A neuroendocrine (Merkel) cell carcinoma with coexisting intraepidermal squamous cell carcinoma of the skin. Its growth accelerated by an extrinsic factor

A case of neuroendocrine (Merkel) cell carcinoma with coexisting intraepidermal squamous cell carcinoma of the skin was studied histologically, immunohistochemically and ultrastructurally as well as with tissue-culture and transplantation into nude mice. The primary tumor found in the lower leg of a 68-year-old Japanese man had remained thumb-sized for five years and, after contusion, had begun to enlarge rapidly up to 5 cm in size during one month. The patient died of metastatic neuroendocrine cell carcinoma nine months after excision of the primary tumor. Histologically the primary tumor was composed of neuroendocrine cell carcinoma extending down to subcutaneous adipose tissue and a small amount of intraepidermal squamous cell carcinoma, not associated with a wide range of necrosis, hemorrhage, granulation tissue or fibrosis. The tumor cells of the former were diffusely positive for neuron-specific enolase. They contained a few secretory granules, 100 nm in diameter. The tumor cells both cultured in media and transplanted into nude mice died two months later. The present case is the first report of Merkel cell carcinoma in which the growth accelerated by an extrinsic factor was proved. Histogenesis of neuroendocrine cell carcinoma with coexisting squamous cell carcinoma is also discussed.     

A NEUROENDOCRINE (MERKEL) CELL CARCINOMA WITH COEXISTING INTRAEPIDERMAL SQUAMOUS CELL CARCINOMA OF THE SKIN

A case of neuroendocrine (Merkel) cell carcinoma with coexisting intraepidermal squamous cell carcinoma of the skin was studied histologically, immunohistochemically and ultrastructurally as well as with tissue-culture and transplantation into nude mice. The primary tumor found in the lower leg of a 68-year-old Japanese man had remained thumb-sized for five years and, after contusion, had begun to enlarge rapidly up to 5 cm in size during one month. The patient died of metastatic neuroendocrine cell carcinoma nine months after excision of the primary tumor. Histologically the primary tumor was composed of neuroendocrine cell carcinoma extending down to subcutaneous adipose tissue and a small amount of intraepidermal squamous cell carcinoma, not associated with a wide range of necrosis, hemorrhage, granulation tissue or fibrosis. The tumor cells of the former were diffusely positive for neuron-specific enolase. They contained a few secretory granules, 100 nm in diameter. The tumor cells both cultured in media and transplantated into nude mice died two months later. The present case is the first report of Merkel cell carcinoma in which the growth accelerated by an extrinsic factor was proved. Histogenesis of neuroendocrine cell carcinoma with coexisting squamous cell carcinoma is also discussed.     

Merkel cell carcinoma presenting as a malignant pleural effusion post-COVID-19 hospitalization: A case report and literature review

Merkel cell carcinoma (MCC) is a rare, highly aggressive neuroendocrine carcinoma of the skin, associated with immunosuppression, UV light exposure, and the Merkel cell polyomavirus (MCPyV). Cases of metastatic MCC diagnosed in body fluid cytology are extremely rare; only five cases have been reported previously in the English literature. We present a case of a 65-year-old male with acute respiratory failure and an enlarged right pleural effusion. He had two hospitalizations for COVID-19 pneumonia 2 months prior, for which he received steroid treatment and tocilizumab. Emergent thoracentesis was done, with pleural fluid sent for cytologic evaluation. Both the Papanicolaou stained ThinPrep slide and cell block demonstrated clusters of predominantly small to medium sized blue round cells with hyperchromatic nuclei, scant cytoplasm and fine chromatin, in a background of rare mesothelial cells, macrophages and numerous lymphocytes. Tumor cells were positive for CD56, chromogranin, synaptophysin, SAT2B, MCPyV, and CK20 in perinuclear dot like pattern, while negative for TTF-1 and CD45 immunostains. Ki67 proliferative index was approximately 40%. The patient had a history of MCC of the right ulnar forearm 4 years before the current presentation, which was unknown to us at the time of cytologic evaluation. To the best of our knowledge, this is the sixth case of metastatic MCC diagnosed by fluid cytology and the first reported in a patient receiving immunosuppressive treatment for COVID-19. Further reporting of such cases may increase awareness, especially when prior history is not readily available, such as in our case.     

Metastatic renal cell carcinoma in a meningioma: a case report

Tumor-to-tumor metastasis is rare. We report a case of metastatic renal cell carcinoma in meningioma. A 67-year-old woman presented a two-week history of motor dysphagia and decreased short-term memory. She had undergone a left radical nephrectomy for a renal cell carcinoma 7 years ago, and had not received any adjuvant therapy. MRI disclosed a 3.0 x 3.0 x 3.0-cm sized round tentorial-based extraaxial mass with peritumoral edema in the left posterior temporal lobe. During operation, the tumor was found to be an encapsulated mass firmly attached to the tentorium. Histologically, the tumor was a meningotheliomatous meningioma extensively infiltrated by metastatic renal cell carcinoma, accompanying widespread coagulative necrosis. Immunohistochemical staining for cytokeratin revealed strong positivity only in the renal cell carcinoma component. The patient's postoperative course was uneventful. Post-operative radiation therapy was applied to the whole brain. Three months after operation, the patient developed right hemiparesis and dysphagia. Brain MRI at that time did not reveal recurrence or any other causative lesions, although the whole body scan disclosed uptake at the second lumbar vertebra and rib. The patient refused further treatment.     

Renal cell carcinoma metastatic to the testis and its adnexa: a report of five cases including three that accounted for the initial clinical presentation

Five cases of renal cell carcinoma metastatic to the testis or its adnexa are described, including 3 that represented the initial presentation and mimicked primary testicular neoplasms. The patients ranged from 46 to 85 years of age. Three presented with self-identified testicular masses. One patient was investigated because of fever of unknown origin and was found to have a left rib metastasis. Further work-up led to the discovery of a testicular mass. The final patient had a tumor of the spermatic cord that was examined without knowledge that he had a prior renal neoplasm. All the tumors were unilateral. They ranged from 1.8 to 5.0 cm; multiple tumor nodules were present in one of them but the others were discrete solitary masses. Four tumors were yellow/yellow-tan, and one was gray. On microscopic examination all the tumors were of the clear cell type. Patterns included solid sheets, acini, cysts, alveoli, and trabeculae. Two had prominent vascular invasion. Diagnoses initially entertained in these cases included Sertoli cell tumor, Sertoli-Leydig cell tumor, and clear cell cystadenoma of the epididymis. In 3 cases a kidney tumor was discovered 2 to 4 weeks after the diagnosis of renal cell carcinoma metastatic to the testis was rendered. On follow-up two patients died of tumor, and two were alive (5 months and 1 year) after orchiectomy. The diagnosis of renal cell carcinoma metastatic to the testis should be considered in evaluating a clear cell tumor of the testis, particularly in an older male or if the appearance suggests a Sertoli cell tumor. The differences in survival between metastatic renal cell carcinoma and sex cord-stromal tumors indicate the importance of considering the former in the differential.     

Merkel cell carcinoma with eccrine differentiation: a clinicopathologic study of 7 cases

We described 7 examples of Merkel cell carcinoma of the skin with eccrine and squamous differentiation. Five patients were men, and 2 were women; and their ages ranged from 63 to 81 years (mean age, 73 years). Six tumors arose in the head and neck; and one, on the sole of the right foot. Three tumors recurred locally, and 2 metastasized to the regional lymph nodes. No patient developed distant metastasis. Two patients died of unrelated causes. Five Merkel cell carcinomas showed classic cytology, and 2 were similar to small cell carcinomas of the lung. All 7 tumors showed small eccrine ducts, and 2 exhibited foci of squamous differentiation. The eccrine ducts label with cytokeratin 7 and carcinoembryonic antigen, whereas the predominant endocrine component displayed the characteristic paranuclear dot-like reactivity with cytokeratin 20 and was synaptophysin and chromogranin positive. The lymph node metastasis contained both eccrine ducts and squamous elements, suggesting that they are an integral component of the tumors. Eccrine differentiation in Merkel cell carcinomas similar to small cell carcinomas of the lung and extrapulmonary sites is an important feature in the differential diagnosis because eccrine differentiation has not been described in primary or metastatic small cell carcinomas. The prognosis of these Merkel cell carcinomas with divergent differentiation appears to be less aggressive than that of pure Merkel cell carcinomas. However, larger series of patients with longer follow-ups are needed to confirm this observation.     

Nuclear expression of survivin portends a poor prognosis in Merkel cell carcinoma.

Inhibition of apoptosis is a critical step in tumorigenesis in many cancers, including Merkel cell carcinoma; however, the exact regulatory mechanisms are not fully understood. Survivin is an inhibitor of apoptosis that is undetectable in most terminally differentiated normal human tissues, strongly expressed in embryonic and fetal organs and is strongly expressed in many different human cancers. In this study, we investigated the expression of survivin in cutaneous Merkel cell carcinoma using immunohistochemistry and correlated the findings with long-term clinical follow-up. We collected and immunostained 19 cases of Merkel cell carcinoma with antibodies to survivin. The median patient age was 79 years, with an average follow-up of 17 months, and a male/female ratio of 7:11. All but one sample represented primary lesions and two cases were obtained from one patient. Clinical follow-up was obtained in 15 cases (79%). All 19 cases of Merkel cell carcinoma demonstrated strong immunoreactivity for survivin. Survivin protein was localized and classified into predominately nuclear (N=8) or cytoplasmic (N=4) compartments. A mixed pattern of survivin expression was also seen in three cases. Cases with a nuclear staining pattern were distinguished by an aggressive clinical course, with seven of eight patients developing metastases or dead of disease on follow-up. Furthermore, all of the cases with predominately cytoplasmic survivin localization (N=4) were free of disease on follow-up. Merkel cell carcinomas represent aggressive malignancies regulated by apoptotic pathways. We demonstrate that survivin, a protein with a dual role in inhibition of apoptosis and regulation of cellular proliferation is expressed in Merkel cell carcinoma. Moreover, nuclear subcellular localization of survivin in Merkel cell carcinomas may portend a poor prognosis and identification of these cases may assist clinical management.     

Squamous cell carcinoma of the ovary

A 45-year-old woman developed a grade III and stage III squamous cell carcinoma of the left ovary 12 years after a hysterectomy for treatment of endometriosis. Origin from a teratoma or a Brenner tumor was excluded. Despite extensive surgery with additional radiation therapy and chemotherapy, the patient died five months after the malignancy was diagnosed. Squamous cell carcinoma of the ovary, either de novo or arising from endometriosis, has rarely been reported. We describe a case of ovarian squamous cell carcinoma in which endometriosis is strongly favored as the origin, but that remains speculative.     

Changing from cyclosporine to tacrolimus as salvage therapy for chronic graft-versus-host disease.

Chronic graft-versus-host disease (GVHD) is the principal cause of transplantation-related morbidity and nonrelapse mortality late after allogeneic hematopoietic stem cell transplantation. The safety and potential efficacy of tacrolimus for the salvage treatment of chronic GVHD was evaluated in a single-arm, open-label phase 2 study. A total of 39 evaluable patients with chronic GVHD who failed previous immunosuppressive therapy with cyclosporine and prednisone were treated with tacrolimus starting at a median of 20 months (range, 3-68 months) after transplantation. At 3 years after the start of treatment, 5 patients (13%) had discontinued tacrolimus and were in complete remission, and 3 were considered clinically stable but not able to discontinue tacrolimus. A total of 31 patients (79%) experienced treatment failure; 22 (56%) who failed therapy had a change in immunosuppressive regimen because of progression (n = 18) or toxicity (n = 4). Nine patients (23%) died during continued treatment with tacrolimus. Two patients were lost to follow-up, at 11 and 19 months. The median duration of treatment with tacrolimus was 9 months (range, 1-29 months). Infections (144 episodes) were the most frequent adverse event. Nephrotoxicity occurred in 16 patients (41%); tacrolimus was discontinued in only 2 patients because of progressive deterioration in renal function. The Kaplan-Meier estimate of survival was 64% (95% confidence interval, 49%-79%) at 3 years posttransplantation. Seven patients had discontinued all immunosuppression at last contact, leading to an estimated 29% probability of stopping all immunosuppression by 3 years posttransplantation. Four patients died after relapse of malignancy. The response rate is consistent with previous reports of salvage treatment for chronic GVHD, indicating that a small group of patients failing cyclosporine may respond or stabilize with tacrolimus.     

The spectrum of Merkel cell polyomavirus expression in Merkel cell carcinoma, in a variety of cutaneous neoplasms, and in neuroendocrine carcinomas from different anatomical sites

Most Merkel cell carcinomas display pure neuroendocrine differentiation (pure Merkel cell carcinoma), whereas a minority show combined neuroendocrine and nonneuroendocrine elements (combined Merkel cell carcinoma). Recent identification of Merkel cell polyomavirus DNA and Merkel cell polyomavirus large T antigen expression in a proportion of Merkel cell carcinomas has suggested viral-induced oncogenesis. To date, Merkel cell polyomavirus immunohistochemistry has shown an absence of viral large T antigen expression in combined Merkel cell carcinoma as well as select non-Merkel cell carcinoma cutaneous lesions and visceral neuroendocrine tumors. In our series, we aimed to further characterize the frequency and pattern of Merkel cell polyomavirus large T antigen expression by CM2B4 immunohistochemistry in primary and metastatic Merkel cell carcinoma (pure Merkel cell carcinoma and combined Merkel cell carcinoma) and various non-Merkel cell carcinoma lesions from patients with Merkel cell carcinoma, patients without Merkel cell carcinoma, and individuals with altered immune function. Merkel cell polyomavirus large T antigen was detected in 17 (63%) of 27 pure Merkel cell carcinomas and absent in all 15 (0%) combined Merkel cell carcinomas. Furthermore, complete concordance (100%) of Merkel cell polyomavirus large T antigen expression was observed in 10 cases of primary Merkel cell carcinoma and subsequent tumor metastases. We also evaluated 70 non-Merkel cell carcinoma lesions including 15 cases each of pulmonary and gastrointestinal neuroendocrine tumors. All 70 non-Merkel cell carcinoma lesions were negative for Merkel cell polyomavirus by CM2B4 immunohistochemistry, irrespective of any known Merkel cell carcinoma diagnosis and immune status. In summary, our identification of Merkel cell polyomavirus large T antigen expression in a subset of Merkel cell carcinoma and lack of findings in combined Merkel cell carcinomas and non-Merkel cell carcinoma lesions concur with earlier findings and implicate Merkel cell polyomavirus-independent pathogenesis in these cases. Overall, CM2B4 immunohistochemistry appears to be a specific method for Merkel cell polyomavirus detection and has the potential to play an important role in the diagnosis and classification of Merkel cell carcinoma in the future.     

Merkel cell carcinosarcoma: Merkel cell carcinoma with embryonal rhabdomyosarcoma-like component

Merkel cell carcinoma is an uncommon primary neuroendocrine neoplasm of the skin that may exhibit divergent differentiation. However, rhabdomyosarcomatous differentiation has only been rarely described and takes the form of isolated rhabdomyoblasts. We describe a case of cutaneous Merkel cell carcinoma with biphasic morphology imparted by discrete patches of embryonal rhabdomyosarcoma-like spindle cells alternating with islands of neuroendocrine small round cells, justifying a designation of "Merkel cell carcinosarcoma." The former component showed positive immunostaining for desmin and myogenin; and the later component, pan-cytokeratin, cytokeratin 20, synaptophysin, and chromogranin. The patient was an elderly man who presented with a temporal skin mass, and the biphasic morphology was evident in the recurrence and metastasis that developed 2 months after incomplete excision of the skin lesion.     

Lung transplantation for bronchiolitis obliterans after allogeneic hematopoietic stem cell transplantation

Bronchiolitis obliterans (BO) is a late onset complication of allogeneic hematopoietic stem cell transplantation (HSCT), and treatment outcome is dismal if it does not respond to immunosuppressive therapy. A 21-year-old male diagnosed with acute myeloid leukemia received an allogeneic HSCT from human leukocyte antigen- identical sibling donor. Twenty one months after transplantation, he developed progressive dyspnea and was diagnosed BO. Despite standard immunosuppressive therapy, the patient rapidly progressed to respiratory failure and Novalung® interventional lung-assist membrane ventilator was applied in the intensive care unit. Three months after the diagnosis of BO, the patient underwent bilateral lung transplantation (LT) and was eventually able to wean from the ventilator and the Novalung®. Since the LT, the patient has been under a strict rehabilitation program in order to overcome a severe lower extremity weakness and muscle atrophy. Histologic findings of the explanted lungs confirmed the diagnosis of BO. Nine months after the LT, the patient showed no signs of rejection or infectious complications, but still required rehabilitation treatment. This is the first LT performed in a patient with BO after allogeneic HSCT in Korea. LT can be an effective therapy in terms of survival for patients with respiratory failure secondary to development of BO following HSCT.     

Small cell carcinoma of the kidney: a clinicopathologic study of 14 cases

Small cell carcinoma of the kidney is distinctively rare. We searched pathology files in 2 institutions and found 14 cases of renal small cell carcinoma. The patients' mean age at diagnosis was 59 years (range, 22-75 years); 8 were women, and 6 were men. Patients usually presented with hematuria (n = 6) and abdominal pain (n = 5). The mean tumor size was 7.1 cm (range, 3.5-14.0 cm). The small cell carcinoma was pure in 9 cases and mixed with high-grade urothelial carcinoma in 5 cases. None was associated with any type of renal cell carcinoma. Tumor necrosis was present in all cases, and lymphovascular invasion was identified in 6 cases. The tumor invaded the perinephric adipose tissue in 13 cases and was confined to the kidney in only 1 case. Lymph node metastases were identified in all patients who underwent lymph node dissection (5/5). On immunostains, the small cell carcinoma cells were positive for pancytokeratin (11/12), chromogranin (6/9), and synaptophysin (8/9). Follow-up data were available for 13 patients, and 11 died of small cell carcinoma at a mean of 15 months (range, 4-31 months) after diagnosis. Of the 2 surviving patients, 1 was alive at 5 months after diagnosis, and the other, whose disease was confined to the kidney, was alive with no evidence of disease at 137 months. In summary, renal small cell carcinoma is a highly aggressive disease that often presents at an advanced stage with widespread metastases. Patients usually have a poor clinical outcome despite multimodal therapy. The frequent coexistence of small cell carcinoma with urothelial carcinoma suggests that renal small cell carcinomas may evolve from a preexisting urothelial carcinoma.     

Angiosarcoma of the kidney with minute clear cell carcinomas: A case report

A case of renal angiosarcoma with minute clear cell carcinomas in a 61-year-old male is described. The tumor was clinically considered a renal cell carcinoma. The lesion, removed by nephrectomy, was an unencapsulated hemorrhagic mass measuring 8.0 cm in diameter. The tumor was histologically characterized by anastomosing vascular channels lined by cytologically atypical endothelial cells. The tumor cells reacted positively with CD31, factor-VIII related antigen, and CD34. A few minute clear cell carcinomas measuring less than 1 mm were observed in the periphery of the angiosarcoma. There was no transition between angiosarcoma and renal cell carcinoma. The patient died of a widespread disease 13 months after surgery. This tumor is considered a primary renal angiosarcoma with clear cell carcinomas and not a sarcomatoid carcinoma.     

A review of the epidemiology and treatment of Merkel cell carcinoma

Merkel cell carcinoma is a very rare and aggressive neoplasm. Due to its rarity, therapeutic guidelines are not well established, especially for regionally advanced disease. Articles in English, French, Italian, Portuguese, and Spanish from the last 20 years were identified in MEDLINE and reviewed. The key word "Merkel" was used for the search, relevant articles were selected, and their references were examined. The most important articles related to epidemiology, genesis and treatment were reviewed. The incidence of Merkel cell carcinoma is increasing due to the advancing age of the population, higher rates of sun exposure and an increasing number of immunocompromised individuals. With regard to etiology, the recently described Merkel Cell polyomavirus is thought to play a role. Either local or regional surgical intervention remains the standard of care, but adjuvant radiotherapy or radiotherapy as a primary treatment have been discussed as reasonable therapeutic options. An update on this rare neoplasia is essential because of its increasing incidence and changing treatment options.     

A Case Series of Post-Transplantation Cyclophosphamide in Unrelated Donor Hematopoietic Cell Transplantation for Aplastic Anemia

Patients with severe aplastic anemia (SAA) who fail immunosuppressive therapy have a dismal prognosis. Hematopoietic stem cell transplantation (HSCT) from an unrelated donor (URD) is one of the most effective treatment options. Two institutions have independently adopted a post-transplantation cyclophosphamide (PTCy) approach for patients with SAA undergoing HSCT from a URD. Thirteen patients were included, 11 of whom had been treated with immunosuppressive therapy. Eight patients had a mismatched URD. All patients were conditioned with fludarabine, cyclophosphamide, and total body irradiation, in various dosage combinations. PTCy was given at a dose of 100 mg/kg. Two patients died, and overall survival was 85% at 2 years. All patients engrafted, but 1 patient developed secondary graft failure. Of the 11 patients alive after 2 years, 9 had complete donor chimerism. All surviving patients were transfusion-independent. Ten patients (77%) had cytomegalovirus reactivation, and 2 patients had more than 1 reactivation. No Epstein-Barr virus reactivation or post-transplantation lymphoproliferative disease was observed. Four patients had mild hemorrhagic cystitis. In summary, our findings show that PTCy is a promising treatment for patients with SAA undergoing URD HSCT.     

Sarcomatoid Renal Cell Carcinoma Metastatic to the Heart: Report of a Case

An unusual case of metastatic sarcomatoid renal cell carcinoma is presented. Fifteen months after nephrectomy for a typical clear cell carcinoma, a 63-year-old man presented with bilateral pleural effusions, cardiomegaly, and tamponade. A pericardial biopsy showed an anaplastic spindle cell tumor that was strongly keratin positive and showed desmosomes ultrastructurally. The patient died shortly thereafter, and the autopsy revealed massive tumor infiltration of the heart, pulmonary and adrenal metastases, and tumor nodules at the incision site of his nephrectomy. The differential diagnosis of sarcomatoid renal cell carcinoma is discussed.