Teratomas excluding monodermal teratomas

9 I] [:Ifli[lt,'l I J i l l

PATHOLOGY Mini-symposium: germ cell tumours of the ovary (part II)

Teratomas excluding monodermal teratomas

P. B. Clement and R. H. Y o u n g

IMMATURE TERATOMA

are frequently present, and rarely, one or more large cysts occupy most of the specimen. Grossly evident dermoid cysts can be identified in approximately 25% of cases. 6 The solid areas, which are usually predominantly composed of neural tissue, are typically soft, fleshy, and gray to pink, and may be focally haemorrhagic or necrotic. Areas of bone and cartilage may be visible or palpable. Bilateral involvement is very rare in the absence of extraovarian spread, but the opposite ovary harbours a dermoid cyst or less often another benign tumour in approximately 10% of the cases. 6 The sine qua non for the diagnosis of immature teratoma is the presence of at least some immature tissue resembling that of the normal embryo; the amount of such tissue varies from rare loci to a predominant component. Most or all of the immature tissue is immature neuroectodermal tissue (Fig. 1), usually in the form of neuroepithelial rosettes and tubules, cellular foci of mitotically active glia, and in occasional cases, small areas resembling glioblastoma or neuroblastoma. The neuroepithelium may be pigmented. Immature or embryonal epithelium of various types, both ectodermal and endodermal, including hepatic tissue, 8,9,13 as well as immature mesenchymal elements, such as cartilage and

Clinical features Although only 3% of ovarian teratomas are immature, they account for almost 20% of primitive germ cell tumours and for 10-20% of ovarian cancer in the first two decades, the age group in which these tumours typically occur.14 There is usually a palpable abdominal or pelvic mass, frequently accompanied by pain. Rarely, an immature teratoma is preceded by an ipsilateral dermoid cyst that was resected months to years previously; the risk of an immature teratoma in such patients may be increased if the dermoid cysts are bilateral, multiple, or associated with rupture. 5,6 Two-thirds of the patients with immature teratomas have an elevated serum level of alpha-fetoprotein (AFP) at presentation, although the levels are usually lower than those encountered in patients with yolk sac tumours. 7-9 Occasional patients have had an elevated HCG, sometimes associated with sexual pseudoprecocity. 1~ As many as one-third of the tumours have extraovarian spread at the time of operation, usually in the form of peritoneal implants, less commonly nodal metastases, and rarely, hematogenous metastases. 24,8,1~ The risk of extraovarian implants may be increased in tumours that have ruptured or those with adhesions. 11,12

Pathological features Immature teratomas are usually large (medial diameter, 18 cm) encapsulated masses, although capsular rupture is encountered in almost half the casesJ 1'a2 The sectioned surfaces are predominantly solid but small cysts containing mucinous, serous, or bloody fluid or hair Philip B. Clement, MD, Vancouver Hospital and Health Sciences Centre and the University of British Columbia, Department of Pathology and Laboratory Medicine (Anatomical Pathology), Vancouver, British Columbia. Robert H. Young, MD, the James Homer Wright Pathology Laboratories of the Massachusetts General Hospital and the Department of Pathology, Harvard Medical School, Boston, USA. Current Diagnostic Pathology (1995)2, 208-213 9 1995PearsonProfessionalLtd

Fig. I--Immature teratoma. Neuroepithelial tubules surrounded by cellular glial tissue. H&E. 208

are

TERATOMAS EXCLUDINGMONODERMALTERATOMAS 209

Differential diagnosis

Fig. 2--Peritoneal gliomatosis involving omental fat. H&E.

skeletal muscle, are also common. Mature tissues identical to those encountered in mature teratomas are typically present. Uncommon findings include immature renal tissue, JI syncytiotrophoblastic giant cells (SGC), and yolk-sac-like tissue. <)Nogales et al H have described two unusual immature teratomas composed predominantly of endodermal structures without neuroectodermal elements. Primary and metastatic immature teratomas are histologically graded by the amount of immature tissue, which is usually neural. Accurate grading obviously depends on thorough sampling of the tumour, which is at least one block per cm of lumour diameter. Grade 1 has been applied to tumours with rare foci of immature neural tissue, occupying less than one low-power field (LPF) per slide, grade 2 lo tumours with moderate quantities of immature neural tissue, occupying more than 1 but 3 or fewer LPF per slide, and grade 3 to {umours with large quantities of inlmature neural tissue, occupying 4 or more LPF per slide) O'Connor and Norris 15 have recenily proposed a two-grade system, in which grade 1 is left unchanged but grades 2 and 3 (which have a similar behaviour) are combined. Rarely, immature teratomas, as well as mature solid teratomas, are associated with peritoneal implants composed exclusively or mainly of mature ('grade 0') glial tissue ('peritoneal gliomatosis') (Fig. 2). i1-12 i(, Mature epithelial elements or mature cartilage are also occasionally present. In occasional cases, the glial implants have been intimately admixed with f'oci of endometriosis, j7 Similar glial tissue is sometimes encountered in pelvic and para-aortic lymph nodes, either in association with peritoneal implants or in their absence, s,~2 It is important to sample the implants generously as immature implants may co-exist with mature implants. The neuroectodermal tissues are immunoreactive for one or more of a variety of neural markers, although their demonstration is rarely necessary for diagnosis. AFP-immunoreactivity in immature teratomas is typically confined to hepatic tissue, yolk-sac-like vesicles, and intestinal-type epithelium. ~j'~3 SGC, if present, are immunoreactive for HCG.

Distinction from mature solid teratomas (see below) is based on the identification of even minor loci of immature tissue; predominantly solid teratomas should therefore be extensively sampled to exclude immature loci. The presence of fetal type tissue such as cartilage and developing cerebral cortex and cerebellum is not diagnostic of immature teratoma; brain tissue normally continues to develop with mitotic activity into the early postnatal months. The presence of microscopic immature foci in an otherwise typical dermoid cyst (see below) should not lead to a diagnosis of immature teratoma. Distinction from neuroectodermal tumours is discussed elsewhere in this mini-symposium (see Monodermal teratomas, mini-symposium (part Ili)). Malignant mesodermal mixed turnouts, in contrast to immature teratomas, typically occur in older women, are almost always composed of only mesodermal elements, and contain loci of obvious adenocarcinoma; cartilage, if present, usually resembles chondrosarcoma.

Prognosis Before the use of combination chemotherapy the survival of patients with high grade immature teratomas, particularly of those with high grade implants, was poor. In contrast, almost all of the patients in subsequent studies treated with combination chemotherapy have had a sustained remission. I a,~0.1s Chemotherapy is typically followed by disappearance of high grade implants with the remaining implants composed cxchisively of mature tissue, necrotic turnout, or fibrous tissue, or combinations thereof. Mature implants may continue to grow and occasionally inwide local structures, requiring reopcraiion ('growing teratoma sy ndrome'). *-Js- e,~ (Figs 3 & 4). Patients who present with exclusively mature implants, which as noted above are typically glial, almost always have a benign clinical course even with-

Fig. 3--Recurrent teratoma ('growing teratoma syndrome'). The patient had a stage III immature teratoma of the ovary treated by oophorectomy and chemotherapy. Shortly therafter, this large solid and cystic pelvic mass developed. The cysts were filled with mucinous material. The same case is illustrated in Figure 4.

210 CURRENTDIAGNOSTICPATHOLOGY

Fig. 4--Recurrent teratoma ('growing teratoma syndrome'). The mass illustrated in Figure 3 consists entirely of mature (grade '0') tissues on microscopic examination. In this field respiratory and mucinous epithelium are separated by smooth muscle. H&E. out postoperative treatment. 12,~6Rare cases of malignant transformation of mature peritoneal gliomatosis have been reported. 16,21 SOLID M A T U R E T E R A T O M A This tumour is composed exclusively of mature elements and is solid or predominantly solid. In four small unselected series, it accounted for 15-20% of solid teratomasY -25 The tumour has the same age distribution as the immature teratoma, and in contast to dermoid cysts, is rarely, if ever, seen after the menopause. The occasional patients who have had mature peritoneal glial implants at presentation are younger than those without implants (mean age, 12 years vs 19 years). 12 All of the reported patients, including those with mature implants, have had a benign clinical course, 1~with the exception of one in whom the adequacy of sampling of the tumour was questionable. 26 The macroscopic appearance is similar to that of the immature teratoma except that soft, necrotic, and haemorrhage loci are much less common. Mature tissues representing all three germ layers are present, and mature glial tissue may be the predominant element. Mitotic figures are absent or exceedingly rare. The differential diagnosis is mainly with immature teratomas (see above). D E R M O I D CYST (MATURE C Y S T I C TERATOMA)

Clinical features Dermoid cysts are the most common ovarian tumour, accounting for up to 44% of them and for up to 58% of benign ovarian tumours. 27'2s Over 80% of the tumours occur during the reproductive years, but they are also found in children, accounting for up to half the ovarian neoplasms in the first two decades. 29 Some tumours are not detected until years after the menopause. Dermoid cysts are often associated with the typical symptoms and signs of benign ovarian tumours, although

in some series as many as 60% of them have been asymptomatic. 3~ A radiological diagnosis can be made in a high proportion of cases? ~ Dermoid cysts are prone to a variety of complications and may be associated with a number of unique clinical manifestations. As many as 15% of them undergo torsion; infarction, perforation, haemoperitoneum, and autoamputation, alone or in combination, may be secondary complications in these c a s e s . 30-33 Infection of the cyst occurs in approximately 2% of cases; the organisms may reach the ovary by lymphatic, haematogenous, or direct routes. Perforation into the peritoneal cavity or a hollow viscus, a complication more likely to occur during pregnancy, is encountered in l - 2 % of the cases. A slow leakage into the abdominal cavity results in a localized or generalized granulomatous peritonitis, which may mimic metastatic carcinoma or tuberculosis at operation. Sudden rupture rarely leads to an acute abdominal crisis with shock related to the expulsion of the irritating cyst contents into the peritoneal cavity. Rarely, cysts rupture into the urinary bladder, vagina, or bowel, or through the anterior abdominal wall, leading to unusual manifestations that have included the passage of hair, teeth, bony fragments, or gas in the urine, the formation of urinary calculi containing hair or teeth, and the passage of hair, teeth, or even the intact cyst through the vagina or rectum. Four cases of pigmentation of the peritoneum ('melanosis'), have been associated with dermoid c y s t s ; 34-37 in two of these cases the cysts had ruptured pre-operatively. At laparotomy, focal or diffuse, tan to black, peritoneal staining or similarly pigmented, turnout-like nodules were encountered within the pelvis, and in some cases, the omentum. Rare dermoids have been associated with a haemolytic anaemia that disappears after removal of the tumour. 38

Pathological features Dermoid cysts are bilateral in approximately 15% of the cases, and are occasionally multiple in o n e o v a r y . 6 The typical gross features include contents of yellow to brown sebaceous material and hair, a lining that resembles skin, and one or more rounded, polypoid masses (mamillae or Rokitansky's protuberances) usually composed predominantly of fat. Teeth are present in onethird of the cases, either in the cyst wall or cavity; occasionally they are embedded in a rudimentary mandible or maxilla. Bone, cartilage, mucinous cysts, adipose tissue, thyroid, and soft brain tissue may be seen grossly. Rarely, partially developed organs such as bowel, appendix, skull, vertebrae, limb buds, external genitalia, and eyes, may be present. Some of the locules within the dermoid cysts associated with peritoneal melanosis have had pigmentation of their contents and lining. The tumours are composed of adult-type tissues, usually representing all three germ layers, which are sometimes arranged in an organoid fashion. Microscopic foci of immature or fetal-type tissues, however, have been encountered rarely in otherwise typical dermoid cysts, and appear to have no prognostic significance. 6

TERATOMAS

Ectodermal derivatives predominate in almost all the cases, including keratinized epidermis, sebaceous and sweat glands, hair follicles, and neuroectodermal elements. The latter typically consist of glial and peripheral nervous tissue, but cerebrum, cerebellum, and choroid plexus are also relatively common. The last tissue may sometimes be confused with a papillary carcinoma. Mesodermal derivatives in the form of smooth muscle, bone, teeth, cartilage, and fat, are usually present. Common endodermal derivatives include respiratory and gastrointestinal epithelium and salivary gland tissue. Rare tissues include retina, pancreas, thymus, adrenal, pituitary, kidney, lung, breast, and prostate. Respiratory epithelium and glial tissue occasionally line portions of the cyst. Mitotic figures are absent or rare. Rare, presumably secondary, changes that have been encountered in the tissues within dermoid cysts include compound naevi, thyroiditis, lactational changes within breast tissue, dental caries, and peptic ulceration within gastric mucosa. Focal cyst rupture may result in a foreign-body inflammatory reaction to keratin, hair, or to the oily cyst contents. The latter incites a characteristic lipogranulomatous response in the wall of the cyst or the surrounding ovarian tissue, in which variably sized, clear

--7" "

EXCLUDING

MONODERMAL

TERATOMAS

211

spaces are surrounded by inflammatory ceils, including histiocytes and foreign-body type giant cells, often accompanied by dense fibrosis (Fig. 5). 39 In the cases of peritoneal melanosis, the ovarian and peritoneal pigmentation consists of pigment-laden histiocytes within a fibrous stroma (Fig. 6). The source of the pigment and its precise nature (although considered melanin in some reports) is not clear. 37

M A T U R E T E R A T O M A S WITH S E C O N D A R Y TUMOUR As many as 2% of mature teratomas have harboured a cancer of adult type, accounting for approximately 1% of all ovarian cancers in some series, a~ In the most recent large study, however, malignant transformation was found in only 0.17% of dermoid cysts) ~ Over 75% of the cases, and an even higher proportion of the squamous cell carcinomas, have been detected between the ages of 30 and 70 years, with most patients between 40 and 60 years. 4~ The clinical presentation varies from that of a typical dermoid cyst to that of an advanced ovarian cancer, depending on the extent of the secondary tumour. Malignant change in a dermoid cyst should be suspected at the time of laparotomy, especially in women over the age of 40 years, when the cyst is adherent to surrounding structures or has areas of nodularity, thickening of the wall, haemorrhage, or necrosis. In many cases, the tumour has spread throughout the abdomen or to adjacent organs by the time of operation. Haematogenous metastases have been associated with sarcomas more often than with carcinomas.

Pathological features

2

5 - - L i p o g r a n u l o m a t o u s reaction in the wall of a dermoid cyst. Note clear spaces surrounded by histiocytes, including f o r e i g n - b o d y - t y p e giant cells. H&E.

Fig.

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Fig. 6 - - M e l a n o s i s peritonei. Pigmentation of the peritoneum was noted at the time of o o p h o r e c t o m y for a d e r m o i d cyst. Note b r o w n granular p i g m e n t in histiocytes.

Dcrmoid cysts harbouring a malignant tumour tend to be larger than typical dermoid cysts, with over 90% of them between 10 and 2 0 c m in maximal dimension, a~ Squamous cell carcinomas and other forms of cancer may appear as cauliflower-like masses protruding into the cavity of the cyst, as a mural nodule or plaque, or if extensive, a solid tumour mass that almost obliterates the dermoid cyst. Foci of haemorrhage and necrosis within the malignant component are common. Smaller cancers may not be apparent on gross examination. In all of the reported cases the cancer has been unilateral, although a dermoid cyst without malignant change has been present in the opposite ovary in 10-15% of the cases. 4~ Approximately 80% of malignant tumours arising in dermoid cysts have been squamous cell carcinomas, almost always invasive, but rarely in situ. 4~ Rarely, the invasive squamous cell carcinoma takes the form of a spindle cell carcinoma. Hirakawa et a142 found that the squamous cell carcinoma usually arises from columnar epithelium or metaplastic squamous epithelium rather than from epidermis. If one excludes carcinoid tumours, tumours of thyroid-type, neuroectodermal turnouts, and sebaceous tumours (see Monodermal teratomas, minisymposium (part II1)), the remainder of the tumours arising in dermoid cysts have been adenocarcinomas,

212

CURRENT DIAGNOSTIC PATHOLOGY

i n c l u d i n g P a g e t ' s disease, a d e n o s q u a m o u s c a r c i n o m a s , u n d i f f e r e n t i a t e d c a r c i n o m a s i n c l u d i n g small cell c a r c i n o ma, s a r c o m a s ( f i b r o s a r c o m a , l e i o m y o s a r c o m a , c h o n d r o s a r c o m a , o s t e o s a r c o m a , m a l i g n a n t fibrous h i s t i o c y t o m a , r h a b d o m y o s a r c o m a ) , and m a l i g n a n t m e l a n o m a s . 4~ P r o o f of origin of a malignant m e l a n o m a within a dermoid cyst requires an a b s e n c e o f an extrauterine primary m e l a n o m a a n d the p r e s e n c e o f j u n c t i o n a l activity w i t h i n the e p i d e r mis o f the cyst. Rare e x a m p l e s o f l y m p h o m a or basal cell c a r c i n o m a arising w i t h i n d e r m o i d c y s t s h a v e also b e e n e n c o u n t e r e d , 4~ a n d rare b e n i g n t u m o u r s h a v e i n c l u d e d A C T H or p r o l a c t i n s e c r e t i n g pituitary a d e n o m a s 4446 and h a e m a n g i o m a s 47,48

Prognosis T h e 5 - y e a r survival rates for p a t i e n t s w i t h s q u a m o u s cell c a r c i n o m a c o n f i n e d to the o v a r y (stage I) w a s 7 7 % in o n e study, in c o n t r a s t to 11% in t h o s e w i t h e x t r a o v a r i a n spread. 42 P r o g n o s t i c factors for stage I s q u a m o u s cell c a r c i n o m a s in the s a m e study i n c l u d e d t u m o u r g r a d e and the p r e s e n c e o f v a s c u l a r invasion. W e l l d i f f e r e n t i a t e d tumours

were associated with a 78%

survival rate,

w h e r e a s n o n e o f the p a t i e n t s w i t h m o d e r a t e l y or p o o r l y d i f f e r e n t i a t e d t u m o u r s survived. All the patients w i t h o u t v a s c u l a r i n v a s i o n survived, w h e r e a s all o f t h o s e w i t h v a s c u l a r i n v a s i o n d i e d f r o m their disease. A d e n o c a r c i n o m a s h a v e a b e h a v i o u r similar to that o f s q u a m o u s cell c a r c i n o m a s . 49 In contrast, a l m o s t all patients w i t h sarcom a s h a v e d i e d o f t u m o u r . 4~176 A p p r o x i m a t e l y h a l f o f the p a t i e n t s w i t h m a l i g n a n t m e l a n o m a s w i t h f o l l o w - u p data h a v e d i e d f r o m t u m o u r p r o g r e s s i o n . 52

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