UNUSUAL PRESENTATION OF METASTATIC CARCINOMA TO THE EYE Tatyana Milman, MD,*† Codrin Iacob, MD,* Richard B. Rosen, MD,† Gault M. Farrell, MD,‡ Stuart A. Quinn,§ Ben Z. Cohen, MD,¶ Steven A. McCormick, MD*†
Purpose: To describe four patients with an unusual presentation of metastatic carcinoma to the eye, diagnosed by histopathologic and immunohistochemical evaluation of vitrectomy material. Methods: Retrospective case series of four patients with metastatic carcinoma to the retina/vitreous. The New York Eye and Ear Infirmary database was searched to identify patients with metastatic carcinoma to the retina or vitreous, diagnosed from 1995 to 2006. Diagnoses were established through histopathologic and immunohistochemical evaluation of vitreous fluid obtained via pars plana vitrectomy. Results: The New York Eye and Ear Infirmary Pathology database search resulted in 19,149 vitrectomy specimens, 4 of which were positive for metastatic carcinoma. The diagnosis was clinically unsuspected in three patients. The oncologic work-up revealed the origin of metastases to be from the breast in two patients and from the lung in two patients. Conclusion: Metastatic carcinoma to the eye can present with clinically innocuous metastases, masquerading as epiretinal membrane and macular hole, central serous chorioretinopathy, rhegmatogenous retinal detachment, retinal granuloma, and endophthalmitis. These findings suggest that submission of vitrectomy specimens for pathologic evaluation should be considered in patients with an oncologic history or in those with atypical clinical presentation. RETINAL CASES & BRIEF REPORTS 4:65– 69, 2010
From the *Department of Pathology and Laboratory Medicine, The New York Eye and Ear Infirmary; †Department of Ophthalmology, The New York Eye and Ear Infirmary; ‡Eye Care for the Adirondacks, New York; §Retina Associates of New York PC; and ¶The New York Eye and Ear Infirmary, New York, New York.
known history of cancer suggests the diagnosis of metastatic disease, the lack of these findings makes the accurate clinical diagnosis challenging. Herein, we report our experience with four patients with metastatic carcinoma to the eye, diagnosed through histopathologic and immunohistochemical examination of the vitreous fluid. The diagnosis was unsuspected in three of the patients, and two patients presented with clinically unapparent metastases.
A
lthough metastases to the choroid are regarded as the most common intraocular malignancy, metastatic carcinoma to the retina/vitreous is extremely rare. Approximately 22 cases of isolated retina/vitreous metastases appear in the literature.1– 4 Review of these reports shows that, although the clinical presentation of a retinal mass or of a white retinal infiltrate in association with vitreous cells in a patient with a
Materials and Methods Search of the pathology database at the New York Eye and Ear Infirmary from January 1995 through January 2006 revealed 19,149 vitrectomy specimens. Six of these, coded with an additional diagnosis of “metastases” or “carcinoma,” were selected for review. Institutional Review Board/Ethics Committee approval was not required for this retrospective case series.
Supported in part by the NYEEI Pathology Research Fund (Dr. Milman). Reprint requests: Tatyana Milman, MD, Associate Attending Pathologist, The New York Eye and Ear Infirmary, 310 East 14th Street, New York, NY 10003; e-mail: [email protected]
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Unknown
VOLUME 4
*Age at the time of vitrectomy. †Adenocarcinoma. ‡Pigment epithelial detachment. §Central serous choreoretinopathy. ¶Posterior vitreous detachment. **Epiretinal membrane.
OD Female 4
76
OD Female 3
64
OS 61 Male 2
59
OS
2Vision, floaters
Retinal infiltrate, vascular No sheathing, vitritis 2Vision, photophobia, Multiple PEDs‡, retinal Not at the time of initial micropsia, detachment presentation; later was metamorphopsia diagnosed with lung CA 2Vision, Macular hole, ERM** Yes, breast CA 22 years metamorphopsia prior to presentation; was believed to be in remission 2Vision, floaters Vitreous debris, retinal Yes, breast CA nodule
Toxocara granuloma vs. metastasis
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Male
Preoperative Diagnosis History of Primary Clinical Findings Symptoms
2010
1
Patient 1. A 58-year-old previously healthy man presented with a 3-month history of increasing floaters in the left eye. Visual acuity was 20/20 in the right eye and 20/200 in the left eye. Examination of the right eye was remarkable for 1⫹ vitreous cell. Examination of the left eye showed dense vitreous cell with vitreous “puffs” and macular thickening, associated with inner retinal clouding. Fluorescein angiography showed an enlarged foveal avascular zone and macular leakage with staining of the adjacent retinal vessels. Optical coherence tomography revealed thickening and irregularity of the inner retina overlying serous elevation of the neurosensory retina (Figure 1). Bloodwork for suspected “uveitis, retinitis, and vasculitis” was negative. Chest X-ray revealed no focal abnormalities. Magnetic resonance imaging of the brain for possible central nervous system lymphoma showed ring-enhancing lesions in the left frontal lobe and in the left cerebellum. Diagnostic vitrectomy revealed numer-
Age* (Years) Site
Case Reports
Sex
The clinical presentations of the patients and preoperative diagnoses are summarized in Table 1. The histopathologic and immunohistochemical features of the vitreous fluid are summarized in Table 2. The diagnosis was clinically unsuspected in three patients. The primary tumor sites were lung in men and breast in women. Two patients had no history of cancer at the time of clinical presentation. One patient died from diffuse metastatic disease 10 months after the diagnosis of metastatic carcinoma to the vitreous. Two patients are alive with follow-ups of 1 year and 2 years, respectively. One patient was lost to follow-up. Selected patients are presented below.
Patient
Results
Table 1. Clinical Features of the Patients
The entire contents of the pars plana vitrectomy cassettes were agitated slightly, poured into 50-mL test tubes, and centrifuged at 2,500 rpm for 10 minutes. After the supernatant was discarded, 3 drops to 8 drops of human plasma and 3 drops to 8 drops of dissolved thromboplastin with calcium (Dade Thromboplastin C Plus, cat. #B4212-100, Dade Behring) were added to the cell sediment and mixed. The resultant formed clot was wrapped in lens paper, placed in a processing-embedding cassette, fixed in 10% neutral-buffered formalin, and processed for routine histologic (H&E and Periodic acid-Schiff) examination. When the amount of tissue was sufficient, immunohistochemical examination was performed with antibodies for the following antigens: cytokeratins (CK7, CK20, CAM5.2 (CK8/18), low molecular weight CK, high molecular weight CK (AE1/AE3), thyroid transcription factor-1, estrogen and progesterone receptors, neural crest marker S-100 protein, neuroendocrine and neuroectodermal markers chromogranin and synoptophysin, and macrophage marker CD68.
Oncologic Work-Up After Vitrectomy
Vitreous Preparation
●
Uveitis, retinitis, Lung CA† with diffuse vasculitis metastatic disease CSCR§, retinal No additional foci of detachment, metastatic disease secondary to PVD¶ Idiopathic macular 2 possible regional hole, associated lymph nodes; with ERM awaiting biopsy
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UNUSUAL PRESENTATION OF METASTATIC CARCINOMA TO THE EYE Table 2. Patient 1 2 3 4
67
Histopathologic and Immunohistochemical Features of Vitreous Fluid
Histopathologic Characteristics Glandular collections of atypical mucin-producing cells Glandular collections of atypical mucin-producing cells Glandular collections of atypical cells Glandular collections of atypical cells
Immunohistochemical Characteristics CK7⫹, CK20⫺, TTF-1⫹, CAM5.2⫹, LMW-CK⫹, HMW-CK⫺, chromogranin-, synoptophysin⫺ S-100⫺ CK7⫹, CK20⫺, TTF-1⫺, AE1/AE3⫺, PR⫺, ER⫺, S-100⫺ AE1/AE3⫹, S-100⫺, CD68⫺
CK7, cytokeratin-7; CK20, cytokeratin-20; TTF-1, thyroid transcription factor-1; CAM5.2, cytokeratin 8/18; LMW-CK, low molecular weight cytokeratin; HMW-CK, high molecular weight cytokeratin; AE1/AE3, cytokeratin cocktail; PR, progesterone receptor; ER, estrogen receptor.
ous aggregates of large malignant mucin-producing cells with glandular configurations and immunohistochemical profile suggestive of lung primary (Figure 2). A week later, computed tomography scan of the chest demonstrated a right middle lobe nodule and enlarged mediastinal and right axillary lymph nodes. Axillary lymph node biopsy revealed cells with histopathologic and immunohistochemical characteristics identical to the vitreous biopsy, consistent with metastatic adenocarcinoma of the lung. The patient underwent radiation and chemotherapy with partial resolution of ocular and brain metastases. He died 9 months later from neurologic complications of metastatic carcinoma.
Patient 2. A 50-year-old man without significant medical history had metamorphopsia, micropsia, photophobia, and floaters in the left eye for 1 week. Visual acuity was 20/20 in the right eye and
Fig. 1. Clinical presentation of Patient 1. A, Fundus photograph of the left eye shows retinal opacification, associated with vitreous haze, in the region of the macula. Fluorescein angiography demonstrates staining of the blood vessels and leakage in the macular region. B, Optical coherence tomography shows “fluffy” inner retinal thickening and serous detachment of the neurosensory retina.
20/30 in the left eye. Examination of the left eye showed several retinal pigment epithelial (RPE) detachments, associated with serous subretinal fluid, but was otherwise normal (Figure 3). Examination of the right eye was unremarkable. He was diagnosed with central serous chorioretinopathy (CSCR), was recommended observation, and improved spontaneously over the next 4 months. Nine years later, the patient developed exacerbation of CSCR with decrease in visual acuity to 20/60. Six weeks after this presentation with CSCR recurrence, he returned with worsening vision to the level of 20/400 and was found to have a new onset of a rhegmatogenous retinal detachment, associated with acute posterior vitreous detachment. The patient promptly underwent retinal detachment repair. During the course of the surgery, although aspirating the subretinal fluid through the peripheral tear, it was noted that subretinal fluid was unusually viscous and almost globular in consistency. Histopathologic and immunohistochemical evaluation of the vitrectomy material revealed glandular collections of malignant mucin-producing cells, suggestive of metastatic adenocarcinoma (Figure 4). Subsequent investigation revealed that 5 years after the patient’s initial presentation for ocular complaints, and 4 years before exacerbation of CSCR, he was diagnosed with poorly differentiated adenocarcinoma of the lung by bronchial biopsy. At that time, the patient underwent left upper lobectomy with adjuvant chemother-
Fig. 2. Vitrectomy specimen contains malignant cells, focally arranged in a glandular pattern. Some cells display foamy cytoplasm, suggestive of mucin production (stain, H&E; original magnification, ⫻250).
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Fig. 3. Clinical presentation of Patient 2. A, Fundus photograph of the left eye shows multiple RPE detachments at the region of superotemporal arcade. Fluorescein angiography shows areas of pooling, consistent with RPE detachments. B, Optical coherence tomography demonstrates several RPE detachments, associated with serous detachment of neurosensory retina. No appreciable choroidal involvement is observed.
apy and radiation therapy and was declared free of metastatic disease. Comparison of the vitreous cells with the adenocarcinoma of the lung showed cytologic similarity (Figure 4). The patient’s oncologic work-up for other foci of metastatic disease was negative. His retinal repair was successful with vision returning to the level of 20/40⫹, and he remains well 2 years after vitrectomy.
Discussion Metastatic carcinoma to the retina/vitreous is quite rare compared with the frequency of metastases to the
Fig. 4. A, Vitrectomy specimen contains glandular collections of malignant, focally mucin-producing cells (stain, H&E; original magnification, ⫻250). B, Bronchial biopsy specimen (right) taken 4 years earlier shows similar-appearing mucin-producing adenocarcinoma cells (stain, H&E; original magnification, ⫻250).
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choroid. Some of the reasons advanced to explain this finding include the differences in the anatomy of the vascular tree between the choroidal and the retinal circulations and the “the soil” or local environment, which may influence the seeding and growth of the metastatic cells.5,6 Metastatic cancer to the eye has, not without reason, been assigned to the category of “great masqueraders.” Although metastatic carcinoma to the retina/vitreous classically presents with a white retinal nodule or an infiltrate in association with white vitreous “puffs” in a patient with an oncologic history, the presentation can vary greatly. In this series, 2 of 4 patients (Patients 1 and 4) had clinical findings suggestive of retina/vitreous metastases. One of these patients (Patient 4) had a known history of breast cancer, which aided in the derivation of the accurate clinical diagnosis. The other patient had no history of cancer, and the diagnosis of metastatic carcinoma was not suspected. Patient 3 had a remote history of breast cancer and was in remission. She presented with a macular hole, associated with an epiretinal membrane. No vitreous cell, retinal infiltrates, or hemorrhages were observed. Although metastatic carcinoma to the retina can rarely present as a neoplastic epiretinal membrane and can cause a retinal break, these findings are usually associated with clinically apparent retinal infiltrates or hemorrhages and with vitreous opacities.1,7 Absence of these findings in our patient is suggestive of microscopic and clinically innocuous foci of retinal and preretinal involvement by the metastatic cells. Patient 2 had an extremely unusual presentation with exacerbations and remissions of RPE detachments, suggestive of CSCR, followed by a rhegmatogenous retinal detachment. This clinical presentation and the unusual viscosity of subretinal fluid during vitrectomy are suggestive of microscopic choroidal involvement by the metastatic cancer, which has focally affected the RPE, leading to its detachment and to the accumulation of subretinal fluid and of subretinal metastatic cells. Although such a presentation of metastatic carcinoma is unusual, Leff et al8 have reported a patient with a possible RPE tear or dehiscence overlying a region of metastatic choroidal tumor. It is further possible that a fortuitous retinal tear, caused by an acute vitreous detachment, liberated subretinal metastatic cells into the vitreous cavity, thus enabling detection of the metastatic cancer. Alternatively, a microscopic focus of retinal involvement by the metastasis (either via direct extension from subretinal space or via hematogenous dissemination) may have led to the development of a retinal tear and to subsequent retinal detachment. In this patient, ocular examination normalized before his diagnosis and treatment for lung adenocarcinoma,
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UNUSUAL PRESENTATION OF METASTATIC CARCINOMA TO THE EYE
and worsened 4 years after oncologic treatment, at which point no other foci of metastatic disease could be identified. If the hypothesis that the RPE detachments were a manifestation of metastatic disease is correct, then this prolonged and fluctuating clinical course of metastatic carcinoma to the eye in the absence of oncologic treatment is extremely unusual, although it has been described in a patient with recurrent rhegmatogenous retinal detachment in association with metastatic breast carcinoma to the retina/vitreous.7 Identification of four patients with histopathologically documented metastatic carcinoma in the vitreous fluid at our institution during the span of 11 years seems to be disproportionately high compared with the total number of retina/vitreous metastases reported in the literature and suggests that this condition is more common than traditionally believed. The New York Eye and Ear Infirmary requests all vitrectomy specimens to be submitted for pathologic evaluation, thereby possibly maximizing detection of metastatic cancer in clinically innocuous cases. Special stains and immunohistochemical evaluation of vitreous cytologic material is extremely useful in directing the search for an unknown primary neoplasm or in confirming metastases from a known primary tumor. Intracellular and extracellular mucopolyssaccharide in mucin-producing adenocarcinomas can be documented by Periodic acid-Schiff and acid mucopolysaccharide stains. Pattern of immunoreactivity for cytokeratins is also useful. Immunostains with a broad range of anticytokeratin antibodies, AE1/AE3 and CAM 5.2, are helpful in identifying complex and simple epithelia and carcinomas. Lung, breast, thyroid, salivary gland, ovarian, and uterine carcinomas are usually CK7⫹/CK20⫺. Upper gastrointestinal, pancreatic, and billiary tree carcinomas are frequently CK7⫹/CK20⫹. Renal, liver, and prostate carcinomas are typically CK7⫺/CK20⫺, whereas adenocarcinomas of the colon are CK7⫺/CK20⫹. Lung and thyroid carcinomas are usually immunoreactive for thyroid transcription factor-1, whereas breast and ovarian
carcinomas are immunoreactive for estrogen and progesterone receptors. Small cell carcinomas of the lung and carcinoid tumors can demonstrate immunoreactivity for synoptophysin and chromogranin. In summary, we described four patients with unusual presentations of metastatic carcinoma to the eye, diagnosed by pathologic evaluation of the vitreous fluid. Metastases masqueraded not only as retinitis, vitritis, and granuloma, but also as more common retinal conditions, such as macular hole, epiretinal membrane, CSCR, and rhegmatogenous retinal detachment. Ophthalmologists should have a high index of suspicion for metastatic carcinoma to the retina/ vitreous in patients with oncologic history who present with retinal pathology. If a vitrectomy in such patients is clinically indicated, then submission of the vitreous fluid for pathologic evaluation is prudent. Key words: carcinoma, epiretinal membrane, innocuous, macular hole, metastasis, pigment epithelial detachment, retina, unsuspected, vitreous. References 1. 2.
3.
4.
5. 6.
7.
8.
Zaldivar RA, Michels M, Grant KF, et al. Metastatic breast carcinoma to the vitreous. Retina 2004;24:226 –230. Mehriyar M, Jahadi SH, Kavian N, et al. Testicular germ cell tumor metastatic to the retina: vitreous fluid cytologic findings. Acta Cytol 2003;47:531–533. Sirimaharaj M, Hunyor AP, Chan WC, et al. Unusual ocular metastasis from breast cancer. Clin Experiment Ophthalmol 2006;34:74 –76. Kaushik S, Gupta V, Singh R, et al. Disseminated metastasis following periampullary cancer resection masquerading as uveitis. Indian J Ophthalmol 2005;53:57–59. Young SE. Retinal metastases. In: Schachat AP, ed. Retina. 2nd edition, volume 1. St. Louis, MO: Mosby; 1990:660 – 665. Troung SN, Fern CM, Costa DL, et al. Metastatic breast carcinoma to the retina: optical coherence tomography findings. Retina 2002;22:813– 815. Piro P, Pappas HR, Erozan YS, et al. Diagnostic vitrectomy in metastatic breast carcinoma in the vitreous. Retina 1982;2: 182–188. Leff SR, Yarian DL, Shields JA, et al. Tumor-associated retinal pigment epithelial proliferation simulating retinal pigment epithelial tear. Retina 1989;9:267–269.
Purpose: To describe four patients with an unusual presentation of metastatic carcinoma to the eye, diagnosed by histopathologic and immunohistochemical evaluation of vitrectomy material. Methods: Retrospective case series of four patients with metastatic carcinoma to the retina/vitreous. The New York Eye and Ear Infirmary database was searched to identify patients with metastatic carcinoma to the retina or vitreous, diagnosed from 1995 to 2006. Diagnoses were established through histopathologic and immunohistochemical evaluation of vitreous fluid obtained via pars plana vitrectomy. Results: The New York Eye and Ear Infirmary Pathology database search resulted in 19,149 vitrectomy specimens, 4 of which were positive for metastatic carcinoma. The diagnosis was clinically unsuspected in three patients. The oncologic work-up revealed the origin of metastases to be from the breast in two patients and from the lung in two patients. Conclusion: Metastatic carcinoma to the eye can present with clinically innocuous metastases, masquerading as epiretinal membrane and macular hole, central serous chorioretinopathy, rhegmatogenous retinal detachment, retinal granuloma, and endophthalmitis. These findings suggest that submission of vitrectomy specimens for pathologic evaluation should be considered in patients with an oncologic history or in those with atypical clinical presentation. RETINAL CASES & BRIEF REPORTS 4:65– 69, 2010
From the *Department of Pathology and Laboratory Medicine, The New York Eye and Ear Infirmary; †Department of Ophthalmology, The New York Eye and Ear Infirmary; ‡Eye Care for the Adirondacks, New York; §Retina Associates of New York PC; and ¶The New York Eye and Ear Infirmary, New York, New York.
known history of cancer suggests the diagnosis of metastatic disease, the lack of these findings makes the accurate clinical diagnosis challenging. Herein, we report our experience with four patients with metastatic carcinoma to the eye, diagnosed through histopathologic and immunohistochemical examination of the vitreous fluid. The diagnosis was unsuspected in three of the patients, and two patients presented with clinically unapparent metastases.
A
lthough metastases to the choroid are regarded as the most common intraocular malignancy, metastatic carcinoma to the retina/vitreous is extremely rare. Approximately 22 cases of isolated retina/vitreous metastases appear in the literature.1– 4 Review of these reports shows that, although the clinical presentation of a retinal mass or of a white retinal infiltrate in association with vitreous cells in a patient with a
Materials and Methods Search of the pathology database at the New York Eye and Ear Infirmary from January 1995 through January 2006 revealed 19,149 vitrectomy specimens. Six of these, coded with an additional diagnosis of “metastases” or “carcinoma,” were selected for review. Institutional Review Board/Ethics Committee approval was not required for this retrospective case series.
Supported in part by the NYEEI Pathology Research Fund (Dr. Milman). Reprint requests: Tatyana Milman, MD, Associate Attending Pathologist, The New York Eye and Ear Infirmary, 310 East 14th Street, New York, NY 10003; e-mail: [email protected]
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NUMBER 1
Unknown
VOLUME 4
*Age at the time of vitrectomy. †Adenocarcinoma. ‡Pigment epithelial detachment. §Central serous choreoretinopathy. ¶Posterior vitreous detachment. **Epiretinal membrane.
OD Female 4
76
OD Female 3
64
OS 61 Male 2
59
OS
2Vision, floaters
Retinal infiltrate, vascular No sheathing, vitritis 2Vision, photophobia, Multiple PEDs‡, retinal Not at the time of initial micropsia, detachment presentation; later was metamorphopsia diagnosed with lung CA 2Vision, Macular hole, ERM** Yes, breast CA 22 years metamorphopsia prior to presentation; was believed to be in remission 2Vision, floaters Vitreous debris, retinal Yes, breast CA nodule
Toxocara granuloma vs. metastasis
●
Male
Preoperative Diagnosis History of Primary Clinical Findings Symptoms
2010
1
Patient 1. A 58-year-old previously healthy man presented with a 3-month history of increasing floaters in the left eye. Visual acuity was 20/20 in the right eye and 20/200 in the left eye. Examination of the right eye was remarkable for 1⫹ vitreous cell. Examination of the left eye showed dense vitreous cell with vitreous “puffs” and macular thickening, associated with inner retinal clouding. Fluorescein angiography showed an enlarged foveal avascular zone and macular leakage with staining of the adjacent retinal vessels. Optical coherence tomography revealed thickening and irregularity of the inner retina overlying serous elevation of the neurosensory retina (Figure 1). Bloodwork for suspected “uveitis, retinitis, and vasculitis” was negative. Chest X-ray revealed no focal abnormalities. Magnetic resonance imaging of the brain for possible central nervous system lymphoma showed ring-enhancing lesions in the left frontal lobe and in the left cerebellum. Diagnostic vitrectomy revealed numer-
Age* (Years) Site
Case Reports
Sex
The clinical presentations of the patients and preoperative diagnoses are summarized in Table 1. The histopathologic and immunohistochemical features of the vitreous fluid are summarized in Table 2. The diagnosis was clinically unsuspected in three patients. The primary tumor sites were lung in men and breast in women. Two patients had no history of cancer at the time of clinical presentation. One patient died from diffuse metastatic disease 10 months after the diagnosis of metastatic carcinoma to the vitreous. Two patients are alive with follow-ups of 1 year and 2 years, respectively. One patient was lost to follow-up. Selected patients are presented below.
Patient
Results
Table 1. Clinical Features of the Patients
The entire contents of the pars plana vitrectomy cassettes were agitated slightly, poured into 50-mL test tubes, and centrifuged at 2,500 rpm for 10 minutes. After the supernatant was discarded, 3 drops to 8 drops of human plasma and 3 drops to 8 drops of dissolved thromboplastin with calcium (Dade Thromboplastin C Plus, cat. #B4212-100, Dade Behring) were added to the cell sediment and mixed. The resultant formed clot was wrapped in lens paper, placed in a processing-embedding cassette, fixed in 10% neutral-buffered formalin, and processed for routine histologic (H&E and Periodic acid-Schiff) examination. When the amount of tissue was sufficient, immunohistochemical examination was performed with antibodies for the following antigens: cytokeratins (CK7, CK20, CAM5.2 (CK8/18), low molecular weight CK, high molecular weight CK (AE1/AE3), thyroid transcription factor-1, estrogen and progesterone receptors, neural crest marker S-100 protein, neuroendocrine and neuroectodermal markers chromogranin and synoptophysin, and macrophage marker CD68.
Oncologic Work-Up After Vitrectomy
Vitreous Preparation
●
Uveitis, retinitis, Lung CA† with diffuse vasculitis metastatic disease CSCR§, retinal No additional foci of detachment, metastatic disease secondary to PVD¶ Idiopathic macular 2 possible regional hole, associated lymph nodes; with ERM awaiting biopsy
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UNUSUAL PRESENTATION OF METASTATIC CARCINOMA TO THE EYE Table 2. Patient 1 2 3 4
67
Histopathologic and Immunohistochemical Features of Vitreous Fluid
Histopathologic Characteristics Glandular collections of atypical mucin-producing cells Glandular collections of atypical mucin-producing cells Glandular collections of atypical cells Glandular collections of atypical cells
Immunohistochemical Characteristics CK7⫹, CK20⫺, TTF-1⫹, CAM5.2⫹, LMW-CK⫹, HMW-CK⫺, chromogranin-, synoptophysin⫺ S-100⫺ CK7⫹, CK20⫺, TTF-1⫺, AE1/AE3⫺, PR⫺, ER⫺, S-100⫺ AE1/AE3⫹, S-100⫺, CD68⫺
CK7, cytokeratin-7; CK20, cytokeratin-20; TTF-1, thyroid transcription factor-1; CAM5.2, cytokeratin 8/18; LMW-CK, low molecular weight cytokeratin; HMW-CK, high molecular weight cytokeratin; AE1/AE3, cytokeratin cocktail; PR, progesterone receptor; ER, estrogen receptor.
ous aggregates of large malignant mucin-producing cells with glandular configurations and immunohistochemical profile suggestive of lung primary (Figure 2). A week later, computed tomography scan of the chest demonstrated a right middle lobe nodule and enlarged mediastinal and right axillary lymph nodes. Axillary lymph node biopsy revealed cells with histopathologic and immunohistochemical characteristics identical to the vitreous biopsy, consistent with metastatic adenocarcinoma of the lung. The patient underwent radiation and chemotherapy with partial resolution of ocular and brain metastases. He died 9 months later from neurologic complications of metastatic carcinoma.
Patient 2. A 50-year-old man without significant medical history had metamorphopsia, micropsia, photophobia, and floaters in the left eye for 1 week. Visual acuity was 20/20 in the right eye and
Fig. 1. Clinical presentation of Patient 1. A, Fundus photograph of the left eye shows retinal opacification, associated with vitreous haze, in the region of the macula. Fluorescein angiography demonstrates staining of the blood vessels and leakage in the macular region. B, Optical coherence tomography shows “fluffy” inner retinal thickening and serous detachment of the neurosensory retina.
20/30 in the left eye. Examination of the left eye showed several retinal pigment epithelial (RPE) detachments, associated with serous subretinal fluid, but was otherwise normal (Figure 3). Examination of the right eye was unremarkable. He was diagnosed with central serous chorioretinopathy (CSCR), was recommended observation, and improved spontaneously over the next 4 months. Nine years later, the patient developed exacerbation of CSCR with decrease in visual acuity to 20/60. Six weeks after this presentation with CSCR recurrence, he returned with worsening vision to the level of 20/400 and was found to have a new onset of a rhegmatogenous retinal detachment, associated with acute posterior vitreous detachment. The patient promptly underwent retinal detachment repair. During the course of the surgery, although aspirating the subretinal fluid through the peripheral tear, it was noted that subretinal fluid was unusually viscous and almost globular in consistency. Histopathologic and immunohistochemical evaluation of the vitrectomy material revealed glandular collections of malignant mucin-producing cells, suggestive of metastatic adenocarcinoma (Figure 4). Subsequent investigation revealed that 5 years after the patient’s initial presentation for ocular complaints, and 4 years before exacerbation of CSCR, he was diagnosed with poorly differentiated adenocarcinoma of the lung by bronchial biopsy. At that time, the patient underwent left upper lobectomy with adjuvant chemother-
Fig. 2. Vitrectomy specimen contains malignant cells, focally arranged in a glandular pattern. Some cells display foamy cytoplasm, suggestive of mucin production (stain, H&E; original magnification, ⫻250).
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Fig. 3. Clinical presentation of Patient 2. A, Fundus photograph of the left eye shows multiple RPE detachments at the region of superotemporal arcade. Fluorescein angiography shows areas of pooling, consistent with RPE detachments. B, Optical coherence tomography demonstrates several RPE detachments, associated with serous detachment of neurosensory retina. No appreciable choroidal involvement is observed.
apy and radiation therapy and was declared free of metastatic disease. Comparison of the vitreous cells with the adenocarcinoma of the lung showed cytologic similarity (Figure 4). The patient’s oncologic work-up for other foci of metastatic disease was negative. His retinal repair was successful with vision returning to the level of 20/40⫹, and he remains well 2 years after vitrectomy.
Discussion Metastatic carcinoma to the retina/vitreous is quite rare compared with the frequency of metastases to the
Fig. 4. A, Vitrectomy specimen contains glandular collections of malignant, focally mucin-producing cells (stain, H&E; original magnification, ⫻250). B, Bronchial biopsy specimen (right) taken 4 years earlier shows similar-appearing mucin-producing adenocarcinoma cells (stain, H&E; original magnification, ⫻250).
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choroid. Some of the reasons advanced to explain this finding include the differences in the anatomy of the vascular tree between the choroidal and the retinal circulations and the “the soil” or local environment, which may influence the seeding and growth of the metastatic cells.5,6 Metastatic cancer to the eye has, not without reason, been assigned to the category of “great masqueraders.” Although metastatic carcinoma to the retina/vitreous classically presents with a white retinal nodule or an infiltrate in association with white vitreous “puffs” in a patient with an oncologic history, the presentation can vary greatly. In this series, 2 of 4 patients (Patients 1 and 4) had clinical findings suggestive of retina/vitreous metastases. One of these patients (Patient 4) had a known history of breast cancer, which aided in the derivation of the accurate clinical diagnosis. The other patient had no history of cancer, and the diagnosis of metastatic carcinoma was not suspected. Patient 3 had a remote history of breast cancer and was in remission. She presented with a macular hole, associated with an epiretinal membrane. No vitreous cell, retinal infiltrates, or hemorrhages were observed. Although metastatic carcinoma to the retina can rarely present as a neoplastic epiretinal membrane and can cause a retinal break, these findings are usually associated with clinically apparent retinal infiltrates or hemorrhages and with vitreous opacities.1,7 Absence of these findings in our patient is suggestive of microscopic and clinically innocuous foci of retinal and preretinal involvement by the metastatic cells. Patient 2 had an extremely unusual presentation with exacerbations and remissions of RPE detachments, suggestive of CSCR, followed by a rhegmatogenous retinal detachment. This clinical presentation and the unusual viscosity of subretinal fluid during vitrectomy are suggestive of microscopic choroidal involvement by the metastatic cancer, which has focally affected the RPE, leading to its detachment and to the accumulation of subretinal fluid and of subretinal metastatic cells. Although such a presentation of metastatic carcinoma is unusual, Leff et al8 have reported a patient with a possible RPE tear or dehiscence overlying a region of metastatic choroidal tumor. It is further possible that a fortuitous retinal tear, caused by an acute vitreous detachment, liberated subretinal metastatic cells into the vitreous cavity, thus enabling detection of the metastatic cancer. Alternatively, a microscopic focus of retinal involvement by the metastasis (either via direct extension from subretinal space or via hematogenous dissemination) may have led to the development of a retinal tear and to subsequent retinal detachment. In this patient, ocular examination normalized before his diagnosis and treatment for lung adenocarcinoma,
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UNUSUAL PRESENTATION OF METASTATIC CARCINOMA TO THE EYE
and worsened 4 years after oncologic treatment, at which point no other foci of metastatic disease could be identified. If the hypothesis that the RPE detachments were a manifestation of metastatic disease is correct, then this prolonged and fluctuating clinical course of metastatic carcinoma to the eye in the absence of oncologic treatment is extremely unusual, although it has been described in a patient with recurrent rhegmatogenous retinal detachment in association with metastatic breast carcinoma to the retina/vitreous.7 Identification of four patients with histopathologically documented metastatic carcinoma in the vitreous fluid at our institution during the span of 11 years seems to be disproportionately high compared with the total number of retina/vitreous metastases reported in the literature and suggests that this condition is more common than traditionally believed. The New York Eye and Ear Infirmary requests all vitrectomy specimens to be submitted for pathologic evaluation, thereby possibly maximizing detection of metastatic cancer in clinically innocuous cases. Special stains and immunohistochemical evaluation of vitreous cytologic material is extremely useful in directing the search for an unknown primary neoplasm or in confirming metastases from a known primary tumor. Intracellular and extracellular mucopolyssaccharide in mucin-producing adenocarcinomas can be documented by Periodic acid-Schiff and acid mucopolysaccharide stains. Pattern of immunoreactivity for cytokeratins is also useful. Immunostains with a broad range of anticytokeratin antibodies, AE1/AE3 and CAM 5.2, are helpful in identifying complex and simple epithelia and carcinomas. Lung, breast, thyroid, salivary gland, ovarian, and uterine carcinomas are usually CK7⫹/CK20⫺. Upper gastrointestinal, pancreatic, and billiary tree carcinomas are frequently CK7⫹/CK20⫹. Renal, liver, and prostate carcinomas are typically CK7⫺/CK20⫺, whereas adenocarcinomas of the colon are CK7⫺/CK20⫹. Lung and thyroid carcinomas are usually immunoreactive for thyroid transcription factor-1, whereas breast and ovarian
carcinomas are immunoreactive for estrogen and progesterone receptors. Small cell carcinomas of the lung and carcinoid tumors can demonstrate immunoreactivity for synoptophysin and chromogranin. In summary, we described four patients with unusual presentations of metastatic carcinoma to the eye, diagnosed by pathologic evaluation of the vitreous fluid. Metastases masqueraded not only as retinitis, vitritis, and granuloma, but also as more common retinal conditions, such as macular hole, epiretinal membrane, CSCR, and rhegmatogenous retinal detachment. Ophthalmologists should have a high index of suspicion for metastatic carcinoma to the retina/ vitreous in patients with oncologic history who present with retinal pathology. If a vitrectomy in such patients is clinically indicated, then submission of the vitreous fluid for pathologic evaluation is prudent. Key words: carcinoma, epiretinal membrane, innocuous, macular hole, metastasis, pigment epithelial detachment, retina, unsuspected, vitreous. References 1. 2.
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Zaldivar RA, Michels M, Grant KF, et al. Metastatic breast carcinoma to the vitreous. Retina 2004;24:226 –230. Mehriyar M, Jahadi SH, Kavian N, et al. Testicular germ cell tumor metastatic to the retina: vitreous fluid cytologic findings. Acta Cytol 2003;47:531–533. Sirimaharaj M, Hunyor AP, Chan WC, et al. Unusual ocular metastasis from breast cancer. Clin Experiment Ophthalmol 2006;34:74 –76. Kaushik S, Gupta V, Singh R, et al. Disseminated metastasis following periampullary cancer resection masquerading as uveitis. Indian J Ophthalmol 2005;53:57–59. Young SE. Retinal metastases. In: Schachat AP, ed. Retina. 2nd edition, volume 1. St. Louis, MO: Mosby; 1990:660 – 665. Troung SN, Fern CM, Costa DL, et al. Metastatic breast carcinoma to the retina: optical coherence tomography findings. Retina 2002;22:813– 815. Piro P, Pappas HR, Erozan YS, et al. Diagnostic vitrectomy in metastatic breast carcinoma in the vitreous. Retina 1982;2: 182–188. Leff SR, Yarian DL, Shields JA, et al. Tumor-associated retinal pigment epithelial proliferation simulating retinal pigment epithelial tear. Retina 1989;9:267–269.
