnosis is typically straightforward, the interpretation can be problematic, because of superimposed fracture causing them to resemble aneurysmal bone cysts and other tumours. EWSR1–NFATC2 or FUS–NFATC2 fusions, which are characteristic of a subset of aggressive round cell sarcomas, have been recently detected in simple bone cysts. The aim of this study was to examine the clinicopathological and molecular features in a series of simple bone cysts.Methods and results: Using RNA‐based next‐generation sequencing and/or fluorescence in‐situ hybridisation, we investigated the presence of EWSR1 or FUS rearrangements in nine simple bone cysts. The patients were five females and four males, aged 3–23 years (median, 14 years); the tumours ranged from 19 mm to 160 mm (median, 46 mm) in size, and involved the femur (n = 3), humerus (n = 2), fibula (n = 2), tibia (n = 1), and iliac wing (n =1). We identified three cases with EWSR1–NFATC2 fusion (showing identical breakpoints to those in EWSR1–NFATC2 sarcomas) and one additional case with FUS rearrangement. Unlike in EWSR1–NFATC2 sarcomas, immunohistochemical expression of NKX3.1 and NKX2.2 was absent in two simple bone cysts tested.Conclusions: More than 40% of simple bone cysts harbour genetic alterations confirming that they are neoplastic, investigation of EWSR1 and/or FUS rearrangement may help to distinguish simple bone cysts from mimics, and NFATC2 rearrangement is not pathognomonic of malignancy.

Giant cell tumor of bone is a locally aggressive, rarely metastasizing neoplasm. Evidence suggests that the neoplastic cells may be osteoblastic in differentiation. Standard treatment is surgical removal, but medical therapy with denosumab, an inhibitor of receptor activator of nuclear factor-κβ ligand, has become a component of patient management in select cases. Denosumab-treated giant cell tumor of bone (DT-GCTB) shows drastic morphologic changes including the presence of abundant bone. To further determine the relationship of the neoplastic cells to osteoblast phenotype, we performed a morphologic and immunohistochemical study on a series of DT-GCTB. Cases of DT-GCTB were retrieved from surgical pathology files, available slides were reviewed, and immunohistochemistry for H3.3 G34W, SATB2, and p63 was performed. The cohort included 31 tumors from 30 patients (2:3 male:female), ages 15 to 73 years (median=36 y). The morphology of post–denosumab-treated tumors ranged from tumors composed of an abundant bone matrix with few spindle cells to spindle cell-predominant tumors. Five had focal residual classic CGTB, and 2 manifested mild nuclear atypia. The majority expressed all markers: 86.2% for H3.3 G34W, 96.7% for SATB2, and 100% for p63. All markers stained the various tumor components including spindle cells and the cells on the surface of and within the treated tumor bone matrix. Most markers were also positive in reactive-appearing woven bone adjacent to tumor: 84.6% for H3.3 G34W, 100% for SATB2, and 68% for p63. These findings suggest that denosumab treatment of giant cell tumor of bone results in osteoblastic differentiation with bone production.