Pulmonary neuroendocrine neoplasms: A review of clinicopathologic and cytologic features

Neuroendocrine tumors form a distinct group of lung neoplasms sharing characteristic cytohistologic, immunohistochemical, ultrastructural, and molecular features. The objective of this review article is to discuss the diagnostic classifications and the morphologic cytologic–histologic features for the different categories of neuroendocrine tumors of the lung. An accurate characterization of the neuroendocrine tumors of the lung requires knowledge of specific criteria separating the major categories, which is highly essential for determining prognosis and treatment options for these patients. Diagn. Cytopathol. 2010;38:607–617. 2009 Wiley‐Liss, Inc.     

头颈部小圆细胞恶性肿瘤临床特点分析

目的 探讨头颈部小圆细胞恶性肿瘤的临床、影像学、病理特点,为临床早期诊断提供理论依据。方法 回顾青岛大学附属医院耳鼻咽喉科2008年6月~2018年5月诊治的组织病理学特点为小圆细胞的恶性肿瘤290例患者的病历资料,总结其临床特点、影像学及病理特点。结果 ①头颈部小圆细胞恶性肿瘤主要好发于鼻腔、鼻窦、鼻咽及颅底区,耳及喉部极少见,可向颅内、眼眶等临近部位浸润,也可转移至颈部淋巴结或远处转移。临床症状以鼻塞、鼻出血、嗅觉减退等为主;②小细胞神经内分泌癌和非角化性癌以男性多见,恶性黑色素瘤和小细胞神经内分泌癌见于40岁以上的中老年人群。横纹肌肉瘤各年龄段均可发生;③所有肿瘤影像学上均可见软组织占位及骨质破坏,病理组织形态学均表现为分化差的小圆细胞肿瘤。结论 头颈部小圆细胞恶性肿瘤发病率低,其发病部位及症状无明显特异性,病理学形态、影像学及临床特征多无明显特异性,难以鉴别,容易误诊。目前免疫组织化学检测仍是小圆细胞恶性肿瘤确诊的主要方法,而此类疾病恶性程度较高、侵袭性强,往往确诊时病变范围已较大,影响治疗及预后,早期诊断早期治疗可以提高患者生存率。     

Large Cell Neuroendocrine Carcinoma of the Ovary Associated with Serous Carcinoma with Mucin Production: A Case Report and Literature Review

Large cell neuroendocrine carcinoma (LCNEC) of the ovary is a rare entity and is frequently associated with ovarian surface epithelial tumors. However, its association with serous carcinoma has only been described recently in one case. We report another case of such with mucin production in a 68-year old woman. Immunohistochemistry and mucicarmine stain confirmed the diagnosis. Its clinicopathologic association is discussed and the literature is reviewed.     

Primary Small Cell Neuroendocrine Carcinoma of the Kidney: Morphological, Immunohistochemical, Ultrastructural, and Cytogenetic Study of a Case and Review of the Literature

Poorly differentiated neuroendocrine carcinomas (PDNECs) of the kidney are extremely rare high-grade cancers accounting for only 42 cases reported in the literature. In this paper, we describe the morphological, immunohistochemical, ultrastructural, and for the first time, cytogenetic features of a renal PDNEC. In addition, we have reviewed the literature and compared the published clinicopathological data with our morphological and genetic results. The tumor arose within the kidney parenchyma and showed the typical histological features of a pure small cell PDNEC. Fluorescence in situ hybridization study demonstrated a complex chromosomal assessment indicative of a high degree of chromosome instability with gain of multiple chromosomes, loss of p53, and amplification of myc gene. These results suggest that renal PDNEC has a different genetic background to renal clear cell carcinoma, mainly characterized by the loss of the short arm of chromosome 3. Conversely, genetic alterations seem to resemble those of type 2 papillary renal cell carcinoma. The review of the literature demonstrated that PDNECs are associated with poor prognosis and that parenchymal tumors show some differences from those arising in the pelvis, in that parenchymal tumors are purely neuroendocrine while pelvic tumors are mostly mixed neuroendocrine–exocrine neoplasms.     

Malignant Melanoma of Soft Parts Involving the Head and Neck Region: Review of Literature and Case Report

Malignant melanoma of soft parts (MMSP) was originally described as a distinct entity by Enzinger in 1965 and was termed “clear cell sarcoma of tendons and aponeuroses” because of its association with tenosynovial structures. It has been shown immunophenotypically and ultrastructurally that this tumor is derived from neuroectoderm and shares a number of features with cutaneous melanoma. Over 95% of MMSPs present in the extremities, with the head and neck region (1.9%) being an unusual site. This study presents an additional case of MMSP of the head and neck region involving the posterior cervical region in a 15-year-old Hispanic male and reviews the literature on MMSP. Ultrastructural examination showed rudimentary cell attachments, smooth cell membranes, discontinuous basal lamina, scanty glycogen, and occasional premelanosomes in some tumor cells. Cytogenetic analysis showed a reciprocal translocation between the long arms of chromosomes 12 and 22 [t(12:22)(q13;q12.2)], characteristic for MMSP and not seen in cutaneous melanoma. Survival in MMSP has been correlated with tumor size, tumor necrosis, and ploidy status. Overall reported clinical outcome for this tumor is as follows: died of disease, 45%; alive with disease, 23%; no evidence of disease, 30%; and died of other causes, 2%. MMSP represents a distinct entity with a characteristic ultrastructural appearance and a tumor defining cytogenetic translocation.     

Basaloid squamous carcinoma of the oesophagus: a distinct neoplasm with multipotential differentiation

AIMS: Basaloid squamous carcinoma (BSC) is an uncommon variant of squamous cell carcinoma, with its prevalent sites being the hypopharynx, tongue base and larynx. In the oesophagus, BSC is rarer than in the head and neck region. This study was aimed to document the clinicopathological features of BSCs of the oesophagus, and to present their relative incidence and immunohistochemical findings. METHODS AND RESULTS: Eighteen cases of BSC of the oesophagus, comprising 3.6% of 502 oesophageal carcinomas, were reviewed for their pathological and clinical features, and examined for the immunohistochemical expression of neuroendocrine markers, cytokeratins, p53, pRb and bcl-2. Oesophageal basaloid squamous carcinomas tended to be biphasic or multiphasic carcinomas, most commonly with basaloid and squamous components (eight cases), or with additional adenocarcinoma (three cases) or with small cell carcinoma (two cases). Each component was microscopically clearly distinguishable from the others, and metastasized separately, chiefly the basaloid component. The remaining five cases were apparently pure basaloid carcinomas, being characterized by lobules and nests of monotonous round undifferentiated cells with frequent comedo necrosis. They resembled, but were differentiated from, the small cell carcinoma on the basis of neuroendocrine markers and cytokeratin expression. p53, pRb and bcl-2 oncoprotein, which are known to normally present in the basal/parabasal cells of the oesophageal epithelium, were detected in 40-50% of cases, with a heterogeneous expression pattern. The patients were all male, with the age ranging 47-74 years (median 57) and presented at variable stages. The plotted 3 years survival rate was 51%, and the immunohistochemical expression of p53, pRb and bcl-2 was not related to the survival of the patients. CONCLUSION: Basaloid squamous carcinoma of the oesophagus is a peculiar neoplasm with a capacity of multidirectional differentiation, often with heterogeneous oncogene expression, probably reflecting the pluripotential stem cell origin.     

Neuroendocrine Carcinoma of the Skin (Merkel Cell Carcinoma): Ultrastructural and Immunohistochemical Demonstration of Neurofilaments

In this study we characterized a skin tumor that grew in the temporal region of a 69-year-old woman. On the basis of tumor morphology, a metastasis from a small cell carcinoma of the lung was initially suggested, but X-ray and bronchoscopic studies were negative. The tumor recurred twice within a year, yet no tumors were found elsewhere in the body. Ultrastructurally, cytoplasmic organelles compatible with neuroendocrine storage granules and perinuclear aggregates of intermediate-sized (8-10 nm) filaments were found in many tumor cells. Indirect immunofluorescence microscopy revealed neurofilament-type intermediate filaments in the tumor cells but no keratin-or vimentin-type filaments. Our results further demonstrate neural properties of this tumor type, which is generally considered to have its origin from Merkel cells, the cutaneous neuroendocrine cells.     

Neuroendocrine Carcinoma of the Skin (Merkel Cell Carcinoma): Ultrastructural and Immunohistochemical Demonstration of Neurofilaments

In this study we characterized a skin tumor that grew in the temporal region of a 69-year-old woman. On the basis of tumor morphology, a metastasis from a small cell carcinoma of the lung was initially suggested, but X-ray and bronchoscopic studies were negative. The tumor recurred twice within a year, yet no tumors were found elsewhere in the body. Ultrastructurally, cytoplasmic organelles compatible with neuroendocrine storage granules and perinuclear aggregates of intermediate-sized (8–10 nm) filaments were found in many tumor cells. Indirect immunofluorescence microscopy revealed neurofilament-type intermediate filaments in the tumor cells but no keratin-or vimentin-type filaments. Our results further demonstrate neural properties of this tumor type, which is generally considered to have its origin from Merkel cells, the cutaneous neuroendocrine cells.     

A study of eleven cutaneous malignant melanomas in adults with small-cell morphology: emphasis on diagnostic difficulties and unusual features

AIMS: To describe the clinicopathological and immunohistochemical features of cutaneous malignant melanomas with a pure or mixed small-cell pattern in 11 adult patients, and to discuss the diagnostic difficulties encountered. METHODS AND RESULTS: Haematoxylin and eosin-stained sections of each case of cutaneous small-cell malignant melanoma, together with locally recurrent skin lesions and, where available, metastatic deposits, were re-examined. Available immunohistochemical sections were evaluated. Clinical follow-up data were obtained in each case. One patient presented with metastatic disease, the others presented with cutaneous lesions. Suggested initial diagnoses included malignant melanoma, non-Hodgkin's lymphoma, Merkel cell carcinoma and sarcoma. All the tumours were in the vertical growth phase. Nine had a junctional component, often inconspicuous. The lesions showed either a pure small-cell pattern or a mixed pattern with more conventional areas. In one case, there was colonization of a basal cell carcinoma by invasive malignant melanoma. Variable retention of small-cell morphology in local recurrences and metastases was observed, although in some cases more typically pleomorphic cells were present. In the cases tested, there was strong immunostaining for S100 protein and NKI-C3, and variable immunostaining for HMB45 and Melan-A. Non-melanocytic markers were negative. CONCLUSIONS: The possibility of a small-cell malignant melanoma should be considered in the assessment of cutaneous and non-cutaneous small-cell neoplasms. The correct diagnosis requires careful evaluation for junctional activity, melanin production and the use of a panel of melanocytic markers.     

Recurrent Intrapulmonary Malignant Small Cell Tumor of the Thoracopulmonary Region with Metastasis to the Oral Cavity: Review of Literature and Case Report

Malignant small cell tumor of the thoracopulmonary region (MSCT) was first described in 1979 and has been referred to as the Askin tumor. This malignant neoplasm is a member of the peripheral primitive neuroectodermal tumor (PPNET) family and typically involves the periosteum, soft tissue, and extrapulmonary tissue of the thoracic wall. MSCT may also involve the lung parenchyma by local extension or may arise de novo in peripheral lung tissue. Local recurrence, abdominal involvement by tumor extravasation across the diaphragm, and skeletal metastatic disease are relatively common. However, metastasis to the head and neck region and in particular to the oral cavity is extremely rare. We present a recurrent intrapulmonary MSCT with metastasis to the oral cavity in an adolescent Hispanic boy, and review the literature regarding this member of the PPNET family. Differentiation from neuro-blastoma may be made based on immunoreactivity for β₂ microglobulin and HBA71 and lack of immunoreactivity for chromogranin in PPNET and MSCT. Ultrastructural features commonly seen in MSCT and PPNET are round to ovoid tumor cells with occasional cytoplasmic processes with relatively few pleomorphic dense core granules. These tumors lack the gangliocytic and Schwann cell differentiation that is characteristic of neuroblastoma. MSCT and PPNET have a common reciprocal cytogenetic translocation [t(11;22)q(24;q12)], which is shared with Ewing's sarcoma. Prognosis in MSCT is quite dismal, with a 2-year survival of 38% and a 6-year survival of only 14%.     

Recurrent Intrapulmonary Malignant Small Cell Tumor of the Thoracopulmonary Region with Metastasis to the Oral Cavity: Review of Literature and Case Report

Malignant small cell tumor of the thoracopulmonary region (MSCT) was first described in 1979 and has been referred to as the Askin tumor. This malignant neoplasm is a member of the peripheral primitive neuroectodermal tumor (PPNET) family and typically involves the periosteum, soft tissue, and extrapulmonary tissue of the thoracic wall. MSCT may also involve the lung parenchyma by local extension or may arise de novo in peripheral lung tissue. Local recurrence, abdominal involvement by tumor extravasation across the diaphragm, and skeletal metastatic disease are relatively common. However, metastasis to the head and neck region and in particular to the oral cavity is extremely rare. We present a recurrent intrapulmonary MSCT with metastasis to the oral cavity in an adolescent Hispanic boy, and review the literature regarding this member of the PPNET family. Differentiation from neuro-blastoma may be made based on immunoreactivity for β₂ microglobulin and HBA71 and lack of immunoreactivity for chromogranin in PPNET and MSCT. Ultrastructural features commonly seen in MSCT and PPNET are round to ovoid tumor cells with occasional cytoplasmic processes with relatively few pleomorphic dense core granules. These tumors lack the gangliocytic and Schwann cell differentiation that is characteristic of neuroblastoma. MSCT and PPNET have a common reciprocal cytogenetic translocation [t(11;22)q(24;q12)], which is shared with Ewing's sarcoma. Prognosis in MSCT is quite dismal, with a 2-year survival of 38% and a 6-year survival of only 14%.     

Metastatic mixed acinar‐neuroendocrine carcinoma of the pancreas to the liver: A cytopathology case report with review of the literature

A case of metastatic mixed acinar‐neuroendocrine carcinoma (MANEC) of the pancreas to the liver is reported. A diagnostic percutaneous US‐guided FNA and core biopsy of a liver nodule was performed. The FNA smears were cellular and showed neoplastic cells in clusters with acinar formation, isolated single cells, and scattered naked nuclei. The cytoplasm was finely granular. The nuclei were relatively uniform, some with speckled chromatin and prominent nucleoli. The immunohistochemistry performed on the cell block showed strong positivity for cytokeratin AE1/AE3, chromogranin, and synaptophysin. Furthermore, the tumor cells were weakly positive for α1‐antichymotrypsin. The Ki‐67 mitotic index was up to 50%. Based on the morphology and supporting immunohistochemical stains, the final cytopathologic diagnosis rendered was “Positive for malignant cells. Carcinoma with mixed acinar and endocrine features.” To our knowledge, this is the first report of a metastatic MANEC to the liver diagnosed based on cytology with confirmatory histology. The difficulties in the cytopathologic diagnosis and differential diagnosis of MANEC are discussed in this article. Diagn. Cytopathol. 2013. © 2011 Wiley Periodicals, Inc.     

Clinicopathologic and molecular aspects of high-grade neuroendocrine carcinoma of the uterine cervix: emphasis on novel chemotherapeutic strategies

High-grade neuroendocrine carcinomas (HGNEC) of the cervix are rare and carry an extremely poor prognosis. Fortunately, there have been recent advances in our molecular understanding of these carcinomas and some advances offer novel therapeutic options. The vast majority of HGNEC of the cervix are associated with human papillomavirus (HPV) and would be prevented by currently available vaccines. TP53 mutations are variably identified and likely drive a second pathway, one unrelated to high-risk HPV. Most carcinomas express VEGF and some patients have seen durable response to therapy with the addition of a VEGF inhibitor. PIK3CA mutations are among the most common mutations identified and mTOR inhibitors may be considered in these cases. KRAS mutations can be identified; an impressive response to MEK inhibitors has been seen in one case. PD-L1 positivity is frequently seen and complete responses to PD-1/PD-L1 inhibitors have been reported. These molecular advances offer numerous approaches to targeted personalized therapy.     

Correlation of Choline/Creatine and Apparent Diffusion Coefficient values with the prognostic parameters of Head and Neck Squamous Cell Carcinoma

The aim of this study was to measure choline/creatine (Ch/Cr) levels through ¹H‐MRS and apparent diffusion coefficient (ADC) values through diffusion‐weighted MRI, and to correlate these values with the prognostic parameters of head and neck squamous cell carcinoma (HNSCC). The institutional review board approved this study and informed written consent was obtained from all study participants. A prospective study of 43 patients (31 men and 12 women; mean age, 65 years) with HNSCC was conducted. Single‐voxel ¹H‐MRS was performed at the tumor or metastatic cervical lymph node with point‐resolved spectroscopy (PRESS) at TE = 135 ms. Diffusion‐weighted MR images with b values of 0, 500 and 1000 s/mm² and contrast MRI of the head and neck were performed. The Ch/Cr levels and ADC values of HNSCC were calculated. The gross tumor volume (GTV) was also calculated. The degree of tumor differentiation was determined through pathological examination. The HNSCC Ch/Cr level was negatively correlated with the ADC value (r = ?0.662, p = 0.001). There was a significant difference in the Ch/Cr and ADC values at different degrees of tumor differentiation (p = 0.003 and p = 0.001) and with different GTVs (p = 0.122 and p = 0.001). The following prognostic parameter categories were used: (i) poorly differentiated and undifferentiated versus well differentiated to moderately differentiated; and (ii) HNSCC with GTV < 30 cm³ versus GTV > 30 cm³. The cut‐off values for Cho/Cr and ADC for each category were 1.83, 0.95 and 1.94, 0.99, respectively, and the areas under the curve were 0.771, 0.967 and 0.726, 0.795, respectively, for each category. We conclude that the Ch/Cr levels determined using ¹H‐MRS and the ADC values are well correlated with several prognostic parameters of HNSCC. Copyright © 2016 John Wiley & Sons, Ltd.     

Peripheral Nerve Sheath Tumors of the Thyroid Gland: A Series of Four Cases and a Review of the Literature

Primary peripheral nerve sheath tumors (PNSTs) of the thyroid gland are exceptionally rare. Two schwannomas and two malignant PNSTs (MPNSTs), arising primarily within the thyroid gland, were identified in the files of the Endocrine Tumor Registry at the Armed Forces Institute of Pathology. The patients included two females, age 69 and 80 yr, and two males, age 18 and 33 yr. The patients presented with a mass in the thyroid gland confined to a single lobe of the thyroid without involvement of the cervical neck region. None of the patients had a history of neurofibromatosis. The benign tumors were encapsulated, one of them cystic, with the characteristic cellular and nuclear features of schwannomas. The MPNSTs were invasive tumors, effacing the thyroid parenchyma, with a fascicular pattern of growth composed of neural appearing cells with increased cellularity, increased mitotic activity and with focal necrosis. Immunoreactivity for S-100 protein and vimentin was seen in all tumors. The patients with schwannomas, treated only by surgical resection, were alive without evidence of disease, over a period of 5–33 yr. Both patients with MPNSTs died of the disease 8 mo and 42 mo, respectively, with widely disseminated disease. Primary thyroid PNSTs are exceptionally rare tumors. MPNSTs, in this limited experience, have a fatal outcome irrespective of aggressive adjuvant therapy. This work was presented at the 85th Annual Meeting of the US and Canadian Academy of Pathology, Washington, DC, March 1996.     

Small cell carcinoma of the prostate expressing prostate-specific antigen and showing syndrome of inappropriate secretion of antidiuretic hormone: an autopsy case report

An autopsy case of primary small cell carcinoma (SCC) of the prostate in a 68-year-old man is reported. The patient was admitted to hospital because of a bloody stool and suspected rectal cancer. However, a diagnosis of prostate cancer was made on the basis of a digital rectal examination, the serum level of prostate-specific antigen, and a needle biopsy of the prostate. The patient also experienced a syndrome of inappropriate secretion of antidiuretic hormone. He died 29 days after admission. At autopsy, the tumor had invaded the rectum, bladder and pelvic peritoneum. Metastases to the heart, vertebrae and lymph nodes were observed. Microscopically, the tumor was composed of small round cells that showed a solid growth pattern. Rosette formations were observed. Immunohistochemically, the tumor cells were positive for a prostatic epithelial marker and neuroendocrine markers. A high level of antidiuretic hormone was detected in the tumor tissue. To our knowledge, this is the first reported case of SCC of the prostate in which both a prostatic epithelial marker and neuroendocrine markers have been found in the same tumor. This finding supports the hypothesis that SCC of the prostate originates from a multipotential stem cell of the prostatic epithelium.     

Collision tumor of the esophagus: report of a case with mixed squamous cell carcinoma and gastrointestinal stromal tumor

Esophageal cancer is mainly divided into squamous cell carcinoma and adenocarcinoma. Epidemiologically, the former contributes to 90% of worldwide esophageal cancer cases, while adenocarcinoma contributes to two-thirds of cases in developed countries. Although other rare types and collision with multiple histological types of tumors do occur in the esophagus, it is very rare for a gastrointestinal stromal tumor (GIST) to collide with an epithelial malignant tumor. To date, only three cases have been reported in the literature. The current study reported a 69-year-old male patient with squamous cell carcinoma and GIST in the middle esophagus. There was no merging of tissue components between these tumors. This study together with a literature review indicates that esophageal collision tumors have been increasingly reported in recent years. Histology and immunohistochemistry are needed to make a differential diagnosis. The exact oncogenic mechanism or the interaction of two independent neoplasms still remains to be determined, and further investigation, such as electron microscopy and genetic analysis, may help to elucidate the pathogenesis of the colliding tumors.     

Fine‐needle aspiration cytology in the diagnosis of malignant proliferating trichilemmal tumor: Report of a case and review of the literature

Malignant proliferating trichilemmal tumor is a rare cutaneous neoplasm derived from the outer root sheath of the hair follicle. Fine‐needle aspiration cytology is being increasingly used in the investigation of primary and metastatic cutaneous tumors. However, there are few reports on the cytology of trichilemmal tumors in the literature. We describe the cytological features of this uncommon adnexal tumor presenting as a scalp mass in a 58‐year‐old woman. In view of its aggressive biological behavior, it is crucial for cytologists to be aware of this rare lesion and distinguish it from primary cutaneous squamous‐cell carcinoma. The differences on fine‐needle aspiration cytology can be subtle and pose problems in diagnosis. Diagn. Cytopathol. 2009. © 2009 Wiley‐Liss, Inc.