Diagnostic utility of SOX10 immunostaining in benign lichenoid keratosis: A study of 21 cases.

BACKGROUND: Benign lichenoid keratosis (BLK) is a cutaneous lesion that can clinically mimic malignancy and may represent regression of a pre-existing lesion. BLK may show epidermal pseudo-nests prompting evaluation for a melanocytic lesion. False positivity of MART-1/Melan-A immunostaining in pseudonests has been showed; however, the value of SRY-related HMG-box 10 (SOX10) staining in BLK with features suspicious for a melanocytic proliferation has not been previously reported. METHODS: Twenty-one cases of BLK from 2015 to 2020 were identified. Slides were reviewed and SOX10 immunohistochemistry was performed on each case. Subsequently, Melan-A immunohistochemical staining was performed on all cases. RESULTS: In 10 cases (47.6%), unexpected SOX10 staining was seen in rare to numerous small, single cells in the epidermis above the basal cell layer. No malignancy was identified. Of the 10 cases, 8 (80%) showed suprabasal SOX10 staining did not show similar suprabasal Melan-A staining; 2 (20%) cases showed scattered suprabasal cells positive for Melan-A. CONCLUSION: SOX10 immunostaining in BLK can highlight scattered cells in the epidermis (not easily noticeable on routine stain). Performing SOX10 immunostain alone on BLK can prompt a misdiagnosis of a melanocytic lesion and should be done with caution.

Recurrent Neuroendocrine Primary Cutaneous Mucinous Carcinoma of the Scalp After Complete Excision.

ABSTRACT: Primary cutaneous mucinous carcinoma is a rare, indolent malignancy with a debated history regarding cell of origin. Recurrence is rare but has been documented in up to a third of cases. Recent literature reviews have recognized 2 possible subtypes-neuroendocrine and nonneuroendocrine- with different possible prognostic implications for patients. We describe a case of recurrent primary cutaneous mucinous carcinoma in a 50-year-old man with subtle neuroendocrine features not initially recognized on routine H&E staining but highlighted by immunohistochemical studies. We underscore the importance of immunohistochemical use in these rare cases and emphasize that awareness of these neuroendocrine and nonneuroendocrine subtypes is essential for a complete diagnosis.

Ibrutinib skin toxicities: Report of two cases.

Ibrutinib is a Bruton tyrosine kinase inhibitor used to treat many hematologic conditions, most commonly B-cell lymphomas and leukemias. Reportedly, skin rash is an adverse event in up to 27% of treated patients. Histopathologic description of these lesions is limited. We present two cases of ibrutinib-associated skin toxicities showing diverse histopathologic features. Case 1: A 72-year-old man was started on ibrutinib for chronic lymphocytic leukemia. Two months later, he developed multiple erythematous crusted papules on the chest, abdomen, and extremities. Biopsies revealed varied histopathology including poorly formed granulomatous dermatitis, epidermal necrosis, ulceration, and panniculitis. Ibrutinib was discontinued and his skin lesions resolved within 1 month. Case 2: A 48-year-old man received ibrutinib after failing standard therapy for primary central nervous system EBV positive diffuse large B-cell lymphoma. Two months after initiation of ibrutinib, he developed multiple firm, red, non-tender nodules on the forehead, buttock, and thigh. Biopsies revealed "pseudolymphoma"-like reaction with dense pandermal lymphohistiocytic inflammation and granulomas. His skin toxicity resolved without cessation of therapy. Awareness of the spectrum of histopathologic features that may be encountered in skin lesions of patients treated with ibrutinib, as illustrated by these two cases, will be critical for optimal patient management.

Multiple clear cell acanthomas and a sebaceous lymphadenoma presenting in a patient with Cowden syndrome - a case report.

Cowden syndrome (CS) is an uncommon autosomal dominant multiorgan/system genodermatosis. It is characterized by the development of multiple hamartomas of endodermal, mesodermal and ectodermal origin, an increased lifetime risk of breast, thyroid, endometrial and other cancers and an identifiable germline mutation. Mucocutaneous hamartomas are the most common lesions seen and mainly include facial trichilemmomas, oral mucosal papillomas and benign acral keratoses. Herein, we report a case of a 63-year-old Caucasian male with a long-established diagnosis of CS and history of thyroid cancer, colonic polyps, and innumerable trichilemmomas, seborrheic keratoses, squamous papillomas and non-melanoma skin cancers excised in the past. He presented in four separate occasions with small skin-colored papulonodular lesions that upon excision revealed to be clear cell acanthomas. He also developed a tumor in the preauricular area that was completely resected and was found to be a sebaceous lymphadenoma (SLA) of the parotid gland. This is to our knowledge, the second report of clear cell acanthoma and also the second reported case of SLA in a patient with CS.

Cutaneous metastasis of papillary thyroid carcinoma to the neck: a case report and review of the literature.

Papillary thyroid carcinoma, the most common subtype of thyroid malignancy, rarely presents with cutaneous metastatic spread. Despite metastatic cutaneous lesions presenting as slow and indolent growing nodules of the head and neck, such lesions most frequently appear in the setting of diffuse and dramatic metastatic disease and a bleak prognosis. Given the rarity of these metastatic lesions, the diagnosis may be delayed, and often the initial diagnosis is incorrect. Several case reports have been published in the literature noting unusual or interesting presentations of thyroid carcinoma with cutaneous metastasis. Here we present a classic case of a patient with a prior diagnosis of thyroid carcinoma presenting with a slowly growing ulcerated lesion on the neck nine years after partial thyroidectomy and characteristic histopathology on microscopic examination. Furthermore we review the literature regarding papillary thyroid carcinoma with cutaneous metastasis and the diagnostic challenge these lesions present to practitioners.

Fine-needle aspiration of amyloidoma: A critical analysis.

BACKGROUND: Amyloid, presenting as a mass, is termed amyloidoma. Among the reported cases, fine-needle aspiration (FNA) of amyloid is often misinterpreted as acellular nondiagnostic material. METHODS: A computer search of all FNAs was performed and cases diagnosed as amyloidoma were identified. RESULTS: Among 11,956 cases and 20,634 FNAs, there were six cases and 12 FNAs of amyloidoma. One case with mucin/myxoid matrix was misinterpreted as amyloid, which on our review was Congo red negative. All five other cases of amyloidoma were adequate for evaluation. The smears showed most of the aspirated contents in the middle of the slide and it did not spread when smeared. The amyloid was present as large chunks of waxy, smooth, orangophilic/cyanophilic fragments on Papanicolaou stain and as basophilic fragments on Diff-Quik stain in a clean background. In cases with lymphoma/myeloma, there were admixed lymphocytes and/or plasma cells. Unlike fibrous tissue, amyloid aspirates well and provides adequate material for interpretation. The clean background distinguishes it from mucin/myxoid matrix. Congo red stain was positive with apple green birefringence in all five cases. Further subtyping by mass spectrometry showed AL (κ) type in three patients and AIns (insulin) type in one patient. In one patient with lymphoma, the subtyping was not done. CONCLUSION: FNA of amyloidoma is rare (0.04%), but an optimal method for diagnosis and subtyping, avoiding unwanted surgical interventions. Although mistaken for fibrous tissue, which aspirates poorly, abundant acellular orangophilic/cyanophilic material on FNA should raise a suspicion for amyloid. Unlike mucin/myxoid matrix, amyloid does not smear the background.

AIns (insulin) type amyloidoma of the extremity diagnosed by fine-needle aspiration.

Amyloid is an extracellular deposition of Congo red positive material which shows apple green birefringence under polarized light. A cytopathologist can uncommonly encounter such cases. Among the reported cases, a fine-needle aspiration (FNA) of amyloid is frequently misinterpreted as acellular nondiagnostic material. We report a case of amyloidoma of the right upper arm in a 68-year-old man with history of renal transplantation for diabetic nephropathy who presented with loss of appetite and weight loss. Physical exam showed a 7 cm hard nodular subcutaneous mass in the right upper arm. FNA yielded abundant acellular, irregular fragments of dense material, which was Congo red positive with apple green birefringence by polarized light, consistent with amyloid. Further subtyping of the amyloid by mass spectrometry, showed AIns (insulin)-type amyloid deposition. After further questioning, the patient admitted to injecting insulin at the same site for many years. Awareness of the cytological features is important for diagnosis. This is especially important when dealing with uncommon sites and without adequate clinical information.

Ibrutinib-associated cutaneous mucormycosis due to an Apophysomyces species: report of a case and review of the literature.

The use of ibrutinib, a Bruton tyrosine kinase inhibitor, has been associated with invasive fungal infections (IFIs). We describe a case of Apophysomyces infection associated with long-term use of ibrutinib for the treatment of chronic lymphocytic leukemia as well as perform a literature review of Mucormycosis infections in patients on ibrutinib. Our review found that the onset of IFI can occur within months to years of starting tyrosine kinase inhibitors. These reports provide a more complete picture of the risk of IFI while patients are on ibrutinib. Our case also demonstrates the utility of molecular techniques in the diagnosis of IFI, as the diagnosis was made using 28S rDNA/internal transcribed spacer PCR.

Vascular tumors have increased p70 S6-kinase activation and are inhibited by topical rapamycin.

Vascular tumors are endothelial cell neoplasms whose cellular and molecular mechanisms, leading to tumor formation, are poorly understood, and current therapies have limited efficacy with significant side effects. We have investigated mechanistic (mammalian) target of rapamycin (mTOR) signaling in benign and malignant vascular tumors, and the effects of mTOR kinase inhibitor as a potential therapy for these lesions. Human vascular tumors (infantile hemangioma and angiosarcoma) were analyzed by immunohistochemical stains and western blot for the phosphorylation of p70 S6-kinase (S6K) and S6 ribosomal protein (S6), which are activated downstream of mTOR complex-1 (mTORC1). To assess the function of S6K, tumor cells with genetic knockdown of S6K were analyzed for cell proliferation and migration. The effects of topical rapamycin, an mTOR inhibitor, on mTORC1 and mTOR complex-2 (mTORC2) activities, as well as on tumor growth and migration, were determined. Vascular tumors showed increased activation of S6K and S6. Genetic knockdown of S6K resulted in reduced tumor cell proliferation and migration. Rapamycin fully inhibited mTORC1 and partially inhibited mTORC2 activities, including the phosphorylation of Akt (serine 473) and PKCα, in vascular tumor cells. Rapamycin significantly reduced vascular tumor growth in vitro and in vivo. As a potential localized therapy for cutaneous vascular tumors, topically applied rapamycin effectively reduced tumor growth with limited systemic drug absorption. These findings reveal the importance of mTOR signaling pathways in benign and malignant vascular tumors. The mTOR pathway is an important therapeutic target in vascular tumors, and topical mTOR inhibitors may provide an alternative and well-tolerated therapy for the treatment of cutaneous vascular lesions.

The rate of melanoma transection with various biopsy techniques and the influence of tumor transection on patient survival.

BACKGROUND: Depth of melanoma invasion is critical because it dictates patient treatment and prognosis. Recent reports indicate melanoma transection with initial biopsy does not impact patient survival; however, tumor transection can lead to misdiagnosis and inaccurate staging. OBJECTIVE: This study assessed the rate of melanoma transection with various biopsy techniques and the impact of tumor transection on patient survival. METHODS: We conducted a retrospective review of all melanoma cases at our institution between 2000 and 2008. Of the 490 melanoma cases identified, 479 met inclusion criteria for the study. The transection rates of biopsy techniques were determined. Cases of transected tumors were matched with nontransected cases in a retrospective case-control fashion to evaluate survival. RESULTS: The rate of melanoma transection was 1.5% for excisional biopsies, 4.1% for punch biopsies, and 9.0% for saucerization biopsies. The means of disease-free survival for the control and transected groups were 911 days and 832.7 days, respectively (P value .67). Overall survival for the control group was 1073.7 days versus 1012.4 days for the transected group (P value .72). LIMITATIONS: The study used a select population. The sample size of transected biopsies was limited, in turn limiting the power of the study. Residents performed the majority of biopsies. CONCLUSION: Punch and saucerization biopsies were more likely to transect tumors than excisional biopsies. The transection of melanoma did not affect overall disease-free survival or mortality in the population studied.

Secretory Carcinoma with ETV6-NTRK3 Gene Fusion and Lymph Node Metastasis in Maxillary Gingiva: A Case Report with Pathological and Molecular Correlative Studies.

Secretory carcinoma (SC), also known as mammary analogue secretory carcinoma (MASC), is a rare salivary gland neoplasm with distinctive morphology that harbors a diagnostic ETV6 gene rearrangement. MASC was first described as a type of salivary gland neoplasm in 2010 and resembles breast secretory carcinoma. It is often mistaken for other neoplasms. It usually acts as an indolent tumor but can occasionally behave in an aggressive manner. We present a rare case of a patient with an aggressive SC/MASC of maxillary gingivobuccal sulcus with microcystic, solid and papillary patterns that showed ETV6 gene rearrangement by fluorescence in situ hybridization. Next-generation sequencing revealed t(12;15)(p13;q25) ETV6-NTRK3 translocation. Because SC/MASCs harbor the ETV6-NTRK3 translocation, molecular studies and immunostains are crucial to confirm the diagnosis and direct therapy.

Effectiveness of an electronic health record-based intervention to improve follow-up of abnormal pathology results: a retrospective record analysis.

BACKGROUND AND OBJECTIVE: On March 11, 2009, the Veterans Health Administration (VA) implemented an electronic health record (EHR)-based intervention that required all pathology results to be transmitted to ordering providers by mandatory automated notifications. We examined the impact of this intervention on improving follow-up of abnormal outpatient pathology results. RESEARCH DESIGN AND SUBJECTS: We extracted pathology reports from the EHR of 2 VA sites. From 16,738 preintervention and 17,305 postintervention reports between 09/01/2008 and 09/30/2009, we randomly selected about 5% and evaluated follow-up outcomes using a standardized chart review instrument. Documented responses to the alerted report (eg, ordering follow-up tests or referrals, notifying patients, and prescribing/changing treatment) were recorded. MEASURES: Primary outcome measures included proportion of timely follow-up responses (within 30 d) and median time to direct response for abnormal reports. RESULTS: Of 816 preintervention and 798 postintervention reports reviewed, 666 (81.6%) and 688 (86.2%) were abnormal. Overall, there was no apparent intervention effect on timely follow-up (69% vs. 67.1%; P=0.4) or median time to direct response (8 vs. 8 d; P=0.7). However, logistic regression uncovered a significant intervention effect (preintervention odds ratio, 0.7; 95% confidence interval, 0.5-1.0) after accounting for site-specific differences in follow-up, with a lower likelihood of timely follow-up at one site (odds ratio, 0.4; 95% confidence interval, 0.2-0.7). CONCLUSIONS: An electronic intervention to improve test result follow-up at 2 VA institutions using the same EHR was found effective only after accounting for certain local contextual factors. Aggregating the effect of EHR interventions across different institutions and EHRs without controlling for contextual factors might underestimate their potential benefits.

HIV photodermatitis presenting with widespread vitiligo-like depigmentation.

HIV photodermatitis encompasses a variety of clinical manifestations. We report a rare clinical presentation of HIV photodermatitis with widespread vitiligo-like depigmentation.

Pyogenic granuloma-like Kaposi sarcoma: a diagnostic pitfall.

Pyogenic granuloma-like Kaposi sarcoma (PG-like KS) is a clinicopathologic variant of Kaposi sarcoma (KS), a vascular tumor caused by human herpesvirus-8 (HHV-8). PG-like KS is a challenging entity to diagnose because its clinical and histological features encompass both pyogenic granuloma (PG) and KS characteristics. Immunhistochemical staining with HHV-8 latent nuclear antigen-1 (LNA-1) has been shown to exhibit high sensitivity and specificity for diagnosing KS. Therefore, the integration of clinical features and context, histopathogical findings, and immunohistochemical analysis is important in obtaining the correct diagnosis of PG-like KS. We report a case of PG-like KS in an HIV-positive man.

Squamous cell carcinoma arising in an epidermal inclusion cyst.

Squamous cell carcinoma (SCC) arising from an epidermal inclusion cyst (EIC) is uncommon. We present a case of a 70-year-old man with a scalp nodule with persistent discharge that was resected based on the clinical impression of an EIC. Histopathologic exam showed an infundibular EIC with an epidermal type of squamous epithelium; however, some of the cyst lining and lumen was replaced by squamous proliferation with malignant features. There are 56 cases of SCC arising in EICs reported in the English literature. Though suspected EICs are commonly benign, a thorough pathologic evaluation is required to rule out malignancy.

PAX 8 expression in non-neoplastic tissues, primary tumors, and metastatic tumors: a comprehensive immunohistochemical study.

PAX 8 is a transcription factor that is essential for embryonic development of the kidney, Müllerian organs, and thyroid. It may also have a role in tumor development in these organs. The diagnostic utility of PAX 8 has not been comprehensively studied. Formalin-fixed, paraffin-embedded tissue samples for non-neoplastic tissues (n=1601), primary neoplasms (n=933), and metastatic neoplasms (n=496) were subjected to PAX 8 immunostain. In non-neoplastic tissues, PAX 8 was consistently noted in glomerular parietal epithelial cells, renal collecting ductal cells, atrophic renal tubular epithelial cells regardless of nephronic segments, and epithelial cells of the endocervix, endometrium, fallopian tube, seminal vesicle, epidydimis, thyroid, pancreatic islet cells, and lymphoid cells. PAX 8 was not seen in the rest of the tissue samples. In primary neoplasms, PAX 8 was expressed by 194 of 240 (89%) renal cell neoplasms, by 238 of 267 (89%) Müllerian-type neoplasms, by 65 of 65 (100%) thyroid follicular cell neoplasms, by 8 of 8 (100%) nephrogenic adenomas, and by 17 of 17 (100%) lymphomas. Weak focal staining was noted in 5 of 12 (42%) cases of parathyroid hyperplasia/adenoma and in 6 of 17 (35%) well-differentiated neuroendocrine tumors of the pancreas. PAX 8 was not seen in other neoplasms. In metastatic neoplasms, PAX 8 was expressed by 90 of 102 (88%) metastatic renal cell carcinomas, by 57 of 63 metastatic Müllerian tumors (90%), and by 6 of 6 metastatic papillary thyroid carcinomas (100%). There was also weak focal staining for 1 of 15 metastatic small cell carcinomas and for 1 of 9 metastatic well-differentiated neuroendocrine carcinomas. PAX 8 was not seen in other metastatic neoplasms. It can be successfully identified in routinely processed tissue samples, and its expression is mostly nuclear. PAX 8 expression in non-neoplastic mature tissues is limited to the organs, the embryonic development of which depends on this transcription factor. This tissue/cell-specific expression is maintained during both neoplastic transformation and metastasis. PAX 8 is a sensitive and specific marker for tumors of renal, Müllerian, or thyroid origin in both primary and metastatic sites.

Amelanotic subungual melanoma after trauma: An unusual clinical presentation.

Amelanotic subungual melanoma (SUM) is difficult to clinically diagnose owing to its rarity and variable presentation. We describe a case of a 63-year-old gentleman with an amelanotic SUM that developed after local trauma and presented as a persistent non-healing ulcer which was initially mistaken for a chronic infection. Because amelanotic SUM can mimic other lesions, the physician should have a high index of suspicion for SUM when managing atypical nail lesions to ensure prompt recognition and treatment. The prior trauma to the nail also suggests that posttraumatic inflammation may play a role in SUM development.

Papillary Renal Cell Carcinoma in Lynch/Muir-Torre Syndrome with Germline Pathogenic Variant in MSH6 and Molecular Analysis: Report of a Case and Review of the Literature.

Lynch syndrome (LS) is an autosomal dominant inherited disorder due to pathogenic variations in the mismatch repair genes, which predisposes to malignancies, most commonly colon and endometrial carcinoma. Muir-Torre syndrome is a subset of LS with cutaneous sebaceous adenoma and keratoacanthoma in addition to the malignancies. Renal cell carcinoma (RCC) in patients with LS is extremely rare. Only 26 cases have been reported and among them, only two cases of papillary RCC. We report a case of synchronous papillary RCC and colonic adenocarcinoma in an 85-year-old male with Lynch/Muir-Torre syndrome. The LS was diagnosed when he presented with multiple sebaceous adenomas and genetic testing showed a pathogenic variant in MSH6 mismatch repair gene. A colonoscopy at that time showed multiple tubular adenomas with high-grade dysplasia. He was lost to follow-up and presented with gastrointestinal bleeding after 20 years. A right colonic mass, and a solid mass in the lower pole of the right kidney, was detected by imaging. Right Colectomy showed a T3N0 mucin-producing adenocarcinoma. Right nephrectomy showed a T3a papillary RCC which was microsatellite stable with MSH6, and KRAS mutation. The 36-month follow-up exams showed additional sebaceous neoplasms, and an absence of metastatic carcinoma. Analysis of the reported cases of RCC in LS show clear cell RCC as the most common type. These tumors showed MLH1 mutation most commonly, unlike the urothelial malignancies in LS which involve MSH2. Among the 4 cases of RCC with MSH6 mutation, three were in females, indicating some gender differences.

The contribution of human papilloma virus infection to cutaneous squamous cell carcinoma in patients with chronic lymphocytic leukemia.

Patients with chronic lymphocytic leukemia (CLL), a B-cell malignancy characterized by impaired humoral and cellular immunity, are at increased risk of developing cutaneous squamous cell carcinoma (cSCC). Human papilloma virus (HPV) is the most common sexually transmitted infection worldwide and it has been associated with various malignancies, including cSCC. Impaired cell-mediated immunity is considered a primary risk factor in HPV-induced cSCC. We examined cSCC lesions from CLL patients with consensus review and HPV genetic analysis to further characterize the relationship between HPV and prevalence of cutaneous malignancy in this population. Eleven patients with CLL contributed 35 cSCCs. Treatment with chemotherapy shortened the latency time to first cSCC. HPV was detected in 54% of the lesions. Among the HPV-positive cSCC lesions, 84% of the lesions contained alpha-genus HPV, 42% contained beta-genus HPV, and 26% of the lesions contained both genera. There was a significant association between HPV-containing lesions and peritumoral lymphocytic inflammation, suggesting this as a future area for further characterization. The majority of the lesions, including those with alpha-genus HPV, occurred in sun-exposed areas, such as the scalp and face. These findings may lead to practice-changing recommendations for skin cancer, including the use of vaccinations to reduce HPV-associated skin cancer.

Synchronous renal and adrenal masses: an analysis of 80 cases.

Synchronous renal and adrenal masses are uncommon. Although adrenal masses in the context of renal cell carcinoma (RCC) are often suspected as metastasis, other adrenal lesions with different therapeutic and prognostic implications may coexist with RCC. In a retrospective review of 550 radical nephrectomies with ipsilateral adrenalectomy, 80 cases of coexisting renal and adrenal masses were identified. The renal masses included 76 RCCs, 3 oncocytomas, and 1 malignant pheochromocytoma of adrenal gland involving the kidney. Although the gross pathologic impression of adrenal masses in the presence of RCC was metastasis, on histologic examination, 56% of them were found to be benign lesions (mostly adrenal adenoma/hyperplasia), whereas malignant involvement from RCC was seen in 43%. The benign and malignant nature of the adrenal lesions in the context of RCC could not be discriminated based on the size of adrenal mass. Because of the prognostic implication of direct or metastatic involvement of adrenal gland in the setting of RCC and the possibility of finding small metastatic foci, a meticulous gross and microscopic examination of adrenal glands is emphasized. Rare unusual combinations of renal and adrenal lesions such as RCC and adrenal histoplasmosis, RCC and adrenal myelolipoma, renal oncocytoma, and adrenal pheochromocytoma are also described.