Primary Cilia as a Tumor Marker in Pituitary Neuroendocrine Tumors.

Pituitary neuroendocrine tumors (PitNETs) account for approximately 15% of all intracranial neoplasms. Although they usually appear to be benign, some tumors display worse behavior, displaying rapid growth, invasion, refractoriness to treatment, and recurrence. Increasing evidence supports the role of primary cilia (PC) in regulating cancer development. Here, we showed that PC are significantly increased in PitNETs and are associated with increased tumor invasion and recurrence. Serial electron micrographs of PITNETs demonstrated different ciliation phenotypes (dot-like versus normal-like cilia) that represented PC at different stages of ciliogenesis. Molecular findings demonstrated that 123 ciliary-associated genes (eg, doublecortin domain containing protein 2, Sintaxin-3, and centriolar coiled-coil protein 110) were dysregulated in PitNETs, representing the upregulation of markers at different stages of intracellular ciliogenesis. Our results demonstrate, for the first time, that ciliogenesis is increased in PitNETs, suggesting that this process might be used as a potential target for therapy in the future.

Pancreatic panniculitis revisited: A series of 34 patients.

BACKGROUND: Pancreatic panniculitis is a rare form of panniculitis generally associated with acute or chronic pancreatitis, and less frequently with pancreatic carcinoma. Clinically, it presents with subcutaneous nodules usually located in the lower extremities, however, it presents an almost pathognomonic histopathological finding with enzymatic fat necrosis in the adipose tissue. METHODS: In this retrospective case series of five hospitals, biopsy specimens of cutaneous lesions of pancreatic panniculitis were reviewed. Clinical information was obtained through medical records. RESULTS: A total of 34 cases were included, 23 women and 11 men, aged between 31 and 92 years. The most common associated pancreatic disease was acute pancreatitis (23 cases) and its main triggering cause was gallstones (17 cases). In two patients it was related to chronic pancreatitis and six cases were associated with malignancy. Histopathological findings were always the key to diagnosis. In the biopsies reviewed, mostly lobular panniculitis with the characteristic necrosis of the adipocytes was observed. In addition, nine of the cases presented with Splendore-Hoeppli phenomenon. CONCLUSIONS: We present the largest series of pancreatic panniculitis. Clinically, the female predominance and biliary lithiasis as the main cause of acute pancreatitis are to be emphasized. Histopathologically, a peripheral eosinophilic striated rim surrounding aggregates of ghost adipocytes consistent with Splendore-Hoeppli is an additional clue to its diagnosis.

Graft-versus-host disease-associated angiomatosis with striking lipomatous metaplasia.

Sclerodermatous graft-versus-host disease (GvHD) is one of the many clinicopathological variants of chronic GvHD. One of the rarest forms of this variant is GvHD-associated angiomatosis (GvHD-AA). We describe the case of a 62-year-old male with sclerodermatous GvHD who presented, in consecutive years, two different lesions that showed characteristics of GvHD-AA. The first lesion fitted perfectly with the previously known features of this rare entity. However, the second lesion was more interesting, as the angiomatoid lesion was surrounded by newly appeared adipocytes, something not previously described. The appearance of this peculiar adipose tissue may be explained as related to an important dermal atrophy, as a concomitant appearance of a lipomatous nevus and GvHD-AA, or, finally, as mature adipose tissue related to a previous inflammatory process, that is, lipomatous metaplasia. Both lesions were diagnosed as GvHD-AA, and the second one was considered to be associated with dermal lipomatous metaplasia. We also considered whether hypoxia could be related to both lesions. In the present report, we review previously published cases of GvHD-AA and discuss the different hypotheses that could explain the appearance of metaplasia associated with the second lesion.

Cutaneous vascular calcification. Perieccrine calcification as a diagnostic key for calciphylaxis.

BACKGROUND: Attempts have been made to establish discriminative criteria between classic calciphylaxis (CPX) and those cases in which cutaneous vascular calcification (CVC) represents an incidental finding (epiphenomenon). METHODS: Retrospective, observational cohort study of patients with CVC to distinguish clinicopathological features between CVC as classic CPX (CVC in cutaneous lesions with erythematous-violaceous plaques with or without ulceration) or as an epiphenomenon (CVC in cutaneous lesions with known diagnosis). Different clinicopathological parameters and the presence of perieccrine calcification and pseudoxanthoma elasticum (PXE)-like changes were evaluated. RESULTS: Sixty-six patients were studied. The CPX group showed a significantly higher percentage of renal failure, hypertension, altered laboratory parameters, painful lesions, and mortality rate. Histopathologically, the CPX group was associated with more than one vessel per field involved with subintimal concentric calcification and perieccrine calcification (observed exclusively in the CPX group), while PXE-like changes, although more frequent in the CPX group, were also observed in the epiphenomenon group. CONCLUSION: Perieccrine calcification and the presence of more than one vessel per field involved by concentric pattern calcification could be used as a diagnostic marker of CPX. Although PXE-like changes are not an exclusive marker, they could suggest CPX diagnosis.

Neutrophilic Infiltrates in Panniculitis: Comprehensive Review and Diagnostic Algorithm Proposal.

Neutrophilic infiltrates in panniculitis can be seen in different clinical-pathological entities. There are a "mostly neutrophilic inflammatory infiltrate" in some entities classically defined as neutrophilic panniculitis and already included in algorithms, such as enzymatic panniculitis, infective and factitial ones, erythema induratum, or subcutaneous Sweet syndrome, but there are also other panniculitis where neutrophils are frequently observed such as panniculitis associated with inflammatory bowel disease or rheumatoid arthritis, or drug-induced panniculitis associated with BRAF inhibitors, and finally, some panniculitis are better classified in other panniculitides groups but may present with neutrophil-rich variants, such as the neutrophil-rich subcutaneous fat necrosis of the newborn. We review the main clinical and histopathological features of most of these panniculitides and construct a diagnostic algorithm including these diseases.

Immunohistochemical Study of 2 Cases of Coxsackie A6-Induced Atypical Hand-Foot-and-Mouth Disease.

An atypical clinical variant of hand-foot-and-mouth disease (HFMD) with more extensive lesions and affecting adults has emerged during the past years, usually associated to the Coxsackievirus serotype A6 (CV-A6). We present a 19-year-old woman with a 3-day evolution eruption of papulovesicular lesions, which first appeared around the mouth and frontal area and rapidly spread. In addition, we present a 61-year-old man with a 4-day evolution asymptomatic eruption of papulovesicular lesions in both the hands and feet after suffering a cold 1 week before. Skin biopsies of both patients showed intraepidermal vesicles with spongiosis and ballooning, leading to reticular degeneration, apoptotic keratinocytes, and epidermal necrosis of the upper layers with neutrophil sloughing. Immunohistochemical studies for Coxsackie, Enterovirus, herpes virus, adenovirus, and measles were all negative. Cultures of blister fluid, reverse transcription polymerase chain reaction of skin biopsies, blood tests and serologies for exanthematic virus, and serum viral arrays were also negative. Only reverse transcription polymerase chain reaction of blister fluid confirmed Cocksakie A6. In conclusion, immunohistochemical studies with the commercially available viral antibodies do not seem to be useful in atypical HFMD cases. In these cases, to determine the typical histopathological features in HE is the fastest diagnostic aid.

Bilateral Facial Apocrine Fibrosing Hamartoma Mimicking Microcystic Adnexal Carcinoma.

An otherwise healthy 50-year-old woman was evaluated for the presence of 2 erythematous, and slightly pruritic plaques, involving both cheeks for 30 years. Left-side skin biopsy showed a diffuse proliferation of ductal structures horizontally arranged and involving the reticular dermis that resembled tubular adenoma embedded in a sclerotic stroma and surrounded by a peculiar periductal desmoplasia. Nuclear atypia or mitosis was not found. Contralateral biopsy showed identical findings. Differential diagnosis included microcystic adnexal carcinoma (MAC) and plaque-like syringoma and a peculiarly horizontally arranged tubular adenoma. We ruled out MAC as the lesions were long-standing, without infundibular cysts, solid strands, or perineural infiltration. Our case closely resembled those previously described as sweat duct proliferation associated with aggregates of elastic tissue and atrophoderma vermiculatum, although striking differences were observed, as our case did not present aggregates of elastic tissue, did not involve the papillary and superficial reticular dermis, and presented evidences of decapitation secretion as a sign of apocrine differentiation. We consider our case as a MAC simulator and we propose the descriptive name of bilateral facial apocrine fibrosing hamartoma.

Clinico-Pathological Study of 4 Cases of Pseudoherpetic Grover Disease: The Same as Vesicular Grover Disease.

INTRODUCTION: Grover disease (GD) was described with 4 histopathological patterns, but later wide histopathological studies found additional ones including vesicular GD. From 2014, 2 new patterns, GD with epidermolytic hyperkeratosis and pseudoherpetic GD, have been proposed. OBJECTIVES: The authors present 4 cases of pseudoherpetic GD and review the 6 previously published cases to better characterize this variant clinically and histopathologically. RESULTS: Half of the patients were men. Mean age at diagnosis was 70, 25 years old. All the patients were immunosuppressed, and 75% of them were treated with chemotherapy. Lesions were asymptomatic or itchy papules sometimes crusted and intermingled with isolated vesicles or pustules mostly in the trunk. Skin biopsies showed intraepidermal vesicles filled with plasma (50%) with floating grouped acantholytic cells. No viral inclusions were found, and immunostaining for herpes virus and varicella zoster was negative. DISCUSSION: Vesicular pattern in GD is described exclusively from a histopathological point of view, and it is defined as the presence of an intraepidermal vesicle filled with plasma and with dyskeratotic cells in the upper part of the vesicle. After reviewing all the described cases, pseudoherpetic GD presents the same histopathological features than vesicular GD, but authors paid attention to the presence of grouped acantholytic cells mimicking multinucleated cells of herpes infection. The authors consider that the so-called pseudoherpetic GD is a vesicular GD, where clinical suspicion of varicella raises this differential diagnosis and leads us to check viral nuclear cytopathic changes, and the authors favor the use of vesicular GD in the dermatopathologist report.

Specific skin infiltration as first sign of localized stage Hodgkin's lymphoma involving an epitrochlear node.

Cutaneous manifestation as the first sign of Hodgkin lymphoma (HL) is very rare and diagnostically challenging; especially, because the clinical presentation of specific skin involvement by HL is polymorphous. We present a 44-year-old man with erythematous indurate papules and plaques in the right forearm and arm where skin biopsy showed an HL. He also has an enlarged epitrochlear node, and later histopathologic study confirmed the diagnosis of HL subtype-mixed cellularity. Immunohistochemical stains in both biopsies showed that the atypical cells were positive for CD30 and CD15, and negative for CD20 and CD3. PAX5 stained the nuclei of the atypical large lymphoid cells weakly and Oct-2 staining was negative in the atypical cells. EBER and LMP1 protein were negative in both biopsies. Epitrochlear involvement in HL, like in our case, is a rare event (<1%). We reviewed data about prognosis, clinical appearance, and treatment of all the cases of HL specific skin involvement published after Sioutos et al, emphasizing the cases where HL specific skin involvement was the first sign of the disease as in our patient.

Hypopigmented macules secondary to imatinib for the treatment of chronic myeloid leukemia: a histopathologic and immunohistochemical study.

BACKGROUND: A few series addressing the cutaneous side effects related to imatinib in the skin have been published, but only one described scarce histopathologic information in seven patients. OBJECTIVE: To characterize these lesions and compare the number of melanocytes between hypopigmented lesions and normal appearing skin. METHODS: We retrieved clinical data of the patients and performed 24 skin biopsies (13 from hypopigmented skin and 11 from normal-appearing skin) within a cohort of 41 patients with chronic myeloid leukemia treated with imatinib. We classified the biopsies into three patterns. RESULTS: About 45% of patients presented with periocular hypopigmentation. Perifollicular fibrosis was observed in hypopigmented skin biopsies (76.9%) and in normal-appearing skin (45.5%). Epidermal melanin, as determined with Masson-Fontana staining, and melanocyte number, as evaluated with MiTF, Melan A and c-kit immunostains, were lower in hypopigmented skin. CONCLUSIONS: Histopathologic study of hypopigmented macules demonstrates the presence of melanin with a statistically significant decrease in the number of melanocytes. Therefore, these findings differ from vitiligo, as melanocytes are present. Three histopathological patterns may be found, namely (a) perifollicular fibrosis, (b) lichen planopilaris-like and (c) apparently normal skin. One of the most striking histopathologic finding consisted of the presence of perifollicular fibrosis in both hypopigmented lesions and apparently normal skin.

Perforating folliculitis in a patient treated with nilotinib: a further evidence of C-kit involvement.

We present a case of perforating folliculitis in a patient treated with nilotinib, a kinase inhibitor. A 48-year-old man presented with a severely pruritic follicular rash for several months that started after reaching a complete molecular response of his myeloid chronic while treated with nilotinib. Clinical examination showed predominantly follicular pinpoint papules on trunk and proximal extremities and a biopsy showed a slightly dilated hair follicle with a focal disruption of the infundibular follicular epithelium. Other diseases related with perforating folliculitis were ruled out. The temporary relationship between the treatment and the appearance of the lesions suggests some pathogenic role of nilotinib. Relationship with nilotinib is also supported by previous similar cases related with sorafenib therapy. Both drugs inhibit c-kit and PDGF-R. PDGF-R has been previously involved in murine and human in vitro models of hair follicle cycle. So, our case supports in vivo the previous evidence of the importance of PDGF-R, a kinase, in the normal hair follicle development.