Preferential association of human papillomavirus with high-grade histologic variants of penile-invasive squamous cell carcinoma.

BACKGROUND: Human papillomavirus (HPV) is causally associated with cervical squamous cell carcinoma (SCC) and its precursor lesions. By analogy, HPV is believed to play a role in penile cancer through progression of HPV-associated penile squamous intraepithelial lesions (SIL). HPV DNA has been reported to be present in 100% of high-grade penile SIL, but the percentage of invasive or infiltrating penile SCC that was positive for HPV DNA has varied from study to study (positivity values ranging from 32% to 82%). PURPOSE: To ascertain whether HPV is associated with penile cancer, we used a polymerase chain reaction (PCR)-based assay to test specimens of penile SCC for the presence of HPV DNA. METHODS: A total of 117 formalin-fixed, paraffin-embedded specimens of penile cancer from an equal number of patients who had been diagnosed either at the Memorial Sloan-Kettering Cancer Research Center in New York City between 1964 and 1992 or the Universidad Nacional de Asunción in Paraguay between 1980 and 1992 were analyzed. Specimens were examined without prior knowledge of the histology of the lesions. Methods were used that minimized sample contamination, thus avoiding false-positive results. PCR and Southern blot analyses were used to determine HPV type. The presence of HPV DNA was studied for association with the tumor properties histopathology, growth pattern, tumor grade, regional lymph node status, and anatomic location. Two-sided statistical tests were used to determine P values. RESULTS: HPV DNA was detected in 26 (22.2%) of 117 specimens. In 23 (88.5%) of the 26 HPV-positive specimens, HPV type 16 (only) was identified. HPV DNA was frequently associated with SCC in areas showing basaloid and/or warty changes (nine [47.4%] of 19 specimens were HPV positive; P = .0125). More highly significant was the association of virus with basaloid SCC (nine [75%] of 12 specimens were HPV positive; P = .0005). However, HPV was not found to be associated with typical SCC of the penis (five [11.1%] of 45 specimens were HPV positive). Virus DNA was more often associated with high-grade tumors (P = .0278) exhibiting aggressive growth (P = .0382) localized to the glans penis (P = .0324). Stepwise logistic regression analysis revealed that only tumor histopathology was a significant predictor of an HPV association. CONCLUSIONS: The presence of HPV DNA was found to be significantly associated only with those penile SCC exhibiting basaloid changes. Furthermore, HPV DNA sequences tended to be associated with higher grade and more aggressive tumor localized to the glans penis. The low frequency of HPV in penile SCC implies that only a small proportion of these cancers arise from HPV-associated penile SIL.

Morphological patterns of primary nonendocrine human pancreas carcinoma.

The study of histological sections of 406 cases of nonendocrine pancreas carcinoma at Memorial Hospital indicated that morphological patterns of pancreas carcinoma could be delineated as follows: duct cell adenocarcinoma (76%), giant-cell carcinoma (5%), microadenocarcinoma (4%), adenosquamous cancinoma (4%), mucinous adenocarcinoma (2%), anaplastic carcinoma (2%), cystadenocarcinoma (1%), acinar cell carcinoma (1%), carcinoma in childhood (under 1%), unclassified (7%). In 195 cases of patients with pancreas carcinoma, search was made for changes in the pancreas duct epithelium and these were compared to duct epithelium in a control group of 100 pancreases from autopsies of patients with nonpancreatic cancer. The following incidences were found for pancreas cancer and nonpancreatic cancer, respectively: mucous cell hypertrophy, 39 versus 28%; pyloric gland metaplasia, 28 and 17%; epidermoid metaplasia, 6 and 12%; papillary hyperplasia, 42 and 12%; atypical duct hyperplasia, 14% and none; cancinoma in situ in 19% and none in the control group. Mucin in the majority of pancreas cancers suggested that the cell type of origin of the common pancreas cancer is the mucin-producing duct epithelium. The association of atypias and carcinomas in situ in the patients with pancreas carcinoma implies, by analogy to other organs, that there may be a significant latent period between the appearance of carcinoma in situ and the grossly recognizable pancreas cancer.

Morphological lesions associated with human primary invasive nonendocrine pancreas cancer.

In 227 cases of human pancreas cancer (100 pancreatectomy specimens and 127 autopsies), pancreas duct epithelium not involved by invasive cancer was examined. Pancreas duct epithelium from 100 autopsies of patients with nonpancreatic cancer, matched by age and sex to the pancreas cancer autopsy cases, was used for control studies. The prevalence of squamous metaplasia, pyloric gland metaplasia, mucous hypertrophy, and focal epithelial hyperplasia was not greatly different in the two groups. Ductal papillary hyperplasia was three times more prevalent in pancrease cancer than in controls. Marked atypia occurred in 20%, and carcinoma in situ, in 18% of the pancreas cancer cases, but neither change was seen in the control cases. It is possible that focal epithelial hyperplasia was a precursor change but that it was overgrown by the cancer. Papillary hyperplasia could not be properly evaluated as a precursor lesion because of duct obstruction, but practically all cases of marked atypia and carcinoma in situ occurred in papillary lesions. Marked atypia and carcinoma in situ, by analogy to other cancers, would appear to be precursor lesions, and their presence in association with invasive cancer lends hope to the possibility that there is a significant, recognizable, in situ phase of the disease before invasive cancer occurs.

Microadenocarcinoma of the pancreas--morphologic pattern or pathologic entity? A reevaluation of the original series.

The term microadenocarcinoma was first proposed for a subtype of pancreatic carcinoma by Cubilla and Fitzgerald in 1975 based largely on the morphological features of 15 cases. Since that time, no independent studies have appeared in the English literature to address whether microadenocarcinoma represents a distinctive tumor or a pattern of growth, and some authors have questioned its existence as a definable entity. Immunohisto-chemistry is now available to allow the identification of lines of differentiation in pancreatic neoplasms, on which their classification is largely based. Reasoning that heterogeneity of differentiation between different cases would not justify the separation of microadenocarcinomas from other better defined pancreatic neoplasms, we reevaluated 12 cases from the original series using antibodies for acinar, endocrine, and ductal differ-entiation. Two distinctive morphological patterns were identified: microglandular and solid cribriform. The microglandular cases (n = 6) were not separable from typical ductal adenocarcinomas either morphologically or immunophenotypically. Of the solid-cribriform cases (n = 6), immunohistochemistry revealed three to be acinar cell carcinomas, one an endocrine carcinoma, one a mixed endocrine-ductal carcinoma, and one a ductal adenocarcinoma. We concluded that with the benefit of further study, most of these cases could be reclassified as other types of pancreatic carcinoma. Microadenocarcinoma is best regarded as a pattern of growth associated with an aggressive clinical course rather than a distinctive entity.

Pathologic features of epidermoid carcinoma of the penis. A prospective study of 66 cases.

We report a whole-organ-section pathologic study of 66 cases of epidermoid carcinoma of the penis. Specimens were divided into three compartments: glans (G), coronal sulcus (COS), and foreskin (F) with 24, 4, and 12 histologic sections each. Four types of carcinomas were found: (a) superficially spreading (42%), a biphasic infiltrating and extensive carcinoma in situ usually involving more than one compartment and radially growing along the surface of G, BPS, F, or even urethra; (b) vertical growth (32%), unifocal high-grade, deeply invasive neoplasms with minimal or no carcinoma in situ component; (c) verrucous (18%), low-grade papillary or endophytic; and (d) multicentric (8%), two or more independent primary tumors separated by non-neoplastic mucosa. Inguinal lymph node metastasis were found in 82, 42, and 33% of pathologic types vertical growth, superficially spreading, and multicentric carcinomas, respectively; verrucous tumors did not show metastasis. The morphologic diversity of penile cancer may be related to different causative factors. Metastatic involvement suggests a distinctive biological behavior of the tumor. The widespread extension of superficially spreading and multicentric carcinomas to anatomical compartments indicate penile mucosa as one "field" prone to malignant transformation. These findings may be important for the selection of appropriate therapy and emphasize the need for a close follow-up of patients undergoing less than a complete removal of the three compartments.

Surface adenosquamous carcinoma of the penis. A report of three cases.

Three patients, aged 37, 72, and 74 years, with adenosquamous carcinoma of the penis are described. The duration of disease was 6, 9, and 144 months, respectively. Grossly a firm, white-gray granular exophytic mass was noted (7.6 cm average diameter). Microscopically, a mixed carcinoma showing squamous and glandular elements was present; the squamous component predominated. In two cases the adenocarcinoma was located in the perimeatal area of the glans. The periurethral glands were not involved. The glandular foci were discrete and had minimal admixture with the squamous carcinoma. Mucin material was present in the lumina, apical border, and cytoplasm. Immunohistochemically, cells showed positivity for carcinoembryonic antigen in glandular areas. The squamous cell carcinomas were of the "warty" variant in two cases and of the usual squamous cell type in the other case. In one patient, metastatic adenosquamous carcinoma was noted in one inguinal node and showed mucin secretion. This patient is alive and well 102 months after diagnosis. Another patient is alive with no evidence of disease 12 months after surgery, and the third was lost to follow-up. Adenosquamous carcinomas of the penis are unusual neoplasms probably originating in penile surface epithelium and in embryologically misplaced mucus glands of the perimeatal region of glans mucosa.

Extra-adrenal paragangliomas of the retroperitoneum: A clinicopathologic study of 12 tumors.

The clinical and pathologic features of 12 extra-adrenal paragangliomas of the retroperitoneum are presented. The patients (eight men, four women) had an average age of 43 years at the time of diagnosis; three had symptoms related to excess catecholamine secretion. Complete surgical resection was attempted in each case but was possible for only four patients. Five tumors were malignant; four patients died from regional and/or distant metastases 17 months to 10 years after surgery. One patient was alive with metastatic paraganglioma 25 years after initial treatment. Each patient with metastatic or locally recurrent paraganglioma had incomplete resection of the primary tumor. An important microscopic feature of each paraganglioma was the presence of cytoplasmic argyrophilia. Three of the five metastasizing paragangliomas showed readily identifiable mitoses or evidence of vascular invastion; the two other cases and all of the benign tumors lacked these features. Our findings suggest that in some cases histology may prove helpful in evaluating the malignant potential of these tumors.

Anatomic levels: important landmarks in penectomy specimens: a detailed anatomic and histologic study based on examination of 44 cases.

The majority of squamous cell carcinomas of the penis arise from the glans, and the prognosis is related significantly to the depth of invasion of crucial anatomic landmarks. Accurate information related to this can only be obtained when specimens are carefully evaluated grossly. Most pathologists in developed countries encounter resected specimens of penile carcinoma infrequently, and gross evaluation is occasionally suboptimal, potentially preventing obtaining reliable prognostic information. The four distinct levels of the glans penis are the epithelium, lamina propria, corpus spongiosum, and corpus cavernosum. A simple method for pathologic evaluation of the glans is presented. Noteworthy findings in our study of a South American population were that the distance from the lamina propria to tunica albuginea ranged from 7 to 13 to 6 mm at the dorsal, central, and ventral areas of the corpus spongiosum, respectively. The most distal portion of the corpus cavernosum was located within the glans in 34 of 44 cases and in the body of the penis in only 10. The corpus spongiosum was thinner in the former cases. These anatomic variations may bear on prognosis.

Warty (condylomatous) squamous cell carcinoma of the penis: a report of 11 cases and proposed classification of 'verruciform' penile tumors.

Within the spectrum of penile squamous cell carcinomas, those that we descriptively refer to collectively as the "verruciform" lesions are particularly difficult to subclassify. In a review of 50 such tumors, we found 11 distinctive neoplasms with condylomatous features conforming to the appearance of so-called "warty (condylomatous) carcinoma." The average patient age was 55 years and the average duration of disease was 19 months. The primary tumor involved multiple anatomic sites (glans, coronal sulcus, and foreskin) in seven cases and a single site (glans or foreskin) in four cases. Grossly, white to gray cauliflower-like tumors typically measuring approximately 5 cm were noted. Histologically the tumors were mainly papillomatous with acanthosis and hyperkeratosis. The papillae had prominent fibrovascular cores. The most conspicuous microscopic findings were striking nuclear atypia of koilocytotic type and clear cytoplasm. The interface between tumor and stroma was irregular in the majority of cases; deep invasion of corpus cavernosum was noted in five cases. The differential diagnosis included verrucous carcinoma, low-grade papillary squamous cell carcinoma, not otherwise specified, and giant condyloma acuminatum. Among other differences, the first two lesions show no koilocytotic changes and the last lacks malignant features and irregular stromal invasion. Metastatic spread occurred in two patients; both are alive with evidence of recurrent disease 12 and 72 months after initial diagnosis. A third patient was alive with recurrent disease 12 months after diagnosis. Five patients were free of disease 8, 12, 24, 52, and 108 months after diagnosis. Three patients were lost to follow up. Warty (condylomatous) carcinomas of the penis are morphologically distinctive verruciform neoplasms with features of human papillomavirus-related lesions and should be distinguished from other verruciform tumors so that differences in behavior, if any, between these tumors will become established.

Basaloid squamous cell carcinoma: a distinctive human papilloma virus-related penile neoplasm: a report of 20 cases.

Most penile neoplasms are squamous cell carcinomas (SCC), but there are subtypes that show morphologic and possibly etiologic differences. Clinicopathologic features of 20 patients with basaloid carcinoma (BC), an unusual variant of squamous cell carcinoma, are presented. Median age was 52 years, and all tumors were located in the glans, three confined to the perimeatal region. Average tumor size was 3.8 cm. Microscopically, nests of small, basophilic cells with numerous mitosis were present. Human papillomavirus DNA sequences (type 16), using the polymerase chain reaction (PCR), were found in 9 of 11 cases. Differential diagnosis included urethral transitional cell, basal cell, small cell neuroendocrine, and metastatic carcinoma. Factors more significantly associated with regional metastasis and mortality were tumor thickness greater than 10 mm and infiltration of the corpus cavernosum. A comparison with typical squamous cell carcinoma showed basaloid carcinoma to have a higher histologic grade, a deeper invasion of penile anatomic levels, and a higher mortality rate. Of 17 patients observed, 10 were dead of disease (average time, 34 months), one was alive with disease 6 months after diagnosis, and 5 were alive and free of disease (average time, 71 months); the remaining patient died of other causes. Basaloid carcinoma is a distinctive morphologic subtype of squamous cell carcinoma frequently associated with the human papilloma virus.

Solitary fibrous tumor of the thyroid gland: report of seven cases.

Solitary fibrous tumor is a soft tissue neoplasm initially described in the pleura but subsequently reported in a wide variety of locations. The clinical behavior is usually benign, but the existence of aggressive cases has been documented both in the pleura and in extrapleural sites. In this report clinical and pathologic features of seven solitary fibrous tumors of the thyroid gland are presented. Patients' ages ranged from 43 to 64 years (mean 52 years), and tumor sizes varied from 2 to 6 cm. Grossly, the tumors were white-tan and well circumscribed. Microscopically, there was a variegated, wavy, storiform, hemangiopericytic or desmoid-like arrangement of spindle cells. Trapped thyroid follicles within the tumor and peripheral jagged tumor infiltration among follicles were common. There was immunohistochemical reactivity for CD34, CD99, and bcl-2, and ultrastructural analysis of one tumor was consistent with a fibroblastic lineage. The differential diagnosis included other benign and malignant mesenchymal tumors of the thyroid, spindle cell follicular adenoma, Riedel's thyroiditis, the spindle cell, and paucicellular variants of anaplastic carcinoma, papillary thyroid carcinoma with exuberant nodular fasciitis-like stroma, and the spindle epithelial tumor with thymus-like differentiation. The cumulative data of 13 cases (comprised of the seven present cases and the six previously reported) suggest a benign clinical behavior for thyroid SFT.

Classification of pancreatic cancer (nonendocrine).

From the records of 757 patients listed as having had pancreatic cancer at Memorial Hospital during the years 1949 through 1972, adequate clinical data and pathologic tissue were available for study in 508 patients. Review of these cases led to a histologic classification into 11 subcategories and one unclassified group. The most common type was the duct cell adenocarcinoma (75%), and the remaining subgroups each made up less than 5% of the total. All except one of the subtypes were well-known carcinoma patterns that occur in other organs. A small-gland carcinoma, the microadenocarcinoma, has not usually been associated with the pancreas. Some types were associated with short survival periods of a few months after diagnosis--for example, duct cell, giant cell, acinar cell, and adenosquamous carcinomas and microadenocarcinoma. Patients with mucinous carcinoma had a mean survival period of a few months longer, and the few patients with mucinous cystadenocarcinoma had a much longer median survival. Two rare types--papillary cystic tumor and pancreaticoblastoma--are mentioned and illustrated. It is hoped that one or more of these types can be associated with an etiologic agent, some clinical feature, or responsiveness to a therapeutic regimen.

Paragangliomas of the head and neck region. A pathologic study of tumors from 71 patients.

The histopathology of 72 paragangliomas originating in the head and neck region of 71 patients is presented. There were 45 carotid body, 13 vagal body, eight jugulotympanic, and three nasal paragangliomas. In addition, two arose in the larynx and one in the area of the aortic arch. Tumors occurred in four unrelated families. The two most important histologic features leading to a diagnosis of paraganglioma were zellballen and the presence of cytoplasmic argyrophil granules in all cases in which staining with the Grimelius technique was carried out. Ultrastructural study of three carotid body and two vagal body paragangliomas revealed both light and dark chief cells. Tumor cells contained membrane bound, electron dense neurosecretory types of granules, which usually ranged in diameter from 120 to 200 nm. Follow-up information was available for 67 patients (94 per cent). Two of the three nasal paragangliomas, 50 per cent of the jugulotympanic paragangliomas, 17 per cent of the vagal body paragangliomas, and 10 per cent of those of the carotid body recurred locally following attempted surgical resection. All patients treated with radiation had persistent tumor. Four (9 per cent) of the carotid body paragangliomas were malignant, all four patients dying with widespread metastases. One vagal body paragangliomas metastasized to regional lymph nodes (the patient was alive and well at five years), and another caused death by direct intracranial extension. In contrast to the benign tumors, malignant paragangliomas tended to show foci of necrosis and vascular invasion. Mitotic figures, which usually were not identified in the benign cases, were seen in all malignant tumors.

Histologic classification of penile carcinoma and its relation to outcome in 61 patients with primary resection.

A retrospective review of the clinical and pathologic features of 61 cases of penile squamous cell carcinoma (SCC), all treated by primary surgical resection at the Memorial Sloan Kettering Cancer Center during the period 1949-1992, was undertaken. Inguinal lymph node dissection material was evaluated in 40 cases. All carcinomas were of squamous cell type and were classified as follows: usual type, 36 cases (59%); papillary, not otherwise specified (NOS), 9 cases (15%), basaloid, 6 cases (10%); warty (condylomatous), 6 cases (10%); verrucous, 2 cases (3%), and sarcomatoid, 2 cases (3%). A high rate of nodal metastasis and poor survival were found for the basaloid and sarcomatoid neoplasms (5 of 7 patients with metastasis, 71%, and 5 of 8 dead of disease, 63%). Only 1 patient with a verruciform tumor (defined as a tumor of nonspecific papillary, warty, or verrucous type) had inguinal node metastasis and none died from penile cancer. An intermediate rate of metastasis and mortality (14 of 26, 54%, and 13 of 36, 36%, respectively) was found for typical SCC. Penile carcinomas are morphologically heterogeneous, and there is a correlation of histologic type and biologic behavior. This mandates accurate histologic subtyping by the pathologist.

Morphological features of epithelial abnormalities and precancerous lesions of the penis.

There is a heterogenous spectrum of abnormalities and atypical lesions in the penile epithelium. The terminology used to designate precursor lesions is variable but squamous intraepithelial lesions of low and high grade or penile intraepithelial neoplasia I, II and III are the recommended terms. Other probable precursor lesions are squamous hyperplasia and bowenoid papulosis. Low- and high-grade squamous intraepithelial lesions may be classified into squamous or simplex, the most frequent types, or warty (condylomatous) and basaloid. There is a striking morphological correspondence between precancerous lesions of the penis and their respective invasive lesions. The presence of two groups of lesions in the precancerous as well as invasive carcinomas, the squamous typical and the warty basaloid, is consistent with the bimodal hypothesis of the existence of non-HPV (the typical squamous) and HPV-related (warty or basaloid) tumors.

Human papillomavirus prevalence and type distribution in penile carcinoma.

BACKGROUND: Penile carcinoma is an uncommon and potentially mutilating disease with a heterogeneous aetiology. Several risk factors have been established for its development. Human papillomavirus (HPV) infection seems to play an important role in the development of a subset of these carcinomas and its presence is thought to be related to the histological type. HPV prevalence in penile tumours is reported to be associated to a variety of morphological changes. Its determination will provide a better estimate for HPV related cancer burden and its preventable fraction. METHODS: A systematic and comprehensive literature review of the major penile cancer studies published from 1986 until June 2008 evaluating the HPV prevalence among the different histological types was carried out. RESULTS: 31 studies including 1466 penile carcinomas were reviewed. Global HPV prevalence was 46.9%. Relative contribution was: HPV-16 (60.23%), HPV-18 (13.35%), HPV-6/11 (8.13%), HPV-31 (1.16%), HPV-45 (1.16%), HPV-33 (0.97%), HPV-52 (0.58%), other types (2.47%). Assessment of multiple infections contribution is limited due to study design. Basaloid and warty squamous cell carcinomas were the most frequent HPV-related histological types, but keratinising and non-keratinising subtypes also showed prevalence rates of around 50%. CONCLUSIONS: About half of the penile tumours were associated with HPV 16-18 with little presence of other genotypes. Research on the mechanisms behind penile carcinogenesis is warranted. Available HPV vaccines are likely to be effective in penile tumours.

Islet cell carcinoma of the pancreas.

Thirty cases of islet cell carcinoma of the pancreas diagnosed at Memorial Hospital were studied. There were 17 male and 13 female patients. The average age was 44 years. Most of the tumors were located in the body or tail of pancreas; in 25 instances, the primary tumor was larger than 6 cm. Epigastric pain, hypoglycemia, and jaundice were frequent primary clinical presentations. No morphological differences were found between functioning and nonfunctioning tumors. Size of tumor, local tissue infiltration, and vascular invasion were helpful; but they were not absolute parameters aiding in the differentiation of benign and malignant tumors. Twenty-six patients had metastatic disease at time of diagnosis. Liver, regional lymph nodes, bones, and peritoneum were common sites of metastases. The average survival was 3.9 years. The cumulative five-year survival rate was 65%.